Drugs

DRUGS
2008, Vol 68, No. 3

Drugs
Issue Table of Contents

2008, Volume 68, Issue 3
Page # Article/Title
Current Opinion
259 Pharmacological Therapy for Female Sexual Dysfunction: Has Progress Been Made?
Susan R Davis; Esme A Nijland

Therapy In Practice
265 Current and Future Therapeutic Options in the Management of Invasive Aspergillosis.
Suganthini Krishnan-Natesan; Pranatharthi H Chandrasekar

ReviewArticle
283 Treatment of Acute Severe Hypertension: Current and Newer Agents.
J oseph Varon

299 Locally Advanced and Metastatic Gastric Cancer: Current Management and New Treatment Developments.
Kathryn Field; Michael Michael; Trevor Leong

319 Adult-Onset Still's Disease: Pathogenesis, Clinical Manifestations and Therapeutic Advances.
Apostolos Kontzias; Petros Efthimiou

339 Drugs for Cardiovascular Disease Prevention in Women: Implications of the AHA Guidelines - 2007 Update.
Nanette K Wenger

Adis Drug Profile
359 Human Papillomavirus Types 16 and 18 Vaccine (Recombinant, AS04 Adjuvanted, Adsorbed) [Cervarix(TM)].
Susan J Keam; Diane M Harper

373 Amlodipine/Valsartan: Fixed-Dose Combination in Hypertension.
Greg L Plosker; Dean M Robinson

Adis Drug Evaluation
383 Sildenafil: A Review of its Use in Pulmonary Arterial Hypertension.
Katherine F Croom; Monique P Curran

Drugs 2008; 68 (3): 259-264
CURRENT OPINION 0012-6667/08/0003-0259/$53.45/0
2008 Adis Data Information BV. All rights reserved.
Pharmacological Therapy for Female
Sexual Dysfunction
Has Progress Been Made?
Susan R. Davis
1
and Esme A. Nijland
2
1 Womens Health Program, Department of Medicine, Monash University, Prahran,
Victoria, Australia
2 Department of Sexuology and Psychosomatic Obstetrics/Gynaecology, Academic Medical
Center, Hanzeplein 1, Groningen, The Netherlands
The investigation of female sexual dysfunction (FSD) is an evolving area in Abstract
which definitions and models for female sexual functioning are being continually
reviewed and revised. The lack of consensus amongst experts in the field and
regulating authorities regarding appropriate inclusion and exclusion criteria for
FSD trials, and main outcome measures appropriate for the evaluation of drug
interventions has somewhat hampered progression in this area. Nonetheless, there
is evidence from randomized controlled trials that androgen therapy improves the
quality of the sexual experience for postmenopausal women with low libido, and
preliminary data that this may also apply to premenopausal women.
The study of female sexual dysfunction (FSD) Available data indicate the most commonly re-
ported sexual problems in women relate to desire,
has lagged behind research into male sexual health,
arousal, pleasure and global satisfaction. It has been
resulting in very slow progress in the development
proposed that each of these present different diagno-
of pharmacological therapy for FSD. Historically,
ses and should be researched and treated different-
the problem was that researchers tried to approach
ly.
[1]
However, for most women these problems are
FSD from a male perspective, which has increasing-
part of a continuum of the sexual experience and are
ly been acknowledged as inappropriate. The next
inextricably related.
limitation to emerge was the lack of a definition for
Population-based studies indicate that the preva-
normal female sexual function and the continuous
lence of sexual problems among women ranges
evolution of the definition of FSD. Furthermore,
from 9% to 43%.
[2-5]
However, the validity and
there is no gold standard self-assessment instrument
reliability of these data is uncertain as epidemiologi-
for the evaluation of female sexual function and thus
cal studies on female sexual function are constrained
data of sexual behaviour across the adult female
by the limited response rate, the limited use of
lifespan are lacking. validated instruments, and the lack of information
260 Davis & Nijland
about the duration and context of sexual problems.
[6]
ies of PDE
5
inhibitors in the general population have
The US FDAs 2000 draft guidance document for been disappointing.
[13]
Similarly, studies of other
FSD clinical trials recommends the use of the agents, such as apomorphine and bupropion, have
change in the frequency of successful satisfactory not as yet provided evidence of significant benefit
sexual events recorded in a daily diary as the prima- and have been reviewed elsewhere.
[13]
ry endpoint and self-administered questionnaires as
secondary endpoints.
[7]
Although this approach re- 2. Tibolone for FSD
mains controversial,
[6]
it has been the primary ap-
Tibolone is a selective tissue estrogenic activity
proach adopted by the pharmaceutical industry in-
regulator. It is metabolized in the gastrointestinal
vestigating new therapies for FSD in order to meet
tract to the 3 and 3 metabolites, which then
the requirements set down by the FDA in 2000.
circulate predominantly in their sulfated inactive
Furthermore, inclusion and exclusion criteria for
forms. These metabolites become estrogenically ac-
recruitment to the large randomized control trials
tive when desulfated in target tissues, such that
(RCTs) of pharmacological agents for FSD indicate
tibolone is effective in the treatment of estrogen
acknowledgement of the multi-factorial nature of
deficiency symptoms. Thus, the global effect of
FSD. Thus, in general, women with poor relation-
tibolone would be expected to be estrogenic. There
ships, depression, ill health and other identifiable
are some data to suggest that tibolone may improve
factors that may underpin their FSD have been ex-
sexual function, particularly sexual desire and
cluded. Therefore, the positive findings from the
arousal, to a greater extent than traditional estrogen-
published data are specific to the populations that
progestogen therapy in healthy postmenopausal
have been studied and cannot be extrapolated to
women. These effects have been attributed to (i) the
women with FSD complicated by other conditions.
intrinsic capacity of a tissue metabolite of tibolone
(the 4-isomer) to activate the androgen receptor;
[14]
1. Potential Approaches for Treating
and (ii) the reduction in sex hormone binding globu-
Female Sexual Dysfunction (FSD)
lin (SHBG) and hence the increase in bioavailable
testosterone.
Early research suggested some benefits of testos-
Whether tibolone is more likely to restore sexual terone therapy for women
[8,9]
and these findings
well-being than conventional or transdermal es- formed the basis of ad hoc administration of testos-
trogen-progestogen therapy in postmenopausal terone to women by individual practitioners. Subse-
women presenting with FSD was explored in a quently, research approaches to the treatment of
multicentre RCT. In this study, after exclusion of FSD have included primarily selective phosphodies-
major study violators, sexual function improved in terase (PDE) inhibitors and androgen therapy, spe-
the tibolone group when compared with transdermal cifically testosterone. PDE
5
inhibitors are effective
estrogen-progestogen therapy.
[15]
These data sug- in the treatment of male erectile dysfunction. Stud-
gest that for postmenopausal women with FSD, a ies of the PDE
5
inhibitor sildenafil in the treatment
trial of tibolone therapy should precede initiation of of symptoms of FSD suggest that this therapy may
testosterone with or without estrogen therapy. be useful for some women with genital arousal
disorder rather than the larger group of women with Over the last decade, a number of large RCTs
low desire and subjective arousal.
[10,11]
Other sub- have evaluated the use of testosterone therapy for
sets of women, such as women with type 1 diabetes postmenopausal women and, as a result, transdermal
mellitus, may also benefit.
[12]
However, large stud- testosterone has been approved for the treatment of
2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (3)
Pharmacological Therapy for Female Sexual Dysfunction 261
estrogen-treated surgically menopausal women with not appear to change across menopause; hence,
hypoactive sexual desire disorder (HSDD) in Eu- women in their late reproductive years are just as
rope. Therefore, the remainder of this review focus- likely to have low testosterone levels as women in
es on the evidence for the use of testosterone in
their early menopausal years.
[22,23]
A small pilot,
women.
randomized, cross-over trial showed that preme-
nopausal women treated with testosterone had sig-
3. Testosterone for the Treatment of
nificant improvements in sexual functioning and in
Hypoactive Sexual Desire Disorder
well-being compared with placebo.
[24]
Subsequent-
ly, a larger RCT compared three different doses of
A Cochrane review of the earlier studies of the
transdermal testosterone with placebo and reported
use of testosterone in postmenopausal women for
an increase in the frequency of the number of satis-
low libido concluded that there are benefits in terms
factory sexual events in women treated with the
of improved sexual function with the addition of
middle dose of testosterone versus placebo.
[25]
The
testosterone to standard postmenopausal hormone
links between postmenopausal estrogen-proges-
therapy.
[16]
Subsequent large RCTs in both surgical-
togen use and both breast cancer and cardiovascular
ly menopausal
[17-19]
and naturally menopausal
disease, have created a level of concern regarding
women
[20]
for which the frequency of satisfactory
any form of hormone use in women.
[26]
Testosterone
sexual events was the primary endpoint, demon-
has been widely used by women as an unapproved
strate that treatment with a transdermal testosterone
therapy for decades. There is no evidence from
patch, which delivers 300 g of testosterone per day
studies of premenopausal women or postmenopaus-
(but not a patch delivering 450 g/day), significant-
al women using systemic estrogen treated with tes-
ly increased the number of self-reported sexually
tosterone for up to 24 months, or studies of women
satisfying events per month when compared with
with chronic androgen excess due to polycystic ova-
placebo. These studies also demonstrated significant
rian syndrome, that elevated testosterone levels,
improvements in desire, arousal, responsiveness, or-
even above what is considered physiologically nor-
gasm, pleasure and satisfaction.
mal, are associated with altered breast cancer
An analysis of data from a number of these
risk.
[27,28]
Primate and human studies suggest that
studies indicates that women with a SHBG level
testosterone may in fact protect the breast from
>160 nmol/L or who are taking concurrent conjugat-
estrogen-induced breast cell proliferation.
[29-31]
ed equine estrogen (CEE) are unlikely to benefit
However, this is an area of considerable controversy
from testosterone therapy.
[21]
The former is because
that needs to be addressed in post-marketing surveil-
testosterone binds to SHBG with high affinity;
lance research. There is also no evidence that in
therefore, having an elevated SHBG results in a very
women without insulin resistance, testosterone ad-
low level of free or bioavailable testosterone. The
versely affects cardiovascular disease risk. We re-
interaction between CEE therapy and exogenous
cently demonstrated that endogenous testosterone testosterone is unclear, but it may be that a compo-
and the adrenal pre-androgens per se are not signif- nent of CEE interferes with the binding of testoster-
icant independent determinants of circulating one to the androgen receptor in addition to increas-
cardiovascular disease risk markers (C-reactive pro- ing SHBG.
tein and lipoprotein lipids).
[32]
However, uncertainty There is a paucity of data pertaining to the use of
as to the consequences of restoring testosterone testosterone in premenopausal women. Testosterone
levels decline in women prior to menopause and do levels to those of premenopausal women in those
262 Davis & Nijland
who are many years past menopause remains. Now 5. Current Therapeutic Choices
that the testosterone patch has been approved for
As oral estrogen therapy tends to result in an
surgically menopausal women with HSDD despite
increase in SHBG and hence lower free testoster-
estrogen therapy (other than CEEs) in Europe, these
one,
[34]
it would be worth while initially changing
data will eventually be forthcoming from post-mar-
women from oral estrogen to transdermal therapy
keting-surveillance studies of women in the com-
and reviewing after at least 3 months to evaluate
munity.
whether this has resulted in an improvement in
sexual interest. This approach seems to be least
4. Who to Treat
effective for women who have a low endogenous
testosterone level prior to changing formulations.
A pragmatic concern is which women are candi-
For postmenopausal women, tibolone, where avail-
dates for pharmacotherapy for FSD? To date, no
able, should be considered as first-line therapy. As
clinically applicable diagnostic algorithm has
part of the efficacy of tibolone may reside in the
achieved acceptance. A low serum testosterone level
reduction of SHBG and hence increase in free tes-
is not predictive of a diagnosis of low libido nor
tosterone, it may be that women with very low
does it predict likelihood of therapeutic response.
[33]
testosterone levels, such as those who have had a
The assessment of a woman presenting with low
surgical menopause, will benefit less. However,
sexual well-being requires a comprehensive clinical
there is no clinical data to support this hypothesis.
evaluation with a full history and physical examina-
Tibolone should not be used by premenopausal
tion. One must ascertain whether the woman has
women. Safety issues regarding tibolone and the
experienced a decline in sexual function from a
breast have been raised in a large observational
previously satisfactory situation. Women who have
study.
[35]
However, strong treatment bias in this
never experienced satisfactory sexual function need study make the findings uncertain.
to be assessed differently. Then, relationship issues,
Transdermal testosterone patch therapy has only
partner health, depression, personal social issues
been approved in Europe for women who have
(e.g. children and work pressures) and adverse ef-
undergone surgical menopause. Further large stud-
fects of other psychoactive therapies need to be
ies of testosterone in naturally menopausal women
considered. Menstrual and menopausal status must are currently underway and it is highly likely that the
be evaluated and other potentially contributing con- approval will eventually be extended to naturally
ditions sought and, if identified, treated. These in- menopausal women.
clude estrogen deficiency, vaginismus, dyspareunia,
There has been considerable clinical experience
thyroid disease and other systemic illnesses. If no
with the administration of testosterone implants in
clearly identifiable factor can be found in an other- postmenopausal women and these are approved for
wise healthy woman, whether she be premenopausal use in women in the UK. These implants are fused
or postmenopausal, a trial of testosterone therapy crystalline implants, 4
5 mm in diameter, contain-
might be considered. Women who have undergone ing testosterone BP (British Pharmacopoeia) as the
premature ovarian failure or surgical menopause, or active ingredient. A dose of 50 mg is effective
[36]
who have adrenal insufficiency or hypopituitarism, and does not cause virilizing adverse effects. This
are known to have loss of androgen production and dose can be obtained by bisecting a 100-mg implant
also merit consideration for treatment if they exhibit under sterile conditions. The implant is inserted
symptoms of sexual dysfunction. subcutaneously (under local anaesthesia), usually
Pharmacological Therapy for Female Sexual Dysfunction 263
3. Fugl-Meyer AR, Fugl-Meyer KS. Sexual disabilities, problems
into the lower anterior abdominal wall, using a
and satisfaction in 18 to 74-year-old Swedes. Scan J Sexology
trocar and cannula. This therapy provides a slow
1999; 2 (2): 79-105
4. Fugl-Meyer KS, Arrhult H, Pharmanson H, et al. A Swedish
release of testosterone with an approximate duration
telephone help-line for sexual problems: a 5-year survey. J Sex
of effect of 3
6 months for a 50-mg implant. There

Med 2004; 1 (3): 278-83
is marked individual variation in this period; there- 5. Mercer CH, Fenton KA, Johnson AM, et al. Sexual function
problems and help seeking behaviour in Britain: national
fore, testosterone levels must be carefully moni-
probability sample survey. BMJ 2003; 327 (7412): 426-7
tored, with a testosterone level measured prior to the
6. Nijland E, Davis S, Laan E, et al. Female sexual satisfaction and
pharmaceutical intervention: a critical review of the drug inter-
administration of each subsequent implant.
vention studies in female sexual dysfunction. J Sex Med 2006;
Other modes of delivery of testosterone, includ-
3 (5): 763-77
ing transdermal gel, skin spray and nasal spray, are 7. US Food and Drug Administration. FDA guidance document,
guidance for industry. Female sexual dysfunction: clinical
currently in the research pipeline.
development of drug products for treatment. Washington, DC:
US FDA, 2000
8. Studd JWW. Oestradiol and testosterone implants in the treat-
6. Conclusions
ment of psychosexual problems in postmenopausal women. Br
J Obstet Gynaecol 1977; 84: 314-8
FSD remains a complex, controversial and
9. Sherwin BB, Gelfand MM. Sex steroids and affect in the surgi-
cal menopause: a double blind, cross-over study. Psychoneuro- under-researched clinical issue. Women experienc-
endocrinology 1985; 10 (3): 325-35
ing FSD have the right to treatment with effective
10. Berman JR, Berman LA, Toler SM, et al. Safety and efficacy of
and safe therapeutic options. Progress in this field
sildenafil citrate for the treatment of female sexual arousal
disorder: a double-blind, placebo controlled study. J Urol
has been slow, such that testosterone remains the
2003; 170 (6 Pt 1): 2333-8
only treatment specifically approved for the treat-
11. Basson R, Brotto LA. Sexual psychophysiology and effects of
ment indication of FSD, and this approval is limited sildenafil citrate in oestrogenised women with acquired genital
arousal disorder and impaired orgasm: a randomised control-
oophorectomised women and to European coun-
led trial. BJOG 2003; 110 (11): 1014-24
tries. However, there is widespread off-label use by
12. Caruso S, Rugolo S, Mirabella D, et al. Changes in clitoral blood
flow in premenopausal women affected by type 1 diabetes
women of testosterone products approved for men
after single 100-mg administration of sildenafil. Urology 2006;
and extensive prescription of compounded testoster-
68 (1): 161-5
one products for women in clinical practice. One
13. Carey JC. Pharmacological effects on sexual function. Obstet
Gynecol Clin North Am 2006; 33 (4): 599-620
might conclude that an uncontrolled clinical trial of
14. Kloosterboer H. Tibolone: a steroid with tissue-specific mode of
the safety of testosterone is ongoing in the com-
action. J Steroid Biochem Mol Biol 2001; 76: 231-8
munity. 15. Nijland E, Weijmar Schultz WCM, Nathorst-Boos J, et al.
Tibolone and transdermal E2/NETA for the treatment of fe-
male sexual dysfunction in naturally menopausal women: re-
Acknowledgements
sults of a randomized active-controlled trial. J Sex Med. In
press
Dr Davis is a consultant to Acrux Australia Ltd, and an 16. Somboonporn W, Davis S, Seif M, et al. Testosterone for peri-
and postmenopausal women. Cochrane Database Syst Rev
investigator for Procter and Gamble and Acrux Australia. Dr
2005; (4): CD004509
Nijland has no conflicts of interest that are directly relevant to
17. Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch
the content of this review. No sources of funding were used in
for low sexual desire in surgically menopausal women: a
the preparation of this review.
randomized trial. Obstet Gynecol 2005; 105 (5): 944-52
18. Braunstein G, Shifren J, Simon J, et al. Testosterone patches for
the treatment of low sexual desire in surgically menopausal
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Drugs 2008; 68 (3): 265-282
THERAPY IN PRACTICE 0012-6667/08/0003-0265/$53.45/0
Current and Future Therapeutic
Options in the Management of
Invasive Aspergillosis
Suganthini Krishnan-Natesan
1,2
and Pranatharthi H. Chandrasekar
1
1 Department of Internal Medicine, Division of Infectious Diseases, Wayne State University
School of Medicine, Detroit, Michigan, USA
2 Department of Medicine, Division of Infectious Diseases, John D. Dingell VA Medical Center,
Detroit, Michigan, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
1. Diagnosis of Invasive Pulmonary Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
2. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
2.1 Definitive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
2.2 Prophylactic Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
2.3 Empirical Antifungal Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
2.4 Pre-Emptive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
2.5 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
2.6 Salvage Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
2.7 Role of Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
3. Future Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
3.1 Antifungal Agents in the Pipeline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
3.2 Immunomodulatory Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
3.2.1 Recombinant T Helper Cell Type 1 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
3.2.2 Donor Granulocyte Transfusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.2.3 Recombinant Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
3.2.4 Pentraxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
3.2.5 Pathogen-Specific Immune Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
3.3 Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
4. Antifungal Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
The past decade has witnessed significant progress in the management of Abstract
invasive aspergillosis. Potent, relatively non-toxic antifungal drugs, data on early
chest CT scanning and the availability of a non-invasive diagnostic test (serum
galactomannan) are the key advances; among these, the contribution of the
recently available drugs is the most significant. Safer and earlier intervention
resulting in reduced mortality and improved outcome is being demonstrated.
Newer strategies enable clinicians to provide drug therapy in a highly targeted
manner, such that empirical use of antifungal drugs may decline. Voriconazole
has become the drug of choice for primary therapy, while posaconazole shows
266 Krishnan-Natesan & Chandrasekar
promise as a prophylactic drug. Echinocandins are effective for salvage therapy
and are under evaluation for primary therapy. Preliminary data for efficacy of
combination therapy with a mould-active azole plus an echinocandin are of
promise and clinical trials are under way. Reports of emergence of less-suscepti-
ble Aspergillus spp. during azole therapy are of concern and close monitoring is
needed. Remarkably, the era of polyenes appears to be nearing the end in the
therapy of invasive aspergillosis. The promise of newer classes of drugs, immune-
modulating therapies and vaccines are exciting future additions to the arsenal
against invasive aspergillosis.
Aspergillosis comprises a wide variety of mani- individuals at risk of the infection as a result of
festations, the principal entities being acute invasive advances in modern medicine, such as bone marrow
forms, notably pulmonary disease with or without and solid organ transplantation, and prolonged sur-
dissemination, and chronic forms, namely chronic vival of critically ill and susceptible patients. In
necrotizing aspergillosis, pulmonary/sinus aspergil- addition, the aging of the population has increased
loma (fungal balls) and allergic bronchopulmonary the number of susceptible individuals.
aspergillosis. Although several species of Aspergil-
The number of patients undergoing transplanta-
lus have been reported as human pathogens, A. fumi-
tion has vastly increased in recent years. Transplant
gatus is the most common aetiological agent of
recipients are among the most significant subgroups
aspergillosis followed by A. flavus (table I);
[1]
the
of immunosuppressed hosts at risk for invasive as-
organs primarily affected being the lungs and the
pergillosis.
[2-4]
Transplantation practices, immuno-
sinuses. The most devastating infection in immuno-
suppressive regimens and the characteristics of pa-
compromised (cancer/transplant) patients is the in-
tients undergoing transplantation have continued to
vasive form with a 357% increase in mortality rates
evolve. Current data show that invasive aspergillosis
reported in the US between 1980 and 1997.
[2]
This
in stem cell recipients now predominantly occurs
trend is probably related to the increased number of
late after engraftment in non-neutropenic patients in
whom graft-versus-host disease (GVHD) and its
management with increasingly intense immunosup-
pression have emerged as major risk factors.
[5]
De-
spite the heightened awareness of the profiles of
patients at risk for invasive aspergillosis and a num-
ber of therapeutic options today (table II),
[6]
the
mortality rate remains high. High mortality from
invasive aspergillosis has been due to compromised
host immunity, delayed diagnosis and the limited
availability of safe and effective antifungal drugs.
[7]
1. Diagnosis of Invasive
Pulmonary Aspergillosis
This section is a brief overview of the recent
advances in the diagnostic techniques of invasive
aspergillosis. For a detailed discussion, the reader is
referred to a review by Hope et al.
[8]
Table I. Characteristics of various pathogenic Aspergillus spp.
Species Frequency in Clinical significance
clinical
infection (%)
A. fumigatus 65 Most common cause of IPA.
Resistance to triazoles reported
A. flavus 14 Frequent cause of sinusitis and
skin infections. Resistance to
triazoles reported
A. niger 5 Role in invasive infections less
well established. Less pathogenic
probably because larger conidia
do not reach the alveoli
A. terreus 5 Usually susceptible to triazoles.
Increasing reports of resistance to
amphotericin B. Blood cultures
may be positive
A. ustus 1 Intrinsically higher MIC values
(resistance) to triazoles and
polyenes
IPA = invasive pulmonary aspergillosis; MIC = minimum inhibitory
concentration.
Management of Invasive Aspergillosis 267
Table II. An overview of antifungal drugs approved for invasive aspergillosis
[6]
Drug Absorption/protein binding Metabolism Mechanism of action
Triazoles
Voriconazole Bioavailability 96%; food absorption; not pH dependent; CYP3A4, CYP2C9/19 Inhibit lanosterol
60% protein binding Excreted in bile and stools demethylase
Good CNS concentrations
Posaconazole No IV formulation; food with fat absorption; not pH CYP3A4 only
dependent; bioavailability 96%; 98% protein binding Excreted in bile and stools
Good CNS concentrations
Itraconazole IV not pH dependent CYP3A4 only
Oral pH dependent; food absorption; bioavailability Excreted in bile and stools
55%; 99.8% protein binding
Minimal CNS concentrations
Echinocandins
Caspofungin Significant protein binding No CYP metabolism Inhibit 1,3--D-
Minimal to undetectable CNS concentrations N-acetylation in liver glucan
Tissue concentrations are unknown Eliminated in bile and stools
(35%), urine (41%)
Micafungin Hepatic-aryl sulfatase, COMT
and hydroxylation
Eliminated in stools
Anidulafungin Chemical degradation to a ring-
opened peptide that lacks
antifungal activity
Polyenes
AMB deoxycholate AMB deoxycholate and liposomal AMB have significant No CYP metabolism Bind to ergosterol
AMB colloidal protein binding Metabolism pathway unclear resulting in
dispersion CNS concentrations of liposomal AMB are more than membrane pores
Liposomal AMB deoxycholate, lipid complex and colloidal dispersion AMB
AMB lipid complex Peak concentrations in liver, spleen and lung
Excreted in urine and stools
AMB = amphotericin B; COMT = catechol-O-methyl transferase; CYP = cytochrome P450 enzyme; IV = intravenous; indicates increase;
indicates decrease.
The lack of reliable and non-invasive diagnostic Galactomannan is a polysaccharide cell wall
procedures remains a major obstacle in the success- component of Aspergillus spp. that is released into
ful early intervention of invasive pulmonary asper-
the circulation during fungal growth in the tissues.
[9]
gillosis. Clinical signs and symptoms are non-spe-
The double-sandwich, enzyme-linked immunosor-
cific, culture and microscopy of lower respiratory
bent assay, which can detect galactomannan, is a
tract specimens have a low sensitivity, and tissue for
useful tool for the early diagnosis of Aspergillus
histopathological examination is not easy to obtain
infection. Studies evaluating the role of galactoman-
because of the frequent presence of thrombocyto-
nan assay in the diagnosis of invasive aspergillosis
penia and coagulation abnormalities. Thus, most
have largely been conducted with patients undergo-
clinical cases of invasive pulmonary aspergillosis
ing cancer chemotherapy or haematopoietic stem
are classified as possible or probable infections in
cell transplantation (HSCT) recipients. In these pa-
view of the diagnostic difficulty. In recent years,
tients, a sensitivity of 67100% and a specificity of
efforts have been directed towards identifying non-
8698.8% has been documented. When serially
invasive markers for rapid and reliable diagnosis of
monitored, the galactomannan test preceded the
invasive aspergillosis. In particular, tests based on
diagnosis of invasive aspergillosis by an average of identifying fungal antigens or metabolites released
into the circulation have become available. 614 days. False positives with this assay are not
uncommon; cross-reactivity of Platelia
1
Aspergil- Chest radiographic findings are not sensitive and
lus galactomannan enzyme immunoassay (EIA) a high-resolution chest CT scan is the preferred
with Penicillium spp. and bacteria, such as method to detect early changes of invasive pulmon-
Bifidobacterium spp., has been noted but is deemed ary aspergillosis; radiographic contrast is not re-
to be of little clinical relevance as these are rarely quired. However, the radiological signs (halo sign
pathogens in humans.
[5,10]
The use of antifungal and air crescent sign) are not specific and other
agents may lower the sensitivity of the galactoman- entities may mimic invasive pulmonary aspergillo-
nan assay by decreasing the fungal load. Use of sis.
[13]
piperacillin/tazobactam and amoxicillin/clavulanic
2. Management acid may result in a false-positive test for galac-
tomannan.
[11]
The timing of collection of the sample
may influence the test results, with false-positive
2.1 Definitive Therapy
results being less likely in samples collected at
trough concentrations or prior to the administration
The drugs currently approved for the primary
of the dose. Despite the shortcomings of the test,
management of invasive aspergillosis include
galactomannan antigen testing is under active scruti-
amphotericin B deoxycholate (conventional formu-
ny for the diagnosis of invasive aspergillosis, espe-
lation) and voriconazole;
[14-16]
echinocandins are
cially in the transplant population.
also under investigation
[17]
(table II). Amphotericin
1,3--D-Glucan is an integral component of the B has been the gold standard for the treatment of
cell walls of a number of pathogenic yeasts and invasive aspergillosis for many decades; however,
filamentous fungi. In addition to aspergillosis and its toxicities, particularly renal toxicity, are well
candidiasis, it may be detected in infections caused known. The therapeutic advantages of amphotericin
by less common fungi (e.g. Fusarium, Tri- B include excellent fungicidal activity, rapid clear-
chosporon, Acremonium and Saccharomyces spp.). ance of organisms from tissue and the paucity of
The sensitivity and specificity of the test has ranged emergence of resistant organisms.
[6]
from 67% to 100% and 84% to 100%, respective-
The landmark study that led to the approval of
ly.
[10]
voriconazole for the primary treatment of invasive
Polymerase chain reaction (PCR)-based molecu- aspergillosis was published in 2002 by Herbrecht et
lar diagnostic tests for Aspergillus are not commer- al.
[18]
The study was performed in patients with
cially available and remain largely nonstandardized. haematological malignancy, including those who
Such assays, when performed on blood or underwent HSCT. This randomized, open-label trial
bronchoalveolar lavage samples, have shown a neg- evaluated 144 patients in the voriconazole group and
ative predictive value for invasive aspergillosis 133 patients in the amphotericin B deoxycholate
ranging from 92% to 99%. PCR results are usually group. Patients were followed for a period of
positive when the galactomannan assay is highly 12 weeks; at the end of the study period, the clinical
positive; 12 of 20 PCR assays that yielded a positive response rate was 52.8% among voriconazole recip-
result were observed in association with high ients (complete response in 20.8% and partial res-
galactomannan values.
[12]
ponse in 31.9%) and 31.6% among amphotericin B
A prospective comparison of real-time PCR, recipients (complete response in 16.5% and partial
galactomannan and 1,3--D-glucan assays as week- response in 15%). There was a significant difference
ly screening for invasive aspergillosis in patients in drug adherence between the two groups; 62 of
with haematological disorders showed that the 144 patients in the voriconazole arm continued to
galactomannan test was relatively more sensitive in take the drug, compared with only 2 of 133 patients
predicting the diagnosis.
[12]
in the amphotericin B arm, reflecting poor tolerance
1 The use of trade names is for identification purposes only and does not imply endorsement.
to the latter drug. The difference in survival rate at conazole in certain situations as follows: (i) previous
the end of 12 weeks was statistically significantly use of a mould-active drug for prophylaxis or empir-
between the two groups, with 71% and 58% surviv- ic therapy; (ii) concomitant use of drugs with major
ing in the voriconazole and amphotericin B arms,
interactions with voriconazole, such as sirolimus,
respectively. Similar results were observed in the
rifampin or warfarin; (iii) presence of significant
intent-to-treat population that included all random-
hepatic impairment; (iv) high suspicion for zygo-
ized patients. Since the publication of this study,
mycosis; or (v) the presence of cardiac risk factors
voriconazole is widely accepted as the drug of first
such as prolonged QT interval and cardiomyopathy.
choice for the treatment of invasive aspergillosis.
Echinocandins have undergone very limited
Whether initial therapy with higher than standard
evaluation as first-line therapy for invasive aspergil-
doses (35 mg/kg) of a lipid form of amphotericin B
losis. The study by Candoni et al.
[17]
reported 32 pa-
would have a better outcome has been debated. A
tients with haematological malignancies who re-
recent, randomized, double-blind, prospective trial
ceived caspofungin as primary or first-line therapy
(AmBiLoad Trial) compared the safety and efficacy
for probable or proven aspergillosis. Most patients
of a high-dose regimen of liposomal amphotericin B
(97%) were neutropenic and had pulmonary local-
versus the standard dose as initial therapy for inva-
ization. All patients with neutropenia (97%) re-
sive aspergillosis. The standard-dose group received
ceived granulocyte colony-stimulating factor (G-
3 mg/kg/day and the high-dose group received
CSF) in addition to caspofungin. The overall res-
10 mg/kg/day of liposomal amphotericin B for
ponse rate was 56%, with neutrophil recovery and
14 days, followed by 3 mg/kg/day in both groups.
stable haematological disease (remission) associated
The favourable response to treatment at 12 weeks
with a favourable response rate. A small proportion
was similar in both study groups: 50% with the
of patients who had partial response were rescued
standard dose and 46% with the high dose. Survival
with voriconazole. The second study by Denning et
rate at 12 weeks was similar as well, with 72% and
al.
[14]
evaluated the efficacy of micafungin alone or
59% with the standard-dose and high dose-regi-
in combination with other antifungal agents. Al-
mens, respectively. Nephrotoxicity occurred in 14%
though there were 331 patients enrolled in the study,
of the standard-dose group versus 31% of the high-
the group that received micafungin alone was small
dose group (p < 0.02). The authors concluded that
(23 patients) and the response rate was 50% in that
there was no beneficial effect with administration of
group. Although echinocandins appear promising,
a high loading dose of liposomal amphotericin B
monotherapy with echinocandins for invasive asper-
and, in fact, the high dose was associated with an
gillosis is not recommended pending data from de- increased risk of nephrotoxicity.
[19]
finitive studies.
In an analysis of 85 allogeneic HSCT recipients
(78% with invasive aspergillosis) treated with With the established diagnosis of invasive asper-
amphotericin B lipid complex, the overall response
gillosis, primary therapy must be initiated with vori-
rate was 41%, with a 44% response in patients with
conazole. With clinical and radiological improve-
GVHD.
[20]
These results are comparable to those
ment, therapy is continued for a period of at least
achieved with other available drugs.
3 months. Lack of response or progression of infec-
tion could be secondary to host factors or drug
With its better tolerability, voriconazole is pre-
failure. If drug failure is suspected, switching to a
ferred to amphotericin B or its lipid formulations.
[21]
different class of antifungal agents or addition of a
It is to be noted that the efficacy of voriconazole has
second agent (i.e. echinocandin) has become a com-
not been compared with that of a lipid formulation
mon clinical practice. In situations where there is a of amphotericin B and such a study is unlikely to be
concern with the pharmacokinetics (specifically, performed. Amphotericin B, either conventional or
drug absorption), the drug concentration should be a lipid formulation, may be preferred to vori-
Invasive aspergillosis
Improvement
- clinical
- radiological
- immunological
Start voriconazole
(second choice is a lipid formulation of amphotericin B)
Continue therapy
(duration: 3 months or longer)
1. Check voriconazole
concentrations
2. Change drug therapy to
an echinocandin or a lipid
amphotericin
3. Add an echinocandin
1. Decrease immunosuppression
2. Surgical debridement
3. Immunomodulation
No improvement or progression
of infection
Yes
Host factors Drug failure +/
Fig. 1. An algorithm for the clinical management of invasive aspergillosis.
obtained and the dose of voriconazole adjusted ac- bination (fluconazole plus itraconazole) as prophy-
cordingly (figure 1). laxis against invasive fungal infections in patients
undergoing induction chemotherapy for newly diag-
nosed acute myelogenous leukaemia or myelodys-
2.2 Prophylactic Therapy
plastic syndrome. A total of 49% of the liposomal
amphotericin B group and 48% of the fluconazole
Institution of therapy for aspergillosis in a high-
plus itraconazole group completed prophylactic
risk patient without any clinical and/or radiological
therapy and the azole combination, as expected, had
evidence or history of aspergillosis is considered
a better tolerability profile. There was no difference
primary prophylaxis. Several factors should be con-
observed in the incidence of infection or the mor-
sidered prior to initiating prophylactic therapy, in-
tality rates between the two groups. The concept of
cluding the frequency and outcome of infection,
using two azoles simultaneously for prophylaxis
difficulty with early diagnosis, drug efficacy, drug
may not be appealing to most clinicians.
interactions, safety and cost. The antifungal drugs
that may be effective as prophylaxis against invasive A meta-analysis of 13 randomized controlled
aspergillosis include itraconazole, voriconazole, po- trials compared the efficacy of itraconazole versus
saconazole, conventional or lipid formulations of fluconazole for the primary prophylaxis of invasive
amphotericin B, caspofungin, micafungin and fungal infections in neutropenic patients with
anidulafungin (table II).
[6]
haematological malignancies. The study assessed
Mattiuzzi et al.
[22]
performed a randomized, 3597 patients and concluded that itraconazole sig-
open-label trial to compare the efficacy and safety nificantly decreased the incidence of and mortality
of liposomal amphotericin B versus an unusual com- from invasive fungal infections. A statistically sig-
nificant reduction (48 21%) in the incidence of 16% in the posaconazole group versus 22% in the
standard azole group (p = 0.048). Posaconazole was invasive aspergillosis was observed in the itracona-
superior to fluconazole and itraconazole as prophy- zole (solution) group. Importantly, the authors noted
laxis treatment against invasive aspergillosis and that the effect of prophylaxis was dependent on the
was as well tolerated as the other two drugs. pharmacokinetics and oral bioavailability of itra-
conazole.
[23]
The solution is preferred to the capsule
As GVHD is a significant risk factor for invasive
formulation and the frequent drug-drug interactions
aspergillosis in HSCT recipients, Ullmann et al.,
[27]
with itraconazole make it a not-so-desirable drug.
[6]
in an randomized, double-blind international trial,
compared the prophylactic efficacy of posaconazole
Two clinical trials have compared the prophylac-
(301 patients) versus fluconazole (299 patients) in
tic efficacy of fluconazole versus itraconazole
this population. At the end of the fixed 112-day
against invasive fungal infections in patients under-
treatment period, posaconazole was found to be as
going allogeneic HSCT. The earlier study by Win-
effective as fluconazole in preventing all invasive
ston and colleagues
[24]
involved 138 patients who
fungal infections (5.3% vs 9%; p = 0.07) but was
received either itraconazole or fluconazole prophy-
superior to fluconazole in the prevention of invasive
laxis and were followed for a period of 180 days
aspergillosis (2.3% vs 7%; p = 0.006) and was
post-HSCT. In this relatively small study, itracona-
associated with a lower incidence of breakthrough
zole prevented more invasive fungal infections than
fungal infections (2.4% vs 7.6%; p = 0.004), partic-
fluconazole, probably because of the efficacy of the
ularly invasive aspergillosis (1% vs 5.9%;
former drug against invasive moulds. The second
p = 0.001).
trial by Marr et al.
[25]
found no difference between
the efficacies of fluconazole and itraconazole during
In summary, while itraconazole has lost its ap-
the study period; however, in a subset of patients
peal in view of its unfavourable adverse effect pro-
who tolerated itraconazole, fewer patients devel-
file, posaconazole appears to be an effective prophy-
oped invasive mould infection while receiving pro-
lactic drug in high-risk patients and data for vori-
phylaxis. The trial had to be terminated because of
conazole are awaited. Lack of an intravenous
the high incidence of adverse effects (renal and
formulation of posaconazole at the present time is a
hepatic toxicities) reported in the itraconazole
drawback, particularly in cancer and transplant pa-
group, which were perhaps due to a larger than
tients with gastrointestinal abnormalities. Addition-
standard dose of itraconazole (200 mg three times
ally, drug interactions involving azoles remain a
daily) that was administered.
significant concern.
Recently, Cornely and colleagues
[26]
compared Echinocandins are attractive agents for prophy-
the prophylactic efficacy of posaconazole and either laxis, as they have good anti-Aspergillus activity
fluconazole or itraconazole in patients with pro- and have an excellent adverse effect profile with
longed neutropenia in the setting of acute myeloge- minimal drug interactions. Caspofungin has been
nous leukaemia or myelodysplastic syndrome. In evaluated as a prophylactic agent in comparison
this randomized multicentre study, a total of 304 pa- with intravenous itraconazole in patients undergoing
tients received posaconazole and 298 patients reinduction chemotherapy for high-grade myelodys-
ceived fluconazole (240 patients) or itraconazole plastic syndrome or acute myelogenous leukaemia.
(58 patients). Proven or probable invasive fungal There was no significant difference in the incidence
infections were reported in 7 patients (2%) in the of invasive fungal infections in the two groups (5 of
posaconazole group and in 25 patients (8%) in the 86 in the itraconazole group and 7 of 106 in the
fluconazole or itraconazole group; the difference caspofungin group).
[28]
Van Burik et al.
[29]
compared
was statistically significant. Posaconazole reduced the prophylactic efficacy of micafungin with fluco-
the number of invasive fungal infections and im- nazole against invasive fungal infections during pre-
proved survival, with an all-cause mortality rate of engraftment neutropenia in patients undergoing
HSCT. Both drugs had comparable efficacy in the 2.3 Empirical Antifungal Therapy
prevention of candida infection. However, there
Empirical treatment is antifungal therapy pro-
were few patients with invasive aspergillosis be-
vided to high-risk patients with signs and symptoms
cause the study was conducted during the relatively
suggestive of invasive fungal infection, such as pa-
short pre-engraftment neutropenic period. The dis-
tients with neutropenia and fever unresponsive to
advantages of echinocandins include the lack of an
broad-spectrum antibacterials. The difficulties asso-
oral formulation and their relatively narrow spec-
ciated with the early diagnosis of invasive fungal
trum of activity.
infections led to the introduction of empirical anti-
There are no data addressing the issue of how fungal therapy in the early 1980s. The scientific
rationale for such treatment was based on two prolong the prophylaxis should continue and so
spective randomized trials. The first trial, with a
clinicians frequently opt to provide chemopro-
modest number of patients, concluded that empirical
phylaxis during long periods of intense immunosup-
antifungal therapy resulted in a lower incidence of
pression (e.g. neutropenia or GVHD treated with
invasive fungal infections, particularly invasive can-
high-dose corticosteroids).
didiasis.
[31]
The second larger EORTC (European
The term secondary prophylaxis is used when
Organisation for Research and Treatment of Cancer)
the drug is administered to patients previously treat-
trial assessed the role of adding empirical antifungal
ed for invasive aspergillosis but who are still at risk
therapy to antibacterial therapy after 4 days of per-
because of continued immunosuppression. A com- sistent febrile neutropenia in 132 patients. The clin-
ical response rate in the amphotericin B arm was
mon example is a patient who has a history of
69% versus 53% in the control group. There were
aspergillosis and is receiving reinduction chemo-
six (9%) documented fungal infections in the control
therapy for relapsed leukaemia. Voriconazole has
group and one (1%) in the amphotericin B group. No
largely replaced the use of itraconazole or a polyene
fungal-related deaths occurred in the amphotericin
for secondary prophylaxis. A retrospective review
B group compared with four (6%) in the control
by Martino et al.
[30]
analysed the outcome of 129 pa-
group (p = 0.05).
[32]
tients with a history of invasive aspergillosis who
Although the emphasis in these trials was on
underwent allogeneic HSCT, of whom 57 (44%)
invasive candidiasis, they paved the way for further
received a reduced-intensity conditioning. Overall,
studies in empirical therapy for invasive aspergillo-
27 patients with invasive aspergillosis relapsed or
sis.
[33]
Subsequently, there have been several trials
recurred after the allogeneic HSCT (cumulative in-
that have evaluated empirical therapy with different
cidence at 2 years of 22%). Antifungal drugs used antifungal drugs. Either liposomal or conventional
amphotericin B was compared with different anti- for prior therapy included liposomal amphotericin
fungal drugs: fluconazole,
[34-37]
itraconazole,
[38]
B, amphotericin B lipid complex, caspofungin and
voriconazole
[39-41]
or caspofungin.
[42,43]
Most trials
voriconazole. Since several different strategies of
have used composite endpoints. Excluding the tox-
drug therapy were used for secondary antifungal
icities associated with the conventional ampho-
prophylaxis during conditioning and post-transplan-
tericin B preparation, similar outcomes were observ-
tation follow-up, it was difficult to identify differ-
ed with liposomal or conventional amphotericin B
ences among specific strategies. However, a subset
with respect to clinical response, survival and the
analysis showed that the use of voriconazole for
number of cases of breakthrough aspergillosis. Itra-
secondary prophylaxis reduced the risk of progres-
conazole was found to be as effective as ampho-
sion of invasive aspergillosis (12% in 31 vori-
tericin B when used for empirical therapy in patients
conazole recipients compared with 22% in the re-
with cancer and persistent febrile neutropenia, al-
maining 98 patients; p < 0.15). though significant nephrotoxicity was seen in the
latter group.
[38]
More recently, voriconazole failed to A recent study by Maertens and colleagues
[46]
meet the pre-specified non-inferiority criteria in a assessed the value of pre-emptive therapy in patients
prospective, randomized, open-label, multicentre, with acute leukaemia or allogeneic HSCT and per-
international trial, when compared with liposomal sistent febrile neutropenia, based on serum galac-
amphotericin B. When defervescence, a less sensi- tomannan antigen test results. A total of 88 patients
tive endpoint, was removed from the composite
received prophylactic therapy with fluconazole and
endpoint, results with voriconazole were im-
were followed with daily serum galactomannan test-
proved.
[39]
Walsh et al.
[42]
have showed caspofungin
ing and thorax CT scans if needed. Liposomal
to be as effective and better tolerated than liposomal
amphotericin B was instituted as pre-emptive ther-
amphotericin B for empirical therapy of patients
apy in patients with positive galactomannan tests or
with persistent febrile neutropenia. Importantly, a
compatible radiological findings with culture or his-
meta-analysis of 24 randomized trials published in
topathological confirmation. A total of 19 patients
1997 has questioned the role of empirical antifungal
had proven or probable invasive aspergillosis. Over-
therapy in the management of patients with persis-
all, 35% of patients met criteria for empirical ther-
tent febrile neutropenia.
[44]
apy (i.e. persistent febrile neutropenia), whereas on-
It is clear that antifungal drugs, when given em-
ly 7% of patients received therapy based on the pre-
pirically, are frequently administered to a large
emptive strategy; there was a 78% reduction in the
number of patients with no fungal infection. With
use of antifungal agents between the two strategies.
the availability of non-invasive diagnostic markers
It is noteworthy that the galactomannan antigen test
(e.g. chest CT scan and serum galactomannan anti-
could be falsely negative in the presence of circulat-
gen test), it is anticipated that the high-risk patients
ing Aspergillus antibodies or in patients receiving
can be better identified and hence empirical therapy
anti-Aspergillus drugs for prophylactic or empirical
may decline in clinical practice.
therapy; the test could be falsely positive in patients
receiving -lactam drugs (e.g. piperacillin/tazobac-
2.4 Pre-Emptive Therapy
tam).
[11]
Lin et al.
[47]
used a PCR screening assay
with panfungal primers for the early detection of
Pre-emptive therapy for invasive aspergillosis is
invasive fungal infections and therapy with ampho-
gaining momentum with the availability of the
tericin B was instituted only in patients with two
galactomannan antigen test for invasive aspergillo-
positive PCR results. The authors showed that a
sis. This strategy is a risk-based intervention for
PCR-based therapeutic approach reduced mortality
high-risk patients with persistent febrile neutropen-
in cancer patients with febrile neutropenia and fun-
ia plus the presence of other evidence of inva-
gal infections. Although employing PCR tests for
sive fungal infection, such as positive surveillance
pre-emptive strategies appears promising, the tests
cultures, radiological features or a positive
are not standardized and are not yet commercially
galactomannan antigen test.
[45]
The concept of pre-
available.
emptive therapy for invasive aspergillosis is akin to
Chest CT scans play a critical role in the early
the utilization of antigen/PCR measurement for cy-
diagnosis of invasive pulmonary aspergillosis.
tomegalovirus (CMV) infection in transplant pa-
Greene et al.
[48]
evaluated baseline chest CT scan
tients. On the basis of the currently available diag-
findings in 235 patients with invasive pulmonary
nostic tests, pre-emptive therapy is considered ap-
aspergillosis. The authors compared the response to
propriate in the setting of compatible radiological
treatment and survival after 12 weeks of treatment in findings and antigen tests in high-risk patients.
143 patients with a halo sign (a feature of early However, the false positives/negatives associated
infection) to 79 patients with other CT findings. The with the galactomannan antigen test and the non-
former group had a significantly better response to standardized PCR techniques make it difficult for a
treatment (52% vs 29%; p < 0.001) and improved reliably uniform pre-emptive approach.
[8]
survival (71% vs 53%; p = 0.01). Thus, early initia- echinocandins may provide additive or synergistic
tion of antifungal treatment on the basis of identifi- activity in combination with triazoles.
[53,54]
cation of a halo sign on the chest CT scan was
The combination of voriconazole and caspofun-
associated with a better outcome. Also, a prospec-
gin (n = 40) as primary therapy for invasive asper-
tive review of the baseline imaging and treatment
gillosis in solid organ transplant recipients was in-
response of 343 immunocompromised patients re-
vestigated by Singh et al.
[52]
in a prospective multi-
ported that patients at risk for developing invasive
centre study. The authors reported that combination
pulmonary aspergillosis and presenting with com-
therapy was independently associated with an im-
patible radiological findings benefit from early anti-
proved 90-day survival, particularly in patients with
fungal therapy.
[49]
One study noted that detection of
renal failure or A. fumigatus infection.
serum galactomannan antigen by EIA did not pre-
Marr et al.
[55]
conducted a retrospective study of
cede detection of compatible lesions on a thoracic
47 patients with invasive pulmonary aspergillosis
CT scan.
[50]
after HSCT and chemotherapy. Most patients in this
Since daily galactomannan testing may not be a
study received amphotericin B as primary therapy
practical approach, Stephanie et al.
[45]
have pro-
and were switched to either voriconazole alone or a
posed determining serum galactomannan levels at
combination of voriconazole plus caspofungin as
the time of onset of fever, repeated after 72 hours
salvage therapy. The mortality rate in patients who
with a chest CT scan if fever persists and then twice
received the combination was lower than that in the
weekly thereafter.
monotherapy group. At present, the sequential addi-
On the basis of data from these studies, chest CT
tion of an echinocandin is being increasingly used as
scans and serum galactomannan antigen tests are
a salvage strategy.
being increasingly utilized in pre-emptive strategies
The pilot Combistrat trial (n = 30 patients) stud-
for the management of invasive aspergillosis. There
ied the efficacy of the combination of caspofungin
is considerable overlap between the empirical and
plus liposomal amphotericin B (3 mg/kg/day) versus
pre-emptive strategies. As non-invasive diagnostic
monotherapy with high-dose liposomal ampho-
tools become refined and more reliable for early
tericin B (10 mg/kg/day) as primary therapy for
diagnosis, the empirical approach may be replaced
invasive aspergillosis. At the end of treatment
by pre-emptive therapy.
period, the favourable overall response rate was
67% for the combination versus a relatively low
27% for the high-dose liposomal amphotericin B
2.5 Combination Therapy
group (p = 0.028). The study concluded that the
combination of caspofungin and liposomal ampho-
In recent years, compared with amphotericin B,
tericin B could be more efficacious in high-risk
voriconazole has contributed to improved outcomes
patients with haematological malignancies. As this
in invasive aspergillosis. Nevertheless, therapeutic
was a phase IV clinical trial, carefully controlled and
success rates continue to be suboptimal, particularly
well designed randomized clinical trials are needed
in stem cell recipients. In a further attempt to im-
before any firm recommendations are made.
[56]
prove outcome, based on data from in vitro and
Another echinocandin, micafungin, was evalu-
animal studies, several antifungal drug combina-
ated in two- and three-drug combinations with
tions have been tried with variable success.
[51,52]
In
amphotericin B and azoles as salvage therapy. The
the past, the concurrent use of amphotericin B and
combination was found to be well tolerated and
an azole elicited controversy, given the potential
effective for refractory aspergillosis in bone marrow
antifungal antagonism. The introduction of the echi-
transplant patients.
[57]
nocandin class of drugs with a different target site
has invigorated the prospects of combination ther- At present, for patients with refractory/progres-
apy. There are in vitro and animal data to show that sive aspergillosis, the addition of a second agent (an
echinocandin) may be reasonable (figure 1). In prac- subjects. The overall success rate was 42% for the
tice, an azole plus an echinocandin as initial therapy posaconazole group and 26% for the control sub-
in seriously ill patients is becoming common place jects (p = 0.006). This benefit was observed as early
in the absence of evidence based data. As the two as 30 days into salvage therapy and continued to the
drug classes target entirely different sites, potential end of the study; survival advantage was also noted
synergism is a reasonable expectation. However, as with posaconazole. Perfect et al.
[60,61]
studied the use
drug-related toxicities and cost may negate the po- of voriconazole as salvage therapy for refractory
tential clinical benefits, a randomized trial for pri- fungal infections, including invasive aspergillosis.
mary therapy comparing a single drug (triazole) to a The efficacy rate of voriconazole for invasive asper-
combination (triazole plus echinocandin) of drugs gillosis was 43.7%; the drug was well tolerated and
needs to be performed. treatment-related discontinuation occurred in <10%
of patients.
2.6 Salvage Therapy Salvage therapy is generally instituted at the time
of clinical failure of initial therapy. Studies of sal-
Lipid amphotericin B formulations and caspo-
vage therapy show an 40% response rate regardless
fungin have been approved by the US FDA for
of the second drug type (40% rule). As physicians
salvage therapy of invasive aspergillosis. The lipid
become desperate because of clinical failure, the
amphotericin formulations maintain a broad spec-
addition of one, two or more drugs to existing ther-
trum of antifungal activity with fewer infusion relat-
apy commonly occurs. Besides drug failure, other
ed toxicities. However, the EORTC group
[16]
dem-
possible causes for therapeutic failure need to be
onstrated that the initial choice of antifungal therapy
evaluated and managed accordingly (figure 1).
is critical to a successful outcome. In their study of
139 patients, patients received initial therapy with 2.7 Role of Surgery
either voriconazole or amphotericin B deoxycholate
The indications for surgery in invasive aspergil-
and were switched to other licensed therapies as
losis include infected catheters, infection of skin and
needed. The overall response rate was 30% in the
soft tissue, chest wall or pericardial invasion,
amphotericin B group and 55% in the voriconazole
haemoptysis from a single pulmonary lesion, select-
group, independent of the salvage therapy that was
ed cases of invasive sinusitis, amenable solitary
administered.
CNS lesions, endocarditis and osteomyelitis. Be-
The efficacy of caspofungin as salvage therapy
sides lobectomy, open-wedge resection and video-
was evaluated in an open-label, non-comparative,
assisted thoracoscopic surgical interventions are
multicentre trial that demonstrated a 45% favoura-
also feasible.
[62]
In a retrospective analysis compar-
ble response to caspofungin therapy.
[58]
This led to
ing medical and surgical treatment, lung resection
the use of caspofungin as salvage therapy for inva-
was associated with a better survival rate and re-
sive aspergillosis in North America and Europe.
duced mortality, especially for solitary pulmonary
Echinocandin as initial monotherapy for invasive
lesions.
[63]
Lung resection should be considered in
aspergillosis is under evaluation. In addition, it is
patients with clinical and radiological signs of soli-
unclear whether higher than standard doses of
tary/localized lesions with severe haemoptysis.
[64]
echinocandin may have improved efficacy against
invasive aspergillosis.
3. Future Approaches
In an open-label, multicentre study, Walsh et
al.
[59]
investigated the efficacy and safety of posaco-
3.1 Antifungal Agents in the Pipeline
nazole in patients with invasive aspergillosis and
other mycoses who were refractory to or intolerant Several new classes of antifungal agents with
of conventional antifungal therapy. The study in- anti-Aspergillus activity are in development or have
cluded 107 posaconazole recipients and 86 control been tested in animals.
[65-67]
Ravuconazole, a derivative of fluconazole, has 3.2 Immunomodulatory Therapies
demonstrated good activity when compared with
The increasing incidence of invasive aspergillo-
that of amphotericin B and itraconazole in a neutro-
sis, the limited efficacy of the available drugs and
penic rabbit model of disseminated aspergillosis and
the high mortality underscore the need for additional
a murine model of invasive pulmonary aspergillo-
or alternative treatment strategies. It is well known
sis.
[68]
that host defence (neutrophils, monocytes/macro-
The polyene liposomal nystatin has shown good
phages) is paramount in the management of these
in vitro activity against Aspergillus spp. It was also
infections and, therefore, immunomodulatory ther-
effective against disseminated aspergillosis in neu-
apy is a rational approach. Phagocytosis and killing
tropenic rabbits where it prolonged survival and
of conidia requires optimal monocyte/macrophage
reduced residual tissue fungal burden. The EORTC
function, while neutrophils are essential for the
group conducted a study of 26 patients with prob-
phagocytosis of the hyphal elements. Corticosteroid
able or definite aspergillosis and concluded that
use is a well known risk factor for invasive aspergil-
liposomal nystatin could be effective for salvage losis through its inhibition of the phagocytic activity
therapy of invasive aspergillosis, although infusion- of neutrophils and macrophages, chemotaxis, oxida-
related toxicity has limited its further develop- tive bursts and activity against hyphae. Since neu-
trophil count and function are both essential for the ment.
[69]
primary defence against Aspergillus spp., most stud-
The pradimicins and the structurally similar
ies on immunomodulatory therapy
[65-67]
revolve
benanomicins constitute a unique class of fungicidal
around augmentation of the quantity as well as the
antibiotics derived from the culture filtrates of Acti-
quality of neutrophils and T cells. Also, withdrawal
nomycetes. Both have activity against Aspergillus
or reduction in the dosages of immunosuppressive
spp. The pradimicin BMS-181184 was associated
drugs is a key principle for the successful restoration
with severe hepatotoxicity in early clinical trials and
of the immune function.
had to be withdrawn from clinical investigation.
[70]
Nikkomycins are potent inhibitors of chitin-syn-
3.2.1 Recombinant T Helper Cell Type 1 Cytokines
thase and recent in vitro studies have demonstrated
Although neutrophils play an important role in
synergistic activity against A. fumigatus when used
the defence against invasive aspergillosis, HSCT
in combination with an azole.
[71]
recipients remain susceptible to this infection long
after neutrophil recovery because of a prolonged and
Sordarins are natural fungal products that exert
defective T cell immune response that is seen in
their antifungal effects by inhibition of the protein
these patients. The most important cytokines that are
synthesis elongation cycle in yeasts without affect-
pertinent to host defence against invasive aspergillo-
ing the protein synthesis machinery in mammalian
sis include interleukins (ILs) and interferon (IFN)-
systems. Sordarin derivatives, GM222712 and
.
[65-67]
GM237354, have shown good activity against a
wide range of pathogenic fungi, including certain
Interleukins
filamentous fungi. Pharmacokinetic, safety and in
Host invasion by A. fumigatus results in the stim-
vivo data are pending and will delineate if this class
ulation of two subsets of CD4+ (T helper [T
h
]) cells.
of drugs can be further developed.
[72]
Novel -D-
Generally, T
h
1 cells confer protection against fungal
glucan synthase inhibitors, such as the glycolipid
diseases and T
h
2 cells are associated with disease
papulacandins and the acidic terpenoids, are under
progression. Activated CD4+ T
h
1 cells that secrete
investigation. Terbinafine is an allylamine that has
various cytokines, including IFN, IL-2 and IL-15,
demonstrated good fungicidal activity in vitro and in and macrophages that produce IL-12 have been
vivo against various Aspergillus spp., including shown to confer protection against invasive asper-
A. terreus.
[66,67]
gillosis.
[73,74]
Animal studies have demonstrated re-
3.2.2 Donor Granulocyte Transfusions
sistance to disease progression associated with ele-
The major predictors of invasive aspergillosis
vated production of these cytokines. However, in-
during chemotherapy or in the early post-transplant
creased levels of IL-12 in animals has also been
period are the severity and the duration of neutro-
shown to be deleterious because of the induction of a
penia. Donor granulocyte infusions have been in use
profound immune-inflammatory response that has
since the 1960s.
[65,67]
Transfusions have been used
been a major concern for use in humans.
[73-75]
for primary prophylaxis during the engraftment
Interferon-
period or as secondary prophylaxis in patients with a
A. fumigatus stimulates IFN release by T
h
cells,
recent history of invasive aspergillosis with some
which in turn promote tumour necrosis factor
encouraging results. The prognostic factors asso-
(TNF)- production by the monocyte-macrophage
ciated with a successful outcome include an ade-
system. IFN has been shown to increase the oxida-
quate dose of infusion used, granulocyte compatibil-
tive burst and fungicidal activity of polymorphonu-
ity between donor and recipient, and a short duration
clear cells against A. fumigatus hyphae in vitro; it
of neutropenia. However, randomized prospective
also restores the corticosteroid-induced suppressed
trials are needed to investigate their clinical efficacy
activity of monocytes and leucocytes. The use of
before any strong recommendation can be made.
IFN in humans has not been extensively evaluated,
with the exception of a study that showed its prophy-
3.2.3 Recombinant Growth Factors
lactic efficacy in patients with chronic granuloma-
Large prospective data with colony stimulating
tous disease. There are some case reports of its use
factors to treat invasive aspergillosis are not avail-
in combination with other cytokines and antifungal
able, although there is anecdotal evidence that they
drugs in immunocompromised patients with varia-
may favourably alter the course of the disease pro-
ble success.
[76]
cess when used in conjunction with antifungal ther-
Tumour Necrosis Factor- apy. G-CSF not only increases the number of circu-
lating neutrophils, but also enhances the phagocytic TNF is a pro-inflammatory cytokine secreted
activity and oxidative burst metabolism of circulat- by activated macrophages in response to respiratory
ing polymorphonuclear leukocytes. Prophylaxis pathogens, including A. fumigatus. In vitro, it has
with human G-CSF and amphotericin B or itracona- demonstrated crucial activity at the time of invasion,
zole has shown some additive effect in neutropenic with increases in oxygen radical production, activa-
animal models of invasive aspergillosis. In a neutro- tion of alveolar macrophages and phagocytosis. It
penic murine model, human G-CSF, by itself, was also potentiates late defence with increased recruit-
ineffective but in combination with amphotericin B ment of polymorphonuclear lymphocytes. Adminis-
demonstrated synergistic fungicidal activity.
[67]
tration of granulocyte-macrophage colony-stimulat-
ing factor (GM-CSF) and TNF has been shown to Unlike G-CSF, GM-CSF promotes the differ-
counteract the immune deficiency associated with entiation and proliferation of mononuclear cells in
corticosteroid therapy both in vitro and in vivo. addition to neutrophils.
[78]
It also prevents the defec-
Treatment with neutralizing antibodies to TNF tive in vitro antifungal activity of corticosteroid-
reduced neutrophil migration to the lungs and is treated monocytes and enhances the phagocytic ac-
associated with a delay in fungal clearance.
[67,77]
tivity of polymorphonuclear leukocytes. An in vivo
Murine studies have also revealed that intratracheal murine model demonstrated that GM-CSF adminis-
administration of TNF 3 days prior to inoculation tered prior to dexamethasone prevented the deleteri-
with A. fumigatus conidia (results in macrophage ous effects but if given after dexamethasone could
priming) showed survival benefits but not with si- not undo the damage on macrophages.
[79]
GM-CSF
multaneous administration.
[76]
However, the toxicity has also been shown to reduce the fungal infection
associated with the effective doses has been a major associated mortality from 19% to 2% in a clinical
impediment for further use. trial of patients with acute myelogenous leukae-
mia.
[80]
A note of caution is the rapid return of Improved understanding of the pathogenesis of
neutrophils in the presence of CSF, resulting in an invasive pulmonary aspergillosis at the molecular
exuberant inflammatory response and subsequent level, and of the complex interaction of the host
clinical deterioration. Fatal haemoptysis has been immunity and pathogen at the cellular level will
reported in the presence of such an exaggerated provide critical information, essential to further
inflammatory response.
[67]
Adjuvant treatment with evaluate the role of immunomodulating agents in the
G-CSF or GM-CSF could be considered in select management of invasive aspergillosis.
groups of HSCT recipients with serious infections
3.3 Vaccines
and in those patients receiving systemic corticoster-
oid therapy, especially in the setting of GVHD.
The development of a vaccine against aspergillo-
Treatment with IFN and growth factors may be
sis in immunocompromised hosts is a new and chal-
attempted as salvage therapy for patients with
lenging paradigm in vaccinology.
[81-84]
The difficul-
refractory invasive aspergillosis. However, use of
ty of designing a vaccine lies with the diversity of
these immunemodulators must be considered early
the immunocompromised population and the hetero-
in the course of therapy, especially in the severely
geneity of immune defects that predisposes patients
immunocompromised hosts, since introducing them
to invasive aspergillosis. To date, several studies
late in the course of fungal infection may not have a
have demonstrated protection using crude A. fumi-
significant impact on the outcome.
[65]
gatus vaccines.
[85,86]
Most murine models have a
3.2.4 Pentraxin single immune-deficiency state.
[87]
Therefore, it is
unclear if vaccine-induced protection covers a wide Pentraxin is a highly conserved super family of
range of immune deficits, such as those resulting proteins secreted by diverse cell types, including
from T-cell dysfunction, CMV disease, corticoster- mononuclear phagocytes, dendritic cells and endo-
oid therapy, neutropenia and GVHD. Current efforts thelial cells, in response to pro-inflammatory signals
have focused on active immunisation protocols us- such as TNF, IL-1 and selected microbial moieties.
ing crude antigen preparations or individual anti- Laboratory studies have been encouraging and show
gens. Novel adjuvants, cytokines and other im- a potential therapeutic role in preventing fungal
munomodulators may be used to increase the effi- infections and a possible role as an adjuvant
cacy of these vaccines.
[86-89]
Cenci et al.
[90,91]
used a immune-enhancing agent in combination with anti-
killer anti-idiotype monoclonal antibody to protect fungal drug therapy. Additional studies are needed
mice from a lethal A. fumigatus challenge during to elucidate the role of this novel agent and its
experimental bone marrow transplantation. An in- potential applicability in clinical practice.
[65]
triguing approach is the use of adoptive transfer of
3.2.5 Pathogen-Specific Immune Therapy
previously immunised cells providing a combina-
In addition to the non-specific augmentation of
tion of active and passive immunisation. Adoptive
the host immunity, there are immunotherapies di-
transfer of Aspergillus-specific donor T cells is
rected at the specific pathogen. Potential targeted
under investigation for the treatment of invasive
therapies include the use of transfer factors to poten-
aspergillosis.
[65]
Although the initial results from
tiate the immune response to fungal antigens, ad-
preliminary studies appear encouraging, one of the
ministration of a specific inactivated fungal antigen
major concerns is the susceptibility of patients to
to induce active immunity, pathogen-directed intra-
other unrelated fungal pathogens such as Fusarium
venous immunoglobulin and the use of specific
and Zygomycetes spp.
[92]
monoclonal antibodies by genetic engineering.
[77]
Most of the research in this field has been conducted
4. Antifungal Drug Resistance
in patients with candidaemia or disseminated candi-
diasis, and data pertaining to invasive aspergillosis Despite 50 years of amphotericin B use, resis-
are lacking. tance to the drug has been rarely documented in
most Aspergillus spp. In fact, resistance is rare even Acknowledgements
as a secondary event either during or after therapy
No sources of funding were used to assist in the prepara-
with amphotericin B. In contrast, although vori-
tion of this review. Dr Chandrasekhar has received honoraria
from Pfizer, Merck & Co. and Schering-Plough, and grant
conazole has only been in use for the past 3 years,
support from Pfizer. Dr Krishnan has no conflicts of interest
several transplant centres have already reported
that are directly relevant to the content of this review.
breakthrough infections with less susceptible Asper-
gillus and Candida spp., and the innately resistant
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Drugs 2008; 68 (3): 283-297
REVIEW ARTICLE 0012-6667/08/0003-0283/$53.45/0
Treatment of Acute
Severe Hypertension
Current and Newer Agents
Joseph Varon
1,2,3
1 The University of Texas Health Science Center at Houston, Houston, Texas, USA
2 The University of Texas Medical Branch at Galveston, Galveston, Texas, USA
3 St Lukes Episcopal Hospital/Texas Heart Institute, Houston, Texas, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
1. Classification of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
2. Hypertensive Crises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
2.1 Hypertensive Urgencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
2.2 Hypertensive Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
2.2.1 Operative and Postoperative Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
2.2.2 Hypertension in Acute Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
2.3 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3. Initial Management of Severe Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3.1 Pharmacological Agents Used in the Treatment of Hypertensive Crises . . . . . . . . . . . . . . . . . . . . 287
3.1.1 Enalaprilat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
3.1.2 Labetalol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
3.1.3 Esmolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
3.1.4 Clevidipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
3.1.5 Nicardipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
3.1.6 Nifedipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
3.1.7 Fenoldopam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
3.1.8 Hydralazine and Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
3.1.9 Nitroglycerin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
3.1.10 Sodium Nitroprusside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Approximately 72 million people in the US experience hypertension. World- Abstract
wide, hypertension may affect as many as 1 billion people and be responsible for
7.1 million deaths per year. It is estimated that 1% of patients with hypertension
will, at some point, develop a hypertensive crisis. Hypertensive crises are further
defined as either hypertensive emergencies or urgencies, depending on the degree
of blood pressure elevation and presence of end-organ damage. Immediate reduc-
tion in blood pressure is required only in patients with acute end-organ damage
(i.e. hypertensive emergency) and requires treatment with a titratable, short-
acting, intravenous antihypertensive agent, while severe hypertension without
acute end-organ damage (i.e. hypertensive urgency) is usually treated with oral
antihypertensive agents.
284 Varon
The primary goal of intervention in a hypertensive crisis is to safely reduce
blood pressure. The appropriate therapeutic approach of each patient will depend
on their clinical presentation. Patients with hypertensive emergencies are best
treated in an intensive care unit with titratable, intravenous, hypotensive agents.
Rapid-acting intravenous antihypertensive agents are available, including
labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. Newer
agents, such as clevidipine and fenoldopam, may hold considerable advantages
to other available agents in the management of hypertensive crises. Sodium
nitroprusside is an extremely toxic drug and its use in the treatment of hyperten-
sive emergencies should be avoided. Similarly, nifedipine, nitroglycerin and
hydralazine should not to be considered first-line therapies in the management of
hypertensive crises because these agents are associated with significant toxicities
and/or adverse effects.
In the US, it is estimated that approximately 120 mmHg] complicated by evidence of impending
72 million people experience hypertension (defined or progressive target organ dysfunction) that require
as systolic blood pressure [SBP] >140 mmHg and/or
immediate BP reduction (not necessarily to normal)
diastolic [DBP] >90 mmHg; taking antihypertensive
to prevent or limit target-organ damage, or hyper-
medication; or being told at least twice by a physi-
tensive urgencies (i.e. situations associated with
cian, or other health professional, that one has high
severe elevations in BP without progressive target-
blood pressure [BP]).
[1]
Affecting 30% of the US
organ dysfunction).
population aged >20 years old, hypertension is one
Although not specifically addressed in the JNC 7
of the most common chronic medical conditions,
[2,3]
report, patients with a SBP >179 mmHg or a DBP
and occurs almost twice as often in African-Ameri-
>109 mmHg are usually defined as having severe
cans than in Caucasians.
[4-6]
Moreover, the incidence
or accelerated hypertension, and should be ad-
of hypertension increases with age
[7]
and affects
dressed as hypertensive crises. Accelerated hyper-
men at a slightly higher rate than women. World-
tension is defined as a recent significant increase wide, hypertension may affect as many as 1 billion
over baseline BP that is associated with target-organ people and be responsible for 7.1 million deaths
per year.
[8]
damage. The term malignant hypertension, a syn-
drome characterized by elevated BP accompanied
1. Classification of Hypertension
by encephalopathy or nephropathy,
[11,14]
has been
used in the past; however, this term is a misnomer.
The classification and approach to hypertension
Hence, it has been removed from National and Inter-
undergoes periodic review by the Joint National
national Blood Pressure Control guidelines and is Committee (JNC) on Detection, Evaluation, and
Treatment of High Blood Pressure.
[9-15]
The most
recent report, JNC 7, classifies high BP in the fol-
lowing four stages: (i) normal; (ii) prehypertension;
(iii) stage I; and (iv) stage II (table I).
The JNC 7 complete report
[16,17]
identifies pa-
tients with a SBP of >180 mmHg or a DBP
>120 mmHg as having a hypertensive crisis. This
report goes on to define the operational classifica-
tion of hypertensive crisis as either hypertensive
emergencies (i.e. severe elevations in BP [>180/
Table I. Joint National Committee (JNC)-7 classification of blood
pressure for adults (reproduced from Chobanian et al.,
[16]
with per-
mission)
BP classifications Systolic BP (mmHg) Diastolic BP (mmHg)
Normal <120 <80
Prehypertension 120139 8089
Stage I 140159 9099
Stage II 160 100
Hypertensive crises >180 >120
BP = blood pressure.
Acute Severe Hypertension 285
best referred to as a hypertensive emergency or
acute severe hypertension.
[14,15]
2. Hypertensive Crises
The epidemiology of hypertensive crises are sim-
ilar to that of hypertension (i.e. higher among Afri-
can-Americans and the elderly); however, men are
affected approximately two times more frequently
than women.
[18-21]
It is estimated that 1% of pa-
tients with hypertension will, at some point, develop
a hypertensive crisis.
[22,23]
Table II. Examples of acute severe hypertension related conditions
Condition
Acute coronary syndrome
Acute left ventricular failure with pulmonary oedema
Acute myocardial infarction/unstable angina pectoris
Acute renal failure
Dissecting aortic aneurysm
Eclampsia
HELLP syndrome
Hypertensive encephalopathy
Intracerebral haemorrhage
Microangiopathic haemolytic anaemia
Pulmonary oedema with respiratory failure
Severe pre-eclampsia
HELLP = haemolysis, elevated liver enzymes, low platelets.
2.1 Hypertensive Urgencies
2.2 Hypertensive Emergencies
Hypertensive urgencies are hypertensive crises
Hypertensive emergencies (i.e. acute severe hy-
associated with severe elevations in BP without
pertension) are hypertension crises characterized by
progressive target-organ dysfunction.
[16,17,20,24-28]
severe elevations in BP (>180/120 mmHg) compli-
Examples include upper levels of stage II hyperten-
cated by evidence of impending or progressive tar-
sion associated with severe headache, shortness of
get-organ dysfunction. Organ dysfunction is uncom-
breath, epistaxis or severe anxiety. The majority of
mon with a DBP <130 mmHg (except in children
these patients present as noncompliant or inade-
and pregnancy).
[33]
They require immediate BP re-
quately treated hypertensive individuals, often with
duction (not necessarily to normal levels) to prevent
little or no evidence of target-organ damage.
or limit target-organ damage.
[34,35]
Examples of hy-
In patients with hypertensive urgencies, BP con-
pertensive crises are summarized in table II.
[29,36]
trol can be achieved within a few hours to prevent
A SBP >169 mmHg or a DBP >109 mmHg in a
organ damage.
[25,29]
Unfortunately, the term hyper-
pregnant woman is considered a hypertensive emer-
tensive urgency has led to overly aggressive man-
gency requiring immediate pharmacological man-
agement of many patients with severe, uncomplicat-
agement.
[37]
ed hypertension. Aggressive administration of intra-
2.2.1 Operative and Postoperative Hypertension venous drugs or even oral agents to rapidly lower BP
may be associated with significant morbidity.
[30-32]
In the surgical setting, a hypertensive crisis may
Oral loading doses of antihypertensive agents can be encountered during cardiac surgery, major vascu-
lead to cumulative effects causing hypotension. The lar surgery (e.g. carotid endarterectomy, aortic sur-
BP of patients with hypertensive urgencies should gery), neurosurgery, head and neck surgery, renal
be gradually lowered over a period of 2448 hours, transplantation or major trauma (e.g. burns or head
usually with oral medication.
[33]
Such patients may injury). In addition, hypertension, and hypertensive
benefit from treatment with a short-acting agent, crises, are very common in the early postoperative
such as oral captopril, intravenous labetalol or oral period and are related to increased sympathetic tone
clonidine,
[34,35]
followed by several hours of obser- and vascular resistance.
[38]
Postoperative hyperten-
vation.
[16,17]
Examples of hypertensive urgencies in- sion (arbitrarily defined as SBP 190 mmHg and/or
clude upper levels of stage II hypertension asso- DBP 100 mmHg on two consecutive readings fol-
ciated with, but not necessarily caused by, severe lowing surgery)
[15,39]
may have significant adverse
headache, shortness of breath, epistaxis or severe sequelae in both cardiac and noncardiac patients.
anxiety. The incidence of postoperative hypertensive crises
286 Varon
varies depending on the population examined, being Many patients with severe hypertension (DBP
reported in 435% of patients shortly after the surgi- >110 mmHg) have no acute end-organ damage.
cal procedure.
[40-42]
The transient nature of post- Why some patients with severe hypertension de-
operative hypertension and the unique clinical fac- velop end-organ damage (hypertensive emergency)
tors present in the postoperative period require that while others do not (hypertensive urgency) remains
this clinical syndrome be given individual consider- unclear. Rapid antihypertensive therapy in the hy-
ation. Like other forms of accelerated hypertension, pertensive urgency setting may be associated with
a history of hypertension is commonly seen in pa- significant morbidity.
[30,31,50]
However, there are
tients with perioperative hypertension. true hypertensive emergencies in which the rapid
(controlled) lowering of BP is indicated.
[22,51,52]
2.2.2 Hypertension in Acute Stroke
Control of hypertension in patients with acute
3. Initial Management of
stroke is directed at maintaining adequate cerebral
Severe Hypertension
blood flow to minimize ischaemic damage and con-
trol of intracerebral pressure. There is currently con-
On initial evaluation, most patients with severe
troversy about whether or not to treat elevated BP
hypertension will have no evidence of end-organ
caused by stroke as it is theorized that elevation of
damage, and thus present as hypertensive urgency.
BP is likely to be neuroprotective. With adequate
Since there is no preliminary indication of acute
blood flow around the central area of the stroke or
end-organ damage, these patients may present for
penumbra, cells may be salvaged.
[43-46]
Hence, the
evaluation of another complaint, and the elevated
inappropriate lowering of the BP in acute stroke
BP may represent an acute recognition of chronic
may increase neurological damage. As a result of the
hypertension. Utilizing oral medications, such as
complexities associated with the management of
captopril, labetalol or clonidine, to lower the BP
hypertension in acute stroke, this subject warrants a
gradually over 2448 hours is one approach to the
review that is beyond the scope and size limitations
management of these patients.
[16,17]
The use of sub-
of this article, and thus will not be addressed further.
lingual nifedipine capsules in hypertensive emer-
The reader is encouraged to consult other published
gencies should be abandoned
[53]
as the US FDA
literature on the subject.
[47]
concluded the practice of administering sublingual/
oral nifedipine was neither safe nor efficacious.
[54]
2.3 Pathophysiology
Rapid correction of severely elevated BP below the
The pathophysiology of hypertensive crises is not autoregulatory range of critical arterial beds (cere-
fully understood, but it is thought to be due to abrupt bral, coronary and renal) can result in a marked
increases in systemic vascular resistance that are reduction in perfusion, causing ischaemia and in-
likely to be related to humoral vasoconstrictors.
[48,49]
farction, and may be associated with significant
A hypertensive crisis can develop de novo, or can morbidity in hypertensive urgencies or emergencies
complicate underlying essential or secondary hyper- due to a shift to the right in the pressure/flow
tension. The acute nature of onset suggests a trigger- autoregulatory curve in these vascular beds.
[32]
BP
ing factor superimposed on pre-existing hyperten- must be reduced in these patients; however, it must
sion.
[36]
be lowered in a slow and controlled fashion to
prevent organ hypoperfusion. Hypertensive urgen- With severe elevations of BP, endothelial injury
cies do not mandate admission to a hospital. occurs and fibrinoid necrosis of the arterioles en-
sues.
[48,49]
This vascular injury leads to deposition of On the other hand, patients with a hypertensive
platelets and fibrin, and a breakdown of the normal emergency should be admitted to an intensive care
autoregulatory function. The resulting ischaemia unit (ICU) for continuous cardiac monitoring, and
prompts further release of vasoactive substances, frequent assessment of neurological status and urine
completing a vicious cycle.
[49]
output. Altered autoregulation also occurs in pa-
tients in a hypertensive crisis, and since end-organ 3.1 Pharmacological Agents Used in the
Treatment of Hypertensive Crises damage is already present, rapid and excessive cor-
rection of the BP can further reduce perfusion and
propagate further injury. Therefore, patients with a
A number of drugs are available for the manage-
hypertensive crisis are best managed with a continu-
ment of hypertensive crises (see table III). The agent
ous infusion of a short-acting, titratable antihyper-
of choice in any particular situation will depend
tensive agent. As a result of unpredictable pharma-
on the clinical presentation. The preferred agents
codynamics, the sublingual and intramuscular route
include labetalol, esmolol, nicardipine and fe-
should be avoided.
noldopam. Phentolamine and trimethaphan camsi-
late are less commonly used today; however, they According to the JNC 7 report, The initial goal
may be useful in particular situations, such as cat- of therapy in hypertensive emergencies is to reduce
echolamine-induced hypertensive crises (i.e. phe-
mean arterial BP by no more than 25% (within
ochromocytoma). Sodium nitroprusside may be
minutes to 1 hour) then, if stable, to 160/
used in patients with acute pulmonary oedema and/
100110 mmHg within the next 26 hours. Ad-
or severe left ventricular dysfunction, and in patients
vancing these guidelines, this author believes the
with aortic dissection.
[57]
Oral and sublingual nifedi-
physician would be wise to consider the immediate
pine are potentially dangerous in patients with hy-
goal of therapy in hypertensive emergencies to re-
pertensive crises and are not recommended. Cloni-
duce DBP by 1015%, or to approximately
dine and ACE inhibitors are long acting and poorly
110 mmHg, over a period of 3060 minutes. Sodium
titratable; however, these agents may be useful in
and volume depletion can be significant, and gentle
the management of hypertensive urgencies. ACE
volume expansion with an intravenous saline solu-
inhibitors are contraindicated in pregnancy.
[58,59]
tion will serve to restore organ perfusion and pre-
vent an abrupt decline in BP when antihypertensive
Clevidipine, a third-generation, intravenous, di-
regimens are initiated.
hydropyridine calcium-channel antagonist, is under
investigation for the management of perioperative
For those patients with the most severe clinical
hypertension and other hypertensive crises.
[60]
manifestations or with the most labile BP, intra-
Clevidipine is a potent arterial vasodilator with very
arterial BP monitoring may be prudent. There are a
little or no effect of the myocardial contractility and
variety of rapid-acting intravenous agents that are
venous capacitance, in addition to minimal adverse
available for use in patients with a hypertensive
effects. It has an extremely short half-life and is
crisis, and the agent of choice depends on which
rapidly metabolized by tissue and plasma esterases.
manifestation of end-organ damage is present.
Clevidipine has the potential to protect against organ
Rapid-acting intravenous agents should not be
reperfusion injury through its capability to hamper
used outside of the monitored setting of an ICU to
oxygen free radical-mediated toxicity and cell calci-
prevent steep declines of BP that may have signif-
um overload, and to augment endothelial nitric oxi-
icant morbidity or mortality. In patients with aortic
de bioavailability via antioxidative actions. As a
dissection, the BP should be reduced rapidly (within
result, clevidipine may diminish the severity of low
510 minutes), targeting a SBP of <120 mmHg and
flow myocardial ischaemia and preserve the corona-
mean arterial pressure (MAP) of <80 mmHg.
[55,56]
ry endothelial function, thereby reducing the infarct
Once stable BP control is established with intrave-
size. Because of the positive characteristics of this
nous agents and end-organ damage has ceased, oral parenteral agent, it promises to be the drug of choice
therapy can be initiated as the intravenous agents are for the critical care practitioner for the strict control
gradually down titrated. An important consideration of BP in different clinical scenarios.
[61]
Currently,
prior to initiating intravenous therapy is to assess the clevidipine is not available in the US for use outside
of clinical trials. patients volume status.
288 Varon
Table III. Agents used in the management of hypertensive crises, preferred conditions and dose administration
Agent Conditions Administration
Enalaprilat Congestive heart failure IV injection of 1.25 mg over 5 min every 6 h, titrated by increments of
1.25 mg at 12- to 24-h intervals to a maximum of 5 mg every 6 h
Esmolol Acute myocardial ischaemia
a
Loading dose of 5001000 g/kg over 1 min, followed by an infusion at
2550 g/kg/min, which may be increased by 25 g/kg/min every
1020 min until the desired response to a maximum of 300 g/kg/min
Fenoldopam Acute myocardial ischaemia
b
An initial dose of 0.1 g/kg/min, titrated by increments of 0.050.1 g/
Acute pulmonary oedema/diastolic kg/min to a maximum of 1.6 g/kg/min
dysfunction
a
,
c
Acute ischaemic stroke/intracerebral bleed
Acute renal failure/microangiopathic anaemia
Sympathetic crisis
Labetalol Acute aortic dissection Initial bolus 20 mg, followed by boluses of 2080 mg or an infusion
Acute myocardial ischaemia
a
starting at 12 mg/min and titrated until the desired hypotensive effect is
Acute ischaemic stroke/intracerebral bleed achieved is particularly effective. Bolus injections of 12 mg/kg have
Eclampsia/pre-eclampsia been reported to produce precipitous falls in BP and should therefore
Hypertensive encephalopathy be avoided; maximum cumulative dose of 300 mg over 24 h
Nicardipine Acute myocardial ischaemiac 5 mg/h; titrate to effect by increasing 2.5 mg/h every 5 min to a
Acute renal failure/ microangiopathic maximum of 15 mg/h
anaemia
Acute ischaemic stroke/intracerebral bleed
Eclampsia/pre-eclampsia
Sympathetic crisis/cocaine overdose
d
Nitroprusside Acute pulmonary oedema
a
,
c
0.5 g/kg/min; titrate as tolerated to maximum of 2 g/kg/min
Hydralazine Eclampsia 5 mg bolus then 510 mg IV every 2030 min as needed
Metoprolol Acute pulmonary oedema/diastolic
tartrate dysfunction
a
,
c
Phentolamine Sympathetic crisis Sympathetic crisis: IV 520 mg
Catecholamine toxicity (i.e. Treatment of pralidoxime-induced hypertension (unlabeled use): IV 5 mg
pheochromocytoma) Surgery for pheochromocytoma/hypertension: IM, IV 5mg given 12 h
before procedure and repeated as needed every 24 h
a In combination with nitroglycerin (up to 200 g/min).
b May be added if pressure is controlled poorly with labetalol/esmolol alone.
c In combination with a loop diuretic.
d In combination with a benzodiazepine.
BP = blood pressure; IM = intramuscular; IV = intravenous.
The recommended intravenous antihypertensive for enalaprilat is delayed for 15 minutes, and it
agents currently available are reviewed briefly in
does not reach peak effect for 1 hour, while its
sections 3.1.1 to 3.1.10. The agents are presented
duration of action is 6 hours. The effective half-life
alphabetically by class, not in order of importance or
for accumulation of enalaprilat is approximately
preference.
11 hours.
[62]
The relatively slow onset and long
duration of action make it a poor choice for use in a
3.1.1 Enalaprilat
hypertensive crisis. In addition, ACE inhibitors have
Enalaprilat is an ACE inhibitor available for in-
the potential to cause acute renal failure, acute renal
travenous administration. This class of drugs has
dysfunction or hyperkalaemia in patients in circula-
shown efficacy in the treatment of congestive heart
tory decompensated states or when MAP is insuffi-
failure, essential hypertension, and the prevention of
cient to support renal perfusion. Since surgical pa-
worsening renal function in patients with diabetic
and non-diabetic nephropathy. The onset of action tients are at an increased risk for circulatory decom-
pensation in the post operative period, ACE tion that precipitates anaemia, will prolong its short
inhibitors should not be considered first-line agents half-life. The metabolism of esmolol is via rapid
in the treatment of acute perioperative hypertension. hydrolysis of ester linkages by RBC esterases and is
not dependant on renal or hepatic function
3.1.2 Labetalol
As a result of its pharmacokinetic properties,
Labetalol is a combined selective
1
-adre-
some authors
[33]
consider it an ideal -adrenergic
noceptor antagonist and nonselective -adre-
blocker for use in critically ill patients. Nonethe-
noceptor antagonist (-blocker) with an - to -
less, caution needs to be exercised, particularly
blocking ratio of 1 : 7.
[63]
Labetalol is metabolized
when used in patients with chronic obstructive lung
by the liver to form an inactive glucuronide conju-
disease as this agent can precipitate bronchospasm.
gate.
[64]
The hypotensive effect of labetalol begins
In addition, American College of Cardioglogy
within 25 minutes after its intravenous administra-
(ACC)/American Heart Association (AHA) guide-
tion, reaching a peak at 515 minutes following
lines
[76]
conclude it may be contraindicated for pa-
administration and lasting for about 24 hours.
[64,65]
tients already on -blocker therapy, bradycardic pa-
The elimination half-life of labetalol is approxi-
tients and decompensated heart failure patients, as it
mately 5.5 hours.
[66]
As a result of its -blocking
may compromise their myocardial function.
effects, the heart rate is either maintained or slightly
Esmolol is available for intravenous use both as a
reduced. Unlike pure -adrenergic antagonists that
bolus and as an infusion. Esmolol is particularly
decrease cardiac output, labetalol maintains cardiac
useful in severe postoperative hypertension
[77-83]
and
output.
[67]
Labetalol reduces the systemic vascular
is a suitable agent in situations where cardiac output,
resistance without reducing total peripheral blood
heart rate and BP are increased. Typically, the drug
flow. In addition, the cerebral, renal and coronary
is administered as a 5001000 g/kg loading dose
blood flows are maintained.
[67-70]
This agent has
over 1 minute, followed by an infusion starting at
been used in the setting of pregnancy-induced hy-
50 g/kg/min and increasing up to 300 g/kg/min as
pertensive crisis because little placental transfer oc-
necessary.
curs, mainly due to the negligible lipid solubility of
the drug.
[67]
3.1.4 Clevidipine
Labetalol may be administered as a loading dose
Clevidipine is third-generation, dihydropyridine
of 20 mg, followed by repeated incremental doses of
calcium-channel antagonist that has been developed
2080 mg at 10-minute intervals until the desired
for use in clinical settings where tight BP control is
BP is achieved. Alternatively, after the initial load-
crucial.
[61]
Clevidipine is an ultra short-acting selec-
ing dose, an infusion commencing at 12 mg/min
tive arteriolar vasodilator.
[84,85]
Clevidipine has a
and titrated up to until the desired hypotensive effect
mean blood flow clearance of 0.105 L/kg/min and a
is achieved is particularly effective. Bolus injections
volume of distribution of 0.51 L/kg. The half-life is
of 12 mg/kg have been reported to produce precipi-
around 2 minutes.
[52]
Clevidipine acts by selectively
tous falls in BP and should therefore be avoided.
[71]
inhibiting the influx of extracellular calcium
3.1.3 Esmolol through the L-type channel, relaxing smooth muscle
Esmolol is an ultra short-acting cardioselective, of small arteries and reducing peripheral vascular
-blocker
[72-74]
with an elimination half-life of resistance.
[86]
Similar to esmolol, it is rapidly metab-
9 minutes.
[75]
Esmolol has no direct vasodilatory olized by RBC esterases; thus, its metabolism is not
actions. It decreases atrial pressure by decreasing affected by renal or hepatic function. Clevidipine
heart rate and myocardial contractility, and thus reduces BP by a direct and selective effect on arteri-
cardiac output. The onset of action of this agent is oles, thereby reducing afterload without affecting
within 60 seconds, with a duration of action of cardiac filling pressures or causing reflex tachycar-
1020 minutes;
[72-74]
however, because it is metabo- dia.
[60]
Stroke volume and cardiac output usually
lized by red blood cell (RBC) esterases, any condi- increase. Moreover, clevidipine has been shown to
290 Varon
protect against ischaemia/reperfusion injury in an doses are commonly used (e.g. 3045 mg/hour). A
animal model of myocardial ischaemia, and to main- useful therapeutic benefit of nicardipine is that the
tain renal function and splanchnic blood flow.
[87-89]
agent has been demonstrated to increase both stroke
volume and coronary blood flow with a favourable Several small trials
[90,91]
have shown clevidipine
effect on myocardial oxygen balance.
[96-100]
This to be very effective in the control of postoperative
property is useful in patients with coronary artery hypertension. In a recent randomized, double-blind,
disease and systolic heart failure. In addition, this placebo-controlled, multicentre trial, 152 patients
agent has been recommended in the AHA/American scheduled for cardiac surgery with current or recent
Stroke Associations guidelines for the treatment of hypertension were randomized to receive clevidip-
ischaemic stroke when DBP is >120 mmHg or the ine or placebo preoperatively.
[92]
Patients received
SBP is >220 mmHg.
[101-103]
Familiar adverse effects infusions of either clevidipine (0.48.0 g/kg/min)
of intravenous nicardipine are chiefly related to its or placebo (20% lipid emulsion) for at least 30 min-
antihypertensive effects; however, hypotension, as a utes. Patients treated with clevidipine demonstrated
treatment adverse effect, may be less frequent with a significantly higher rate of treatment success than
nicardipine than with sodium nitroprusside because those in the placebo-treated group (92.5% vs 17.3%;
nicardipine does not cause venodilation. p < 0.0001) and a significantly lower treatment
failure rate than patients receiving placebo (7.5% vs
3.1.6 Nifedipine
82.7%; p < 0.0001). Clevidipine achieved target BPs
Nifedipine has been widely used via oral or sub- (SBP reduced by 15%) at a median of 6 minutes.
lingual administration in the management of hyper- Adverse events for each treatment group were simi-
tensive emergencies, severe hypertension asso- lar.
ciated with chronic renal failure, postoperative hy-
Although no studies have investigated the role of
pertension and pregnancy-induced hypertension.
this drug in hypertensive emergencies, its profile
Nonetheless, the routine use of short-acting nifedi-
makes it a potentially ideal drug for this indication.
pine capsules in hypertensive emergencies should
In the authors own experience, the use of clevidip-
be abandoned.
[53]
Although nifedipine has been ad-
ine in acute hypertension in the emergency depart-
ministered via the sublingual route, the drug is poor-
ment setting is safe and provides a predictable BP
ly soluble and is not absorbed through the buccal
control. In addition, this drug can be safely used as
mucosa, but is rapidly absorbed from the gastroin-
an infusion for as long as 96 hours.
[93]
testinal tract after the capsule has dissolved.
[104]
This
3.1.5 Nicardipine mode of administration has not been approved by
Nicardipine is a second-generation, dihydropyri- the US FDA. The half-life of nifedipine in plasma is
dine derivative calcium-channel antagonist with 2 hours.
[105]
A significant decrease in BP is usually
high vascular selectivity, and strong cerebral and observed 510 minutes after nifedipine administra-
coronary vasodilatory activity. The terminal half- tion, with a peak effect from 30 to 60 minutes, and a
life of the drug after intravenous administration to duration of action of approximately 68 hours.
[106]
humans was about 1 hour.
[94,95]
The onset of action Sudden, uncontrolled and severe reductions in BP
of intravenous nicardipine is from 5 to 15 minutes, accompanying the administration of nifedipine may
with a duration of action of 46 hours. Intravenous precipitate cerebral, renal and myocardial ischaemic
nicardipine has been shown to reduce both cardiac events that have been associated with fatal out-
and cerebral ischaemia.
[96]
The nicardipine dosage is comes.
[53]
Elderly hypertensive patients with under-
independent of the patients bodyweight, with an lying organ impairment and structural vascular dis-
initial infusion rate of 5 mg/hour, increasing by ease are more vulnerable to the rapid and uncon-
2.5 mg/hour every 5 minutes to a maximum of trolled reduction in arterial pressure. Given the
15 mg/hour until the desired BP reduction is seriousness of the reported adverse events and the
achieved.
[33]
In the authors experience, much higher lack of any clinical documentation attesting to a
3.1.8 Hydralazine and Diuretics
benefit, the use of nifedipine capsules for hyperten-
Hydralazine is a direct-acting arteriolar vasodila-
sive emergencies and pseudo emergencies should
tor, often chosen as a first-line agent for critically ill
be abandoned.
[53]
Over 20 years ago, the Cardiorenal
patients with pregnancy-induced hypertension. Fol-
Advisory Committee of the FDA concluded that the
lowing intramuscular or intravenous administration,
practice of administering sublingual/oral nifedipine
there is an initial latent period of 515 minutes,
needed to be abandoned because this agent was
followed by a progressive and often precipitous fall
neither safe nor efficacious.
[54]
Nifedipine is not to
in BP that can last up to 12 hours;
[119,120]
however,
be considered an acceptable therapy in the manage-
its maximum effect is usually noted between 10
ment of either hypertensive emergencies or
and 80 minutes. Although the circulating half-life
urgencies.
[29]
of hydralazine is only approximately 3 hours, the
half-time of its effect on BP is approximately
3.1.7 Fenoldopam
10 hours.
[121,122]
Because of the prolonged and un-
Fenoldopam is unique among the parenteral BP
predictable antihypertensive effects of hydralazine,
agents because it mediates peripheral vasodilation
and the inability to effectively titrate its hypotensive
by acting on peripheral dopamine type 1 receptors.
effect, it is best avoided in the management of
Fenoldopam is rapidly and extensively metabolized
hypertensive crises.
by conjugation in the liver, without participation of
Volume depletion is common in patients with
cytochrome P450 enzymes. The onset of action is hypertensive emergencies and the administration of
within 5 minutes, with the maximal response being a diuretic together with a hypertensive agent can
lead to a precipitous drop in BP. Diuretics should be achieved by 15 minutes.
[107-110]
The elimination
avoided unless specifically indicated for volume half-life of fenoldopam is 5 minutes,
[111]
with a
overload, as occurs in renal parenchymal disease or
duration of action from 30 to 60 minutes, and BP
coexisting pulmonary oedema. Familiar adverse ef-
gradually returning to pretreatment values without
fects of intravenous hydralazine include prolonged
rebound once the infusion is stopped.
[107-109]
No
duration of action in patients with renal dysfunction,
adverse effects have been reported.
[107]
An initial
hypotension, salt retention, fluid retention, tachy-
starting dose of 0.1 g/kg/min is recommended,
phylaxis and drug-induced lupus syndrome.
[123,124]
titrated by increments of 0.050.1 g/kg/min to a
Hydralazine is not to be considered an acceptable
maximum of 1.6 g/kg/min. Fenoldopam improves
primary therapy in the management of either hyper-
creatinine clearance, urine flow rates and sodium
tensive emergencies or urgencies,
[29]
but may be a
excretion in severely hypertensive patients with
suitable adjunct therapy.
both normal and impaired renal function.
[112-114]
The use of fenoldopam as a prophylactic agent to
3.1.9 Nitroglycerin
prevent contrast-induced nephropathy has been dis-
Nitroglycerin is a potent venodilator and only at
appointing.
[115,116]
Moreover, clinical studies with
high doses affects arterial tone.
[125]
It has pharmaco-
fenoldopam have failed to demonstrate a clinically
kinetic properties similar to sodium nitroprusside,
significant reduction in death or renal replacement
and causes hypotension and reflex tachycardia,
therapy in patients at risk for acute renal fail-
which are exacerbated by the volume depletion
ure.
[117,118]
Fenoldopam causes dose-dependent in-
characteristic of hypertensive emergencies. Nitro-
creases in intraocular pressure, and its use should be
glycerin reduces BP by reducing preload and cardiac
avoided in patients at risk for with intraocular hyper-
output, which are undesirable effects in patients
tension and intracranial hypertension. In addition,
with compromised cerebral and renal perfusion. In-
fenoldopam is in a solution that contains a sodium
travenous nitroglycerin has an onset time of
metabisulfate, and patients with potential sulfite 25 minutes, duration of action of 1020 minutes
sensitivity may develop acute allergic reactions. and is eliminated by hepatic metabolism in
292 Varon
14 minutes.
[123,124,126]
Intravenous nitroglycerin is nitroprusside administered. Cyanide is metabolized
generally not considered as a first-line therapy for in the liver to thiocyanate, which is 100-fold less
hypertension as it is not as efficacious as sodium toxic than cyanide.
[136,137]
The thiocyanate generated
nitroprusside, may have little or no efficacy when is excreted largely through the kidneys. Therefore,
used alone and its antihypertensive action is caused cyanide removal requires adequate liver function,
by venodilation. Low-dose administration (approxi-
renal function and bioavailability of thiosulfate.
mately 60 mg/min) may, however, be used as an
Thus, the use of sodium nitroprusside may cause
adjunct to intravenous antihypertensive therapy in
cytotoxicity due to the release of cyanide, with
patients with hypertensive emergencies associated
interference of cellular respiration.
[138,139]
In the au-
with acute coronary syndromes or acute pulmonary
thors experience, patients can develop cyanide tox-
oedema. Familiar adverse effects of intravenous ni-
icity as early as 68 hours after initiation of the
troglycerin include hypotension, hypoxaemia from
infusion of sodium nitroprusside. Cyanide toxicity
ventilation perfusion mismatching, methemoglobi-
has been documented to result in unexplained car-
naemia, reflex tachycardia and tachyphylaxis.
[123,124]
diac arrest, coma, encephalopathy, convulsions and
Nitroglycerin is not to be considered an acceptable
irreversible focal neurological abnormalities.
[128,138]
primary therapy in the management of either hyper-
The current methods of monitoring for cyanide
tensive emergencies or urgencies,
[29]
but may be a
toxicity are insensitive. Metabolic acidosis is usu-
suitable adjunct therapy.
ally a preterminal event. In addition, a rise in serum
thiocyanate levels is a late event and not directly
3.1.10 Sodium Nitroprusside
related to cyanide toxicity. RBC cyanide level (al-
Sodium nitroprusside is an arterial and venous
though not widely available) may be a more reliable
vasodilator that decreases both afterload and pre-
method of monitoring for cyanide toxicity.
[136]
An
load.
[127,128]
Sodium nitroprusside decreases cerebral
RBC cyanide level >40 nmol/mL results in detecta-
blood flow while increasing intracranial pressure,
ble metabolic changes. Levels >200 nmol/mL are
effects that are particularly detrimental in patients
associated with severe clinical symptoms and levels
with hypertensive encephalopathy or following a
>400 nmol/mL are considered lethal.
[136]
Data sug-
cerebrovascular accident.
[129-132]
In patients with
gest that sodium nitroprusside infusion rates >4 g/
coronary artery disease, a significant reduction in
kg/min, for as little as 23 hours may lead to cyanide
regional blood flow (coronary steal) can occur.
[133]
levels in the toxic range.
[136]
The recommended
In a large, randomized, placebo-controlled trial,
[134]
doses of sodium nitroprusside of up to 10 g/kg/min
sodium nitroprusside was shown to increase mor-
results in cyanide formation at a far greater rate than
tality when infused in the early hours after acute
humans can detoxify. Sodium nitroprusside has also
myocardial infarction (mortality at 13 weeks, 24.2%
been demonstrated to cause cytotoxicity through the
vs 12.7%). Sodium nitroprusside is a very potent
release of nitric oxide, with hydroxyl radical and
agent, with an onset of action of seconds, a duration
peroxynitrite generation leading to lipid peroxida-
of action of 12 minutes and a plasma half-life of
tion.
[139-142]
34 minutes.
[127]
As a result of the potency, rapidity
Considering the potential for severe toxicity with of action of this agent and the development of
nitroprusside, this drug should only be used when tachyphylaxis, we recommend intra-arterial BP
other intravenous antihypertensive agents are not monitoring. In addition, sodium nitroprusside re-
quires special handling to prevent its degradation by available and then, only in specific clinical circum-
light. These factors limit the use of this drug.
[135]
stances in patients with normal renal and hepatic
function.
[128]
An initial starting dose should be The molecule of sodium nitroprusside contains
0.5 g/kg/min and then titrated as tolerated. The 44% cyanide by weight.
[136]
Cyanide is released
duration of treatment should be as short as possible non-enzymatically from nitroprusside, the amount
generated being dependent on the dose of sodium and the infusion rate should not be >2 g/kg/min.
An infusion of thiosulfate should be used in patients with significant toxicities and/or adverse effects.
receiving higher dosages (410 g/kg/min) of sodi- Newer agents, such as clevidipine and fenoldopam,
um nitroprusside.
[137]
may hold considerable advantages to other available
agents in the management of hypertensive crises.
4. Conclusion
Acknowledgements
The primary goal of intervention in a hyperten-
The author would like to thank Dr Richard Pistolese for
sive crisis is to safely reduce BP. The appropriate
his assistance in the preparation and review of this article. The
therapeutic approach of each patient will depend on author did not receive support of any kind in the form of
equipment, drugs or grants related to this article. The author
their clinical presentation. Safe and efficacious man-
has received honoraria for lectures from PDL Pharmaceuti-
agement of the patient experiencing hypertensive
cals, Eli Lilly & Company and The Medicines Company, and
crises requires the physician to discriminate the cri-
has served as a consultant for The Medicines Company.
sis as either a hypertensive urgency or hypertensive
emergency.
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St, Houston, TX 77030-3209, USA.
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E-mail: Joseph.Varon@uth.tmc.edu 2000 Jun; 7 (6): 653-62
Drugs 2008; 68 (3): 299-317
REVIEW ARTICLE 0012-6667/08/0003-0299/$53.45/0
Locally Advanced and Metastatic
Gastric Cancer
Current Management and New Treatment Developments
Kathryn Field,
1
Michael Michael
1
and Trevor Leong
1,2
1 Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
2 University of Melbourne, Melbourne, Victoria, Australia
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
1. Commonly Used Chemotherapy Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
1.1 Epirubicin, Cisplatin plus Fluorouracil (ECF) and Other Combinations . . . . . . . . . . . . . . . . . . . . . . 301
1.2 Taxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
1.3 Oxaliplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
1.4 Irinotecan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
1.5 Oral Fluoropyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
1.5.1 Capecitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
1.5.2 S-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
1.5.3 Tegafur/Uracil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
1.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
2. Targeted Therapies and Novel Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
2.1 Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
2.2 Cetuximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
2.3 Gefitinib and Erlotinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
2.4 Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
2.5 Bortezomib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
2.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
3. New Developments in Locally Advanced Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
4. On the Horizon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
4.1 Pharmacogenomic Profiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
4.2 Vaccine Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
4.3 Intraperitoneal Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
4.4 Novel Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
The management of gastric cancer remains a challenge. In recent years, the Abstract
most important advances have been achieved in the adjuvant setting for patients
with locally advanced disease, where significant survival benefits have been
demonstrated for both perioperative chemotherapy and adjuvant chemoradiother-
apy. These findings have changed the standard of care for patients with resectable
disease.
In the setting of metastatic gastric cancer, the development of new cytotoxic
regimens must consider the balance between efficacy and toxicity in patients
300 Field et al.
whose overall prognosis is poor. Major advances in recent years include the
development of orally administered fluoropyrimidine analogues, which can be
used in place of intravenous fluorouracil, and the addition of newer agents such as
oxaliplatin and docetaxel, which have demonstrated efficacy in patients with
advanced disease. Targeted therapies have had a major impact on the management
of certain malignancies, and while their evaluation in the treatment of advanced
gastric cancer remains early, it is likely that these agents will continue to be
developed and studied in combination with chemotherapy.
This article reviews recent advances in the use of chemotherapy for advanced
gastric cancer. Targeted therapies, their mechanisms of action and emerging data
supporting their use in gastric cancer are also discussed. The two randomized
phase III trials supporting adjuvant therapy for locally advanced, resectable
gastric cancer are discussed in detail, together with strategies for future trials in
this area. Overall, there remains optimism that further incremental gains will be
achieved with future studies combining chemotherapy, radiotherapy and targeted
therapies, both in the adjuvant and metastatic disease settings.
Gastric cancer is a common malignancy that, clavicular metastatic nodal deposits, respectively).
despite considerable research effort, remains diffi- Common sites of metastasis from gastric cancer
cult to treat and carries a poor prognosis. The Na- include loco-regional lymph nodes, the liver and the
tional Cancer Institute SEER (Surveillance Epide- peritoneum.
miology and End Results) database projected over There are a number of possible causative factors
11 000 deaths from gastric cancer in the US for 2007 for the development of gastric cancer, including
alone, despite having one of the lowest incidence dietary (e.g. smoked meats, pickled vegetables, salt-
rates in the world.
[1]
There is a large geographical ed fish), which may contribute to the striking region-
variation in incidence rates. In Eastern Asia, 46 per al variations in incidence. Helicobacter pylori infec-
100 000 males and 21 per 100 000 females develop tion, chronic gastritis, pernicious anaemia and pre-
gastric cancer, compared with world figures of 22 vious gastric surgery have also been implicated in its
(male) and 10 (female) per 100 000. Gastric cancer development.
[5]
Genetic predisposition may be a
is the second most common cause of cancer-related contributing factor in a small percentage of individ-
death in the world (after lung cancer), and globally uals. For example, the germline mutations asso-
700 000 deaths annually are attributed to the dis- ciated with hereditary non-polyposis colon cancer
ease.
[2]
Even those initially treated with curative (HNPCC),
[6,7]
and mutations in the gene for E-
intent have a 60% chance of developing loco-re- cadherin are known genetic associations.
[8,9]
gional or distant metastatic disease,
[3]
and the med-
The most common histological subtype is adeno-
ian survival with metastatic disease is generally
carcinoma, occurring in 9095% of patients. Adeno-
<12 months.
[4]
carcinomas have been classified by Lauren
[10]
into
Gastric cancer is diagnosed at a late stage in up to intestinal-type and diffuse-type. Intestinal-type is
80% of patients and may present with symptoms associated with chronic atrophic gastritis, a glandu-
such as asthenia, early satiety, nausea, dysphagia lar structure, sharp margins and minimal invasive-
and weight loss. The disease is almost always ad- ness, while diffuse-type is associated with irregular
vanced by the time any clinical signs become appar- margins, poor differentiation, and invasion of large
ent, such as hepatomegaly, an enlarged stomach, or areas of the stomach often producing linitis plastica
the eponymous Sister Mary Joseph nodule or or leather bottle stomach.
[10]
Lymphomas and gas-
Virchows node (palpable umbilical or left supra- trointestinal stromal tumours also occur in the stom-
New Developments in Gastric Cancer Treatment 301
ach, but are not covered in this review. Of interest, in opinions mean that both doublet and triplet combi-
recent years, there has been a change in the location nations continue to be used worldwide with no true
of the primary tumour in the stomach, with an reference standard.
[15]
increase in the incidence of more proximally (gastric
cardia) located tumours and a decrease in the inci-
1.1 Epirubicin, Cisplatin plus Fluorouracil
dence of distally located tumours.
[5]
Postulated rea-
(ECF) and Other Combinations
sons for this include changing patterns of diet and a
decreased incidence of H. pylori infection.
[11,12]
The ECF regimen consists of epirubicin (an an-
Perhaps of some encouragement is the slight
thracycline) and cisplatin (a platinum agent) given
decline in mortality rates by 3.1% over the years
on day 1, and 5-FU (an antimetabolite) given as a
19942003.
[1]
While effective H. pylori treatment is
21-day continuous intravenous infusion. It is a com-
thought to be a contributing factor, it does not entire-
monly used regimen for the treatment of advanced
ly explain the decline in mortality. This discussion
gastric cancer in some countries including Australia
focuses primarily on chemotherapeutic but also oth-
and the UK, where it is considered standard ther-
er interventional strategies that have contributed in
apy.
[4]
However, to date, it has not been as widely
part to this improvement in mortality rates. The
used as a reference standard in the US over doublet
review also discusses novel therapies, already at the
therapy with cisplatin and 5-FU.
[16,17]
Two random- forefront in other malignancies, which have shown
ized phase III trials have demonstrated superiority of promise in metastatic gastric cancer.
ECF over alternative chemotherapy combinations.
The first compared ECF with FAMTX (5-FU, doxo-
1. Commonly Used
rubicin and methotrexate) and demonstrated superi-
Chemotherapy Regimens
or response rate (45% vs 21%; p = 0.0002) and
median overall survival (8.9 vs 5.7 months;
There is no true gold standard regimen in the
p = 0.0009).
[18]
The second compared ECF with
treatment of advanced gastric cancer. A Cochrane
MCF (mitomycin, cisplatin and 5-FU), and while
meta-analysis of randomized phase II and III trials
response rate and overall survival were similar,
in advanced gastric cancer
[13,14]
concluded that
quality of life was superior in those treated with
chemotherapy produced an overall survival benefit
ECF.
[19]
over best supportive care (hazard ratio [HR] 0.39)
Other chemotherapy combinations have also
and that combination chemotherapy was more effec-
been evaluated. A three-arm, randomized, phase III
tive than single-agent treatment (HR 0.85). A signif-
trial compared FAMTX, ELF (etoposide, folinic
icant survival benefit was seen for regimens that
acid [leucovorin] and 5-FU) and CF (5-FU and
included fluorouracil (5-FU), anthracyclines and
cisplatin), and found no significant differences be-
cisplatin.
tween the three regimens, with median survivals
To date, therefore, the most commonly used
ranging from 6.7 to 7.2 months.
[20]
Another random-
chemotherapy regimen for advanced disease is a
ized study compared ECF with EEC (etoposide,
doublet or triplet regimen based on 5-FU, with cis-
epirubicin and cisplatin) and found no significant
platin and/or an anthracycline. The meta-analysis
differences in response rates or survival.
[21]
Given
also showed that delivering 5-FU as a continuous
that the median overall survival with ECF chemo-
intravenous infusion rather than in bolus form
therapy is <10 months, improvements in systemic
reduces the rate of toxic deaths.
[14]
It should be noted
therapy are clearly needed, and over the last decade
that the meta-analysis has been met with some con-
newer and potentially more active chemotherapeutic troversy with respect to the benefits of triplet (in-
agents have been evaluated in the setting of ad- cluding anthracyclines) over non-anthracycline regi-
vanced gastric cancer (table I). mens utilizing cisplatin and 5-FU only, and differing
302 Field et al.
Table I. Efficacy of newer chemotherapy agents in advanced gastric cancer (selected phase II and III trials)
Study No. of Treatment arms Response rate TTP or PFS Median survival
patients
Oxaliplatin
Al-Batran
[22]
220 FLO vs FLP 34% vs 27% 5.7 vs 3.8 mo NA
(p = 0.08)
Cunningham 964 ECF vs EOF vs ECX vs EOX
a
EOX: 47.9% vs EOX: 7 vs 6.26.7 Oxaliplatin arms:
(REAL-2)
[23]
40.746.4% (p = NS) mo (PFS) [p = NS] 10.4 vs 10.0 mo
(p = NS)
Docetaxel
Elsaid
[24]
64 DCF (carboplatin) vs ECF 66.7% vs 44.1% NA 12.4 vs 8.7 mo
(p = 0.0005)
Van Cutsem et al. 445 DCF (cisplatin) vs CF 37% vs 25% 5.6 vs 3.7 mo 9.2 vs 8.6 mo
(TAX325)
[25]
(p = 0.01) (p < 0.001) (p = 0.02)
Paclitaxel
Murad et al.
[26]
31 Paclitaxel + 5-FU 65% 9 mo (PFS) 12 mo
Kollmannsberger et 45 Paclitaxel + 5-FU + 51% 9 mo (PFS) 14 mo
al.
[27]
folinic acid + cisplatin
Honecker et al.
[28]
29 Paclitaxel + 5-FU + 48% 8 mo (PFS) 11 mo
folinic acid + cisplatin
Irinotecan
Bouche et al.
[29]
134 5-FU + folinic acid + irinotecan 40% vs 13% vs 27% 6.9 vs 3.2 vs 4.9 11.3 vs 6.8 vs
vs 5-FU + folinic acid mo (PFS) 9.5 mo
vs 5-FU + folinic acid + cisplatin
Moehler et al.
[30]
114 ILF vs ELF 43% vs 24% 4.5 vs 2.3 mo (PFS) 10.8 vs 8.3 mo
Pozzo et al.
[31]
115 Irinotecan + 5-FU + folinic acid 42.4% vs 32.1% 6.5 vs 4.2 mo 10.7 vs 6.9 mo
vs irinotecan + cisplatin (p < 0.0001)
Dank (V306)
[32]
337 5-FU + folinic acid + irinotecan NA 5.0 vs 4.2 mo HR 1.08 (p = NS)
vs CF (p = 0.088)
Capecitabine
Cunningham 964 ECF vs EOF vs ECX vs EOX
a
EOX: 47.9% vs EOX: 7 vs 6.26.7 Capecitabine arms:
(REAL-2)
[23]
40.742.4% mo (PFS) 10.9 vs 9.6 mo
(HR 0.89)
Kang (ML07132)
[33]
316 XP vs FP
a
41% vs 29% 5.6 vs 5.0 10.5 vs 9.3 mo
(p = 0.03) mo (PFS) (HR 0.85)
[p = 0.08]
a Powered for equivalence.
5-FU = fluorouracil; CF = cisplatin plus 5-FU; DCF = docetaxel, carboplatin or cisplatin, 5-FU; ECF = epirubicin, cisplatin, 5-FU;
ECX = epirubicin, cisplatin, capecitabine; ELF = etoposide, folinic acid, 5-FU; EOF = epirubicin, oxaliplatin, 5-FU; EOX = epirubicin,
oxaliplatin, capecitabine; FLO = 5-FU, folinic acid, oxaliplatin; FLP = 5-FU, folinic acid, cisplatin; FP = 5-FU plus cisplatin; HR = hazard ratio;
ILF = irinotecan, 5-FU, folinic acid; NA = not available; PFS = progression-free survival; TTP = time to progression; XP = capecitabine,
cisplatin.
1.2 Taxanes peripheral neuropathy and hypersensitivity reac-
tions.
Taxanes are naturally-derived chemotherapeutic
Given the promising results observed in preclini-
agents derived from the bark of yew trees, which
cal and early phase studies, both as a single agent
prevent microtubule depolymerization during mito-
and in combination treatment, docetaxel has been
sis. This process disrupts mitosis of cells and hence
evaluated in a small number of phase III studies.
causes cell cycle arrest. Both paclitaxel and docetax-
A small Egyptian phase III study of 64 patients
el have demonstrated clinical activity in metastatic
gastric cancer. Toxicities include myelosuppression, compared DCF (docetaxel, carboplatin and 5-FU)
with ECF and found an overall response rate of Paclitaxel has thus far been examined only in
phase II studies, both as monotherapy and in combi- 66.7% for DCF versus 44.1% for ECF and median
nation with other agents. Paclitaxel, cisplatin and 5-
survival of 12.4 versus 8.7 months (p = 0.0005).
[24]
FU in various combinations have been studied in a
However, because of the small number of patients in
number of phase II trials,
[27,28,36,37]
where response
the study, these results must be viewed with caution.
rates of about 50% and median survival times up to
A large international phase III trial reported in
14 months have been observed. Similarly to doc-
2006 (TAX325 study) has shown encouraging re-
etaxel, myelosuppression (particularly neutropenia)
sults with a docetaxel-based regimen.
[25]
This study
is the major dose-limiting toxicity. Further studies
of 445 previously untreated patients compared DCF
including randomized phase III trials are necessary
(docetaxel, cisplatin and 5-FU) with CF (cisplatin
to determine the role of paclitaxel in advanced gas-
and 5-FU). Time to progression was 5.6 months
tric cancer.
(DCF) versus 3.7 months (CF) [p < 0.001], and
median overall survival was 9.2 versus 8.6 months
1.3 Oxaliplatin
(p = 0.02). At 1 year, 40% versus 32% of patients
were alive, and at 2 years 18% in the DCF arm were This platinum-based agent acts by forming bulky
platinum-DNA adducts, generating intrastrand and still alive. Toxicity was higher in the DCF arm,
interstrand cross-links and thus blocking DNA repli-
which needs to be carefully considered given its
cation. It is considered standard therapy, in combi-
impact on a patients quality of life and survival.
nation with 5-FU, in the adjuvant and metastatic
Chemotherapy delays were necessary in 64% of
treatment of colorectal cancer. The main toxicity
patients in the DCF arm, the most common reason
associated with oxaliplatin is sensory peripheral
being lethargy. Patients in both arms of the trial
neuropathy, which can be of two types: an acute,
experienced a high incidence of grade 3 and 4 toxici-
temporary cold-related dysaesthesia and a chronic
ties (46% for DCF and 42% for CF). Neutropenia
cumulative, persistent sensory neuropathy, which is
was significant: 82% grade 34 neutropenia for
dose limiting. It is considerably less nephrotoxic
DCF versus 57% for CF. There was a 29% incidence
than cisplatin and is not ototoxic.
of febrile neutropenia and neutropenic infection for
There have been multiple phase II studies evalu-
DCF, and 12% for CF. Even with the use of secon-
ating oxaliplatin for advanced or metastatic gastric
dary granulocyte colony-stimulating factor prophy-
cancer in combination with 5-FU plus folinic acid,
laxis, the rate of neutropenic infection was 12%.
docetaxel or irinotecan, which have demonstrated
Grade 3 or 4 gastrointestinal toxicities were seen in
response rates up to 56% and median survival up to
nearly 50% of patients in both arms. Despite the
11.5 months.
[38-41]
Results of a phase III trial com-
high incidence of toxicities, quality of life, as mea-
paring FLO (5-FU, folinic acid and oxaliplatin) with
sured by global health status questionnaire, was
FLP (5-FU, folinic acid and cisplatin) have recently
found to be significantly better with DCF, as was
been reported.
[22]
In this study of 220 patients, time
time to deterioration of Karnofsky performance sta-
to progression was 5.7 months (FLO) versus
tus. While the results with DCF are encouraging, it
3.8 months (FLP) [p = 0.08], and time to treatment
should be noted that the improvement in median
failure was 5.3 versus 3.1 months (p = 0.028). Over-
survival is small (1820 days) and this needs to be
all survival data are not yet available. Toxicities
balanced against the significant toxicity associated
such as leukopenia, fatigue, alopecia and renal im-
with this regimen. A statistically significant benefit pairment were less in the FLO arm, whereas peri-
does not always translate to a meaningful clinical pheral neuropathy was increased.
benefit, and the balance between efficacy and toxici-
Preliminary results of the REAL-2 study, involv-
ty, as well as failure to actually improve quality of ing 964 patients, have been reported.
[23,42]
This four-
life, has been discussed in recent publications.
[34,35]
arm study uses ECF as the reference arm to compare
304 Field et al.
the efficacy of oxaliplatin with cisplatin and capecit- domized phase II studies have been reported that
abine with 5-FU in a two-by-two factorial design. demonstrate impressive results with irinotecan in
Previously untreated patients with metastatic oe- combination with other agents. Bouche et al.
[29]
re-
sophageal or gastric cancer were randomized to ported a study of 136 patients that compared 5-FU
ECF, EOF (epirubicin, oxaliplatin, 5-FU), ECX and folinic acid either alone, with cisplatin or with
(epirubicin, cisplatin, capecitabine) or EOX
irinotecan and found response rates of 13%, 27%
(epirubicin, oxaliplatin, capecitabine). This study
and 40% and median overall survival of 6.8, 9.5 and
was powered for noninferiority, and this was dem-
11.3 months, respectively. Another study compared
onstrated when comparing oxaliplatin-containing
ILF (irinotecan, 5-FU and folinic acid) with ELF
with cisplatin-containing regimens, as well as cap-
(epirubicin, 5-FU and folinic acid) in 114 patients
ecitabine with 5-FU-containing arms. The median
and found a 43% versus 24% response rate and a
overall survival for the oxaliplatin arms was
10.8- versus 8.3-month median overall survival, in
10.4 months versus 10.0 months for the cisplatin
favour of irinotecan.
[30]
A third randomized phase II
arms. The HR was 0.92 (95% CI 0.8, 1.1), which
study compared ILF with irinotecan and cisplatin in
met the endpoint for noninferiority. Progression-
115 patients, and found a 42.4% versus 32.1% res-
free survival was best for the EOX arm 7.0 months
ponse rate, and median time to progression of 6.5
versus 6.7, 6.5 and 6.2 months for the other arms.
versus 4.2 months (p < 0.0001).
[31]
As a result of this
The best response rate was seen in the EOX arm
trial, ILF was further investigated in a phase III
with a 47.9% response rate (not statistically signifi-
setting (V306 study), which has been reported in an
cantly different from the 40.7% response rate in the
abstract.
[32]
This trial of 337 previously untreated
reference ECF arm; p = 0.112). In terms of toxicity,
patients compared ILF with CF. Time to progression
there was less neutropenia and alopecia, but more
was 5.0 versus 4.2 months (p = 0.088, not signif-
diarrhoea and peripheral neuropathy in the oxalipla-
icant), with no difference in overall survival. The
tin-containing arms. Neutropenia was significantly
irinotecan-containing arm was associated with more
less in the oxaliplatin arms (2730% vs 4150%),
diarrhoea, but the cisplatin arm was associated with
although the rates of febrile neutropenia were simi-
more neutropenia, stomatitis and nausea. Unfortu-
lar (6.79.3% over the four arms). There were also
nately, this phase III study has not confirmed the
significantly fewer thromboembolic events (both ar-
initially promising phase II results; however, it ap-
terial and venous) in the oxaliplatin arms compared
pears that irinotecan is not inferior to cisplatin-
with the cisplatin arms (8.2% vs 15.9%;
containing arms, although the study was not pow-
p = 0.0003).
[43]
On the basis of the results of this
ered to demonstrate this. Although the toxicity
phase III trial, it appears that oxaliplatin can be
profiles are different, it appears that, on balance, the
substituted for cisplatin in terms of efficacy in the
irinotecan-based regimen may be better tolerated
treatment of advanced gastric cancer, and decisions
than the cisplatin-based regimen.
regarding the most appropriate regimen for an indi-
Irinotecan has also been combined with taxanes
vidual may be determined by their different toxicity
in phase II trials, where response rates of 2050%
profiles.
have been observed. However, toxicity has been
considerable and may preclude the routine use of
1.4 Irinotecan
these combinations. Overall, it is likely that irinote-
can can be appropriately added to the range of active
Irinotecan is a camptothecin (natural plant alka-
agents used in combination against metastatic gas- loid) derivative that inhibits topoisomerase I, there-
tric cancer, although there is no efficacy advantage by impeding DNA uncoiling and replication leading
over cisplatin shown to date in the phase III setting. to double-stranded DNA breaks. Toxicities include
Again, it seems that the toxicity profile will be the diarrhoea (in up to 40% of patients in colorectal
main factor deciding the choice of regimen. cancer trials
[44,45]
) and neutropenia.
[46]
Several ran-
1.5 Oral Fluoropyrimidines ical benefit with phase II trials showing response
rates of 1432% and median survivals of
There are a number of new oral prodrugs of 5-FU
6.39.9 months.
[54,55]
undergoing evaluation in phase IIII clinical trials
Two important noninferiority phase III trials in-
for metastatic gastric cancer. The advantage of the
volving capecitabine in metastatic gastric cancer
oral route of therapy is ease of administration. There
have been reported recently. The first study (RE-
is no need for central venous access devices with
AL-2) of 964 patients, which compared ECF, EOF,
their inherent complications such as thrombosis and
ECX and EOX, has been described in section
infection. In addition, oral administration dispenses
1.3.
[23,42]
When comparing the arms containing cap-
with the need for ambulatory pumps and frequent
ecitabine with those containing 5-FU, the median
visits to hospital. Oral delivery, rather than intrave-
overall survival was 10.9 months for capecitabine
nous infusion, is preferred by most patients, and it
versus 9.6 months for 5-FU (HR on multivariate
may be associated with a potentially improved ther-
analysis 0.89; 95% CI 0.89, 1.02). Progression-free
apeutic index and possible pharmacokinetic advan-
survival differences were not statistically signif-
tages. However, caution is required in the elderly or
icant. Overall, the EOX arm demonstrated the best
confused patient, where polypharmacy may result in
overall response (complete and partial responses)
administration or compliance errors with the risk of
with 47.9%, versus 46.4% for ECX, 42.4% for EOF
severe toxicity or reduced efficacy.
and 40.7% for ECF. None of these were statistically
1.5.1 Capecitabine
significantly different from the reference ECF arm.
This oral fluoropyrimidine prodrug is converted
The best overall survival was also seen in the EOX
to 5-FU in three enzymatic steps. The final step
arm (11.2 vs 9.9 months for ECF; p = 0.02).
involves the enzyme thymidine phosphorylase,
The second study, a phase III trial (ML07132) of
which is present at higher concentrations in tumour
316 patients, compared capecitabine and cisplatin
cells, thereby resulting in an increased concentration
(XP) with 5-FU and cisplatin (FP) in previously
of 5-FU at the site of the tumour.
[47]
It is now used
untreated patients with metastatic gastric cancer.
[33]
commonly in the treatment of metastatic breast can-
This study was also powered for noninferiority.
cer, and both in the adjuvant and metastatic setting
Progression-free survival was 5.6 months for XP
for colorectal cancer. In colorectal cancer, capecit-
versus 5.0 months for FP, (HR 0.81; 95% CI 0.63,
abine has been shown to be at least equivalent in
1.04; p = 0.08). Response rates were 41% (XP)
efficacy to bolus 5-FU.
[48]
Therefore, it could poten-
versus 29% (FP) [p = 0.03]. Again, noninferiority
tially be used in place of intravenous infusional
was shown between 5-FU and capecitabine, with a
5-FU in combination chemotherapy for metastatic
superior response rate demonstrated for capecitab-
gastric cancer. The main adverse effects of capecit-
ine. Median overall survival was 10.5 months for
abine are diarrhoea and hand-foot syndrome (red,
XP versus 9.3 months for FP (HR 0.85; 95% CI
dry, cracked palms and soles which in severe cases
0.64, 1.13; p-value not significant).
can be associated with fissuring of the skin).
Overall, capecitabine is a promising new drug in
Numerous phase I and II clinical trials of capecit-
the treatment of metastatic gastric cancer and seems
abine have shown clinical benefit in patients with
likely to move into regular clinical use in the near
gastric cancer.
[49]
Most of these have been in pre-
future. Rather than providing major efficacy advan-
viously untreated patients. As a single agent, res-
tages compared with 5-FU, its main benefit is in the
ponse rates between 6% and 32% have been observ-
ease of administration and thus quality-of-life gains
ed,
[50-52]
and in combination with other agents (cis-
for patients.
platin, taxanes, irinotecan, oxaliplatin) response
1.5.2 S-1
rates up to 67% and median survival rates as high as
17.2 months have been reported.
[53]
Even as second- S-1 has been described as a fourth-generation
line treatment, capecitabine has demonstrated clin- designer drug,
[56]
because the combination of mole-
306 Field et al.
cules used to create the drug is based on the use is already established in the Japanese popula-
tion, despite the fact that to date only phase II pharmacokinetics of 5-FU. It is an oral fluoropyrim-
studies have been completed. idine containing tegafur (a 5-FU prodrug) combined
with 5-chloro-2,4-dihydroxypyridine (an inhibitor
of dihydropyridine dehydrogenase [DPD], which 1.5.3 Tegafur/Uracil
metabolizes 85% of 5-FU
[57]
) and oxonic acid Another oral fluoropyrimidine is tegafur/uracil or
(a pyrimidine phosphoribosyltransferse inhibitor, UFT, which contains the competitive inhibitor of
which reduces phosphorylation of 5-FU in the gas- DPD, uracil. Although early studies with tegafur/
trointestinal tract to potentially reduce gastrointesti- uracil reported response rates between 9% and
40% and median survival times from 5.8 to nal toxicity
[58]
). Thus, in theory, more 5-FU is able
15 months,
[66-69]
these results have not been repro- to be delivered via the oral route with fewer gastro-
duced in the phase III setting. A Japanese, three- intestinal adverse effects. Myelosuppression is more
arm, phase III study comparing tegafur/uracil and common than with other oral fluoropyrimidine de-
mitomycin with 5-FU alone or 5-FU and cisplatin
rivatives.
[59]
S-1 is registered for use in Japan, where
revealed disappointing results, with inferior res-
phase II studies have demonstrated response rates
ponse rate and median overall survival in the
of up to 49% and median survival up to
tegafur/uracil plus mitomycin arm.
[70]
Currently,
16.7 months
[60,61]
when used as a single agent. S-1
there is no evidence to support the use of tegafur/
has also been examined in combination with irinote-
uracil in advanced gastric cancer.
can, paclitaxel and cisplatin in phase I/II studies,
With respect to the oral fluoropyrimidines, it is
again mainly in Japan. For the combination of S-1
likely that future research efforts will be devoted to
and cisplatin, in 19 evaluable patients a response
the development of capecitabine and S-1 in the
rate of 74% was obtained and median survival time
management of advanced gastric cancer.
of 383 days.
[62]
A retrospective review of 110 Japa-
nese patients that compared those who had been
given S-1 versus those treated with any other
1.6 Summary
chemotherapy demonstrated a median survival time
of 429 days for patients treated with S-1 therapy
In summary, the role of chemotherapy in the
compared with 236 days for patients without S-1.
[63]
management of advanced gastric cancer continues
The majority of data supporting the use of S-1 to
to evolve. The recent addition of new and active
date has come from Japan. However, early data from
agents used in various combinations allows the opti-
Western nations do not demonstrate the same degree
mal choice of first-line treatment to be tailored to
of benefit for S-1. A European phase II study of individuals based on patient co-morbidity and the
23 patients found a response rate of 26.1%.
[64]
A US toxicity profiles of particular drugs.
phase II study of 47 patients using S-1 and cisplatin
The optimal duration of chemotherapy in the
was more promising with a response rate of 51% and
metastatic disease setting will depend on treatment
median survival of 10.9 months.
[65]
The differences
response and tolerability. While the duration of
are possibly attributable to ethnic and genetic varia- some chemotherapy agents may be limited by toxic-
tion in enzyme levels. Certainly the degree of toxici- ity (e.g. maximum 68 cycles of anthracycline ow-
ty reported in Western compared with Asian studies ing to cumulative cardiotoxicity; cumulative neuro-
differs; this is thought to be due to genetic pathy with oxaliplatin or taxanes), it is not unreason-
polymorphisms in the cytochrome P450 (CYP) sys- able to continue with chemotherapy if a patient
tem, particularly CYP2A6 responsible for metabo- continues to derive clinical benefit and quality of
lizing tegafur to 5-FU.
[56]
Large phase III trials are life is not adversely affected. However, most trials
currently under way to further evaluate the efficacy have decreed 68 cycles of chemotherapy treatment
of S-1 in combination with cisplatin, but certainly its and this is generally reflected in clinical practice.
Table II. Efficacy of targeted therapies in advanced gastric cancer (phase II)
a
Study No. of Prior Treatment Response rate Median survival
patients treatment
Bevacizumab
Shah et al. (2006)
[71]
47 No Bevacizumab + irinocetan + cisplatin 65% 12.3 mo
Enzinger et al. (2006)
[72]
20 Yes (most) Bevacizumab + docetaxel 27% Ongoing
Cetuximab
Stein (2007)
[73]
13 Yes Cetuximab + irinotecan Tumour control 3.61 mo
rate 62%
Pinto et al. (2007, 2006)
[74,75]
38 No Cetuximab + irinotecan + 5-FU + 44.1% Ongoing (55.3%
folinic acid (FOLFIRI) alive at 11 mo)
Gefitinib
Doi (2003)
[76]
75 Yes Gefitinib monotherapy Disease control Not reported
rate 18.3%
(1 PR, 13 SD)
Erlotinib
Dragovich et al. (2006)
[77]
70 No Erlotinib 0 (for gastric 3.5 mo
cancer)
Bortezomib
Ocean (2007)
[78]
40 Yes (12) Bortezomib monotherapy 9% 5.4 mo
No (28) Bortezomib + irinotecan 44% 4 mo
a Some of these studies have also included gastroesophageal junction.
5-FU = fluorouracil; PR = partial response; SD = stable disease.
2. Targeted Therapies and Novel Agents pathway that regulates cell proliferation, angio-
genesis and cell survival. Its use is already well
Rationally designed inhibitors of circulating
established in the treatment of metastatic colorectal
growth and angiogenic factors, their cell surface
cancer, and promising results have been seen in
receptors and corresponding intracellular down-
trials for breast and lung cancer. In gastric cancer,
stream pathways including those activated by tyro-
the expression of VEGF increases with increasing
sine kinases are being increasingly used, either in
stage and tumour burden.
[79,80]
Shah et al.
[71]
have
combination with or as an alternative to chemother-
recently reported the results of a phase II study
apy (table II). Rather than directly affecting DNA
involving 47 previously untreated patients with met-
and mitosis as with conventional chemotherapy,
astatic gastric or gastroesophageal junction cancer
targeted therapies aim to affect other mechanisms by
who were treated with bevacizumab combined with
which cancer cells grow (i.e. cell proliferation,
irinotecan and cisplatin. In the 34 patients with
apoptosis, angiogenesis, etc.) and are an ever-ex-
measurable disease, the response rate was 65% and
panding component of oncology therapies used
median survival was 12.3 months. However, the
across a range of tumour types.
treatment was associated with considerable toxicity.
Grade 3 hypertension was seen in 28% of patients,
2.1 Bevacizumab
while two patients developed gastric perforation and
one had a myocardial infarction. Twelve patients
Bevacizumab is a humanized monoclonal anti-
(25.5%) developed venous thromboembolism and,
body targeting vascular endothelial growth factor
although this is a recognized complication of
(VEGF), a potent angiogenic factor contributing to
bevacizumab therapy, the observed rate is higher tumour growth. The antibody-bound form of VEGF
than that documented in other tumour types.
[81]
De- is unable to bind to its cell surface receptor, prevent-
ing activation of an intracellular tyrosine kinase spite potentially serious adverse effects, these early
308 Field et al.
encouraging results with bevacizumab warrant fur- that while EGFR activation was reduced, not all
ther evaluation in the treatment of advanced gastric further downstream signalling pathways were inhib-
cancer. The UK Medical Research Council (MRC) ited,
[84]
suggesting that as monotherapy, gefitinib is
has opened a randomized phase II/III study (ST03) not likely to demonstrate significant activity in gas-
that will evaluate perioperative chemotherapy tric cancer.
(ECX) with or without bevacizumab, in patients
Erlotinib is also an oral tyrosine kinase inhibitor
with resectable gastric cancer.
[82]
blocking EGFR-1, with an adverse effect profile
similar to that of gefitinib. A recent phase II trial has
2.2 Cetuximab
been reported in 70 previously untreated patients
with metastatic or unresectable gastroesophageal
Cetuximab is a chimeric monoclonal antibody
junction and gastric cancer.
[77]
No response was seen
targeting the epidermal growth factor receptor
in patients with gastric cancer and median survival
(EGFR)-1 and inhibiting its function. It is adminis-
was only 3.5 months. For gastroesophageal junction
tered intravenously and is currently used in the
tumours, the response rate was 9% and median
treatment of metastatic colorectal cancer. A recently
survival 6.7 months. These results are disappointing
reported study
[73]
examined 13 heavily pretreated
given that with chemotherapy the median survival of
patients with metastatic gastric cancer undergoing
patients with advanced gastric cancer is about
treatment with cetuximab and irinotecan, and report-
10 months. Although the assessment of response by
ed a tumour control rate of 62% and median overall
conventional radiographic techniques can be diffi-
survival of 101 days. The FOLCETUX (FOLFIRI/
cult with targeted therapies (they may be cytostatic
cetuximab) study, a phase II study of 38 previously
without causing marked tumour shrinkage), the poor
untreated patients with advanced gastric or gastro-
median survival suggests that erlotinib as monother-
esophageal adenocarcinoma, used FOLFIRI (bolus
apy has no activity in previously untreated patients
and infusional 5-FU, folinic acid and irinotecan) in
with advanced gastric cancer.
combination with cetuximab, and demonstrated an
On the basis of the limited data available, it
overall response rate of 44.1% and median time to
appears that when used as monotherapy, oral tyro-
progression of 8 months.
[74]
At the time of publica-
sine kinase inhibitors have minimal clinical benefit
tion, the median follow-up time was 11 months and
for pretreated or never-treated patients with ad-
55.3% of the patients were alive. These early results
vanced gastric cancer. To date, their role in combi-
are encouraging, albeit at the expense of some mod-
nation therapy is unknown, but given the relatively
erate toxicity grade 34 neutropenia in 42.1% and
poor results demonstrated in phase II trials, it is
grade 34 rash (a common toxicity of cetuximab) in
unclear whether they will be pursued in further
21.1%.
studies.
2.3 Gefitinib and Erlotinib
2.4 Trastuzumab
Gefitinib is an orally administered tyrosine kin-
ase inhibitor, which blocks signal transduction aris- Trastuzumab is a humanized monoclonal anti-
ing from EGFR-1. This receptor promotes cell proli- body targeting the EGFR-2 (or human epidermal
feration and is overexpressed in up to one-third of receptor HER-2 or erb B2). Its role is established
advanced gastric malignancies.
[83]
Common adverse in the treatment of breast cancer, both in the adju-
effects of tyrosine kinase inhibitors include ac- vant and metastatic disease settings. HER-2 is over-
neiform rash and fatigue. Gefitinib has demonstra- expressed in up to 12% of gastric cancers, with the
ted mixed results when used as monotherapy in highest rate of overexpression seen in patients with
early studies in advanced gastric cancer, with one advanced disease.
[85-89]
Isolated case reports exist
phase II trial in pretreated patients demonstrating an suggesting clinical efficacy with the use of tras-
18.3% disease control rate.
[76]
A substudy showed tuzumab in advanced gastric cancer.
[90,91]
An ongo-
ing phase III study (ToGA study) is currently com- 3. New Developments in Locally
paring trastuzumab and chemotherapy versus Advanced Gastric Cancer
chemotherapy alone for patients with HER-2-posi-
The major advances seen in the last 5 years with
tive previously untreated advanced gastric cancer.
respect to the treatment of gastric cancer have been
in the neoadjuvant and adjuvant settings. Significant
2.5 Bortezomib
progress has been made, with statistically significant
survival advantages being achieved with the addi-
Bortezomib is a proteasome inhibitor, which pre-
tion of perioperative treatment to patients undergo-
vents the degradation of ubiquinated proteins by the
ing curative resection. It is likely that further pro-
mammalian 26S proteasome. This inhibition of pro-
gress will be seen as the newer-generation cytotoxic
teolysis affects multiple signalling pathways within
agents showing promise in metastatic disease are
the cell. Bortezomib is given intravenously and its
evaluated in the adjuvant setting.
use is established in multiple myeloma. Results of a
The majority of patients with potentially curable
phase II trial have been presented in an abstract
[78]
gastric cancer present with stage II or III disease
for both pretreated (n = 12) and treatment-naive
(implying either a large, invasive primary tumour or
(n = 28) patients with advanced gastric cancer. Pre-
node-positive disease). Given that the risk of post-
treated patients (arm A) were given single-agent
operative recurrence is high, multiple trials have
bortezomib, which achieved a response rate of 9%;
been carried out in an attempt to reduce the risk of
untreated patients (arm B) received bortezomib in
recurrence in this setting. Until recently, no survival
combination with irinotecan, which achieved a res-
benefit has been seen for adjuvant radiotherapy or
ponse rate of 44%. However, median overall survi-
chemotherapy treatment. In fact, several meta-anal-
val was poor: 5.4 months in arm A and only
yses evaluating the role of adjuvant chemotherapy in
4 months in arm B. Severe toxicities were observed
the Western world have not demonstrated convinc-
including one cardiac arrest, one stomach perfora-
ing evidence of benefit, although some demonstrate
tion and three toxic deaths. Despite a good response
marginal benefits.
[92-95]
Even more recently pub-
rate for previously untreated patients, the poor over-
lished adjuvant chemotherapy trials have failed to
all survival and considerable toxicity suggest that
show any convincing evidence of benefit.
[96-100]
bortezomib will not become commonly used in the
However, adjuvant chemotherapy is used more
treatment of advanced gastric cancer.
commonly in Asian countries, particularly Japan,
where a number of studies have demonstrated survi-
2.6 Summary
val benefits in this population,
[101-103]
including a
recently reported trial showing an 80.5% versus
In summary, targeted therapies have, to date,
70.1% overall survival benefit at 3 years with S-1
demonstrated only modest clinical activity and ben-
monotherapy when compared with surgery
efit in advanced gastric cancer, although their use
alone.
[104]
will continue to be explored in ongoing and future
The landscape has changed significantly with the trials. Advanced gastric cancer provides an ideal
recent publication of two landmark trials: the US environment for pharmacodynamic studies of mark-
Intergroup trial 0116 (postoperative chemoradia- ers of response to targeted therapies, as it is relative-
tion)
[105]
and the UK MRC MAGIC (Medical Re- ly easy to obtain tissue samples from gastroscopy, as
search Council Adjuvant Gastric Infusional Chemo- well as blood samples at baseline and during ther-
therapy) trial (perioperative chemotherapy).
[106]
apy. Potential markers such as intratumoral EGFR,
phosphorylated EGFR, mitogen-activated protein The Intergroup trial (INT 0116) is the largest
kinase and transforming growth factor- are being adjuvant study in gastric cancer conducted in North
investigated for their role in prediction of clinical America. It randomized 556 patients with resected
outcome.
[77,84]
gastric or gastroesophageal junction adenocarcino-
310 Field et al.
ma to surgery alone or surgery plus postoperative producing adequate systemic benefits. There have
also been concerns regarding the radiotherapy plan- chemoradiation (5 weeks of radiotherapy plus 5-day
ning and treatment techniques used in INT 0116. cycles of daily bolus 5-FU and folinic acid before,
Nevertheless, given the striking survival benefits during and after radiation). A statistically significant
seen, adjuvant chemoradiation has become a median survival benefit of 36 versus 27 months
standard of care after resection of gastric cancer (p = 0.005) was seen for the chemoradiation arm,
with curative intent. with a HR for relapse (without adjuvant treatment)
of 1.52 (p < 0.001). The 3-year survival rate was
The MAGIC trial, published in 2006, randomized
50% in the chemoradiation arm versus 41% in the
503 patients to perioperative chemotherapy or sur-
surgery-alone arm (p = 0.005).
gery alone. The chemotherapy consisted of ECF
given as three cycles before surgery (i.e. neoadju-
The results of this trial have not been embraced
vant) and three cycles postoperatively. There were
by all clinicians, for a number of reasons. There has
no differences in surgical mortality or morbidity
been much debate regarding the quality of the surgi-
following neoadjuvant treatment. The 5-year survi-
cal techniques, in particular the level of nodal dis-
val rate was 36% for perioperative chemotherapy
section. It has been claimed that the benefits of
versus 23% for surgery alone (p = 0.009). The
chemoradiation are only due to the compensation of
hazard ratio for progression was 0.66 (95% CI 0.53,
poor surgery, and that these benefits would not be
0.81; p < 0.001). Neoadjuvant chemotherapy ap-
seen if a D1 (limited) or D2 (extended) node dissec-
peared to downstage tumours, with 69.3% of pa-
tion had been performed. In support of this argu-
tients who received chemotherapy undergoing a cur-
ment, the proponents of this view cite the similar
ative (R0) resection compared with 66.4% in the
survival rates for patients receiving chemoradiother-
surgery-alone group. Eighteen percent of operations
apy in INT 0116 (50%) and patients undergoing D2
in the chemotherapy arm were considered palliative
dissection in the Dutch randomized trial of extended
compared with 28% in the surgery-alone arm. Post-
lymph node dissection (47%).
[107]
However, the pa-
surgical histopathological findings also supported
tient populations for these two studies are different,
the observation of tumour downstaging by chemo-
with patients enrolled to INT 0116 having generally
therapy, with the finding of lower-stage tumours in
more advanced tumours. It is possible that better
the perioperative chemotherapy arm.
surgery using a formal D1 or D2 dissection may
decrease the need for radiation. On the other hand, it
The chemotherapy was difficult to complete. On-
is also possible that when better surgery is combined
ly 54.8% of those assigned to receive chemotherapy
with chemoradiation, there may be a further im-
began postoperative chemotherapy for multiple rea-
provement in local control as seen in INT 0116. In
sons. In total, 104 of 250 patients (42%) completed
addition, the chemotherapy regimen of bolus 5-FU
all six cycles of chemotherapy. Despite this, the
and folinic acid is considered outdated by todays
survival advantages for perioperative chemotherapy
standards given that more active regimens, partic-
were both statistically and clinically significant. Pre-
ularly infusional rather than bolus 5-FU, and newer
operative chemotherapy alone may thus carry a sur-
agents in combination with 5-FU are now available. vival advantage, although the study was not pow-
Toxicities were not insignificant: grade 3 or higher ered for such analysis and does not answer this
haematological and gastrointestinal toxicities were question. Toxicity was acceptable in patients receiv-
seen in 54% and 33% of patients, respectively; and ing chemotherapy, with 25% experiencing grade 3
three patients (1%) died from treatment-related tox- or 4 granulocytopenia, and while nearly all experi-
icity. While local control was improved, the rate of enced some diarrhoea, it was grade 3 or 4 in only
distant metastatic disease was unchanged, sug- 2.6% (preoperatively) and 3.6% (postoperatively).
gesting that this chemotherapy regimen may be Grade 3 or 4 nausea was experienced in 6.4% (pre-
merely acting as a radiation sensitizer rather than operatively) and 12.3% (postoperatively). Perioper-
ative ECF chemotherapy now represents an alterna- ity profile.
[112]
This postoperative regimen is cur-
rently being compared with the INT 0116 regimen tive standard of care for patients seen preoperative-
in an ongoing randomized phase III trial in the ly.
US.
[113]
Other drugs have also been shown to be
Further studies are being proposed to answer
useful radiosensitizers, and both irinotecan and pac-
some of the new questions that have arisen as a
litaxel combined with radiotherapy have demonstra-
result of the INT 0116 and MAGIC trials. For exam-
ted response rates of 5658% in patients with gastric
ple, what are the relative roles of postoperative
cancer.
[114,115]
chemotherapy (as given in MAGIC) versus post-
Neoadjuvant chemoradiation has shown promis-
operative chemoradiation (as given in INT 0116) in
ing results in early phase studies. Ajani et al.
[116]
patients who have received preoperative chemother-
reported a phase II study involving 34 patients with
apy followed by surgery? Another important ques-
potentially resectable gastric cancer, who received
tion relates to the role of preoperative chemotherapy
two cycles of induction chemotherapy (5-FU, folinic
or chemoradiation. Given that the majority of post-
acid and cisplatin) followed by chemoradiation (in-
operative adjuvant chemotherapy trials have been
fusional 5-FU) and then surgery. At surgery, the
negative, interest is now turning to preoperative
pathological complete response rate was 30% and
chemotherapy alone, partly based on the MAGIC
the R0 resection rate was 70%. The median survival
trial results, and some clinicians believe that pre-
time was 34 months and the 2-year survival rate was
operative rather than postoperative chemotherapy
54%. A RTOG (Radiation Therapy Oncology
may be a more effective treatment.
[108]
A previous
Group) phase II study of 49 patients has investigated
trial attempting to address the question of preopera-
the role of preoperative paclitaxel-based chemoradi-
tive versus postoperative chemotherapy was stopped
ation prior to surgery, and achieved an R0 resection
prematurely because of slow accrual.
[109]
Although
rate of 77% and pathological complete response rate
phase II studies of neoadjuvant chemotherapy alone
of 27%.
[117]
These promising results with preopera-
appear promising, its true efficacy remains to be
tive chemoradiation warrant further evaluation in a
proven. A small randomized trial of 59 patients
randomized phase III trial.
demonstrated worse overall survival in the arm re-
These new developments in the management of
ceiving preoperative chemotherapy.
[110]
The role of
locally advanced gastric cancer have resulted in a
preoperative chemoradiation is also being actively
surge of renewed interest in gastric cancer treat-
investigated given the impressive results that have
ment. Researchers will endeavour to improve cure
been obtained in the postoperative setting.
rates even further with new trials under way that
Ongoing trials are now investigating new system-
build on the beneficial information that has come to
ic agents with radiotherapy to establish efficacy
light in the last few years. Currently, patients who
compared with 5-FU and folinic acid. A prospective
present with locally advanced gastric cancer should
study by Leong et al.
[111]
examined 26 patients with
ideally be discussed in a multidisciplinary team set-
either resected or locally advanced unresectable gas-
ting, and considered for clinical trials of preopera-
tric cancer who were treated with one cycle of ECF,
tive plus or minus postoperative therapy where
followed by radiotherapy with continuous infusional
available; beyond this, in the absence of definitive
5-FU and another two cycles of ECF. Grade 3 and 4
guidelines, the choices for such a patient depend on
toxicities occurred in 38% and 15% of patients,
regional and geographical preferences.
respectively (most commonly haematological and
gastrointestinal). This small study suggests that
4. On the Horizon
combining ECF with chemoradiotherapy is indeed
feasible, with an acceptable toxicity profile. A simi- While clinical trials will continue to evaluate new
lar study employing the same regimen in 21 patients cytotoxic agents and targeted therapies, several al-
after surgery also demonstrated an acceptable toxic- ternative and novel methods of managing gastric
312 Field et al.
cancer are being examined, some of which are dis- 3.8 months for immune nonresponders. Successful
cussed in this section. vaccination was shown to be an independent prog-
nostic factor. Given that the response rate and med-
4.1 Pharmacogenomic Profiling
ian survival are similar to published data with
chemotherapy alone, the role of G17DT remains
A recent study has described the results of geno-
uncertain.
typing 13 polymorphisms in nine genes from
175 patients with advanced gastric cancer, and cor-
4.3 Intraperitoneal Chemotherapy
relating these with subsequent outcomes.
[118]
All
Intraperitoneal administration of chemotherapy
patients were treated with 5-FU plus cisplatin-based
following surgery has demonstrated significant sur-
chemotherapy. The study found that chemoresis-
vival benefits in phase III studies for ovarian can-
tance and poor survival was significantly associated
cer.
[120,121]
The basis of its success in this setting is
with certain polymorphisms; in particular, two ge-
that ovarian cancer tends to spread by local shedding
notypes (thymidylate synthase [TS] 5-UTR 3G- and
and seeding of the peritoneal cavity. Early studies
glutathione S-transferase [GST] P1 105A/A). Of the
also suggest benefit in gastric cancer.
[122-124]
The
175 patients, 114 (65%) had either one or both risk
role of intraperitoneal chemotherapy following cur-
genotypes, and their progression-free and overall
ative resection of gastric cancer is to be examined in
survival was significantly worse than for patients
a phase I/II study where patients will receive two
who did not have either of these genotypes. Pretreat-
cycles of intraperitoneal floxuridine (a pyrimidine
ment genotyping may therefore select certain pa-
analogue similar to 5-FU) followed by postoperative
tients who may benefit more from palliative chemo-
chemoradiation as delivered in INT 0116. Although
therapy than others. Alternatively, the future selec-
distant relapse is unlikely to be reduced, intraperito-
tion of which chemotherapy regimen to use may
neal administration of chemotherapy may provide
become guided by an individual patients genotype,
greater tumour control within the abdomen.
thereby allowing individualization of treatment.
Further development in the area of pharmacoge-
4.4 Novel Agents
nomic profiling will need to consider studies in
larger patient cohorts treated in a uniform fashion,
Other therapies continue to be examined for their
and with prospective validation of results.
potential role in the treatment of gastric cancer. For
example, preclinical studies have shown apoptosis
4.2 Vaccine Therapy
of gastric cancer cells in response to pterostilbine
(an active constituent of blueberries) and acacetin (a
Gastrin is a naturally occurring hormone, which
flavonoid compound).
[125,126]
Increasing understand-
is a potent growth factor for gastrointestinal cancers.
ing of other pathways, such as the mitogen activated
A vaccine named G17DT has been developed that
protein (MAP) kinase, phosphoinositide 3 (PI3) kin-
produces an antigastrin antibody, which opposes
ase and mammalian target of rapamycin (mTOR)
gastrin and its effects. Results of a phase II study
pathways, in gastric cancer cells may lead to the
examining the effects of this vaccine have been
development of other potential targets for novel
reported.
[119]
Gastrin, which is trophic to gastric
therapies.
cancer, is overexpressed in gastric malignancies,
and antigastrin antibodies ideally produce an
5. Conclusions
antiproliferative effect. This study examined
103 treatment-naive patients treated with G17DT While progress in the treatment of patients with
combined with cisplatin and 5-FU; the overall res- advanced gastric cancer has been slow, there have
ponse rate was 30% and the median survival was nevertheless been some clear advancements. Clin-
9.0 months, but for immune responders (>60%) ical trials demonstrating efficacy of newer cytotoxic
the median survival was 10.3 months, versus agents including the taxanes, oxaliplatin and irinote-
13. Wagner AD, Grothe W, Behl S, et al. Chemotherapy for ad-
can have resulted in alternative, effective regimens,
vanced gastric cancer. Cochrane Database Syst Rev 2005; (2):
and while work on targeted therapies is still early, it
CD004064
14. Wagner AD, Grothe W, Haerting J, et al. Chemotherapy in
is hoped that future studies will provide evidence of
advanced gastric cancer: a systematic review and meta-ana-
further benefit. The development of orally adminis-
lysis based on aggregate data. J Clin Oncol 2006; 24 (18):
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15. Al-Batran SE, Jager E, Scholz M. Chemotherapy for advanced
ministration will become much easier for patients
gastric cancer. J Clin Oncol 2007; 25 (6): 729; author reply 730
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myth? J Clin Oncol 2000; 18 (23): 4001-3 provements in adjuvant therapy for localized gastric
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1962-4
18. Webb A, Cunningham D, Scarffe JH, et al. Randomized trial
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19. Ross P, Nicolson M, Cunningham D, et al. Prospective random-
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REVIEW ARTICLE 0012-6667/08/0003-0319/$53.45/0
Adult-Onset Stills Disease
Pathogenesis, Clinical Manifestations and
Therapeutic Advances
Apostolos Kontzias
1
and Petros Efthimiou
2,3
1 Department of Medicine, Lincoln Medical and Mental Health Center, New York,
New York, USA
2 Rheumatology Division, Lincoln Medical and Mental Health Center, New York,
New York, USA
3 Weill Cornell Medical College, New York, New York, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
1. Pathogenesis, Clinical Manifestations and Diagnosis of Adult-Onset Stills Disease (AOSD) . . . . . . . 320
1.1 Pathogenetic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
1.1.1 Genetic Component . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
1.1.2 Infectious Component . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
1.1.3 Immune Dysregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
1.2 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
1.2.1 Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
1.2.2 Stills Rash . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
1.2.3 Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
1.2.4 Liver Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
1.2.5 Other Less Common Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
1.3 Laboratory and Radiographic Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
1.3.1 Acute Phase Reactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
1.3.2 Haematological Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
1.3.3 Radiographic Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
2. Conventional Treatment of AOSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
2.1 NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
2.2 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
2.3 Disease-Modifying Antirheumatic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
2.3.1 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
2.3.2 Intravenous Immunoglobulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
2.3.3 Ciclosporin, Chloroquine, Gold, Penicillamine, Azathioprine, Cyclophosphamide and
Tacrolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
3. New Treatments for AOSD: Biological Response Modifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
Adult-onset Stills disease (AOSD) is a rare, systemic inflammatory disease of Abstract
unknown aetiology, characterized by daily high spiking fevers, evanescent rash
and arthritis. Our objective was to review the most recent medical literature
regarding advances in the understanding of disease pathogenesis, diagnosis and
treatment. There is no single diagnostic test for AOSD, and diagnosis is based on
320 Kontzias & Efthimiou
clinical criteria and usually necessitates the exclusion of infectious, neoplastic and
autoimmune diseases. Laboratory tests are nonspecific and reflect heightened
immunological activity with leukocytosis, elevated acute phase reactants and, in
particular, extremely elevated serum ferritin levels. Abnormal serum liver func-
tion tests are common, while rheumatoid factor and antinuclear antibodies are
usually absent. Recent studies of the pathogenesis of the disease have suggested
an important role for cytokines. Interleukin (IL)-1, IL-6 and IL-18, macrophage
colony-stimulating factor, interferon- and tumour necrosis factor (TNF)- are all
elevated in patients with AOSD. Prognosis depends on the course of the disease
and tends to be more favourable when systemic symptoms predominate.
Treatment includes the use of corticosteroids, often in combination with
immunosuppressants (e.g. methotrexate, gold, azathioprine, leflunomide, tacroli-
mus, ciclosporin and cyclophosphamide) and intravenous immunoglobulin. Bio-
logical agents (e.g. anti-TNF, anti-IL-1 and anti-IL-6) have been successfully
used in refractory cases. Further progress has been hampered by the rarity and
heterogeneity of the disease, which has not permitted the execution of randomized
controlled studies.
Adult-onset Stills disease (AOSD) is a rare, Full-text articles relating to human disease were
systemic inflammatory disorder, the cause of which selected for relevance. The following co-indexing
is still under investigation. Classically, it presents terms were used: pathogenesis, etiology and
with evanescent rash, fever and articular involve- treatment. Additionally, a few selected articles
ment, although not all three presentations have to be pertaining to the pathophysiology of systemic-onset
present at the same time.
[1]
Bywaters
[2]
was the first juvenile idiopathic arthritis (JIA) or paediatric
to describe AOSD as a distinct clinical syndrome in Stills disease were retrieved.
1971. According to data extrapolated from a small
1. Pathogenesis, Clinical Manifestations
retrospective French study, the yearly incidence has
and Diagnosis of Adult-Onset Stills
been estimated to be 0.16 per 100 000 popula-
Disease (AOSD)
tion.
[3]
It usually occurs in young people, aged be-
tween 16 and 35 years.
[4]
However, in a Japanese
epidemiological study, the estimated mean age of
1.1 Pathogenetic Concepts
disease onset was 38.1 years.
[5]
Women are affected
An interplay among several factors contributing
equally
[3]
or slightly more frequently than men (fe-
to the mechanism of the disease has been speculated.
male-to-male ratio = 60 : 40),
[6]
although men may
Genetic factors in combination with environmental
be more likely to present at younger ages.
[6]
Interest-
factors, such as infection in the setting of immune
ingly, physically or emotionally stressful conditions
disarray, may lead to the phenotypic expression of
during the year preceding the onset of AOSD have
the disease
been associated with the disease.
[7]
1.1.1 Genetic Component Our objective was to review the most recent
advances in the understanding of the pathogenesis, Although several aetiological parameters have
diagnosis and treatment of AOSD. PubMed and the been investigated in an effort to identify possible
Cochrane Database of Systematic Reviews were disease mechanisms, there is still a long way to go in
searched for articles published from 1971 to 2007 determining the pathophysiology of AOSD. It has
using the terms: Adult-onset Stills disease, been inferred that a genetic component is a predis-
Adult-Onset Stills Disease and Stills disease. posing factor required for the disease to be pheno-
Adult-Onset Stills Disease 321
typically expressed; however, studies conferring ge-
netic associations with the disease and disease pat-
terns are inconclusive. Human leukocyte antigen
(HLA)-B17, HLA-B18, HLA-B35 and HLA-DR2
were associated with AOSD in a retrospective study
of 62 patients.
[8]
Another study found HLA-DR1 to
be negatively associated with AOSD.
[9]
HLA-Bw35
and HLA-DR7 alleles have been reported to be
present in increased frequency among AOSD pa-
tients.
[10]
However, another study found a negative
association between the disease and HLA-Bw35 and
a positive association with HLA-DR4.
[9]
A Korean
study demonstrated that the alleles HLA-DRB1*15
and HLA-DRB1*12 were more frequent in AOSD
patients, whereas HLA-DRB1*04 alleles were less
frequent than in the controls.
[11]
In the same study,
the DRB1*14 allele correlated with the monocyclic
systemic type of the disease.
[11]
By contrast, in a
Japanese cohort study, DRB1*1501 (DR2) and
DRB1*1201 (DR5) alleles were more frequently
found in the chronic articular form than in the sys-
temic form, whereas DQB1*12 was equally fre-
quent in both types.
[12]
In general, the low preva-
lence of the disease, its erratic clinical expression
and the varying genetic background of the patients,
in combination with technical limitations in HLA
typing, may, to some extent, explain the variability
of these genetic associations. Moreover, geographi-
cal variability in phenotypical expression of the
disease depicts the potential importance of environ-
mental and genetic factors in its pathogenesis (table
I).
1.1.2 Infectious Component
It has been suggested that an infectious agent has
a triggering effect on the pathogenetic sequence of
the disease, primarily due to temporal relationships
between disease onset and viral syndromes, and
also, the fact that many viral syndromes closely
resemble the clinical presentation of AOSD (high
spiking fever, lymphadenopathy and splenomega-
ly).
[8]
Viruses that have been reported to interact
with the genetic background of the host include
parvovirus B19,
[23,24]
rubella virus, echovirus 7,
[25]
human herpes virus 6, parainfluenza virus, Epstein-
Barr virus, cytomegalovirus, coxsackievirus B4,
T
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5
9
N
R
6
8
5
0
N
R
6
9
7
5
6
5
N
R
5
0
3
1
N
R
R
a
i
s
e
d

E
S
R

(
%
)
9
6
9
0
1
0
0
9
5
9
4
1
0
0
9
4
1
0
0
1
0
0
1
0
0
8
8
1
0
0
R
a
i
s
e
d

L
F
T

(
%
)
8
5
N
R
7
6
5
1
7
6
8
4
6
4
6
5
3
3
4
3
4
4
6
2
E
S
R

=

e
r
y
t
h
r
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c
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t
e

s
e
d
i
m
e
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t
a
t
i
o
n

r
a
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;

L
F
T

=

l
i
v
e
r

f
u
n
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R

=

n
o
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r
e
p
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r
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d
.
mumps and adenovirus.
[26]
Bacterial infections with 1.2 Clinical Manifestations
Chlamydia pneumoniae,
[27]
Yersinia enterocolitica,
Typical presentation of AOSD consists of a triad
Brucella abortus and Borrelia burgdorferi have also
of symptoms which include a high spiking fever, an
been associated with AOSD,
[26]
a finding that has
evanescent rash, and arthritis or arthralgia. Not all
prompted empirical treatment schemes containing
three symptoms need to be present at disease onset,
clarithromycin.
[28]
and atypical presentations may occur (figure 1).
Overall, the loose associations between infec-
Several sets of validated diagnostic criteria have
tious agents, HLA alleles and AOSD have led inves-
been developed over the years, with those of
tigators in the past to look further into the immuno-
Yamaguchi et al.
[35]
being the most widely used
logical pathways of the disease that seem to be
(table II). Furthermore, the natural history of the
highly affected.
disease may follow clinically distinct patterns.
[36]
In
general, three patterns of the disease have been
1.1.3 Immune Dysregulation
identified (table III).
Currently, it is believed that the immune response
is dysregulated in AOSD patients. Although the
1.2.1 Fever
exact mechanism underlying this is still unclear, it
AOSD is frequently the indolent cause of fever of
has been demonstrated that the proinflammatory
unknown origin.
[38]
Awareness of its pattern can be a
cytokines derived from type 1 T helper cells (T
h
1)
valuable clue to the recognition of the disease. Typi-
[interleukin (IL)-2, interferon (IFN)- and tumour
cally, fever is high (>39C) and spiking, usually
necrosis factor (TNF)-] predominate in favour of
daily and occasionally twice daily.
[39]
The spike is
those derived from type 2 T helper cells (T
h
2) [IL-4,
usually observed late in the afternoon or early even-
IL-5, IL-6 and IL-10].
[29]
In line with this evidence,
ing and resolves spontaneously.
[40]
Fever is consid-
TNF, IL-6, IL-8 and IL-18 were found at signifi-
ered to be a prerequisite for the diagnosis, as its
cantly higher levels in sera and pathological tissues
overall incidence in five of the largest retrospective
of AOSD patients than in healthy controls.
[30]
Stud-
studies was estimated to be 95.7%.
[1]
Symptoms that
ies have demonstrated significant correlations of
occasionally precede the fever or rash and that
IL-6 and IL-8 levels with clinical activity score and
should raise suspicion about the underlying cause
serological markers of inflammation, such as C-
include sore throat, seen in more than 70% of pa-
reactive protein (CRP) levels.
[31]
Additionally, cyto-
tients, as well as constitutional symptoms such as
kines such as IL-6, IFN and IL-1 may account for
anorexia, myalgia or arthralgia, fatigue, nausea and
biochemical abnormalities, such as the extreme se-
weight loss. Wasting, evidenced by metabolic mark-
rum levels of ferritin, commonly seen in AOSD.
[31]
ers, such as low albumin levels, tends to follow the
Among other cytokines, IL-18 is thought to play
inflammatory activity of the disease.
[41]
a pivotal role in the inflammatory cascade by
1.2.2 Stills Rash orchestrating the T
h
1 response and inducing other
cytokines such as IL-1, IL-8, TNF and IFN. No- The rash, which is often named Stills rash,
tably, Japanese patients with a specific genetic poly- after the disease, is characterized by evanescence,
morphism of the IL-18 gene (S01/S01 diplotype) salmon-pink colour and morbilliform maculopapu-
were prone to increased disease severity.
[32]
More- lar eruptions. It commonly involves the proximal
over, IL-18 has been inferred to mediate the limbs and the trunk, while rarely affecting the face
hepatotoxic manifestations of the disease.
[33]
Serum and distal limbs. It presents typically during the
intracellular adhesion molecule-1, which may depict febrile attacks, can be mildly pruritic, and is fre-
inflammatory cytokine activity, was found at signif- quently mistaken for a pharmacogenic rash.
[39,40]
icantly elevated levels in active, untreated AOSD The appearance of new skin lesions in areas pre-
patients, and correlated well with both clinical ac- viously traumatized, known in the literature as
tivity score and biochemical markers.
[34]
Koebners phenomenon, has been reported. Skin
Viral syndromes
Reactive arthritis
Other systemic rheumatic
diseases (dermatomyositis,
etc.)
Kikuchi's lymphadenitis
Haemophagocytic
syndrome (primary,
infection, or malignancy-
associated)
Haematological
malignancies
Fever
Rash
Arthritis
Septicaemia-like
presentation
At least three
negative blood
cultures
Failure of
antibacterials
Response to
corticosteroids
ve RF and ANA
CRP and ESR
Serum ferritin
>1000 ng/mL
Glycosylated
fraction of ferritin
<20% of normal
concentration
AST, ALT (70%)
albumin (76%)
WBC count
>10.0 x 10
9
/L
Mild normocytic
anaemia
Reactive
thrombocytosis
Diagnostic approach in AOSD
Clinical suspicion in the
presence of symptoms
Exclusion of other
systemic conditions
Radiographic evaluation
of the disease
Laboratory evidence
indicative of the disease
Fig. 1. Diagnostic approach to adult-onset Stills disease (AOSD). ANA = antinuclear antibodies; CRP = C-reactive protein; ESR = erythro-
cyte sedimentation rate; RF = rheumatoid factor; WBC = white blood cell; indicates increased; indicates decreased; ve = negative.
biopsy of the affected areas reveals a picture of most commonly affected. Other sites involved in-
chronic inflammation with a perivascular mononu- clude elbows, shoulders, proximal and distal inter-
clear preponderance, vascular dilation and dermal phalangeal joints, metacarpophalangeal (and
oedema.
[14]
The mean incidence of Stills rash has
metatarsophalangeal) joints, temporomandibular
been estimated to be as high as 72.7% in a retrospec-
joints and hip joints. Ankylosing carpal arthritis
tive analysis of large series of AOSD patients.
[1]
seems to be a consistent feature of late (13 years
after onset) AOSD, preceded by gradual, selective,
1.2.3 Arthritis
carpometacarpal and intercarpal non-erosive joint
Clinically, AOSD closely resembles its paedia-
space narrowing.
[42]
Notably, this pericapitate pat-
tric sibling, sudden-onset JIA. Arthritis is a promi-
tern of arthritic involvement has been suggested to
nent feature of the disease with an overall estimated
be a differential diagnostic characteristic between
prevalence ranging from 64% to 100%.
[1]
Arthritis
AOSD and rheumatoid arthritis (RA).
[43]
Severe in-
may initially present as oligoarthritis (i.e. involving
volvement of the hip joint, leading to bilateral hip
fewer than four joints, and then develop into polyar-
destruction in nine patients in less than 4 years has thritis, affecting both large and small joints).
[41]
Al-
been reported from a French group, although the though joint involvement does not follow a specific
pattern, it seems that knees, wrists and ankles are the finding has not been supported by other series.
[44]
Table II. The most commonly used diagnostic criteria for adult-onset Stills disease (AOSD)
Reference Major criteria Minor criteria Diagnosis
Yamaguchi et al.
[35]
1. Fever 39C, lasting 1 week 1. Sore throat Exclusions:
(sensitivity 96.2%; 2. Arthralgia lasting 2 weeks 2. Lymphadenopathy and/or 1. Infections (especially sepsis and infectious
specificity 92.1%) 3. Typical rash splenomegaly mononucleosis)
4. Leukocytosis (10 000/mm
3
) 3. Liver dysfunction 2. Malignancies (especially malignant
including 80% of granulocytes 4. Negative RF and negative lymphoma)
ANA 3. Rheumatic diseases (especially polyarteritis
nodosa and rheumatoid vasculitis with extra-
articular features)
Classification of AOSD requires: 5 or more
criteria including 2 or more major criteria
Cush et al.
[36]
(2 points) (1 point) Probable AOSD: 10 points with 12 weeks
(sensitivity 84%) 1. Quotidian fever >39C 1. Onset <35 years observation
2. Stills (evanescent) rash 2. Arthritis Definite AOSD: 10 points with 6 months
3. WBC count >12 000/mm
3
+ 3. Prodromal sore throat observation
ESR >40 mm/h 4. RES involvement or abnormal
4. Negative RF and ANA LFTs
5. Carpal ankylosis 5. Serositis
6. Cervical or tarsal ankylosis
Fautrel et al.
[37]
1. Spiking fever 39C 1. Maculopapular rash Classification of AOSD requires: 4 or more
(sensitivity 80.6%; 2. Arthralgia 2. Leukocytes 10 000/mm
3
major criteria or 3 major criteria + 2 minor
specificity 98.5%) 3. Transient erythema criteria
4. Pharyngitis
5. PMN 80%
6. Glycosylated ferritin 20%
ANA = antinuclear antibodies; ESR = erythrocyte sedimentation rate; LFT = liver function test; PMN = polymorphonuclear leukocytes;
RES = reticuloendothelial system; RF = rheumatoid factor; WBC = white blood cell.
1.2.4 Liver Abnormalities
take place in the form of interstitial nephritis, suba-
Liver pathology, as indicated by hepatomegaly
cute glomerulitis, renal amyloidosis or collapsing
on physical examination, and elevated aminotrans-
glomerulopathy.
[51-54]
Reactive haemophagocytic
ferases in laboratory tests, is seen in approximately
syndrome (RHS), characterized by unrestrained T-
5075% of patients.
[6,8,14]
Abnormal liver function is
cell and macrophage proliferation with cytokine
thought to be part of the inflammatory process of the
overproduction, although rare, may be life-threaten-
disease itself, yet concomitant use of potentially
ing and may have a higher incidence in AOSD than
hepatotoxic treatments often complicates the causa-
in those with other inflammatory diseases.
[55]
tive mechanisms of the biochemical picture.
[15,39]
Thrombocytopenia or absence of hyperleukocytosis,
Fulminant hepatic failure requiring liver transplan-
lymphopenia, coagulopathy and high triglyceride
tation is extremely rare.
[45,46]
levels are prominent features of this complica-
tion.
[55]
Finally, AOSD can be complicated by
1.2.5 Other Less Common Manifestations
thrombotic thrombocytopenic purpura, pure red
AOSD can affect all organ systems with great
aplasia or can present with neurological complica-
variability. Serositis, in the form of pleuritis and
tions such as cranial neural palsies, seizures or asep-
pericarditis, can be encountered in the clinical pic-
tic meningoencephalitis.
[6,8,56,57]
ture of AOSD, although this is rare. Splenomegaly
has been reported in 43.9% of cases.
[1]
Pulmonary
1.3 Laboratory and
manifestations extend from fibrosis and pleural ef-
Radiographic Abnormalities
fusions to adult respiratory distress syndrome in
very rare cases.
[47-49]
Cardiac tamponade and myo- Although the diagnosis of AOSD remains clin-
carditis leading to fibrinoid necrosis have also been ical, certain laboratory abnormalities may play a
infrequently reported.
[50]
Renal involvement can role in helping clinicians establish a diagnosis.
Immune dysregulation of AOSD is generally not making it a more specific marker of the dis-
reflected by positive titres of rheumatoid factor or ease.
[37,58,59]
Fautrel et al.
[58]
combined the 5-fold
antinuclear antibodies as in other rheumatic dis- increase of serum ferritin with its characteristically
eases, and the absence of positive titres of these low glycosylated fraction increasing the specificity
markers has been used as a classification criteri- (93%) but lowering the sensitivity (43%) of this
on.
[1,35]
diagnostic tool. Unfortunately, except from a few
designated centres, it is not a widely available bio-
1.3.1 Acute Phase Reactants
chemical test, so its use is not meaningful in every-
The erythrocyte sedimentation rate (ESR) is in-
day clinical practice.
variably elevated in AOSD patients,
[8,39]
as is gener-
Another novel candidate acute phase marker of
ally the case with CRP,
[21]
serum amyloid A,
[19]
AOSD, which can also be useful in the differential
haptoglobin and serum complement.
[6]
A character-
diagnosis of diseases characterized by high ferritin
istic laboratory abnormality, although not necessari-
levels, is haem oxygenase 1 (HO-1). HO-1 has anti-
ly diagnostic, is the often extreme, elevated serum
inflammatory properties that are mediated by hae-
level of ferritin, a known acute phase protein. The
ms degradation products. HO-1 levels were signifi-
underlying mechanism of high ferritin levels seems
cantly higher in patients with active haemophago-
to be irrelevant to its role in iron metabolism. It is
cytic syndrome and AOSD than in other rheumatic
probably the by-product of the uninhibited action of
diseases and its levels correlated well with serum
cytokines, such as IL-1, IL-18, TNF and IL-6,
ferritin. Additionally, serum levels of both ferritin
which whip the reticuloendothelial system into
and HO-1 returned to normal after treatment. Of
producing and releasing massive amounts of ferri-
interest, hyperferritinaemia caused by liver diseases
tin.
[26]
Elevated serum ferritin levels (approximately
or frequent transfusions due to haematological dis-
1000 ng/mL), higher than five times the upper limits
eases is not associated with increased HO-1
of normal (40200 ng/mL) may suggest the pres-
levels.
[63]
ence of the disease with an 80% sensitivity and 46%
specificity.
[58,59]
Much higher ferritin levels, ranging 1.3.2 Haematological Abnormalities
up to 30 000 ng/mL, are not infrequent.
[41]
The most commonly associated laboratory find-
Ferritin has been proposed to be a very useful ing in AOSD is, without doubt, the leukocytosis
marker of disease activity, as its levels correlate with (predominantly neutrophilic) resulting from bone
clinical scores and tend to predict clinical response marrow granulocyte hyperplasia.
[64]
Peripheral
to treatment.
[60-62]
Its low specificity reflects the fact blood leukocyte counts >15 10
9
/L were found in
that high ferritin levels can also be found in several 50% of 62 patients, while counts >20 10
9
/L were
other conditions such as liver disease (e.g. encountered in 37% of cases in the same series.
[8]
haemochromatosis, Gauchers disease), infections Anaemia of chronic disease is frequently seen
(e.g. sepsis, HIV), malignancies (e.g. leukaemia, during flares, in contrast to periods of remission
lymphoma) and RHS.
[41,55,59]
The glycosylated frac- when haemoglobin values tend to normalize. Reac-
tion of ferritin, which tends to drop in inflammatory tive thrombocytosis is common. Importantly, if the
diseases, is consistently found below 20% in AOSD, opposite (i.e. thrombocytopenia) is present, then
Table III. Patterns of adult-onset Stills disease and prognostic features
Patterns Features Prognosis
Self limiting/monocyclic Systemic symptoms such as fever, Majority of patients achieve remission within 1 year
rash, serositis, organomegaly of initial episode. Favourable prognosis
Intermittent/polycyclic systemic Recurrent flares with or without Complete remission between episodes that tend to
articular symptoms be far apart and milder than initial episode
Chronic articular Predominance of articular symptoms Joint destruction may occur, necessitating surgical
intervention. Unfavourable prognosis
RHS, a life-threatening complication of AOSD re- of patients.
[6,8]
A subsequent larger, multicentre,
quiring immediate immunosuppressive treatment, randomized French study confirmed the previous
should be strongly suspected.
[55,64]
Coagulation ab- results, providing a comparative description of the
normalities are infrequent and reflected by pro- most prevalent treatment options at that time (i.e.
longed times of prothrombin and partial thrombo- aspirin, NSAIDs and corticosteroids).
[67]
This study
plastin. Rarely, disseminated intravascular coagula- made it clear that aspirin was ineffective, suggested
tion has been reported.
[8]
a modest, adjunct role for NSAIDs, such as napro-
xen or indomethacin, and clearly showed that 88%
1.3.3 Radiographic Imaging Techniques
of the patients studied eventually required cortico-
Initially, as expected, radiographs do not provide
steroids for symptomatic control.
[39]
any specific diagnostic information except for poss-
ible tissue swelling, joint effusion, mild periarticular
2.2 Corticosteroids
demineralization or even normal anatomy.
[8]
Years
later, if the disease follows the chronic articular
When NSAIDs were proven ineffective, the use
form, a distinctive radiographic pattern of inter-
of corticosteroids came to the therapeutic forefront
carpal, pericapitate ankylosis may become apparent.
owing to their potent anti-inflammatory actions.
Additionally, intertarsal and cervical zygapophyseal
These actions include inhibition of the production of
ankylosis has been noted to occur in 19% and 12%
proinflammatory cytokines such as TNF and IL-1
of patients with AOSD, respectively.
[41]
Also, in the
by macrophages and lymphocytes,
[68]
modulation of
chronic articular form, Fujii et al.
[65]
have proposed
the signalling pathway of IFN,
[69]
induction of lym-
the carpo-metacarpal ratio as a radiographic
phocyte apoptosis,
[70]
inhibition of lymphocyte pro-
quantitative index of carpal joint involvement.
liferation
[71]
and inhibition of phospholipase A2,
thereby blocking the production of prostaglandin
2. Conventional Treatment of AOSD
and leukotrienes.
[72]
Most studies support the need
for corticosteroids in the majority of patients at
Until very recently, AOSD was treated with
some point in the course of the disease.
[26]
Predni-
NSAIDs, systemic corticosteroids and traditional
sone proved to be a reliable anti-inflammatory agent
immunosupressants, with methotrexate being the
in a study of 45 patients where 76% of them experi-
most common immunosupressants.
enced improvement of their symptoms.
[9]
The initial
dose of prednisone is usually 0.51.0 mg/kg/day
2.1 NSAIDs
administered orally. In refractory cases, intravenous
pulse methylprednisolone and dexamethasone have Since the initial description of AOSD in 1971,
been used successfully.
[73,74]
Despite their success in our understanding of its underlying inflammatory
suppressing both systemic and articular symptoms, mechanisms has evolved alongside the development
they appear to be ineffective in modifying the proof anti-inflammatory drugs. At the time of the initial
gressive anatomical, and radiographically evident, description of the disease, the most widely used anti-
joint destruction in the chronic articular form of the inflammatory drugs were NSAIDs and corticoster-
disease.
[16]
oids. Therefore, it is understandable why NSAIDs
were initially investigated as treatment for the dis- Long-term corticosteroid use is marred by clini-
ease, in an effort to oppose the overt inflammatory cally significant adverse events. Thinning of the
response. NSAIDs work through inhibition of the skin, cataracts, hypertension, hyperlipidaemia and
cyclo-oxygenase enzyme, thus impairing the trans- osteoporosis are among the common ones. Manage-
formation of arachidonic acid to prostaglandins, ment of cardiovascular risk factors and preventive
prostacyclin and thromboxanes.
[66]
Early studies administration of calcium, vitamin D and bisphos-
were disappointing, as they demonstrated minimal phonates are all indicated for patients taking cortico-
efficacy of NSAIDs as monotherapy in only 715% steroids for long periods of time. Other adverse
effects include gastritis, infection, diabetes mellitus In a study of 26 patients who did not respond to
and mood changes.
[75]
corticosteroids or who developed potentially serious
adverse effects, 18 (69%) achieved complete remis-
2.3 Disease-Modifying Antirheumatic Drugs
sion and 11 (42%) were able to remain symptom
free without taking corticosteroids when a low dose
The use of a disease-modifying antirheumatic
(7.517.5 mg) of methotrexate was administered.
[83]
drug (DMARD) during the course of AOSD treat-
Another retrospective study of 13 Japanese patients
ment often becomes a necessity in refractory cases
not only confirms methotrexates efficacy in con-
where corticosteroids have been given at therapeutic
trolling disease activity but also suggests methotrex-
doses without signs of remission, or as corticoster-
ate be used in patients who have not previously been
oid-sparing agents.
[1]
Additionally, given the fact
treated with conventional agents such as corticoster-
that a portion of symptom-free patients develop
oids.
[84]
In another smaller corroborating study, a
destructive arthritis despite treatment with cortico-
weekly 10-mg dose of methotrexate proved to be
steroids,
[4,9,67]
it has become common practice to add
useful in reducing acute symptoms in four of six
a DMARD early in the course of the disease, espe-
patients, although the risk of flare recurrence was
cially in patients with the prolonged febrile, poly-
not reduced. In addition, it was suggested that a 6-
cyclic, or chronic articular disease patterns.
[19]
Apart
month treatment should be considered to allow the
from methotrexate, other DMARDs used to treat
methotrexate treatment to take effect.
[85]
An 85%
AOSD with variable efficacy are ciclosporin,
[76]
reduction in corticosteroid dosage in a French study
hydroxychloroquine, gold, penicillamine, azathio-
of 13 patients adds to the undoubted value of metho-
prine, leflunomide,
[39,77]
cyclophosphamide
[78]
and
trexate in treating patients not tolerating corticoster-
tacrolimus.
[79]
oid adverse effects.
[67]
Methotrexate has been used
2.3.1 Methotrexate
both alone and in combination with biological
The efficacy of methotrexate in AOSD can prob-
agents, which are starting to gain popularity in
ably be attributed to its pharmacological mecha-
AOSD treatment because of their promising re-
nism, which is characterized by increased adeno-
sults.
[86-99]
Because the treatment regimen in AOSD
sine release and activity. This results from inhibition
patients is established in a stepwise manner depen-
of the enzyme aminoimidazolecarboxami-
ding on its efficacy and tolerability, comparative
doadenosineribonucleotide transformylase, which,
prospective trials investigating methotrexate mono-
in turn, leads to inhibition of adenosine-degrading
therapy and methotrexate in combination with a
enzymes such as adenosine deaminase and adeno-
biological agent are rare.
sine monophosphate deaminase.
[80]
Adenosine inter-
Methotrexate was first indicated for RA in the
feres with neutrophil function and the synthesis of
early 1980s and, therefore, it has a long-studied
proinflammatory cytokines, such as TNF and IL-6,
safety profile. In general, long-term experience
that seem to play an important role in AOSD patho-
shows that methotrexate is relatively safe provided
genesis.
[81,82]
Similar to its use in RA, methotrexate
that monthly full blood counts and liver function
is administered orally, once a week, in doses up to
tests are performed. Most of its adverse reactions are
30 mg/week.
[1]
caused by its antifolate activity. While in RA folate
Bearing in mind the recurrent nature of the dis-
coadministration has proved to be beneficial, espe-
ease, its low prevalence and the different clinical
cially regarding its oral and gastrointestinal adverse
courses it may manifest, the execution of double-
effects,
[100]
in AOSD, randomized, controlled trials blind, randomized trials using different therapeutic
are yet to be carried out. Additionally, there is much protocols is difficult. As a result, treatment of refrac-
scepticism about the fact that folate supplementation tory cases of AOSD with methotrexate was initially
undermines methotrexate efficacy via a competitive empirical, based on extrapolated data from its effec-
affinity of folinic acid and methotrexate for the same tive use in treating RA and systemic-onset JIA.
2.3.2 Intravenous Immunoglobulins
cellular transport molecules.
[101,102]
This explains the
Intravenous immunoglobulin (IVIG) constitutes
lack of consensus concerning folate supplementa-
a mixture of pooled polyspecific IgG derived from
tion in the treatment scheme of either RA or AOSD
the blood of healthy human donors.
[114]
They have
patients.
long been used as immunomodulating agents in the
Adverse reactions in AOSD patients treated with
treatment of several autoimmune and inflammatory
methotrexate include gastrointestinal symptoms
diseases such as Kawasakis disease
[115]
and JIA.
[116]
such as vomiting and nausea, mouth ulcers, head-
Bearing in mind that IVIG possesses potent anti-
ache, acute interstitial pneumonia, liver toxicity,
inflammatory activity, as evidenced by its beneficial
blood test abnormalities, such as neutropenia
[83,84]
or
effects on inflammatory diseases, it seemed logical
pancytopenia,
[103]
and opportunistic infections.
[104]
that it would act similarly in AOSD. The body of
Although most of these adverse effects have a rela-
evidence pointing to the efficacy of IVIG in
tively strong causal relationship with methotrexate,
NSAID-refractory cases of AOSD is not vast and
the cause of the liver toxicity remains to be elucidat-
data collected mostly originate from small, uncon-
ed. AOSD is well known to cause a large spectrum
trolled, nonblinded studies and case reports.
[117-120]
of liver abnormalities, from abnormal laboratory
In such a study, four of seven patients treated early
tests, such as elevated transaminases, to a rare form
with IVIG achieved remission, suggesting that use
of cytolytic hepatitis and liver failure,
[14,15,105,106]
of IVIG prior to corticosteroids can lead to early
although most of the time patients remain asymp-
control of the disease.
[118]
IVIG in combination with
tomatic. In a European single-centre study of 17 pa-
mycophenolate mofetil in an African man with
tients, 76% demonstrated abnormal biochemical liv-
refractory AOSD proved to be beneficial at a dose of
er indices and 47% had hepatomegaly at clinical
0.4 g/kg daily for 5 days.
[51]
The favourable effect of
examination.
[15]
Thus, it is hard for clinicians to
IVIG in AOSD could be explained by its mul-
interpret liver abnormalities in that many available
tifactorial mechanisms of action. Among them,
treatment modalities, even the more innocent ones
modulation of the distorted cytokine network,
[114]
such as NSAIDs, have the potential to cause liver
which in AOSD is skewed in favour of T
h
1 cyto-
toxicity. However, recommended NSAID doses for
kines, can be inferred to be the prevalent mecha-
AOSD, far from being able to induce drug-related
nism.
[29]
Of interest, published data suggest that
hepatitis, usually lead to a complete clinical and
IVIG plays a significant role in restoring the existing
biological recovery in 3 weeks, even in cases of
imbalance of T
h
1 and T
h
2 in various autoimmune
severe hepatitis.
[15,67]
Liver toxicity, in the form of
diseases.
[114]
In view of the plausible efficacious
elevated liver function tests, even due to low-dose
IVIG treatment of patients with AOSD, clinical
methotrexate has been reported in patients with RA,
trials to document its results are imperative.
especially in the initial treatment stages,
[107,108]
as
Most of the adverse effects of IVIG are mild and
well as in AOSD patients.
[84]
Nevertheless, in cases
transient, and include headache, flushing, fever,
of life-threatening hepatitis, treatment options
chills, nausea, fatigue, myalgia, arthralgia, back pain
should be chosen cautiously, as fulminant hepatic
and, especially in patients at risk for hypertension,
failure has been reported in AOSD patients.
[45,109]
elevated blood pressure.
[114]
Elderly patients who
Methotrexate, used to treat other rheumatological are not well hydrated are prone to develop oliguric
disorders, has been known to cause opportunistic acute renal failure, which is transient and preventa-
infections, particularly of the upper respiratory ble with sufficient hydration and a slow infusion
tract,
[110]
such as histoplasmosis in a child with rate. Thromboembolic complications are an addi-
JIA.
[111]
In addition, patients with RA or JIA treated tional issue particularly in high-risk patients such as
with methotrexate seem to be prone to haematologi- in those who are immobilized for prolonged periods
cal malignancies such as lymphoma, especially Ep- or those with diabetes.
[114,121]
Aseptic meningitis is a
stein-Barr virus-associated lymphoma.
[112,113]
rare adverse effect, which resolves spontaneously
and can be prevented with administration of 3. New Treatments for AOSD: Biological
Response Modifiers
NSAIDs.
[122]
Rarely, anaphylactic reactions have
been reported in patients who were IgA deficient,
In light of the growing body of evidence on
but careful screening and administration of IgA-
pathogenetic concepts of the disease and given the
depleted immunoglobulin to these patients is the
fact that many AOSD patients do not respond to the
proper course of action.
[114,123]
Anaphylaxis in pa- broadly accepted first-line treatment (methotrexate,
prednisone NSAIDs), novel treatment modalities
tients with IgA deficiency treated with IVIG is cor-
were sought (figure 2; table IV). These agents, well
related with the presence of anti-IgA antibodies of
known for their efficacy in other inflammatory dis-
the IgG and IgE isotypes in the patients serum.
[124]
eases, such as RA, target biological molecules,
which seem to play a pivotal role in the mechanism
2.3.3 Ciclosporin, Chloroquine, Gold,
of the disease. Consequently, inhibiting the action of
Penicillamine, Azathioprine, Cyclophosphamide
proinflammatory cytokines, such as TNF, IL-1 and
and Tacrolimus
IL-6, was a decisive step forward in the treatment of
The use of combinations of DMARDs became
refractory AOSD patients.
prevalent in non-remissive AOSD patients in an
One of the first TNF inhibitors put to the test in
effort to explore other potential therapeutic strate-
AOSD was etanercept. Etanercept is a fully human-
gies or to minimize adverse effects of the existing
ized fusion protein constructed of two recombinant
regimens. Considering the diverse immunogenetic p75 soluble TNF receptors (CD120b) linked to the
Fc portion of human IgG1.
[140]
Additionally, etaner- background, which might play a role in the thera-
cept binds TNF and, as opposed to infliximab, it
peutic response in AOSD patients, investigators at-
does not lyse cells expressing transmembrane TNF
tempted to override mechanisms of resistance by ad-
in the presence or absence of complement.
[141]
Of
ministering a series of immunosuppressive agents.
note, both etanercept and infliximab, apart from
Nevertheless, their efficacy remains equivocal.
their TNF-inhibiting effect, have proved to
Wouters and van de Putte
[39]
demonstrated a mere
44% (8 of 18 trials) clinical improvement with one
or several of the following: chloroquine (0 of 3
responded), gold (6 of 8), penicillamine (4 of 6) and
azathioprine (0 of 1). In a more recent study of
65 patients who received corticosteroids in combi-
nation with either methotrexate or chloroquine as
first-line treatment, it was demonstrated that 21 of
28 (75%) responded to a corticosteroid/chloroquine
regimen and 30 of 36 (83%) responded to the corti-
costeroid/ methotrexate scheme.
[17]
In the same
study, two patients treated initially with corticoster-
oids and azathioprine clinically improved, whereas a
patient treated with a combination of corticosteroids
and sulfasalazine failed to achieve remission.
[17]
Several case reports with diverse success have emer-
ged in the literature, using agents such as
ciclosporin,
[76]
tacrolimus,
[79]
combined leflunomide
and azathioprine,
[77]
and cyclophosphamide.
[47,125]
AOSD therapeutic approach
Low-dose prednisone +/ methotrexate
Response
No Yes
Yes
Second-line agents: leflunomide,
ciclosporin, IVIG, azathioprine,
cyclophasphamide, tacrolimus, gold
Regular clinical
evaluation until
complete remission
Periodic lab testing
for disease markers
(ferritin) and drug
adverse effects
(CBC, LFTs) as long
as treatment is
needed
Addition of biological agent:
First-line agents: IL-1 receptor
antagonist (anakinra)
Second-line agents: TNF
inhibitors (infliximab > etanercept)
or anti-IL-6 (tocilizumab)
No
Fig. 2. Therapeutic algorithm for adult-onset Stills disease (AOSD).
CBC = complete blood count; IL = interleukin; IVIG = intravenous
immunoglobulin; lab = laboratory; LFT = liver function test;
TNF = tumour necrosis factor; > indicates greater efficacy.
Table IV. Retrospective overall outcome analysis of studies utilizing biological response modifiers in adult-onset Stills disease
Studies No. of patients/cases Total patients Usual treatment scheme Remission
Infliximab
Kraetsch et al.
[126]
6 44 Infliximab + DMARDs + 91% (40/44)
Dechant et al.
[127]
8 corticosteroid
Fautrel et al.
[94]
15
Kokkinos et al.
[89]
4
Cavagna et al.
[88]
3
Huffstutter and Sienknecht
[90]
2
Caramaschi et al.
[92]
1
Bonilla Hernan et al.
[91]
2
Dilhuydy et al.
[93]
1
Michel et al.
[128]
1
Olivieri et al.
[129]
1
Etanercept
Husni et al.
[87]
12 25 Etanercept + methotrexate + 72% (18/25)
Fautrel et al.
[94]
10 corticosteroid
Serratrice et al.
[130]
1
Kumari and Uppal
[131]
1
Asherson and Pascoe
[132]
1
Adalimumab
Benucci et al.
[95]
1 1 Adalimumab + methotrexate + 100% (1/1)
corticosteroid
Anakinra
Haraoui et al.
[133]
4 23 Anakinra + methotrexate + 91% (21/23)
Fitzgerald et al.
[99]
4 corticosteroid
Kotter et al.
[134]
4
Kalliolias et al.
[135]
4
Vasques Godinho et al.
[136]
1
Rudinskaya and Trock
[137]
1
Quartuccio and De Vita
[138]
1
Chu et al.
[139]
4
Tocilizumab
Iwamoto et al.
[96]
1 1 Tocilizumab + methotrexate + 100% (1/1)
corticosteroid
DMARDs = disease-modifying antirheumatic drugs.
downregulate the T-cell production of IFN and ration of their symptoms after etanercept treatment.
granulocyte-macrophage colony-stimulating fac- Nine of the patients received prednisone concomi-
tor,
[142]
which are inferred to participate in the in- tantly and methotrexate was added to the treatment
flammatory process of the disease.
[12,29,31]
Etaner- scheme of five patients during the study.
[87]
Several
cept is administered subcutaneously twice weekly at other case reports contribute to the usefulness of
a dose of 25 mg. As with RA, etanercept is frequent- etanercept in refractory AOSD patients,
[120,130,131]
ly coadministered with methotrexate, even if it is though larger double-blind cohort studies are re-
approved as monotherapy,
[141]
and has been similar- quired in order to validate its potential beneficial
ly used in AOSD. effects.
In a 6-month, open-label pilot study in which Larger-scale etanercept studies may be executed
12 patients participated, 66.7% experienced amelio- taking into consideration several safety issues de-
rived from the long-term experience of its use in RA remission early in the course of the disease, sug-
and JIA. A common adverse effect is injection site gesting that early administration of TNF inhibitors
reaction, such as redness, pain, swelling and itching, might have more beneficial results.
[126]
The latter is
particularly in the first month of treatment. Other inferred in a case of early (1 month) AOSD where
frequent adverse effects that need to be addressed methotrexate was thought to be contraindicated be-
are mild upper respiratory tract infections, pharyngi- cause of hepatitis B virus (HBV) infection with
tis, respiratory disorders, dyspepsia, abdominal dis- persistent low titres of HBV DNA.
[129]
Ten AOSD
comfort and rashes.
[143]
In a 4-year study of 34 pa- patients unresponsive to methotrexate and cortico-
tients with JIA who received etanercept, the rate of steroids achieved remission only after infliximab
serious adverse effects was 0.13 per patient-year and
infusion in several open-label studies.
[89-93]
Al-
the rate of serious infections was 0.04 per patient-
though it is difficult to ascribe the clinical improve-
year in a total etanercept exposure of 225 patient-
ment of each patient to appropriate treatment be-
years.
[144]
Nevertheless, blocking the activity of
cause of the recurrent nature of the disease, it is
TNF leads to a limited and defective protection
postulated that anti-TNF therapy may have a last-
against pathogenic organisms, especially opportu-
ing beneficial effect, as five of eight patients treated
nistic ones such as Mycobacterium tuberculosis,
with infliximab remained in remission in a 5-year
atypical species of Mycobacterium, Candida, His-
follow-up period even after termination of treat-
toplasma, Cryptococcus and Listeria spp.
[141,145,146]
ment.
[127]
Infliximab and etanercept were investigat-
ed in a European, multicentre, observational study
Infliximab is a genetically engineered chimeric
of 20 patients who were previously treated with high
monoclonal antibody, 75% human and 25% mouse
doses of methotrexate and corticosteroids without
in origin, which binds to soluble and transmembrane
success. Clinical response was noted in patients with
TNF but not to TNF. The human portion ac-
a systemic form of the disease as well as in patients
counts for its activity, whereas the mouse portion
with the polyarticular form. Most patients (16 of 25)
contains a variable region binding site. Infliximab
responded partially to the treatment with either one
has been shown in vitro to lyse cells expressing
of the agents (7 of 10 on etanercept and 9 of 15 on
TNF on their surface via complement and anti-
infliximab), while 5 of 20 achieved complete remis-
body-dependent cell-mediated cytotoxicity.
[141]
In-
sion (four on infliximab and one on etanercept). Of
fliximab is administered intravenously and after an
interest, switching between TNF antagonists does
initial infusion, it is administered at 2, 6 and then
not seem to be as effective as it is in RA.
[94]
every 8 weeks thereafter.
[147]
This treatment scheme
applies to RA, although AOSD patients have been
Adalimumab is a fully humanized monoclonal
treated similarly.
antibody, which binds both soluble and membrane
TNF, blocking the interaction with the p55 and
Infliximab has been used successfully in refrac-
p75 receptors. It has been shown to lyse cells ex-
tory cases of AOSD. One of the first reports to
pressing TNF on their surface in the presence of
demonstrate its efficacy was that of Cavagna et
complement.
[141]
Currently, it is indicated for clin- al.,
[88]
who administered infliximab (together with
ical use in RA, psoriatic arthritis, ankylosing spon- methotrexate and prednisone) in three patients at a
dylitis and Crohns disease.
[148]
It is administered dose of 3 mg/kg at weeks 0, 2, 6 and once every
subcutaneously every week or every other week at a 8 weeks for 50 weeks. The overall scheme yielded
dose of 40 mg.
[147]
In AOSD, there is a single case very favourable results in terms of both clinical
report referring to clinical improvement in disease response (fever control) and inflammatory activity
refractory to methotrexate and corticosteroids.
[95]
reflected by biochemical markers (ESR, CRP and
Overall, the experience with this agent is limited in serum ferritin).
[88]
A consequent corroborating small
cohort study of six patients demonstrated very AOSD, as it was the most recently approved by the
promising results as all patients achieved clinical US FDA anti-TNF agent, and probably also be-
cause of the recent shift in attention to IL-1 inhibi- Anakinra was very well tolerated in all of the
patients in the aforementioned study.
[99]
Data extra- tion, discussed in more detail in the next para-
polated from large series of patients with RA treated graph. The most common adverse effects associated
with anakinra for an extended period of time (up to
with adalimumab, derived from experience with its
36 months)
[151,152]
demonstrate that it is well tolerat-
use in RA, include injection site reactions, upper
ed and worth considering for resistant cases of
respiratory tract infections, headache, rash, urinary
AOSD. The most frequent adverse effects reported
tract infections and hypertension.
[147]
include injection site reactions, upper respiratory
Bearing in mind the shared pathogenetic com-
tract infections, headaches, arthralgia, sinusitis, nau-
ponents of JIA and AOSD, and the fact that proin-
sea and diarrhoea. Concomitant corticosteroid use
flammatory cytokines play a significant role in
(which is common in AOSD) is thought to increase
AOSD, some investigators have used IL-1-receptor
the risk of serious adverse effects such as pneumo-
antagonists in cases refractory to conventional
nia and cellulitis.
[152]
Thus, careful monitoring of
agents and TNF inhibitors.
[149]
The purified recom-
patients with additional risk factors for infections
binant human IL-1-receptor antagonist exerts its
is mandatory and justifies the fact that anakinra
effects via the competitive inhibition of binding of
is contraindicated in patients with active infec-
IL-1 and IL-1 to the IL-1 receptor, thereby blunt-
tions.
[152]
The recent death of an AOSD patient
ing the activity of this proinflammatory cyto-
treated with anakinra due to cardiac complica-
kine.
[150]
tions
[153]
and another case of reversible thrombo-
cytopenia associated with the use of anakinra in
In one of the first case reports showing the favou-
AOSD
[138]
pose questions for possible causal rela-
rable response to the IL-1 receptor antagonist
tionships but, as yet, any inferred association re-
anakinra, a patient with a 4-year history of AOSD
mains speculative.
had frequent flares despite being treated with high
doses of corticosteroids (up to 1 mg/day), several
IL-6, a proinflammatory cytokine, is considered
DMARDs and, later on, infliximab. As soon as
to play a reinforcing role in the development of the
anakinra was administered at a dose of 100 mg/day inflammatory process in AOSD. Studies have
subcutaneously in addition to methotrexate, prednis- shown that serum IL-6 levels are higher in AOSD
olone and naproxen, the patient experienced a rapid patients (with both systemic and articular disease)
than in patients with inactive disease or healthy amelioration of her systemic and joint symptoms.
[97]
controls. Furthermore, its levels correlate with clin- A consequent paper corroborating the therapeutic
ical activity and biochemical markers of the disease, benefits of anakinra demonstrated rapid haemato-
making IL-6 a candidate biomarker.
[30,31]
These
logical, biochemical and cytokine defervescence in
data, in addition to the clinical benefit of IL-6 block-
four non-remitting AOSD patients. Of note, when
ade demonstrated in one particularly refractory
anakinra was withheld on two occasions, patients
AOSD case in Japan
[96]
and in related sudden-onset
relapsed, only to improve after reintroduction of the
JIA,
[154,155]
support the rationale of administering
agent. Additionally, it was postulated that the bene-
IL-6 receptor antagonists in AOSD. Tocilizumab,
ficial effects of TNF inhibition are exerted through
formerly known as MRA, is a humanized anti-IL-6
reduced production of IL-1 given that TNF is
receptor monoclonal antibody of IgG1 subclass
known to induce IL-1.
[99]
Although well established
that has been shown to compete for both the mem-
prospective studies comparing anakinra with other
brane-bound and soluble forms of the human IL-6
biological agents are still needed to solidify any
receptor, thus diminishing the proinflammatory ac-
potential therapeutic advantage, emerging evidence
tivity of IL-6.
[156]
supports its use in terms of efficacy, rapidity of
action, corticosteroid-sparing effects and tolerabili- In patients with sudden-onset JIA, safety signals
ty. associated with intravenous infusions of tocilizumab
at doses of up to 8 mg/kg were infections, such as need to be validated in larger studies, and while
herpes simplex mouth ulcers, and a mild elevation of convincing the pharmaceutical industry to design
total cholesterol levels.
[154,155]
In a European study new drugs for rare diseases may be extremely diffi-
where tocilizumab was used to treat RA patients cult, asking them to provide currently available
unresponsive to methotrexate, there was a dose- drugs for new indications may be a more pragmatic
related increase in the mean serum transaminase approach.
level (accentuated by concomitant use of methotrex-
ate), with no evidence of clinical hepatitis. More-
Acknowledgements
over, abnormal serum lipid levels, as evidenced
by elevated total cholesterol levels, triglycerides No sources of funding were used to assist in the prepara-
tion of this article. The authors have no conflicts of interest
and high density lipoproteins, occurred during
that are directly relevant to the content of this review article.
tocilizumab treatment.
[157]
Tocilizumab is in the late
stages of development for the treatment of RA.
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REVIEW ARTICLE 0012-6667/08/0003-0339/$53.45/0
Drugs for Cardiovascular Disease
Prevention in Women
Implications of the AHA Guidelines 2007 Update
Nanette K. Wenger
1,2,3
1 Emory University School of Medicine, Atlanta, Georgia, USA
2 Grady Memorial Hospital, Atlanta, Georgia, USA
3 Emory Heart and Vascular Center, Atlanta, Georgia, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
1. Lifestyle Category (Dietary Intake) Omega-3 Fatty Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
1.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
1.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
2. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
3. Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
4. Lipids: Primary and Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
5. Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
6. ACE Inhibitors/Angiotensin II Receptor Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
7. -Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
8. Aldosterone Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
9. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
10. Folic Acid, and Vitamins B6 and B12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
10.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
10.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
11. Menopausal Hormone Therapy (MHT)/Selective Estrogen Receptor Modulators (SERMs) . . . . . . . . 354
11.1 Primary Prevention: MHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
11.2 Secondary Prevention: MHT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
11.3 Secondary Prevention: SERMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Lifestyle interventions constitute the initial strategy for the primary and Abstract
secondary prevention of cardiovascular disease in women. However, pharmaco-
therapy is often indicated for control of major cardiovascular risk factors, and
340 Wenger
abundant clinical trial data support the morbidity and mortality benefit of a
number of categories of drug therapy following a coronary event. Although
women have increasingly been enrolled in clinical trials of pharmacotherapy,
under representation of women in most research studies limits the gender-specific
assessment of outcomes. Equally importantly, recent randomized clinical trial
data have highlighted inappropriate preventive therapies for women (i.e. those
lacking effectiveness and potentially imparting harm). Decision-making data for
drug therapy for women also derive from a number of clinical trials conducted
solely in women.
The drug classes reviewed in this article include omega-3 fatty acids, aspirin,
ACE inhibitors and angiotensin II receptor antagonists or blockers, -adre-
noceptor antagonists (-blockers), aldosterone antagonists, antioxidants, folic
acid and vitamins B
6
and B
12
, and menopausal hormone therapy and selective
estrogen-receptor modulators.
Information is sparse regarding specific cardiovascular pharmacotherapies for
elderly women, and women of racial and ethnic minorities. Owing to the under
representation of the subset of women in many trials, analysis by age, race and
ethnicity is not appropriate. This information gap presents a major challenge for
future studies, as these subgroups constitute populations of women at high
cardiovascular risk.
Coronary heart disease (CHD) remains the lead- guidelines were conducted either in apparently
healthy women or in women with established CVD. ing cause of mortality among women in the US and
Given the high lifetime risk of CHD for women, among women in many countries worldwide. A
and the documentation that most US women have at pivotal issue is that many risk factors for cardio-
least one coronary risk factor,
[3]
most women are
vascular disease (CVD) and CHD are modifiable or
candidates for preventive therapies. The guideline
preventable, hence, the widespread emphasis on
citations are categorized as follows: (i) lifestyle in-
coronary risk reduction as a means to favourably
terventions, which are recommended for all women,
affect both coronary risk factors and clinical mani-
with virtually all having a class I level of recommen-
festations of CHD.
dation; (ii) major risk-factor interventions; and (iii)
As with the initial 2004 Prevention Guidelines
preventive drug interventions (table II). Highly rele-
for women,
[1]
the emphasis focuses on a partnership
vant are the class III interventions that have not
between women and their healthcare providers, but
proved useful or effective and may impart harm
the 2007 Guideline Update
[2]
displays a simpler
(table III). The classifications and levels of evidence
algorithm for ascertaining cardiovascular risk status,
are those used in most clinical practice guidelines
defining women as at high risk, at risk or at optimal
(table IV).
risk (table I). Furthermore, given the 10-year aver-
The studies included in the systematic search for
age delay in onset of clinical manifestations of CHD
this article were randomized clinical trials or large
in women compared with men, the emphasis of the
prospective cohort studies (>1000 subjects) of
2007 Guideline Update is on reduction of lifetime
cardiovascular risk-reducing interventions, meta-
risk, rather than the limited viewpoint of 10-year
analyses that used a quantitative systematic review
risk. This simplification of the classification of
process or surrogate endpoint studies with at least
cardiovascular risk status derives from the overview ten cases of major clinical CVD endpoints reported.
that most studies providing the evidence base for the A total of 5774 articles were initially identified: 828
Drugs for Cardiovascular Disease Prevention in Women 341
were included for full-text screening, and 246 met 1. Lifestyle Category (Dietary Intake)
Omega-3 Fatty Acids the inclusion criteria and were included in the evi-
dence tables. This article addresses solely those
Following guideline recommendations (class
recommendations that involve pharmacotherapy,
IIb, level B), capsules of omega-3 fatty acids
such that the bibliography encompassing the evi-
(8501000 mg of eicosapentaenoic acid [EPA] and
dence base for the guideline recommendations for
docosahexaenoic acid [DHA]) may be considered,
lifestyle interventions (e.g. smoking cessation,
as an adjunct to diet, in women with established
physical activity, cardiovascular or stroke rehabilita-
CHD. Higher doses (24 g) may be used for the
tion, dietary intake, weight maintenance/reduction
treatment of women with high triglyceride levels.
[2]
or depression screening/referral) is not provided.
1.1 Primary Prevention
The pharmacotherapy bibliography cited in-
cludes those references that provided the basis and
The data regarding omega-3 fatty acids derive
levels of evidence for the clinical recommendations
from four cohort studies
[4-7]
and three meta-analy-
discussed, and includes a review of trial results and
ses.
[8-10]
There was a prospective examination
gender-specific outcomes, when available, pub-
among the 76 763 women in the Nurses Health
lished up to June 2006.
Study who completed a dietary questionnaire at
baseline (1984) of the association between dietary
-linolenic acid, assessed via this questionnaire, and
the risk of sudden cardiac death, other fatal CHD
and nonfatal myocardial infarction (MI). After con-
trolling for coronary risk factors and other fatty
acids, there was an inverse association between -
linolenic acid intake and the risk of sudden cardiac
death, but not the risk of other fatal CHD or nonfatal
MI; risk of sudden cardiac death was 3840% lower
in the highest two quintiles of dietary intake. This
suggests that increased dietary -linolenic acid may
reduce the risk of sudden cardiac death, but not other
coronary events (i.e. it may have antiarrhythmic
properties, but provides no information about ome-
ga-3 fatty acid supplementation).
[4]
Association of
dietary intake of fish and omega-3 fatty acids, based
on a food frequency questionnaire, and the risk of
CHD was examined in 41 578 Japanese men and
women aged 4059 years, free of CVD and followed
for about a decade.
[6]
Based on 196 nonfatal and 62
fatal coronary events, multivariable hazard ratios in
the highest versus the lowest quintiles of fish intake
were 0.63 for total CHD, 0.44 for definite MI and
1.14 for sudden cardiac death. The major reduction
was in the risk of nonfatal coronary events, with a
strong inverse association between the dietary in-
take of omega-3 fatty acids, and the risk of definite
MI and nonfatal coronary events. Results of these
two studies are thus inconsistent.
Table I. Classification of cardiovascular disease (CVD) risk status
in women (reproduced from Mosca et al.,
[2]
with permission,
2007, American Heart Association, Inc.)
Criteria
High risk
Established coronary heart disease
Cerebrovascular disease
Peripheral arterial disease
Abdominal aortic aneurysm
End-stage or chronic renal disease
Diabetes mellitus
10-Year Framingham global risk >20%
a
At risk
1 major risk factors for CVD, including:
cigarette smoking
poor diet
physical inactivity
obesity, especially central adiposity
family history of premature CVD (CVD at <55 years of age in a
male relative and <65 years of age in a female relative)
hypertension
dyslipidaemia
Evidence of subclinical vascular disease (e.g. coronary
calcification)
Metabolic syndrome
Poor exercise capacity on treadmill test and/or abnormal heart
rate recovery after stopping exercise
Optimal risk
Framingham global risk <10% and a healthy lifestyle, with no risk
factors
a Or at high risk on the basis of another population-adapted
tool used to assess global risk.
342 Wenger
Table II. Guidelines for the prevention of cardiovascular disease (CVD) in women: clinical recommendations (reproduced from Mosca et
al.,
[2]
with permission, 2007, American Heart Association, Inc.)
Lifestyle interventions
Cigarette smoking
Women should not smoke and should avoid environmental tobacco smoke. Provide counselling, nicotine replacement and other
pharmacotherapy as indicated in conjunction with a behavioural programme or formal smoking cessation programme (class I, level B)
Physical activity
Women should accumulate a minimum of 30 minutes of moderate intensity physical activity (e.g. brisk walking) on most, and preferably
all, days of the week (class I, level B)
Women who need to lose weight or sustain weight loss should accumulate a minimum of 6090 minutes of moderate intensity physical
activity (e.g. brisk walking) on most, and preferably all, days of the week (class I, level C)
Rehabilitation
A comprehensive risk-reduction regimen, such as cardiovascular or stroke rehabilitation or a physician-guided home- or community-
based exercise training programme, should be recommended to women with a recent acute coronary syndrome or coronary
intervention, new-onset or chronic angina, recent cerebrovascular event, peripheral arterial disease (class I, level A), or current/prior
symptoms of heart failure and an LVEF <40% (class I, level B)
Dietary intake
Women should consume a diet rich in fruits and vegetables; choose whole-grain, high-fibre foods; consume fish, especially oily fish,
a
at
least twice a week; limit intake of saturated fat to <10% of energy, and if possible to <7%, cholesterol to <300 mg/day, alcohol intake to
no more than one drink per day,
b
and sodium intake to <2.3 g/day (approximately 1 teaspoon of salt). Consumption of trans-fatty acids
should be as low as possible (e.g. <1% of energy) [class I, level B]
Weight maintenance/reduction
Women should maintain or lose weight through an appropriate balance of physical activity, caloric intake and formal behavioural
programmes when indicated to maintain/achieve a BMI between 18.5 and 24.9 kg/m
2
, and a waist circumference 35 in (class I, level
B)
Omega-3 fatty acids
As an adjunct to diet, omega-3 fatty acids in capsule form (approximately 8501000 mg of EPA and DHA) may be considered in
women with CHD, and higher doses (24 g) may be used for treatment of women with high triglyceride levels (class IIb, level B)
Depression
Consider screening women with CHD for depression and refer/treat when indicated (class IIa, level B)
Major risk-factor interventions
Blood pressure optimal level and lifestyle
Encourage an optimal blood pressure of <120/80 mmHg through lifestyle approaches such as weight control, increased physical
activity, alcohol moderation, sodium restriction, and increased consumption of fresh fruits, vegetables and low-fat dairy products (class I,
level B)
Blood pressure pharmacotherapy
Pharmacotherapy is indicated when blood pressure is 140/90 mmHg or at an even lower blood pressure in the setting of chronic
kidney disease or diabetes mellitus (130/80 mmHg). Thiazide diuretics should be part of the drug regimen for most patients unless
contraindicated or if there are compelling indications for other agents in specific vascular diseases. Initial treatment of high-risk women
c
should be with -blockers and/or ACE inhibitors/ARBs, with addition of other drugs, such as thiazides, as needed to achieve goal blood
pressure (class I, level A)
Lipid and lipoprotein levels optimal levels and lifestyle
The following levels of lipids and lipoproteins in women should be encouraged through lifestyle approaches: LDL-C <100 mg/dL, HDL-C
>50 mg/dL, triglycerides <150 mg/dL and non-HDL-C (total cholesterol minus HDL-C) <130 mg/dL (class I, level B). If a woman is at
high risk
c
or has hypercholesterolaemia, intake of saturated fat should be <7% and cholesterol intake <200 mg/day (class I, level B)
Lipids pharmacotherapy for LDL-lowering, high-risk women
Utilize LDL-C-lowering drug therapy simultaneously with lifestyle therapy in women with CHD to achieve an LDL-C <100 mg/dL (class I,
level A) and similarly in women with other atherosclerotic CVD, diabetes or 10-year absolute risk >20% (class I, level B)
A reduction to <70 mg/dL is reasonable in very high-risk women
d
with CHD and may require an LDL-lowering drug combination (class
IIa, level B)
Continued next page
Table II. Contd
Lipids pharmacotherapy for LDL-lowering, other at-risk women
Utilize LDL-C-lowering therapy if LDL-C level is 130 mg/dL with lifestyle therapy and there are multiple risk factors and 10-year
absolute risk 1020% (class I, level B)
Utilize LDL-C-lowering therapy if LDL-C level is 160 mg/dL with lifestyle therapy and multiple risk factors, even if 10-year absolute risk
is <10% (class I, level B)
Utilize LDL-C-lowering therapy if LDL-C 190 mg/dL regardless of the presence or absence of other risk factors or CVD on lifestyle
therapy (class I, level B)
Lipids pharmacotherapy for low HDL-C or elevated non-HDL-C, high-risk women
Utilize niacin
e
or fibrate therapy when HDL-C is low or non-HDL-C is elevated in high-risk women after LDL-C goal is reached (class IIa,
level B)
Lipids pharmacotherapy for low HDL-C or elevated non-HDL-C, other at-risk women
Consider niacin
e
or fibrate therapy when HDL-C is low or non-HDL-C is elevated after LDL-C goal is reached in women with multiple
risk factors and a 10-year absolute risk 1020% (class IIb, level B)
Diabetes mellitus
Lifestyle and pharmacotherapy should be used as indicated in women with diabetes (class I, level B) to achieve an HbA1c <7% if this
can be accomplished without significant hypoglycaemia (class I, level C)
Preventive drug intervention
Aspirin, high-risk women
Aspirin therapy (75325 mg/day)
f
should be used in high-risk
c
women unless contraindicated (class I, level A)
If a high-risk
c
woman is intolerant of aspirin therapy, clopidogrel should be substituted (class I, level B)
Aspirin other at-risk or healthy women
In women 65 years of age, consider aspirin therapy (81 mg daily or 100 mg every other day) if blood pressure is controlled and
benefit for ischaemic stroke and MI prevention is likely to outweigh risk of gastrointestinal bleeding and haemorrhagic stroke (class IIa,
level B), and in women <65 years of age when benefit for ischaemic stroke prevention is likely to outweigh adverse effects of therapy
(class IIb, level B)
-Blockers
-Blockers should be used indefinitely in all women after MI, acute coronary syndrome or left ventricular dysfunction with or without
heart failure symptoms, unless contraindicated (class I, level A)
ACE inhibitors/ARBs
ACE inhibitors should be used (unless contraindicated) in women after MI and in those with clinical evidence of heart failure or an
LVEF 40% or with diabetes (class I, level A). In women after MI and in those with clinical evidence of heart failure or an LVEF 40%,
or with diabetes who are intolerant of ACE inhibitors, ARBs should be used instead (class I, level B)
Aldosterone blockade
Use aldosterone blockade after MI in women who do not have significant renal dysfunction or hyperkalaemia who are already receiving
therapeutic doses of an ACE inhibitor and -blocker, and have LVEF 40% with symptomatic heart failure (class I, level B)
a Pregnant and lactating women should avoid eating fish potentially high in methylmercury (e.g. shark, swordfish, king mackerel or tile
fish) and should eat up to 12 oz/wk of a variety of fish and shellfish low in mercury, and check the Environmental Protection Agency
and the US FDAs websites for updates and local advisories about safety of local catch.
b A drink equivalent is equal to a 12 oz bottle of beer, a 5 oz glass of wine or a 1.5 oz shot of 80-proof spirit.
c Criteria for high risk include established CHD, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, end-
stage or chronic renal disease, diabetes, and 10-year Framingham risk >20%.
d Criteria for very high risk include established CVD plus any of the following: multiple major risk factors, severe and poorly controlled
risk factors, diabetes mellitus.
e Dietary supplement niacin should not be used as a substitute for prescription niacin.
f After percutaneous intervention with stent placement or coronary artery bypass grafting within the previous year and in women with
noncoronary forms of CVD, use current guidelines for aspirin and clopidogrel.
ARB = angiotensin receptor blocker; BMI = body mass index; CHD = coronary heart disease; DHA = docosahexaenoic acid;
EPA = eicosapentaenoic acid; HbA1c = glycosylated haemoglobin; HDL-C = high-density lipoprotein-cholesterol; LDL = low-density
lipoprotein; LDL-C = low-density lipoprotein-cholesterol; LVEF = left ventricular ejection fraction; MI = myocardial infarction.
Among 45 722 men without known CVD, assess- 4-year intervals via questionnaire, showed at
ment of diet at baseline (1986) and subsequently at 14 years that omega-3 polyunsaturated fatty acids
344 Wenger
Table III. Class III interventions (not useful/effective and may be harmful) for cardiovascular disease (CVD) or myocardial infarction (MI)
prevention in women (reproduced from Mosca et al.,
[2]
with permission, 2007, American Heart Association, Inc.)
Menopausal therapy
Hormone therapy and selective estrogen-receptor modulators should not be used for the primary or secondary prevention of CVD (class
III, level A)
Antioxidant supplements
Antioxidant vitamin supplements (e.g. vitamin E, C, and carotene) should not be used for the primary or secondary prevention of CVD
(class III, level A)
Folic acid
a
Folic acid, with or without vitamin B6 and B12 supplementation, should not be used for the primary or secondary prevention of CVD
(class III, level A)
Aspirin for MI in women <65 years of age
b
Routine use of aspirin in healthy women <65 years of age is not recommended to prevent MI (class III, level B)
a Folic acid supplementation should be used in the childbearing years to prevent neural tube defects.
b For recommendation for aspirin to prevent CVD in women 65 years of age or stroke in women <65 years of age, please see table
II.
from both seafood and plant sources appeared to pectoris. Daily intake of omega-3 fatty acids for a
reduce coronary risk, but little influence was evident mean duration of 37 months decreased all-cause
from the background omega-3 polyunsaturated fatty mortality by 16% and MI death by 24%, without
acid intake.
[5]
Earlier data from the Cardiovascular significant effect on other outcomes. Data from
Health Study
[7]
examined the cardiac benefits of fish these studies were considered suboptimal to recom-
consumption by the type of fish consumed. In this mend routine fish oil supplementation, with concern
population, aged 65 years (3910 adults at baseline, raised regarding the lack of information in patients
free of known CVD in 198990), consumption of receiving HMG-CoA reductase inhibitors (statins).
tuna or other broiled or baked fish, but not fried fish
2. Depression
or fish sandwiches, was associated with a lower risk
of ischaemic heart disease, particularly arrhythmic
ischaemic heart disease death.
2.1 Secondary Prevention
In addition, the meta-analyses conducted to date
Although the Guidelines recommend screening
relate primarily to dietary intake. The meta-analysis
women with CHD for depression and referral/treat-
of Brouwer et al.
[8]
showed that -linolenic acid
ment when indicated, no specific therapies are ad-
consumption might reduce heart disease mortality,
dressed.
[2]
Nonetheless, some information regarding
but raised concern about the association between
therapy may be relevant. In the ENRICHD trial (see
high dietary -linolenic acid and prostate cancer.
table V for definitions of all study/trial acronyms),
The meta-analysis by Whelton et al.
[9]
suggested
overall use of cognitive behavioural therapy and
that fish consumption was associated with a signifi-
interventions to enhance social support failed to
cantly lower risk of fatal and total CHD, and pro-
improve outcomes in a depressed, socially isolated,
posed this as an important component of lifestyle
postinfarction population. Two subset studies of
modification for CHD prevention.
ENRICHD provide provocative information. In a
post hoc analysis, White men, but not other gender
or ethnic subgroups, appeared to benefit from
The final meta-analysis performed by Yzebe and the ENRICHD intervention; the total cohort includ-
Lievre,
[10]
is the sole examination of the efficacy of ed 973 White men, 424 minority men, 674
omega-3 fatty acid supplementation, addressing the White women and 410 minority women.
[11]
In an-
results of ten randomized controlled trials in other ENRICHD analysis, patients whose depres-
14 727 adults with recent or acute MI or angina sion was refractory to cognitive behavioural therapy
and sertraline were at higher risk for late mortality Pharmacotherapy is indicated when the blood
(i.e. not early after acute MI).
[12]
Finally, a secon- pressure is 140/90 mmHg for all women or 130/
dary analysis examining the effects of antidepres- 80 mmHg in the setting of chronic kidney disease or
sant medication in the ENRICHD cohort
[13]
showed diabetes mellitus. The American Heart Association
benefit of selective serotonin reuptake inhibitors; (AHA) currently recommends a goal blood pressure
users had an adjusted hazard ratio of 0.57 for death
of <130/80 mmHg for those patients at high risk for
or recurrent MI, 0.59 for all-cause mortality and
CHD and <120/80 mmHg when left ventricular
0.53 for recurrent MI. Hazard ratios were 0.72, 0.64
dysfunction is present.
[14]
The pharmacological re-
and 0.73 for death or recurrent MI, all-cause mor-
commendations for women are those of the Seventh
tality or recurrent MI, respectively, for patients tak-
Report of the Joint National Committee on the Pre-
ing nonselective serotonin reuptake inhibitor antide-
vention, Detection, Evaluation, and Treatment of
pressants compared with non-users. The authors
High Blood Pressure (JNC 7).
[15]
Recommendations
suggested that selective serotonin reuptake inhibi-
of JNC 7 do not differ for women and men. Initial
tors in depressed patients following MI might re-
therapy with thiazide diuretics is recommended,
duce subsequent cardiovascular morbidity and mor-
save for high-risk women with specific indications
tality, and indicated the need for randomized con-
for initial use of other drugs including -adre-
trolled trial data.
noceptor antagonists (-blockers), ACE inhibitors/
angiotensin II receptor antagonists (angiotensin II
3. Blood Pressure
receptor blockers [ARBs]), with subsequent addi-
tion of other drugs such as thiazide diuretics as
needed to achieve goal blood pressure. In seven
older randomized controlled trials from the IN-
Lifestyle approaches to hypertension manage-
DANA intervention database, subgroup meta-ana-
ment (including weight control, increase in physical
lysis showed significant treatment benefits in the
activity, moderation of alcohol use, sodium restric-
prevention of CVD for women with the use of
tion, and increased consumption of fresh fruits, veg-
antihypertensive treatment.
etables and low-fat dairy products) are the initial
A number of studies regarding treated hyperten-
interventions recommended for blood pressure con-
sive versus nonhypertensive subjects of the same
trol, with a goal blood pressure of <120/80 mmHg.
age in the general population examined why cardio-
vascular mortality was higher in the treated hyper-
tensive population. One study of 8893 treated hyper-
tensive men and women (47% women) concluded
that their increased cardiovascular mortality was
due mainly to high systolic blood pressure levels
while under treatment, i.e. that the excess risk in
hypertensive patients may be drastically reduced if
systolic blood pressures were better controlled.
[16]
Similar results were found when women and men
were studied separately.
An extensive Cochrane meta-analysis of pharma-
cotherapy of hypertension in the elderly
[17]
conclud-
ed that randomized controlled trials established the
high efficacy of treating healthy older persons with
diastolic or systolic hypertension with low-dose di-
uretics or -blockers for benefits of cardiovascular
Table IV. Classification and levels of evidence (reproduced from
Mosca et al.,
[2]
with permission, 2007, American Heart Associa-
tion, Inc.)
Strength of recommendation
Classification
Class I Intervention is useful and effective
Class IIa Weight of evidenced/opinion is in favour of
usefulness/efficacy
Class IIb Usefulness/efficacy is less well established by
evidence/opinion
Class III Intervention is not useful/effective and may be
harmful
Level of evidence
A Sufficient evidence from multiple randomized trials
B Limited evidence from single randomized trial or
other nonrandomized studies
C Based on expert opinion, case studies or standard
of care
346 Wenger
Table V. List of study/trial/database acronyms and definitions
Study/trial/database acronym Study name
4S Scandinavian Simvastatin Survival Study
AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study
ALLHAT Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial
ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes Trial, Lipid Lowering Arm
CAMELOT Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis
CARE Cholesterol and Recurrent Events
CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and
Avoidance
CHARM Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity
CIBIS II Cardiac Insufficiency BIsoprolol Study II
COPERNICUS CarvedilOl ProspEctive RaNdomIzed CUmulative Survival study
CRUSADE Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes
with Early implementation of the ACC/AHA Guidelines
ENRICHD ENhancing Recovery In CHD
EPHESUS Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUurvival Study
EUROPA EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery
disease
GREACE GREek Atorvastatin and Coronary-heart-disease Evaluation
HERS Heart and Estrogen/Progestin Replacement Study
HOPE Heart Outcomes Prevention Evaluation
HPS Heart Protection Study
INDANA INdividual Data ANalysis of Antihypertensive
INVEST INternational VErapamil SR-Trandolapril
LIPID Long-term Intervention with Pravastatin in Ischaemic Disease
MERIT-HF MEtoprolol CR/XL Randomized Intervention Trial in Heart Failure
MICROHOPE Microalbuminuria, Cardiovascular and Renal Outcomes
MIRACL Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
NORVIT Norwegian Vitamin Trial
PEACE Prevention of Events with Angiotensin Converting Enzyme inhibition
PERSUADE PERindopril SUbstudy in coronary Artery disease and DiabEtes
PROSPER PROspective Study of Pravastatin in the Elderly at Risk
PROVE IT-TIMI 22 PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial
Infarction 22
RALES Randomized ALdactone Evaluation study
RUTH Raloxifene Use for The Heart
SCAT Simvastatin/enalapril Coronary Atherosclerosis Trial
Syst-Eur Systolic Hypertension in Europe
TNT Treating to New Targets
TRACE TRAndolapril Cardiac Evaluation
WAVE Womens Angiographic Vitamin and Estrogen
WHI Womens Health Initiative
ACC = American College of Cardiology; AHA = American Heart Association; CR/XL/SR = controlled release/extended release/sustained
release; CHD = coronary heart disease.
morbidity and mortality, cardiovascular mortality, The ALLHAT study demonstrated superiority
and total mortality. The meta-analysis encompassed of diuretic-based over -adrenoceptor antagonist-
15 trials that included over 21 000 elderly subjects, based antihypertensive treatment for the prevention
most aged 6080 years. of CVD.
[18]
2006 recommendations from the AHA/
American College of Cardiology (ACC) for secon- based regimen resulted in similar cardiovascular
dary prevention for patients with defined coronary outcomes. Women comprised 54% of participants.
and other atherosclerotic vascular disease define a
goal blood pressure of <130/80 mmHg for those
4. Lipids: Primary and
with diabetes or chronic kidney disease. ALLHAT
Secondary Prevention
enrolled 42 448 high-risk hypertensive subjects,
As with hypertension, lifestyle approaches
19 865 of whom were women. Treatment effects
should be the initial interventions for attaining opti-
were similar in women and men.
mal levels of lipids and lipoproteins in women.
[2]
Interesting data are derived from a study of
The goal levels are a low-density lipoprotein-cho-
cardiovascular outcomes in high-risk hypertensive
lesterol (LDL-C) <100 mg/dL, high-density lipopro-
patients in ALLHAT related to baseline glomerular
tein-cholesterol (HDL-C) >50 mg/dL, triglycerides
filtration rate. Patients in this multicentre study were
<150 mg/dL, and non-HDL-C (total cholesterol mi-
stratified by baseline glomerular infiltration rate:
nus HDL-C) <130 mg/dL. Pharmacotherapy using
normal or increased in 8128 patients, mild reduction
LDL-C-lowering drug therapy, preferably with sta-
in 18 109 patients, and moderate or severe reduction
tins, is recommended in high-risk women simultane-
in 5662 patients.
[19]
Women comprised almost half
ously with lifestyle interventions to achieve an
of the cohort, but gender-specific analyses were not
LDL-C <100 mg/dL, with reduction to <70 mg/dL
reported. Older high-risk hypertensive patients with
reasonable for very high-risk women. The Guide-
a reduced glomerular filtration rate were more likely
lines identify that the latter may require LDL-lower-
to develop CHD than to develop end-stage renal
ing drug combinations.
[2]
disease. A low glomerular filtration rate indepen-
The National Cholesterol Education Program
dently predicted increased CHD risk. Neither am-
Adult Treatment Panel III (NCEP ATP III) guide-
lodipine nor lisinopril was superior to chlorthali-
lines recommended statin therapy for women aged
done in preventing CHD, stroke or combined CVD,
4570 years;
[22]
subsequently reported data for
but chlorthalidone was superior to both for prevent-
women >75 years showed benefit for these elderly
ing heart failure. Based on 4695 patients in the Syst-
women in the HPS
[23]
but not in PROSPER.
[24]
Up-
Eur Trial,
[20]
with a minimum age of 60 years, the
dated NCEP ATP III guidelines
[25]
for high-risk
investigators concluded that antihypertensive treat-
patients of both genders confirmed the desirability
ment can successfully control blood pressure in
of an LDL-C goal <70 mg/dL, as well as considera-
most older patients with isolated systolic hyperten-
tion of combining a fibric acid derivative (fibrate) or
sion. Women comprised about two-thirds of the
niacin (nicotinic acid) with an LDL-C-lowering
cohort and there was no gender heterogeneity in
drug for patients with a high triglyceride or low
outcome. Underscoring the necessity of early treat-
HDL-C level.
ment for isolated systolic hypertension was the find-
Almost 20 000 women were included in the pri- ing that immediate compared with delayed pharma-
mary and secondary prevention major lipid-lower- cotherapy with nitrendipine, with possible addition
ing trials of statin therapy. AFCAPS/TexCAPS, of enalapril, hydrochlorothiazide or both, prevented
HPS, ALLHAT and ASCOT-LLA were primary 17 strokes or 25 major cardiovascular events per
prevention trials. PROSPER involved a combina- thousand patients followed for 6 years.
tion of primary and secondary prevention patients.
4S, CARE, LIPID, GREACE and TNT were secon-
dary prevention trials. Benefit ranged from 11% in
Cardiovascular outcomes were evaluated in coro- LIPID
[26]
to 54% in GREACE,
[27]
without signif-
nary patients with diabetes in a diabetic cohort of the icant benefit evident for women in PROSPER,
[24]
in
INVEST trial;
[21]
a verapamil sustained-release- the ASCOT-LLA
[28]
or in ALLHAT. Neither gender
based antihypertensive regimen and an atenolol- showed lipid benefit in ALLHAT.
[29]
In the TNT
348 Wenger
trial,
[30]
1902 of 10 001 enrolled patients with stable zation.
[33]
In a substudy of MIRACL,
[34]
the stroke
rate was reduced by half and there was no increase CHD were women. The comparison was of atorvas-
in haemorrhagic stroke. tatin 10 mg versus 80 mg, with an average follow-up
of 4.9 years. Decreases in LDL-C, total cholesterol
The PROVE IT-TIMI 22 trial
[35]
compared
and triglycerides were comparable by gender.
[31]
pravastatin 40 mg with atorvastatin 80 mg in
There was a significant comparable decrease in the
4162 patients with acute MI. The resultant mean
primary study endpoints of major cardiovascular
LDL-C was 95 mg/dL versus 62 mg/dL, respective-
events, coronary mortality, nonfatal MI, and fatal or
ly. The composite endpoints of all-cause mortality,
nonfatal stroke in both genders affected by intensive
MI, hospitalization for unstable angina, coronary
compared with standard lipid-lowering therapy; the
revascularization and stroke showed benefit for both
hazard ratio was 0.73 for women and 0.79 for men.
women and men; 22% of the population were
Atorvastatin 80 mg was not associated with docu-
women. The Kaplan-Meier curves separated at 30
mented rhabdomyolysis. More women than men
days, with a 26.3% occurrence of endpoint events
(10% vs 6.5%) discontinued therapy as a result of
with pravastatin compared with 22.4% with atorvas-
adverse effects; liver function test abnormalities oc-
tatin.
curred in 2.5% of women compared with 1% of
In the CRUSADE National Quality Improvement
men. Thus, TNT
[31]
documented comparable benefit
Initiative, 41% of the 35 875 patients were women.
for women and men with high dose compared with
Although women had higher risk characteristics at
standard dose atorvastatin.
presentation and had greater inhospital risk, their
initial and discharge therapies were less aggressive
Among the total of 19 335 women represented in
than those for men. Specifically, women were less
these clinical trials of statin therapy, the proportion
likely than men to receive statins at discharge:
of women averaged 1020%, except for two trials:
55.9% versus 63.4%, respectively.
[36]
PROSPER,
[24]
a trial of elderly patients, in which
half of all patients were women, and the lipid lower- Gender-specific data are not available for most
ing arm of ALLHAT, which enrolled 49% women. clofibrate trials. There was no benefit for women
In a systematic review of 11 clinical trials that compared with men in a trial of colestipol versus
involved almost 16 000 women,
[32]
the authors con- placebo, and gender-specific data were not reported
sidered the evidence insufficient for the benefit of for a comparison of niacin and clofibrate versus
lipid-lowering therapy with statin drugs in women placebo in the Stockholm Ischemic Heart Disease
without established CHD; nonetheless, the small study.
[37]
Ezetimibe, added to a statin, comparably
number of outcome events limited the power to lowered LDL-C levels in women and men,
[38]
but
detect a difference. Statin drugs produced a 26% clinical outcome data are lacking.
decrease in coronary mortality, 36% decrease in
Randomized trial data are similarly lacking for
nonfatal MI and 21% decrease in major coronary
women in regard to lipid-altering dietary supple-
events, with insufficient data to determine the effect
ments (e.g. soluble fibre, soy protein, or sterol or
on revascularization in women with established
stanol esters).
CHD; no decrease was evident for total mortality.
A recent systematic review of lipid-lowering
Specific data for the effects of statins in acute therapy in women that included data from large
coronary syndromes in the MIRACL trial showed a multinational statin studies
[39]
concluded that statin
16% decrease in death, nonfatal infarction, resusci- therapy was beneficial in women with established
tated cardiac arrest and recurrent ischaemia requir- CVD in reducing coronary mortality, nonfatal MI
ing hospitalization, but gender-specific data were and revascularization, but without effect on total
not reported for the 1074 of the 3086 patients who mortality. Evidence remains inconclusive about the
were women. The endpoint was powered by the effect of lipid lowering on total CHD mortality in
reduction in recurrent ischaemia requiring hospitali- women without CVD, although some studies sug-
gest a reduction in coronary events. Highly relevant 5. Aspirin
is the impressive safety profile of statin therapy for
Abundant data document that daily aspirin
both women and men.
should be used in the preventive management of
The effect of statin therapy at discharge was
both women and men with established CHD, other
assessed in an observational study of 23 013 Medi-
vascular disease, and coronary risk equivalents such
care patients in the US with a principal discharge
as diabetes and chronic kidney disease. However,
diagnosis of MI.
[40]
Statin therapy lowered mortality
the use of aspirin for primary prevention in women
in patients with acute MI aged <80 years but not in
remained controversial until the publication of data
those aged >80 years, raising the question of gener- from the Womens Health Study.
[44]
alizability of statin benefit to the very old popula-
tion. The effect of preoperative statin therapy on
outcome was evaluated in a retrospective cohort
In the Womens Health Study,
[44]
39 876 healthy
study of patients undergoing coronary artery bypass
women aged 45 years were randomized to aspirin
graft surgery using cardiopulmonary bypass.
[41]
Pre-
100 mg on alternate days compared with placebo
operative statin use was independently associated
and monitored for 10 years for a first major cardio-
with a significant reduction of 7.1% versus 4.6% in
vascular event (nonfatal MI, nonfatal stroke or death
the composite endpoint of 30-day all-cause mor-
from cardiovascular causes). As background, ran-
tality and stroke, respectively.
domized trials had shown that alternate-day low-
dose aspirin decreased the risk of initial MI in men,
A meta-analysis of the efficacy and safety of
with little effect on ischaemic stroke. The 44%
cholesterol-lowering treatment by the Cholesterol
reduction in the risk of initial MI among the 22 071
Treatment Trialists Collaborators included over
apparently healthy men caused the Physicians
90 000 participants in 14 randomized trials,
[42]
Health Study
[45]
to be terminated prematurely be-
where, overall, women comprised 24% of the par-
cause of this extreme benefit. In the Womens
ticipants. Major coronary events were reduced in
Health Study, aspirin lowered the risk of ischaemic
both women and men (i.e. 0.1% vs 7.3% for treated
stroke by 24%, with no significant effect on the risk
vs control women compared with 7.8% vs 10.6% for
of fatal or nonfatal MI. Gastrointestinal bleeding
treated versus control men). The authors concluded
requiring transfusion was more frequent in the aspi-
that statin therapy safely reduces the 5-year inci-
rin than the placebo group. Thus, the routine use of
dence of major coronary events, coronary revascu-
aspirin in healthy women aged <65 years is not
larization and stroke by about one-fifth per mmol/L
recommended to prevent MI (a class III recommen-
reduction in LDL-C, essentially irrespective of the
dation), but it may be considered when the benefit
initial lipid profile or other presenting characteris-
for ischaemic stroke prevention is likely to outweigh
tics. Their recommendations provide reinforcement
the adverse effects of aspirin therapy (class IIb rec-
for considering prolonged statin treatment with sub-
ommendation). In the subgroup of women aged
stantial LDL-C reduction in all patients at high risk
65 years, this aspirin dosage significantly reduced
of any major vascular event.
the risk of major cardiovascular events, ischaemic
Another overview of the use of statins
[43]
as-
stroke and MI, but this benefit was counter-balanced
sessed data from 63 410 participants in 15 trials. It
by an almost comparable occurrence of gastrointes-
similarly concluded that statin treatment reduces the
tinal bleeding, mandating individualization of ther-
relative risk of coronary events, CVD mortality, apy for women aged 65 years (class IIa).
nonfatal stroke and all-cause mortality in the secon-
The conclusion of a recent meta-analysis of six
dary prevention setting, with only small and not trials that included 95 456 individuals
[46]
was that
clinically relevant improvement of cardiovascular aspirin reduced the risk of composite cardiovascular
morbidity and mortality for primary prevention. events for both women and men as a result of its
350 Wenger
reduction of the risk of ischaemic stroke in women 6.2 Secondary Prevention
and MI in men; nonetheless, aspirin significantly
The PEACE trial tested whether patients with
increased the risk of bleeding comparably among
stable CHD and normal or slightly reduced left
women and men.
ventricular function would derive therapeutic bene-
fit from the addition of an ACE inhibitor to modern
conventional therapy.
[49]
Trandolapril was randomly
administered to 4158 patients and placebo to
As noted in sections 1 and 5.1, aspirin at a dose of
4132 patients (18% women); in this population with
75325 mg/day should be used in high-risk women
a lower occurrence of cardiovascular events than in
unless contraindicated, with clopidogrel substituted
previous trials of ACE inhibition in patients with
if a high-risk woman is intolerant to aspirin ther-
vascular disease, no added benefit was conferred by
apy.
[2]
ACE inhibition for cardiovascular death, MI or cor-
In the CHARISMA trial, 15 603 patients (30%
onary revascularization. Gender-specific outcomes
women) with clinical manifestations of CVD or
were not provided.
multiple risk factors were randomized to clopidogrel
TRACE, another study of trandolapril, examined
75 mg/day plus low-dose aspirin 75162 mg/day or
the effects of this ACE inhibitor on mortality and
placebo plus low-dose aspirin, and followed for a
hospitalization in patients with left ventricular sys-
median of 28 months. Overall, clopidogrel plus aspi-
tolic dysfunction following MI: 1749 patients (28%
rin was not significantly more effective than aspirin
women) were randomized to trandolapril versus pla-
alone in reducing the rate of MI, stroke or death
cebo.
[50]
Trandolapril was associated with long-term
from cardiovascular cause.
[47]
There was a sugges-
benefits for all-cause mortality, all-cause hospital-
tion of benefit from clopidogrel in patients with
izations and cardiovascular hospitalizations, includ-
symptomatic atherothrombosis and a suggestion of
ing those for heart failure. The beneficial effect on
harm in patients with multiple risk factors. No bene-
mortality and hospitalization rates was maintained
fit was evident for women.
for at least 1012 years. Gender-specific data were
not provided.
The PERSUADE substudy of the EUROPA trial 6. ACE Inhibitors/Angiotensin II
examined the effect of perindopril on cardiovascular Receptor Blockers
morbidity and mortality in 1502 diabetic patients
(18% women) with CHD but without heart failure.
There was a reduction in major cardiovascular
events in these diabetic patients, similar in magni-
tude to the benefit observed in the general popula- A meta-analysis of 28 clinical outcome trials
tion with CHD.
[51]
Gender-specific data are not involving a total of 179 122 patients examined the
available. In the overall EUROPA trial,
[52]
a low- effect of ACE inhibitors and calcium channel ant-
risk population with stable CHD without apparent agonists versus diuretics, -blockers or placebo in
heart failure, perindopril significantly improved the hypertensive or high-risk patients on the protection
outcome of cardiovascular death, MI or cardiac ar- from CHD and stroke. The authors concluded that
rest, with 50 patients having to be treated for 4 years blood pressure-lowering was fundamental for the
to prevent one major cardiovascular event. Fifteen prevention of both CHD and stroke; beyond blood
percent of EUROPA participants were female, and pressure reduction, ACE inhibitors appeared superi-
benefit was comparable for women and men. or to calcium channel antagonists for CHD preven-
tion, whereas calcium channel antagonists appeared In a retrospective analysis of 1342 Medicare re-
superior to ACE inhibitors for the prevention of cipients with acute MI and chronic kidney disease,
stroke.
[48]
Gender-specific data were not reported. with a derived glomerular filtration rate of
1589 mL/min/1.73m
2
, survival was improved with tion as to the overall numbers of women studied or
gender-specific outcomes. a -blocker plus ACE inhibitor, although these pa-
The timing of use of ACE inhibitors was ad- tients were less likely to be prescribed combination
dressed in 22 trials. Both early and late administra-
cardioprotective therapy after acute MI.
[53]
Although
tion of ACE inhibitors decreased mortality follow-
half of the patients were women, gender-specific
ing MI, but the major benefit occurred for long-term
data were not provided.
mortality.
[57]
Again, the numbers of women in these
A systematic review and meta-analysis of ran-
trials and the comparative outcomes for women and
domized controlled trials addressing ACE inhibitor
men were not presented.
use in CHD patients with preserved left ventricular
The CHARM trial assessed the effect of can-
systolic function included six trials that involved
desartan in patients with New York Heart Associa-
16 772 patients randomized to ACE inhibitor ther-
tion class IIIV heart failure symptoms; 53% of
apy compared with 16 728 patients randomized to
enrolled patients previously had an MI and 24%
placebo. The proportion of women varied from 15%
currently had angina; 32% were female. Risk reduc-
in the EUROPA trial to 28% in CAMELOT, but
tions in cardiovascular death or nonfatal MI were
gender-specific information was not provided. A
similar across predetermined subgroups and the
modest favourable effect included a decrease in
component CHARM trials. The authors concluded
cardiovascular mortality, in nonfatal MI, in all-
that, for patients with heart failure, candesartan sig-
cause mortality and in revascularization rates.
[54]
nificantly reduced the composite outcome of cardio-
Similarly, an overview of seven trials that included a
vascular death or nonfatal MI.
[58]
Benefit was com-
total of 33 960 patients followed for a mean of
parable for women and men.
4.4 years evaluated whether the long-term prescrip-
tion of ACE inhibitors decreased major cardio-
7. -Blockers
vascular events and mortality in coronary patients
with intact left ventricular systolic function. The
proportion of women participants in the trials
analysed varied from 11% in SCAT to 28% in
The clinical efficacy of -blocker therapy was
CAMELOT, but once again the overview did not
studied in 2894 patients in a cohort study that pooled
provide gender-specific outcomes. There was a re-
data from five randomized, controlled trials of
duction in total mortality (odds ratio [OR] 0.86)
abciximab during coronary interventions in patients
and in major cardiovascular endpoints (OR
with acute coronary syndromes.
[59]
At both 30 days
0.770.82).
[55]
and 6 months, -blocker therapy was associated
A third meta-analysis examined the effect of
with a significant reduction in mortality, similar to
ARBs in 24 trials involving 38 080 patients with
the beneficial effects of -blocker therapy seen in
chronic heart failure and high-risk acute MI. ARBs
patients with unstable angina and acute MI.
were associated with a reduction in all-cause mor-
The effect of -blockers in postinfarction patients
tality and heart failure hospitalizations compared
with heart failure receiving contemporary manage-
with placebo; in two comparative trials, there was
ment was a prespecified subgroup analysis of the
no difference between ARBs and ACE inhibitors.
MERIT-HF.
[60]
In this study, metoprolol reduced
Comparing ARBs plus ACE inhibitors versus ACE
total mortality by 40% and sudden death by 50%,
inhibitors alone, all-cause mortality was not reduced
extending the profound reduction in morbidity and
but there was a decrease in heart failure hospitaliza-
mortality from -blockade even in the presence of
tions with the combination. The authors concluded contemporary management, which included early
that ARBs should be regarded as suitable alterna- and late revascularization, ACE inhibitor use, aspi-
tives to ACE inhibitors,
[56]
but provided no informa- rin and statins.
352 Wenger
A meta-analysis of -blockade that included data reduced morbidity and mortality in these patients,
from MERIT-HF, CIBIS II and COPERNICUS con- with a reduction in the primary endpoint of death
firmed that carefully titrated metoprolol controlled/ from cardiovascular causes or hospitalization for
extended release could be instituted safely for the cardiovascular events, and the secondary endpoints
majority of patients with clinically stable systolic of death from any cause or any hospitalization.
heart failure. Comparable benefit was seen with There was also a reduction in sudden cardiac death.
bisoprolol in CIBIS II and carvedilol in COPERNI- Serious hyperkalaemia occurred in 5.5% of the
CUS.
[61]
A meta-analysis of mortality results from eplerenone-treated patients compared with 3.9% of
CIBIS-II, MERIT-HF and COPERNICUS showed placebo patients. Survival was improved for both
very similar survival benefits in women and men; genders, but more so for women, with an interaction
although not all patients in CIBIS-II had an is- term of 0.44, whereas the composite of death from
chaemic aetiology for their heart failure, this was the cardiovascular causes or hospitalization for cardio-
case for most patients, and mortality and admissions vascular events was better for men than women,
to hospital did not differ significantly between with an interaction term of 0.08.
groups for any subgroup of aetiology of heart fail- Again from the EPHESUS study,
[65]
eplerenone
ure. Finally, in 4304 patients without heart failure reduced mortality at 30 days after randomization in
but with angiographically confirmed coronary artery patients following acute MI with left ventricular
disease without acute MI at hospital presentation, systolic dysfunction and clinical heart failure. There
discharge -blocker prescription was associated was a significant decrease in all-cause mortality
with an increased event-free survival, showing that 30 days after randomization when eplerenone was
the -blockade benefit evident with heart failure or added to conventional therapy in these patients with
acute MI extended to patients with confirmed CHD a left ventricular ejection fraction <40% and signs of
without these conditions, providing approximately heart failure; eplerenone was initiated on average
the same mortality benefit.
[62]
7.3 days after MI. Based on the early survival bene-
fit, eplerenone was recommended to be adminis-
8. Aldosterone Antagonists
tered during the hospitalization for acute MI.
9. Antioxidants
Reports have been inconsistent on the relation-
The RALES trial
[63]
involved 1663 patients with
ship between the use of antioxidant vitamin supple-
severe heart failure and a left ventricular ejection
ments and CHD risk.
fraction <35% treated with an ACE inhibitor, loop
diuretic and usually digoxin, randomized to spirono-
lactone 25 mg/day versus placebo; 27% of partici-
pants were women. The addition of spironolactone Based on a detailed food frequency questionnaire
to standard therapy reduced both morbidity and to assess the consumption of vitamin C and other
mortality in these patients with severe heart failure. nutrients in the Nurses Health Study,
[66]
the rela-
Benefit was comparable for women and men. There tionship between total intake of vitamin C and CHD
was minimal serious hyperkalaemia. was assessed in 85 118 female nurses followed for
The effect of the selective aldosterone antagonist up to 16 years. There was a moderate significant
eplerenone was evaluated in 6632 patients with inverse association between total vitamin C intake
acute MI complicated by left ventricular dysfunc- and CHD risk (a relative risk of 0.73). Among the
tion and heart failure (29% female) randomized to women who did not use supplemental vitamin C or
eplerenone versus placebo in EPHESUS.
[64]
The multivitamins, there was a nonsignificant associa-
addition of eplerenone 25 mg/day, titrated to a maxi- tion between dietary vitamin C and CHD incidence.
mum of 50 mg/day, to optimal medical therapy The authors concluded that users of vitamin C sup-
plements appeared to be at lower coronary risk. In that vitamin E supplementation either beneficially
the British Heart Protection Study,
[67]
without sepa- or adversely affected cardiovascular outcomes.
rate analysis reported for women and men, there was
10. Folic Acid, and Vitamins B
6
and B
12 no evidence of benefit for major coronary events
related to the use of vitamin E 600 mg, vitamin C
250 mg or carotene 12 mg daily.
Similarly, in the WAVE study (a mixed primary
There was benefit from whole-grain intake in a
and secondary prevention cohort, examining the ef-
cohort study: the Nurses Health Study,
[75]
based on
fect of hormone replacement and antioxidant vita-
a food-frequency questionnaire at baseline (1984)
min supplements on coronary atherosclerosis in
and again in 1986 and 1990 among 75 521 nurses
menopausal women),
[68]
vitamin E 400 IU and vita-
aged 3863 years. In the same population, examina-
min C 500 mg daily failed to provide cardiac protec-
tion of the intake of folate and vitamin B
6
, again
tion. In the overall HOPE study,
[69]
as was the case
based on a detailed food-frequency questionnaire,
[76]
with the diabetic subset in MICROHOPE, vitamin E
suggested that intake of folate and vitamin B
6
above
400 IU/day failed to affect rates of MI, stroke or
the current recommended dietary allowance may be
cardiovascular death.
[69]
The St Francis Heart Study
important in the primary prevention of CHD in
examined the effect of vitamins C and E in asymp-
women. No specific benefit was evident for vitamin
tomatic adults with elevated coronary calcium
E supplements in these studies.
scores.
[70]
These antioxidant vitamins, as well as low
doses of atorvastatin, did not affect the progression
of coronary calcification.
In the 10-year randomized Womens Health
The efficacy of homocysteine lowering with B
Study,
[71]
there was lack of benefit from 600 IU/day
vitamins was evaluated in the secondary prevention
natural-source vitamin E for major cardiovascular
setting in patients within a week of acute MI
events or total mortality. Nonetheless, differing
in a randomized controlled trial in Norway
from the totality of evidence for all age groups in
(NORVIT).
[77]
Treatment with B vitamins did not
this study, among women aged 65 years, vitamin E
lower the risk of recurrent CVD, but a harmful effect
was associated with a 26% reduction in cardio-
was evident with combined B vitamin treatment (i.e.
vascular mortality and in major cardiovascular
folate, vitamin B
12
and vitamin B
6
).
events.
In the HOPE study,
[78]
which involved over
5000 patients aged 55 years with vascular disease
Several meta-analyses warrant mention. Al-
or diabetes, folic acid 2.5 mg, vitamin B
6
50 mg and
though some epidemiological studies had suggested
vitamin B
12
1 mg daily compared with placebo did
cardiovascular benefit for vitamin E, the meta-ana-
not reduce the risk of major cardiovascular events.
lysis of Eidelman et al.
[72]
reviewing several large-
A combination of folic acid, vitamin B
6
and scale randomized trials failed to show statistically
vitamin B
12
, designed to lower homocysteine levels, significant or clinically important effects of vitamin
was assessed in a randomized controlled trial in E on CVD. A pooled analysis of nine cohorts report-
patients following successful coronary stenting.
[79]
ed by Knekt and colleagues,
[73]
including 293 172
There was a suggestion that, despite the decrease in individuals free of CHD at baseline, suggested a
homocysteine levels, vitamin administration may reduced incidence of major coronary events with
increase the risk of in-stent restenosis and the need high supplemental vitamin C intakes, but a small
for target vessel revascularization. reduction with high vitamin E or carotenoid intakes.
Finally, a review of placebo-controlled randomized In another study of the effect of homocysteine-
trials conducted by Shekelle and associates,
[74]
ad- lowering therapy on percutaneous coronary inter-
dressing 84 eligible trials, failed to find evidence vention,
[80]
553 patients were randomly assigned to
354 Wenger
vitamin therapy compared with placebo after suc- initiated hormone therapy close to menopause
cessful percutaneous coronary intervention. In con- tended to have a reduced coronary risk compared
trast to the prior study, homocysteine-lowering ther- with the increased risk among women more distant
apy with folic acid, vitamin B
12
and vitamin B
6 from menopause, but the trend test was not statisti-
significantly decreased the incidence of major ad-
cally significant. A similar nonsignificant trend was
verse events.
noted for total mortality. Stroke risk was increased
regardless of the years since menopause when hor-
11. Menopausal Hormone Therapy
mone therapy was initiated.
(MHT)/Selective Estrogen Receptor
Further analysis of the estrogen only arm of the
Modulators (SERMs)
WHI,
[84]
specifically examining the coronary end-
Numerous observational studies had suggested
point among these more than 10 000 women, con-
that menopausal hormone therapy (MHT) might
cluded that conjugated equine estrogen did not pro-
provide cardiac protection. Indeed, in the National
tect against MI or coronary death, but suggested a
Cholesterol Education Program Adult Treatment
lower CHD risk among the women aged
Panel II, hormone therapy was the suggested initial
5059 years at baseline.
intervention for the management of dyslipidaemia in
Subanalysis of the estrogen/progesterone arm of
menopausal women.
the WHI
[85]
confirmed the lack of cardiac protection,
but suggested that there might be an increase in risk,
11.1 Primary Prevention: MHT
particularly during the first year of hormone use, in
The role of MHT in healthy women remained
these >16 000 healthy menopausal women.
contentious until the publication of the estrogen plus
Supplementary data are available from cohort
progesterone arm of the WHI trial, using the same
studies. In the Nurses Health Study there was sug-
hormone regimen, and conducted in over 16 000
gestion that the timing of hormone therapy initiation
initially healthy menopausal women.
[81]
The trial
related to onset of menopause or to age might influ-
was terminated prematurely because of an increased
ence coronary risk. Specifically, women beginning
risk of heart attack, breast cancer, venous thrombo-
hormone therapy near menopause had a significant-
embolism, stroke, dementia and ovarian cancer,
ly reduced risk of CHD, a relative risk of 0.66,
counter-balanced by a decrease in hip fracture, colo-
whereas among those who initiated hormone ther-
rectal cancer and endometrial cancer. Quality of life
apy at least 10 years following menopause, there
was not affected. The unopposed estrogen arm of the
was no relationship between such therapy and CHD,
WHI trial, conducted in over 10 000 apparently
with a relative risk of 0.87 for estrogen alone and of
healthy menopausal women with hysterectomy, was
0.90 for estrogen plus progesterone.
[86]
In a prospec-
again terminated prematurely, due to the excess of
tive questionnaire cohort of almost 20 000 Danish
risk compared with benefit. There was an increased
female nurses, about half of whom were menopaus-
risk of stroke and probable dementia or memory
al, there was an increased risk of ischaemic heart
loss, a decrease in hip fracture, and no effect on
disease associated with early ovariectomy, with the
breast cancer or heart disease.
[82]
suggestion that this risk might be reduced with hor-
A secondary analysis from the WHI combined
mone therapy.
[87]
The Kuopio Osteoporosis Risk
the data from these two trials (and some would
Factor and Prevention study, which collected data
question whether it is appropriate to combine these
from 11 667 women aged 5262 years, concluded
two studies, given the different characteristics of
that hormone therapy did not affect overall mortality
women in both arms of the study) and sought to
or coronary mortality in women, but that >5 years of explore whether the time of initiation of hormone
such therapy might increase the risk of breast cancer therapy would influence its effect on cardiovascular
mortality.
[88]
disease.
[83]
The authors concluded that women who
A systematic review and meta-analysis of hor- 12. Conclusion
mone therapy in CVD,
[89]
addressing high-quality
Data specific to women in a number of random-
randomized placebo-controlled trials (seven in to-
ized clinical trials, data for women from single-
tal), showed that hormone therapy did not change
gender clinical trials, coupled with cohort studies
the risk of all-cause mortality, coronary death and
with gender-specific analyses and meta-analyses of
nonfatal MI, but increased the risk of stroke.
these studies, have provided an initial database to
A breast cancer study of adjuvant tamoxifen ther-
guide the use of pharmacotherapy for coronary pre-
apy also examined 5-year CHD mortality.
[90]
There
vention and treatment in women. Clearly, these data
was a favourable effect on breast cancer outcome,
are valuable in guiding clinical practice, but, equally
but the incidence of endometrial cancer was in-
clearly, substantial gaps in knowledge await clarifi-
creased. Coronary mortality was significantly re-
cation.
duced in the 5-year analysis group compared with
the 2-year analysis group, without statistically sig-
Acknowledgements
nificant increases in mortality from other heart dis-
With appreciation to Julia Wright and Jeanette Zahler for
ease, cerebrovascular disease or other vascular dis-
expert assistance in manuscript preparation. The author has
ease.
received research grants and contracts, and has acted on trial
steering committees for Pfizer, Merck and the National Heart,
Lung, and Blood Institute. The author participated in advisory
11.2 Secondary Prevention: MHT
boards and/or acted as a consultant to CV Therapeutics,
Sanofi-Aventis, Schering-Plough, AstraZeneca, Abbott, Mer-
ck and Pfizer.
The 2004 AHA Evidence-Based Guidelines for
Cardiovascular Disease Prevention in Women
[1]
References identified that MHT should not be used for cardiac
1. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guide-
protection. Specifically cited was HERS, in which
lines for cardiovascular disease prevention in women. Expert
2763 menopausal women with established CHD Panel/Writing Group. Circulation 2004; 109 (5): 672-92
2. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guide-
were randomized to conjugated equine estrogen
lines for cardiovascular disease prevention in women: 2007
6.25 mg and medroxyprogesterone 2.5 mg/day com-
update. Circulation 2007; 115: 1481-501
3. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesi-
pared with placebo.
[91]
There was no overall cardio-
ty, diabetes, and obesity-related health risk factors, 2001.
vascular benefit but a trend to early harm was noted.
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Drugs 2008; 68 (3): 359-372
ADIS DRUG PROFILE 0012-6667/08/0003-0359/$53.45/0
Human Papillomavirus Types 16 and
18 Vaccine (Recombinant, AS04
Adjuvanted, Adsorbed) [Cervarix]
Susan J. Keam
1
and Diane M. Harper
2
1 Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Conshohocken, Pennsylvania, USA
2 Womens and Gender Studies Program, Dartmouth College, Hanover, New Hampshire, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
1. Adjuvant System Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
2. Immunogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
3. Prophylactic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
6. HPV 16/18 Vaccine (Cervarix): Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
Abstract
Features and properties of human papillomavirus (HPV)
Cervarix is a prophylactic vaccine comprised of a
types 16 and 18 vaccine (recombinant, AS04 adjuvanted,
mixture of virus-like particles derived from the L1 adsorbed) [Cervarix]
capsid proteins of human papillomavirus (HPV)
types 16 and 18 formulated with the AS04 adjuvant
Indication
system. It is administered by intramuscular injec-
tion as a three-dose vaccine regimen at 0, 1 and
Prevention of high-grade cervical intraepithelial neoplasia (CIN
6 months. The vaccine is indicated for the preven-
grades 2 and 3) and cervical cancer causally related to HPV
types 16 and 18 tion of high-grade cervical intraepithelial neoplasia
(CIN 2 and CIN 3) and cervical cancer causally
related to HPV types 16 and 18. Vaccine composition
In randomized, double-blind, phase II or III trials in
>19 000 women aged 1525 years, the HPV 16/18
Virus-like particles (VLPs) derived from the L1 capsid proteins
of HPV types 16 and 18
vaccine showed high efficacy in preventing CIN 2+
associated with HPV 16/18. Cross-protection
Formulated with a proprietary adjuvant system (AS04), against new incident or 6-month persistent HPV 45
comprised of aluminium hydroxide (0.5 mg per dose) and
or HPV 31 infection was also evident. Phase II
3-O-desacyl-4-monophosphoryl lipid A (50 g per dose)
follow-up was for at least 5.5 years, and the phase
III interim analysis was at 15 months after the first
Dosage and administration
vaccine dose.
In a bridging study, in adolescent girls aged
Route of administration Intramuscular injection
1014 years, the HPV 16/18 vaccine induced twice
the already high antibody titres as it did in young
Dose 0.5 mL (containing 20 g each
women (aged 1525 years). The immune response
of VLPs for HPV types 16 and
in older women (aged 2655 years) at 24 months in
18)
another study was 8-fold higher than antibody
levels reported in younger age groups. Anti-HPV
Administration schedule Three-dose regimen; injections
16/18 antibody responses were greater with an
at months 0, 1 and 6
AS04-adjuvanted HPV 16/18 vaccine than with an
aluminium salt-adjuvanted formulation.
Adverse events
The HPV 16/18 vaccine was generally well tolerat-
ed and injection-site reactions were the most com-
Most common vaccine-related Injection site reactions (pain,
mon vaccine-related adverse events reported.
events redness, swelling)
360 Keam & Harper
Worldwide, cervical cancer is the second most developing world.
[2,5,20]
Because oncogenic HPV in-
common cancer in women after breast cancer.
[1,2]
fection is necessary for the development of cervical
Current statistical analyses estimate that in 2002, cancer,
[20]
a prophylactic vaccine against the most
493 000 new cases of invasive cervical cancer were common oncogenic HPV types is likely to be of
diagnosed and that 274 000 deaths were due to this value as a primary prevention strategy.
[19,21]
malignancy.
[1,3]
The majority (83%) of cervical can-
At least 15 HPV types have been causally linked
cer diagnoses occur in developing countries, and in a
to cervical cancer.
[10,11,22-25]
International epidemio-
number of these, it is the most common cause of
logical studies have shown that HPV 16 and HPV 18
cancer death in women.
[3]
Since the introduction of
are the most common types,
[24]
being present as
cervical screening programmes in the 1960s, includ-
either single or multiple infections in at least 70% of
ing the use of Papanicolaou (Pap) smear tests that
invasive cervical cancers.
[11]
HPV 16 and/or HPV 18
detect precancerous and noninvasive lesions, the
are found in 45% of high-grade squamous in-
incidence of invasive cervical cancer has decreased
traepithelial lesions (cervical intraepithelial neopla-
significantly in developed countries.
[2-5]
sia [CIN] 2 or 3)
[22]
and HPV 16 is present in 25%
This decrease has also been associated with a of low-grade squamous intraepithelial lesions (CIN
shift in the histological type from predominantly 1).
[10]
HPV 16 is the most prevalent cause of cervical
squamous cell carcinomas to an increase in glandu- cancer, occurring in 55% of squamous carcinomas
lar cancers (adenocarcinoma and adenosquamous and 31% of adenocarcinomas. HPV 18, on the other
carcinoma).
[6,7]
Compared with squamous cell ab- hand, causes 12% of squamous cell carcinomas,
normalities, glandular cell abnormalities are less with an additional 38% of adenocarcinomas.
[26]
Six
easy to detect using current screening methods,
[6,7]
other HPV types (types 45, 31, 33, 52, 58 and 35)
and are more likely to progress to high-grade pre- account for an additional 19% of invasive cervical
cancerous lesions or invasive cervical cancer within cancers; of these, the most important are types 45
12 months of detection (<5% vs 85%).
[7,8]
In addi- and 31, which are found in 10% of cases.
[5,11]
To
tion, the risk of death from adenocarcinoma of the date, the development of prophylactic HPV vaccines
cervix is twice that of squamous cell carcinoma.
[6]
has focused on HPV types 16 and 18.
[27]
An essential precursor to the development of Mathematical models of HPV infection and cer-
cervical cancer, regardless of histological type, is vical cancer predict that a prophylactic HPV vaccine
persistent infection with oncogenic human papil- preventing persistent HPV 16/18 infection would
lomavirus (HPV) types.
[5,9-12]
HPV is a common significantly reduce the number of women develop-
sexually transmitted infection,
[5,13,14]
although prev- ing HPV 16/18-associated CIN 2+ (defined histo-
alence of infection and HPV type varies from region logically as CIN 2, CIN 3, adenocarcinoma in situ
to region.
[12,13]
Population-based studies suggest that and invasive carcinoma) and cervical cancer,
[28]
es-
>50% of sexually active women are exposed to at pecially if vaccination strategies targeted girls
least one genital HPV type in their lifetime.
[13]
All around 12 years of age (prior to commencing sexual
ages of women acquire new infections every activity for the majority).
[29,30]
Even greater reduc-
year;
[14-17]
such infections in older women are more tions were predicted if cross-protection against other
likely to persist and develop into cancerous le- oncogenic HPV types was achieved.
[31]
Pharmaco-
sions.
[18]
economic analyses from European,
[32,33]
North
American
[34,35]
and South American
[36]
perspectives
The economic and societal burden associated
suggest that adding a prophylactic HPV 16/18 vac-
with cervical cancer is high, whether it be the direct
cine targeting girls aged 1012 years to a cervical
costs of cervical cancer screening, and treatment of
cancer screening programme could be cost effective.
preinvasive and invasive lesions in the developed
world,
[19]
or the cost to society of a young average The purpose of prophylactic HPV vaccination is
age at death in patients with cervical cancer in the to induce a strong, local, cell-mediated immune
Human Papillomavirus Types 16 and 18 Vaccine: Adis Drug Profile 361
response that provides long-term protection against purpose.
[42,43]
More recently, adjuvant systems, in-
future infection.
[37]
To be effective, anti-HPV anti- cluding those that mimic a Toll-like receptor 4 ago-
bodies induced by an HPV vaccine need to be local- nist, have been developed with the intention of
ized in the genital tract.
[38]
It has been observed that promoting a stronger and more enduring antibody
HPV infections remain localized to the epithelium response.
[42]
of the genital tract in women.
[39]
A successful
One such adjuvant system is AS04, which is
immune response to genital HPV infections is usu-
comprised of aluminium hydroxide and 3-O-desa-
ally established; this is characterized by local cell-
cyl-4-monophosphoryl lipid A (MPL), a detoxified
mediated immunity and lesion regression.
[39]
Type-
form of lipid A that is derived from the lipo-
specific HPV infection occurs equally in women
polysaccharide of Salmonella minnesota R595.
[42]
with or without prior exposure to that specific type
AS04 is currently used as an adjuvant in a hepatitis
of HPV infection. Therefore, antibody levels from
B vaccine (Fendrix
1
)
[44]
and the HPV 16/18 vac-
natural infection are insufficient to protect against
cine Cervarix.
[45]
The commercial formulation of
new HPV infections of the same type.
[40]
The impor-
Cervarix contains HPV 16 and HPV 18 L1 anti-
tance of cell-mediated immune responses in the
gens, consisting of purified C-terminally truncated
resolution and control of HPV infections
[5,9,25,39]
is
recombinant L1 proteins from the HPV type 16 and
confirmed by the greater incidence and progression
type 18 viral capsid, each assembled as VLPs
[46]
and
of HPV infections in immunosuppressed patients.
[39]
prepared using recombinant DNA technology and a
These observations, and results from animal studies,
Baculovirus expression system in Trichoplusnia ni
suggest that a prophylactic vaccine capable of gen-
cells.
[45]
The VLPs are then adsorbed onto the AS04
erating neutralizing antibodies to capsid protein
adjuvant and formulated as an intramuscular injec-
might also confer immunity.
[37-39,41]
tion.
[45]
Humoral immunity against HPV involves expo-
Another HPV vaccine (an aluminium salts-ad-
sure of the immune system to conformational
juvanted quadrivalent HPV types 6, 11, 16, 18 vac-
epitopes found on viral capsids composed of L1
cine [Gardasil
])
[47,48]
is commercially available;
protein and subsequent development of virus neu-
however, this review focuses on the immunogeni-
tralizing antibodies.
[37]
One of the most promising
city, prophylactic efficacy and tolerability of the
options for developing a prophylactic HPV vaccine
AS04-adjuvanted HPV 16/18 vaccine Cervarix.
are L1 virus-like particles (VLPs) synthesized using
microbial or cellular expression systems.
[41]
These
1. Adjuvant System Activity
DNA-empty, noninfectious viral capsids, which
mimic the outer shell of the virion, are antigenically
The mechanism by which the immunostimulato-
similar to natural virions.
[42]
VLPs are highly immu-
ry activity of the MPL component of AS04 is initiat-
nogenic and induce anti-VLP antibody responses
ed is unclear.
[49]
However, in vitro studies indicate
several logs greater than those seen with natural
that MPL activates innate immunity, inducing the
infection.
[37,41]
release of the inflammatory mediators tumour ne-
The role of immune memory in the protection crosis factor- and various interleukins (IL), includ-
against HPV infections in the long term is unclear; ing IL-6, IL-10 and IL-12 from human monocytes
however, for long-term prophylactic efficacy, a cer- and peripheral blood mononuclear cells, thus en-
vical cancer vaccine needs to induce a strong cellu- hancing cellular and humoral immune re-
lar and humoral response.
[37,38]
The addition of an sponses.
[42,49-51]
The safety and good tolerability of
adjuvant to a vaccine significantly increases the AS04 as an adjuvant system in a hepatitis B vaccine
humoral response to the vaccine antigens and, for has been established in studies in healthy volun-
many years, aluminium salts have been used for this teers
[52,53]
and in patients with an impaired immune
1 The use of trade names is for product identification purposes only and does not imply endorsement.
362 Keam & Harper
system.
[54]
In addition, the AS04 adjuvant system the AS04-containing HPV 16/18 vaccine in young
was superior to an aluminium salt adjuvant in these women aged 1525 years with that in early adoles-
studies in terms of magnitude and duration of anti- cent girls aged 1014 years (n = 773)
[55]
and (in
body response.
[52-54]
a separate study) with that in women aged
2655 years (n = 666).
[56-59]
Immunogenicity was
Two phase II studies were designed to compare
also evaluated in subsets of women from large phase
the immunogenicity of an HPV 16/18 vaccine for-
II (n = 1113)
[60-65]
or phase III (n = 18 644)
[66,67]
mulated with different adjuvants (the AS04 adjuvant
trials designed primarily to assess clinical endpoints
system [n = 84] and an aluminium salt adjuvant
(see section 3 for trial design details). Discussion of
[n = 45]).
[38]
Young women aged 1830 years re-
results from these trials focuses on the most recent
ceived either vaccine formulation by intramuscular
data.
[62,63,67]
Currently, no minimum protective anti-
injection at 0, 1 and 6 months.
[38]
Humoral immunity
body threshold level has been established, and it is
was assessed using assays measuring total anti-L1
unknown whether the magnitude of the antibody
VLP 16 and anti-L1 VLP 18 antibodies (ELISA),
response is correlated with efficacy of the HPV 16/
antibodies specific for V5/J4 neutralizing/conforma-
18 vaccine.
[25]
However, neutralizing antibodies are
tional epitopes of HPV 16 and HPV 18 (inhibition
recognized as being critical for, inhibition of early
ELISA) in the subset of women for whom 2-year
infection before viral entry into cells.
[39]
follow-up samples were available, and anti-HPV 16
and anti-HPV 18 neutralizing antibodies (pseudo-
Trial participants received the HPV 16/18 vac-
neutralization assay) in the subset of women for
cine,
[55,56,60,66]
placebo
[60]
or the control hepatitis A
whom 4-year follow-up samples were available.
[38]
vaccine
[66]
by intramuscular injection at 0, 1 and
Complete seroconversion was evident after the

6 months. Serum antibody titres were measured at
three-dose vaccination series.
[38]
Anti-HPV 16/18
baseline, then at months 1,
[60]
2
[56]
6
[60,66]
and/or
antibody responses (measured by ELISA) to an
7
[55,56,60,66]
and/or at prespecified timepoints there-
HPV 16/18 vaccine formulated with the AS04 adju-
after using an ELISA, and were expressed as geo-
vant system were strong and significantly greater
metric mean titres (GMTs) measured as ELISA
than those to an HPV 16/18 vaccine formulated with
units [EU]/mL. Seropositivity was defined as an
an aluminium salt adjuvant (figure 1).
[38]
antibody titre equal to or greater than the assay
At all timepoints from months 2 to 48, anti-V5

threshold (8 EU/mL for HPV 16; 7 EU/mL for HPV
HPV 16 and anti-J4 HPV 18 antibody levels (mea-
18).
[55,60,66]
sured by the inhibition assay) were 1.7- to 2.5-fold
Where reported, immunogenicity analyses were
higher with the AS04-adjuvanted HPV 16/18 vac-
conducted in the according-to-protocol (ATP) popu-
cine than the aluminium salt-adjuvanted HPV 16/18
lation in women who had 1 result for antibodies
vaccine (all p < 0.05).
[38]
against at least one vaccine antigen
[55,56,66]
or for
Anti-HPV 16 and and anti-HPV 18 neutralizing

whom there were results at months 7 and 18
[60]
in
antibody levels were also higher with the AS04-
addition to baseline results. In the phase II trial,
[60]
adjuvanted HPV 16/18 vaccine than the aluminium
seropositivity rates between HPV 16/18 vaccine and
salt-adjuvanted HPV 16/18 vaccine (figure 1).
[38]
placebo groups were compared using Fishers exact
test (p < 0.001 was significant), and GMTs were
2. Immunogenicity
compared using ANOVA and Kruskal-Wallis
test.
[60]
Some results are only available as ab-
The immunogenicity of a prophylactic AS04-
stracts.
[56-59,62-65,67]
adjuvanted HPV 16/18 vaccine in humans has been
evaluated in four randomized, double-blind, phase II

The AS04-adjuvanted HPV 16/18 vaccine show-
or III trials in healthy adolescent girls aged 1014 ed high, persistent immunogenicity in young women
years and in women aged 1555 years. Two phase (aged 1525 years) in a placebo-controlled phase II
III bridging trials compared the immunogenicity of trial.
[60-63]
Seroconversion rates through 5.5 years of
10 000
a
8 000
6 000
4 000
2 000
0
0 8 16 24
*
*
*
*
*
*
Anti-HPV 16
32 40 48
6 000
5 000
4 000
2 000
1 000
3 000
0
0 8 16 24
*
*
*
*
*
*
*
Anti-HPV 18
32 40 48
60 000
b
50 000
30 000
40 000
20 000
10 000
0
0 8 16 24
*
*
*
*
Anti-HPV 16 nAb
32 40 48
12 000
10 000
8 000
4 000
2 000
6 000
0
0 8 16 24
*
*
*
Anti-HPV 18 nAb
32 40 48
1 000
c
800
600
400
200
0
0 8 16 24
* *
*
*
*
*
*
*
*
Anti-V5 HPV 16
A
n
t
i
b
o
d
y

G
M
T
s

(
E
U
/
m
L
)
32 40 48
1 000
800
600
400
200
0
0
Time (months)
8 16 24
*
* *
*
*
*
*
Anti-J4 HPV 18
32 40 48
AS04
AI(OH)
3
Fig. 1. Efficacy of a human papillomavirus (HPV) 16/18 vaccine formulated with an AS04 adjuvant. In two trials, young women were
vaccinated with HPV 16/18 L1 virus-like particles (VLPs) adjuvanted with the AS04 adjuvant system (n = 2137) or an aluminium salt
adjuvant [Al(OH)3] (n = 919). (a) Shows antibody responses against HPV 16 and HPV 18 L1 VLPs by ELISA; (b) shows neutralizing
antibodies (nAb) tested by pseudo-neutralization assay; (c) shows V5/J4 specific antibodies tested by inhibition ELISA. Data from the two
trials were pooled and geometric mean titres (GMTs) were calculated. Arrows indicate vaccination timepoints. * p < 0.05 (reproduced from
Giannini et al.,
[38]
with permission).
follow-up for both HPV 16 and HPV 18 were ciated with HPV types 16 or 18 over the same period
(see section 3).
[62,63]
98%.
[62,63]
Corresponding GMTs for vaccine-in-
HPV 16 and HPV 18 neutralizing antibodies duced antibodies against HPV 16 or HPV 18 were
were evident in 98% of women after at least
substantially higher (11-fold) than those seen in
5.5 years of follow-up, and a strong correlation was
natural HPV 16 or HPV 18 infections at all time-
seen between HPV 16/18 total antibody and HPV
points through 5.5 years (figure 2).
[63]
16/18 neutralizing antibody levels at the months 12,
This sustained antibody response was associated

3338 and 6364 assessments (r = 0.860.96).
[64]
with 100% efficacy in preventing new HPV 16 or

A model that used results from the first
HPV 18 infections and CIN or cervical cancer asso- 48 months of the phase II trial and the modified
364 Keam & Harper
a HPV 16
G
M
T
s

[
E
U
/
m
L
(
l
o
g
)
]

10 000
1 000
100
10
1
Vaccine
Placebo
11-
fold
higher
Natural
infection
b HPV 18
G
M
T
s

[
E
U
/
m
L

(
l
o
g
)
]
10 000
1 000
100
10
1
11-
fold
higher
Natural
infection
0 7 12 18 2532 3338 3944 4550 5156 5762 6364
Total follow-up time (months)
0 7 12 18 2532 3338 3944 4550 5156 5762 6364
Total follow-up time (months)
Fig. 2. Immunogenicity of the AS04-adjuvanted human papillomavirus (HPV) type 16/18 vaccine. Geometric mean titres (GMTs) of (a) anti-
HPV 16 antibodies and (b) anti-HPV 18 antibodies in women aged 1525 years who received three doses of HPV 16/18 vaccine or placebo
via intramuscular injection at months 0, 1 and 6 in a randomized, double-blind trial. GMTs were measured in ELISA units/mL (EU/mL); upper
and lower 95% confidence intervals are also shown (reproduced from Harper and Dubin,
[63]
with permission).
power-law method (which accounts for antibody vaccine in young women aged 1525 years.
[66]
HPV
kinetics over time and -cell immune memory [de- 16/18 seroconversion rates were >99.5% after both
scribed by Fraser et al.
[68]
]) predicted that GMTs for the second and third vaccine doses in women who
HPV 16 and HPV 18 antibodies were likely to were seronegative at study entry for the correspond-
remain stable at 300 EU/mL for up to 50 years (i.e. ing vaccine type.
[66]
almost lifetime persistence).
[65]
At month 7, peak GMTs were 313-fold (HPV 16)
High seroconversion rates and a strong vaccine- and 211-fold (HPV 18) higher than corresponding
induced antibody response were also evident in the values in women who had cleared natural HPV 16/
interim 14.8-month results of PATRICIA (PApillo- 18 infections (9341.5 and 4769.6 EU/mL vs 29.8
ma TRIal against Cancer In young Adults), a large and 22.6 EU/mL).
[66]
The immunogenicity analysis
phase III trial of the AS04-adjuvanted HPV 16/18 was conducted in an ATP subset consisting of
1095 HPV 16/18 vaccine and 1006 control vaccine defined HPV 16/18 endpoint or an incident infection
recipients, respectively.
[66]
with another oncogenic HPV type (n = 776) then
entered a blinded follow-up study (results through
The immunogenicity of the AS04-adjuvanted
5.5 years available).
[61-63,69]
Data from PATRICIA HPV 16/18 vaccine in adolescent girls aged
are limited to interim analyses at a mean 1014 years (n = 150) was similar to that in young
14.8 months follow-up after the first vaccine women aged 1525 years (n = 403) in an immuno-
dose.
[66,67,70,71]
Some results are reported as ab- genicity bridging study, with GMTs in adolescent
stracts.
[62,63,67,69-72]
girls being 2-fold higher than those seen in young
women (anti-HPV 16 GMT 17 272.5 vs 7438.9 EU/
Both studies enrolled nonpregnant young women
mL; anti-HPV 18 GMT 6863.8 vs 3070.1 EU/mL;
aged 1525 years.
[60,66]
Participants in PATRICIA
GMT ratio <0.5).
[55]
received AS04-adjuvanted HPV 16/18 vaccine or a
In another bridging study, anti-HPV 16 and anti-

control hepatitis A vaccine,
[66]
and those in the phase
HPV 18 GMTs in older women (aged 2655 years
II study received AS04-adjuvanted HPV 16/18 vac-
[n = 437]) at month 7 were substantial.
[56]
Although
cine or placebo;
[60]
in both trials, doses were admin-
decreases in antibody titres were observed after the
istered as an intramuscular injection at months 0, 1
first vaccination,
[56,57]
GMTs at month 24 remained
and 6. Gynaecological examinations were conduct-
at least 8-fold higher than those seen in young
ed at baseline and at regular intervals thereafter, and
women after natural infection.
[57,58]
cervical specimens were taken for cytology (liquid-
In both studies, seroconversion rates of 100% for

based Pap smear) and HPV DNA testing. If cervical
each HPV type were maintained throughout in ado-
cytology was abnormal, colposcopy and/or biopsy
lescent girls aged 1014 years,
[55]
younger women
were conducted according to protocol recommenda-
aged 1525 years
[55-58]
and older women aged
tions.
[60,66]
In both trials, cytological and histological
2655 years.
[56-58]
diagnoses were processed and interpreted at a cen-
Anti-HPV antibodies must be present within the

tral laboratory, and CIN endpoints were confirmed
genital tract, at the site of infection, for immuniza-
using a consensus expert histopathology review
tion to be protective.
[38]
Serum HPV 16/18 IgG
panel.
[60,66]
In one trial, women also provided self-
antibodies induced by systemic vaccination with the
obtained cervicovaginal specimens for HPV DNA
AS04-adjuvanted HPV 16/18 vaccine transudated to
testing.
[60]
cervical epithelium, evidenced by a high degree of
In PATRICIA,
[66]
the primary efficacy endpoint
correlation between anti-HPV 16 and anti-HPV 18
was vaccine efficacy against CIN 2+ associated with
antibodies in serum and cervico-vaginal secretions
HPV 16/18 infection in the group of young women
in both younger (aged 1525 years) and older (aged
who were seronegative and DNA negative for HPV
2655 years) women (r = 0.80.89).
[59]
16 and/or 18 at study entry. The interim analysis was
triggered when 23 cases of CIN 2+ associated with
3. Prophylactic Efficacy
HPV 16/18 DNA in the lesion were reported in the
total vaccinated cohort for efficacy, defined as The efficacy of the AS04-adjuvanted HPV 16/18
women with normal or low-grade cytology who vaccine has been evaluated in a randomized, double-
were seronegative for the individual HPV type at blind, placebo-controlled, phase II trial (n =
baseline, and who received at least one vaccine 1113)
[60]
and corroborated by the interim analysis at
dose. Cases were counted from after administration a mean 14.8 months follow-up in the large (n =
of the first vaccine or control dose.
[66]
Attribution of 18 644) phase III PATRICIA.
[66]
In the phase II trial,
causality to HPV DNA type was based on the re- women with no previous exposure to oncogenic
peated presence of an oncogenic HPV type in both HPV types were initially followed for up to 27
the cellular sample prior to the biopsy and in the months.
[60]
Those who had received all three doses
histology sample of the treated excised lesion. of the vaccine or placebo and had no evidence of a
366 Keam & Harper
Secondary efficacy endpoints included vaccine cohort who were seronegative for HPV 16/18 at
efficacy against CIN 1+ (CIN 1 and CIN 2+) and baseline (prescribed endpoint definition; both
prevention of persistent 6- or 12-month infection p < 0.0001 vs control).
[66]
(defined as DNA of the same HPV type present in

At a mean 14.8 months follow-up after the first
two consecutive cervical cellular samples over any
vaccination, there were two cases of CIN 2+ and one
6-month period or in all available cellular samples
case of CIN 1 in the HPV 16/18 vaccine group
over any 12-month period) with HPV 16/18 or per-
(n = 7788) compared with 21 cases of CIN 2+ and
sistent 6-month infection with other oncogenic HPV
seven cases of CIN 1 in the control group
types.
[66]
(n = 7838).
[66]
The primary endpoint in the phase II trial and

Multiple non-vaccine oncogenic HPV types were
extended follow-up study was incident HPV 16 or
present in 14 of the 23 CIN 2+ cases that had HPV
HPV 18 single or combined (i.e. HPV 16/18) infec-
16/18 DNA in lesion samples.
[66,67]
In three of these
tion between months 6 and 18,
[60]
or longer
cases (both cases in the HPV 16/18 vaccine group
term
[61,62]
in women who were seronegative and
and one control recipient), non-vaccine oncogenic
DNA negative for HPV 16/18 at trial entry. Secon-
HPV types were present in all earlier cellular sam-
dary endpoints included 6- or 12-month persistent
ples.
[66,67]
Investigators suggested that, based on the
HPV 16/18 infection,
[60-62]
incident infection asso-
criteria for establishing causality, the CIN 2+ lesions
ciated with other oncogenic HPV types
[61,62]
and
were most likely causally linked to infection with
incidence of cytologically and/or histologically con-
the other oncogenic HPV types (e.g. type 58).
[66]
firmed CIN 1, 2 or 3 or adenocarcinoma at 618 or
Additional analysis with these three cases ex-

27 months
[60]
or longer term.
[61,62]
Analyses were in
cluded (i.e. attributed causality endpoint definition),
the ATP population (defined as women with normal
the HPV 16/18 vaccine showed 100% (97.9% CI 74,
cellular samples who were seronegative for the indi-
100) efficacy in preventing CIN 2+ associated with
vidual HPV type and oncogenic HPV DNA at base-
HPV 16/18 infection (0 cases in the vaccine group
line, received all vaccine doses with no major proto-
vs 20 in the control group) and 96.1% (97.9% CI 72,
col violations and were negative for HPV 16 and
100) efficacy in preventing CIN 1+ associated with
HPV 18 DNA at month 6).
HPV 16/18 infection (1 vs 26 cases) [both
Statistical significance was achieved in PATRI-
p < 0.0001 vs control].
[66]
CIA if the lower limit of the 97.9% confidence
Women who had evidence of previous infection

interval for the between-group difference in vaccine
by one vaccine type (i.e. HPV 16 or HPV 18 sero-
efficacy against CIN 2+ was >0,
[66]
and in the phase
positive, HPV DNA negative at baseline) were pro-
II trial if the lower limit of the 95% confidence
tected by the HPV 16/18 vaccine from developing
interval for the between-group difference in incident
new CIN associated with the remaining HPV
HPV 16/18 infection was >0.
[60]
type.
[70]
When data were analysed using the attribut-
ed causality endpoint definition, the HPV 16/18
Cervical Intraepithelial Neoplasia
vaccine was 100% effective (97.9% CI 78, 100;
p < 0.0001 vs control) in preventing CIN 2+ asso-
The AS04-adjuvanted HPV 16/18 vaccine was

ciated with HPV 16/18 infection (0 vs 23 cases of
effective in preventing CIN associated with HPV
CIN 2+).
[70]
16/18 infection in women with no previous exposure
to HPV 16 and/or HPV 18.
[66]
In the interim analysis

Interim data from PATRICIA also showed that
of PATRICIA, the HPV 16/18 vaccine demonstra- when analysed by individual HPV type, the HPV 16/
ted 90.4% (97.9% CI 53, 99) efficacy in preventing 18 vaccine was effective in preventing CIN. When
CIN 2+ (primary endpoint) and 89.2% (97.9% CI analysed using the attributed causality endpoint def-
59, 99) efficacy in preventing CIN 1+ associated inition, the HPV 16/18 vaccine showed 94% effi-
with HPV 16/18 infection in the total vaccinated cacy in preventing HPV 16-associated CIN (97.9%
CI 54, 100) and 100% efficacy in preventing HPV 12-month (95% CI 54, 100) persistent HPV 16/18
18-associated CIN (97.9% CI 34, 100) in women infection in >700 women participating in the extend-
who were negative for HPV 16/18 at baseline.
[66]
ed follow-up phase (after the primary efficacy study
of up to 27 months) of the phase II placebo-control-
Results from the phase II trial (up to 4.5 years
led trial (results through 5.5 years).
[62]
follow-up) showed that the HPV 16/18 vaccine was
effective in preventing cytological abnormalities
Other Oncogenic HPV types
associated with HPV 16/18.
[61]
Vaccine efficacy was
Cross-protection against incident

[61,62]
or
95.7% (95% CI 84, 100; p < 0.0001 vs placebo) in
6-month persistent
[66,72]
infection with non-vaccine
preventing HPV 16/18-associated atypical squa-
HPV types was also evident in women who received
mous cells of undetermined significance or worse
the AS04-adjuvanted HPV 16/18 vaccine in clinical
and 92.6% (95% CI 71, 99; p < 0.0001) in prevent-
trials.
ing HPV 16/18-associated low-grade squamous in-
In the phase II trial, the vaccine demonstrated

traepithelial lesions or worse (intent-to-treat [ITT]
94% (95% CI 63, 100) efficacy against HPV 45
analysis in combined initial and extended popula-
incident infection and 55% (95% CI 12, 78) efficacy
tion cohorts).
[61]
against HPV 31 incident infection in an ITT analysis
In addition, the HPV 16/18 vaccine demonstrated

after a mean 42 months follow-up.
[61]
Cross-protec-
100% efficacy in terms of preventing HPV 16/
tion against both incident HPV 45 and HPV 31
18-associated CIN 1+ (95% CI 62, 100) or CIN 2+
infection continued to be evident through
(95% CI 33, 100) after at least 5.5 years of follow-
5.5 years.
[62]
up.
[62]
There were no cases of CIN 1+ in HPV 16/18
The HPV 16/18 vaccine also affords cross-pro-

vaccine recipients compared with 11 cases (4 cases
tection against 6-month persistent infection with
of CIN 1, and 7 cases of CIN 2 or CIN 3) in placebo
other oncogenic HPV types, according to interim
recipients.
[62]
analyses of data from PATRICIA.
[66,72]
For instance,
In placebo recipients who were HPV 16/18 ser-

after 14.8 months follow-up, the HPV 16/18 vac-
onegative and oncogenic HPV DNA negative at
cine showed 83% (97.9% CI 43, 97) efficacy in
baseline in the phase II trial, the mean time from
preventing 6-month persistent HPV infection with
first oncogenic HPV infection to detection of squa-
HPV 45 in the subgroup of women who were
mous intraepithelial lesions or CIN was <4 years.
seronegative and DNA-negative to HPV 45 at study
The odds of detecting such lesions within 5.5 years
entry.
[72]
were 169 times greater in women with 2 HPV 16/
18 positive cytology samples 6 or more months
4. Tolerability
apart than in those with negative HPV 16/18 cytolo-
gy (95% CI 37, 769).
[69]
The safety and tolerability of the AS04-adjuvant-
ed HPV 16/18 vaccine has been assessed in clin-
Human Papillomavirus (HPV) Infection
ical trials in which 16 142 girls and women
aged 1072 years received the HPV 16/18 vaccine,
HPV 16/18
and 13 811 received a control (an aluminium salt-
The AS04-adjuvanted HPV 16/18 vaccine show-

adjuvanted hepatitis vaccine or aluminium salt-con-
ed significant and sustained efficacy in preventing
taining placebo that did not include MPL).
[45]
Ap-
both incident and 6- or 12-month persistent HPV 16/
proximately 80% of subjects were aged
18 infection.
[61,62]
1025 years.
[45]
Data from individual trials are
The vaccine was 98% (95% CI 89, 100) effective in women who were followed for a mean
against incident infection with HPV 16 and/or HPV 14.8 months
[66]
or up to 7
[56,73]
or 12
[55]
months after
18 (primary endpoint) and 100% effective in the first vaccination in phase III trials and through
preventing both 6-month (95% CI 81, 100) and 5.5 years in phase II trials.
[60-62]
Of the total safety
368 Keam & Harper
and tolerability population, a predefined subset of

In the total vaccinated population in PATRICIA
HPV 16/18 vaccine recipients (n = 8130) or controls (9319 HPV 16/18 vaccine and 9325 control vaccine
(n = 5786) were closely monitored (using safety recipients), serious adverse events related to vacci-
diary cards to record solicited symptoms occurring nation were uncommon (0.1% vs 0.1%),
[66]
and in
during the first 7 days and unsolicited symp- the phase II trial, no serious adverse events related to
toms
[55,60,66]
) during the first 30 days after each vaccination occurred in either the HPV 16/18 vac-
injection.
[45]
This subset included >4200 adolescent cine or the placebo group.
[60]
girls or young women aged 1025 years
[55,60,66]
and
After follow-up of at least 4 years in the phase II
1003 women aged 26 years
[73]
who received the
trial, new onset chronic disease was uncommon and
HPV 16/18 vaccine, 1522 placebo recipients (alu-
was no more frequent in the HPV 16/18 vaccine
minium salt-containing)
[60,73]
and 3080 control vac-
group than the placebo group (3% vs 5%).
[61]
Like-
cine (aluminium salt-adjuvanted hepatitis A) recipi-
wise, the 14.8-month interim analysis of PATRICIA
ents.
[66]
showed that few women in the HPV 16/18 vaccine
group or the control vaccine group had evidence of
The AS04-adjuvanted HPV 16/18 vaccine was

new onset chronic disease (1.5% vs 1.7%) or
generally well tolerated in adolescent girls,
[55]
autoimmune disease (0.3% vs 0.3%).
[66]
younger women,
[55,56,60-62,66]
and older women.
[57,73]
The safety and tolerability profile of the HPV 16/

In addition, the safety and tolerability profile of the
18 vaccine in adolescent girls did not differ from
HPV 16/18 vaccine in women with prior or current
that in young women in a bridging study,
[55]
and the
HPV 16/18 infection did not differ from that in
type and incidence of adverse events reported
[55]
women with no evidence of prior infection.
[45]
were consistent with those seen in PATRICIA.
[66]
Combined data from clinical trials showed that

injection-site reactions (pain, redness, swelling),
5. Dosage and Administration
which were reported after 78% of vaccine doses
administered, were the most commonly vaccine-
The HPV 16/18 vaccine (Cervarix) contains
related reported adverse event.
[45]
However, most
20 g each of VLPs for HPV types 16 and 18 per
reactions were transient (lasting 23 days
[55,66]
) and
0.5 mL dose and is formulated with the AS04 adju-
were mild to moderate in severity.
vant system, comprised of aluminium hydroxide
(0.5 mg per dose) and 3-O-desacyl-4-monophos-
Results from individual phase II or III trials were

phoryl lipid A (50 g per dose). It is administered as
consistent with the combined results.
[55,60,62,66]
As
a 0.5 mL intramuscular injection in a three-dose
might be expected, transient injection-site reactions
vaccination schedule at 0, 1 and 6 months.
[45]
Local
were the most common solicited adverse event re-
prescribing information should be consulted for spe-
ported more frequently with the HPV 16/18 vaccine
cific details of indications, warnings, contraindica-
than controls within 7 days of vaccination.
[60,66]
tions and precautions.
However, in the extended follow-up through
5.5 years in the phase II trial, the incidence of
6. HPV 16/18 Vaccine (Cervarix):
adverse events with the HPV 16/18 vaccine did not
Current Status
differ from that with placebo.
[62]
Fatigue, headache and myalgia were the most The HPV 16/18 vaccine (Cervarix) is approved
common solicited general adverse events in the or is undergoing the approval process in many coun-
phase III trials, but were not reported more frequent- tries worldwide for the prevention of high-grade
ly in the HPV 16/18 vaccine group than in the CIN (CIN grades 2 and 3) and cervical cancer caus-
control group.
[55,66]
The incidence of solicited local ally related to HPV types 16 and 18.
[74]
In phase II
and generalized symptoms in the HPV 16/18 vac- and III trials, the vaccine was effective in preventing
cine groups did not differ with each subsequent the development of CIN grades 2 and 3 and cervical
vaccine dose.
[55,66]
cancer associated with HPV 16/18, and preventing
The preparation of this review was not supported by any
incident and 6- or 12-month persistent HPV 16/18
external funding. During the peer review process, the manu-
infection. The vaccine was also highly immunogen-
facturer of the agent under review was also offered an oppor-
ic, inducing high, persistent anti-HPV 16/18 anti-
tunity to comment on this article. Changes resulting from
body titres that remained well above natural infec-
comments received were made on the basis of scientific and
tion titres in both adolescents aged 1014 years, editorial merit.
young women aged 1525 years and older women
aged aged 2655 years. The vaccine was generally
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caltrials.gov [Accessed 2007 Oct 24]
Correspondence: Susan J. Keam, Wolters Kluwer
79. Lehtinen M, Apter D, Dubin G, et al. Enrolment of 22,000
Health | Adis, 41 Centorian Drive, Private Bag 65901,
adolescent women to cancer registry follow-up for long-term
Mairangi Bay, North Shore 0754, Auckland, New Zealand.
human papillomavirus vaccine efficacy: guarding against
guessing. Int J STD AIDS 2006 Aug; 17 (8): 517-21 E-mail: demail@adis.co.nz
Drugs 2008; 68 (3): 373-381
ADIS DRUG PROFILE 0012-6667/08/0003-0373/$53.45/0
Amlodipine/Valsartan
Fixed-Dose Combination in Hypertension
Greg L. Plosker and Dean M. Robinson
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
6. Amlodipine/Valsartan: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Features and properties of amlodipine/valsartan Abstract
(Exforge
)
Amlodipine, a dihydropyridine calcium channel
Indication
blocker, and valsartan, an angiotensin II receptor
Indication in the EU: for patients with hypertension whose blood
blocker, are established antihypertensive agents.
pressure (BP) is not adequately controlled with amlodipine or
Fixed-dose combinations of amlodipine/valsartan
valsartan monotherapy
are available in several European countries and in
Indication in the US: for patients with hypertension whose BP is
the US. Individual dose titration with amlodipine
not adequately controlled with amlodipine (or another
dihydropyridine calcium channel blocker [CCB]) alone or with and valsartan is generally recommended before
valsartan (or another angiotensin II receptor blocker [ARB])
changing to the fixed-dose combination.
alone
Amlodipine/valsartan, at approved dosage regi-
Mechanism of action
mens, achieved significantly greater reductions
Combined effects of a dihydropyridine CCB (amlodipine) and an
in mean sitting diastolic and systolic blood pressure
ARB (valsartan)
(BP) than amlodipine or valsartan monotherapy, or
Dosage and administration
placebo in two randomized, double-blind, factorial
Recommended dosage One tablet of amlodipine/ trials in patients with mild to moderate hyperten-
in the EU valsartan (5 mg/80 mg, 5 mg/
sion.
160 mg or 10 mg/160 mg) once
Approximately 8090% of patients receiving ap-
daily
proved dosages of amlodipine/valsartan achieved a
Recommended dosage One tablet of amlodipine/
response, defined as a mean sitting diastolic BP
in the US valsartan (5 mg/160 mg, 10 mg/
160 mg, 5 mg/320 mg or 10 mg/
<90 mmHg or a 10 mmHg reduction from base-
320 mg) once daily
line.
Route of administration Oral
Subgroup analyses of data from the two trials show-
Pharmacokinetic profile (of individual components unless ed that the antihypertensive efficacy of amlodipine/
otherwise stated)
valsartan in the elderly, Black patients and those
Time to peak plasma Amlodipine: 68 h; valsartan: 3 h with stage 2 hypertension was consistent with that
concentration (fixed-dose
observed in the overall study population.
combination)
Marked reductions in BP were also observed in
Absolute bioavailability Amlodipine: 6480%; valsartan
patients whose BP was previously uncontrolled on
23%
monotherapy (with various antihypertensives) who
Volume of distribution Amlodipine: 21 L; valsartan: 17 L
were switched (without washout) to amlodipine/
Plasma protein binding Amlodipine: 97.5%; valsartan:
valsartan in a phase IIIbIV study.
9497%
Amlodipine/valsartan was generally well tolerated
Elimination half-life Amlodipine: 3050 h; valsartan:
in clinical trials. In particular, the incidence of peri-
6 h
pheral oedema was significantly lower in patients
Most frequently reported adverse events
receiving amlodipine/valsartan than in those treated
Peripheral oedema, headache, nasopharyngitis, upper
with amlodipine monotherapy.
respiratory tract infection, dizziness
374 Plosker & Robinson
Numerous drugs from various classes are avail- most likely to be associated with the development of
able for the management of hypertension; however, diabetes.
[9,11]
most patients will require a combination of anti-
The pharmacodynamic properties of amlodip-
hypertensive agents to achieve target blood pressure
ine
[12]
and valsartan
[13,14]
have been reviewed pre-
(BP) levels.
[1,2]
For high-risk patients with hyperten-
viously in some detail; therefore, this section focus-
sion, such as those with diabetes mellitus or renal
es on newer data specifically with combinations of
impairment, combination therapy is almost always
amlodipine/valsartan. Some of these pharmacody-
required (90% of patients) to achieve BP goals
namic studies are available as abstracts,
[15,16]
al-
(<130/80 mmHg).
[2,3]
Fixed-dose combinations of
though one is fully published.
[17]
amlodipine/valsartan (Exforge
)
1
are available in
Plasma noradrenaline levels in patients with mild

several European countries and in the US for once-
to moderate hypertension (mean sitting diastolic BP
daily oral administration in patients with hyperten-
[DBP] >95 and <110 mmHg) were increased by
sion who have not had an adequate response to
amlodipine but not valsartan monotherapy both at
amlodipine or valsartan monotherapy (EU prescrib-
rest and while standing; however, combined therapy
ing information)
[4]
or whose BP is not adequately
with amlodipine/valsartan did not attenuate the
controlled with amlodipine (or another dihydropyri-
amlodipine-induced sympathetic activation.
[17]
Both
dine calcium channel blocker [CCB]) alone or with
drugs provided similar reductions in BP; therefore,
valsartan (or another angiotensin II receptor blocker
results suggest that valsartan has a neutral effect on
[ARB]) alone (US prescribing information).
[5]
This
the sympathetic system despite achieving significant
article provides a brief overview of the pharmaco-
antihypertensive effects. During the first 4 weeks of
logical properties of amlodipine/valsartan and re-
the randomized, double-blind, forced-titration
views the clinical trial data for combinations of
study, 47 patients received monotherapy with either
these antihypertensive agents. Medical literature on
amlodipine 5 mg or valsartan 80 mg once daily,
the use of amlodipine/valsartan in hypertension was
which was increased to amlodipine 10 mg or val-
identified using MEDLINE and EMBASE, supple-
sartan 160 mg once daily through week 8. Patients
mented by AdisBase (a proprietary database). Addi-
whose DBP remained >90 mmHg at week 8 were
tional references were identified from the reference
treated with both drugs.
lists of published articles.
As well as significantly reducing BP, the addi-

tion of valsartan 80 mg/day to amlodipine 5 mg/day
1. Pharmacodynamic Profile
in hypertensive patients with an inadequate response
to amlodipine monotherapy also improved exercise
performance, as assessed by measurements of cardi-
Fixed-dose combinations of amlodipine/valsar-
ac output and total peripheral resistance at rest, after
tan comprise antihypertensive agents with comple-
warm-up and at peak exercise.
[15]
mentary mechanisms of action a dihydropyridine
CCB (amlodipine) and an ARB that acts selectively

Over a 1-year period, the combination of am-
on the receptor subtype AT
1
(valsartan).
[4]
Both lodipine/valsartan 10 mg/160 mg once daily was
drugs have generally neutral effects on metabolic associated with a significantly lower rate of recur-
parameters such as blood lipid levels and insulin rent episodes of atrial fibrillation than amlodipine/
sensitivity,
[6-8]
and the association of antihyperten- atenolol 10 mg/100 mg once daily in a randomized
sive drugs with the development of new-onset dia- study in 250 patients with mild hypertension, well
betes is lowest for ARBs and ACE inhibitors fol- controlled type 2 diabetes and a recent history of
lowed by CCBs,
[9,10]
whereas antihypertensive regi- atrial fibrillation.
[16]
Although reductions in BP were
mens that include a thiazide diuretic are among the similar between groups, 14% of patients treated with
Amlodipine/Valsartan: Adis Drug Profile 375
amlodipine/valsartan experienced 1 recurrent epi- 3. Therapeutic Efficacy
sode of symptomatic or asymptomatic, ECG-docu-
Several large, well designed clinical trials in pa-
mented atrial fibrillation compared with 41% of
tients with hypertension and/or other cardiovascular
those who received amlodipine/atenolol (p < 0.01).
conditions have demonstrated reductions in morbid-
ity and mortality with amlodipine
[3,18-21]
or val-
2. Pharmacokinetic Profile
sartan.
[22-26]
To date, clinical trials with combina-
tions of amlodipine/valsartan have focused on BP
control, as discussed in the following three subsec-
Amlodipine and valsartan exhibit linear pharma-
tions. None of the studies conducted thus far have
cokinetic properties and the pharmacokinetic
evaluated home or 24-hour BP or focused specifical-
profiles of these drugs, when administered as mono-
ly on patients with isolated systolic hypertension.
therapy, are well defined.
[4,12,13]
Limited data are
available on the pharmacokinetics of fixed-dose
Randomized Factorial Studies 1 and 2
combinations of amlodipine/valsartan.
[4,5]
Peak plasma concentrations of amlodipine and

The antihypertensive efficacy of combination
valsartan are reached in 68 hours and 3 hours,
therapy with amlodipine/valsartan has been com-
respectively, following oral administration of
pared with that of amlodipine or valsartan mono-
amlodipine/valsartan in fixed-dose combina- therapy in two randomized, double-blind, placebo-
controlled, factorial studies. These large trials, re- tions.
[4,5]
The rate and extent of absorption of
ferred to as study 1 (n = 1911) and study 2
amlodipine when administered in fixed-dose combi-
(n = 1250), have been published together in a single
nations with valsartan are equivalent to those of
report;
[27]
subgroup analyses have been published
amlodipine when administered as monotherapy.
separately.
[28]
Likewise, valsartan has similar absorption pharma-
The main inclusion criterion for studies 1 and 2
cokinetics whether administered in fixed-dose com-
was mild to moderate essential hypertension, de-
binations with amlodipine or as monotherapy.
fined as a mean sitting DBP 95 and
When administered as individual components,

<110 mmHg.
[27]
Studies 1 and 2 were of similar
amlodipine and valsartan have absolute bioavai-
design, in that they included a 2-week washout
labilities of 6480% and 23%, respectively.
[4]
Both
period followed by a 2- to 4-week single-blind pla-
drugs are highly plasma protein bound and the elim-
cebo run-in period then an 8-week active-treatment
ination half-life is 3050 hours for amlodipine and
period with once-daily oral administration of study
6 hours for valsartan.
medication. However, patients in study 1 could be
randomized to receive 1 of 15 different regimens,
Amlodipine is extensively (90%) metabolized

whereas only six regimens were evaluated in study
in the liver to inactive metabolites, whereas only
2. Also, the amlodipine dose used in study 2 (10 mg)
20% of a valsartan dose is recovered as metabo-
was higher than that used in study 1 (2.5 or 5 mg).
lites.
[4,5]
Valsartan is primarily eliminated in the
Regimens in study 1 that involved low doses of
faeces (83% of a dose) and urine (13% of a dose)
amlodipine (2.5 mg) or valsartan (40 mg) are not
mainly as unchanged drug.
included in this section; only combined amlodipine/
Both amlodipine and valsartan are associated

valsartan dosages approved in the EU or commer-
with drug interactions of potential clinical signifi-
cially available in the US (section 5) are discussed.
cance
[4,5]
and local prescribing information should
The primary efficacy endpoint of studies 1 and 2
be consulted. No drug interaction studies have been
was the change from baseline in mean sitting DBP at
conducted with fixed-dose combinations of am-
the end of the 8-week study period in the intent-to-
lodipine/valsartan and other drugs. treat (ITT) population.
[27]
Important secondary end-
points were response rate, defined as the percentage combined regimen of amlodipine/valsartan and
of patients achieving a mean sitting DBP were significantly (p < 0.05) greater than those
<90 mmHg or a 10 mmHg reduction from baseline, observed with amlodipine (
24.1 mmHg) or val-

and change from baseline in mean sitting systolic sartan (approximately
20 mmHg for both 160 and

BP (SBP). The overall mean age was 54.4 years in 320 mg) monotherapy, or with placebo
study 1, with 18.2% of patients aged 65 years, and (
12.9 mmHg).
[27]
56.9 years in study 2, with 28.6% of patients aged
Almost 90% of patients treated with amlodipine/
65 years. Baseline overall mean sitting BP values
valsartan 10 mg/320 mg (87.5%) or 10 mg/160 mg
in the respective studies were 152.8/99.3 mmHg and
(88.5%) in study 2 met the criteria for response.
[27]
156.7/99.1 mmHg.
In both cases this was significantly (p < 0.05) greater
than the response rate with the same doses of val-
After 8 weeks of treatment with amlodipine/
sartan monotherapy (72% or 74.9%) or with placebo
valsartan 5 mg/80 mg, 5 mg/160 mg or 5 mg/320 mg
(49.3%), although there was little difference in res-
once daily in study 1, reductions from baseline in
ponse rates between the combined regimens and
mean sitting DBP (
14.2 to
15.9 mmHg) were

amlodipine 10 mg monotherapy (86.9%).
significantly (p < 0.05) larger than with the same
Subgroup analyses of studies 1 and 2, conducted doses of amlodipine (
11.5 mmHg) or valsartan

according to the stage of hypertension, age and race, (
9.7 to 13.4 mmHg) monotherapy, or with place-

showed that changes from baseline in mean sitting bo (
6.8 mmHg).
[27]
DBP and SBP in the various subgroups were consis-
Reductions from baseline in mean sitting SBP

tent with findings from the overall study popula-
in study 1 ranged from
19.5 to
22.7 mmHg with

tion.
[28]
The combination of amlodipine/valsartan
amlodipine/valsartan 5 mg/80 mg, 5 mg/160 mg
was associated with numerically greater reductions
or 5 mg/320 mg once daily and were significantly
in BP than with each respective monotherapy or
(p < 0.05) larger than those observed with
placebo across all patient subgroups evaluated, in-
amlodipine (
15.1 mmHg) or valsartan (
12.9 to
cluding elderly (65 years of age) and Black pa-
15.7 mmHg) monotherapy, or with placebo

tients, as well as those with stage 2 hypertension
(
6.7 mmHg).
[27]
(SBP 160 mmHg and/or DBP 100 mmHg). Sta-
More than 80% of patients treated with

tistical analyses were not reported.
amlodipine/valsartan 5 mg/80 mg (84.9%), 5 mg/
160 mg (81.1%) or 5 mg/320 mg (91.3%) in study 1
Phase IIIbIV (Direct Switch) Study
met the criteria for response.
[27]
Response rates were
significantly (p < 0.05) greater than that with place-
A large (n = 894), randomized, double-blind,
bo (40.9%). In addition, amlodipine/valsartan com-
phase IIIbIV trial evaluated a direct switch (with-
binations achieved significantly higher response
out washout) to amlodipine/valsartan 5 mg/160 mg
rates than amlodipine (71.9%) and/or valsartan
or 10 mg/160 mg once daily in patients whose BP
(57.773.4%) monotherapy.
was previously uncontrolled with monotherapy (va-
In study 2, reductions from baseline in mean

rious antihypertensive agents).
[29]
BP control was
sitting DBP were significantly (p < 0.05) greater
defined as SBP/DBP <140/90 mmHg for nondiabet-
after 8 weeks of therapy with amlodipine/valsartan
ic patients and <130/80 mmHg for patients with
10 mg/320 mg (18.6 mmHg) or amlodipine/val-
diabetes. For patients with uncontrolled BP after 8
sartan 10 mg/160 mg (17.6 mmHg) once daily than
or 12 weeks of amlodipine/valsartan therapy, open-
with the same dose of amlodipine (15.6 mmHg) or
label hydrochlorothiazide (HCTZ) 12.5 mg/day
valsartan monotherapy (13.3 mmHg for both 160
could be added; for patients who received concur-
and 320 mg), or with placebo (8.8 mmHg).
[27]
rent HCTZ 12.5 mg/day starting at week 8 and
Reductions from baseline in mean sitting SBP in whose BP remained uncontrolled at week 12, the
study 2 were approximately
28 mmHg with either dose of HCTZ could be increased to 25 mg/day. The

primary endpoint was the proportion of patients
achieving BP control at week 16; BP control at week
8 (i.e. prior to the possible addition of HCTZ) was
an important secondary endpoint. The mean overall
age of the study population was 58.5 years, with
30.6% aged 65 years.
BP control was achieved in 76.4% and 71.1% of

patients (p = 0.03) after 8 weeks of once-daily
therapy with amlodipine/valsartan 10 mg/160 mg
and 5 mg/160 mg, respectively (ITT with last obser-
vation carried forward [LOCF]).
[29]
During the sub-
sequent 8-week period, HCTZ could be added if
necessary, and results at week 16 were similar to
those at week 8, although the difference between
groups was not statistically significant (74.8% for
amlodipine/valsartan 10 mg/160 mg vs 72.7% for
amlodipine/valsartan 5 mg/160 mg), possibly be-
cause more patients in the low-dose group than in
the high-dose group received HCTZ (25% vs 19%).
In general, results were similar between nondiabetic
and diabetic patients.
At week 8, reductions in mean sitting SBP/DBP

were
19.2/
11.3 mmHg with amlodipine/valsartan

10 mg/160 mg and
16.5/
9.3 mmHg with the lower

dosage (p 0.0001 for SBP and DBP comparisons;
ITT with LOCF).
[29]
Similar results were reported
at week 16 (
20.0/
11.6 mmHg vs
17.5/
10.4 mmHg; p < 0.001 for SBP, p < 0.01 for DBP).
Week 8 data for reductions in mean sitting SBP

(ITT without LOCF) are presented in figure 1.
[29]
In
the lower-dosage group, the reduction in SBP was
17.6 mmHg, from 149.5 mmHg at baseline to

131.9 mmHg at week 8 (figure 1a). Amlodipine/
valsartan 10 mg/160 mg was associated with a re-
duction of
21.0 mmHg, from 150.8 mmHg at base-

line to 129.8 mmHg at week 8 (figure 1b). For both
dosage regimens, the magnitude of SBP reductions
was similar regardless of the class of antihyperten-
sive drug used prior to randomization.
Other Studies
Additional efficacy data are also available from
two smaller comparative trials whose primary aim
was to evaluate tolerability data.
[30,31]
Study design
149.5
a
148.5
150.6
150.2
148.9
148.7
131.9
130.1
132.9 132.8
131.4
131.1
155
150
145
140
135
130
125
120
115
M
e
a
n

s
i
t
t
i
n
g

S
B
P

(
m
m
H
g
)
Overall -
blocker
CCB ARB ACE
inhibitor
Diuretic
Class of antihypertensive prior to randomization
17.6 18.4
17.7
17.4
17.5
17.6
b
155
150
145
140
135
130
125
120
115
M
e
a
n

s
i
t
t
i
n
g

S
B
P

(
m
m
H
g
)
Overall -
blocker
CCB ARB ACE
inhibitor
Diuretic
Class of antihypertensive prior to randomization
150.8
153.1 153
150.3
149.2
150
129.8
128.8
131.7
130.8
127.1
130
21.0 24.3
21.3 19.5 22.1 20.0
Baseline (AML/VAL 5 mg/160 mg)
Week 8
Baseline (AML/VAL 10 mg/160 mg)
Week 8
Fig. 1. Mean sitting systolic blood pressure (SBP) at baseline and
8 weeks after switching (without washout) to amlodipine/valsartan
(AML/VAL) in a randomized, double-blind, phase IIIb-IV trial.
[29]
Hy-
pertensive patients with previously uncontrolled blood pressure with
antihypertensive monotherapy were switched (without washout) to
(a) AML/VAL 5 mg/160 mg (n = 423) or (b) AML/VAL 10 mg/160 mg
(n = 410) once daily. ARB = angiotensin II receptor blocker;
CCB = calcium channel blocker.
details and primary safety data for these two studies 1- to 2-week placebo run-in period and then a
are presented in section 4. 6-week active-treatment period.
Amlodipine/valsartan was associated with signif-

None of the clinical trials with amlodipine/val-
icant (p < 0.001) reductions in mean sitting SBP in
sartan specifically excluded patients who could not
the overall patient population (
35.8 mmHg), and in

tolerate amlodipine or valsartan. In studies 1 and 2,
patients with mean sitting SBP 180 mmHg at base-
the total number of patients enrolled in the single-
line (
43.0 mmHg) in a 6-week trial comparing the

blind, placebo run-in phase of the trials was 2478
tolerability profiles of once-daily regimens of
and 1407, respectively, whereas 1911 and 1250 pa-
amlodipine/valsartan 510 mg/160 mg and lisi-
tients entered the randomized phase of the two
nopril/HCTZ 1020 mg/12.5 mg in patients with
trials.
[27]
The most common reasons for discontinua-
stage 2 hypertension.
[31]
Significant (p < 0.001) re-
tion were administrative problems, antihypertensive
ductions in DBP were also observed.
therapy no longer required, abnormal laboratory val-
Another 6-week study focusing on tolerability

ues and withdrawal of consent.
endpoints showed better antihypertensive efficacy
The combined safety population from studies 1

with amlodipine/valsartan 10 mg/160 mg once daily
and 2 included 3155 patients with mild to moderate
than with amlodipine or valsartan monotherapy at
hypertension.
[27]
The most frequently reported ad-
the same dosages.
[30]
verse events with amlodipine/valsartan were peri-
pheral oedema, headache, nasopharyngitis, upper
4. Tolerability
respiratory tract infection and dizziness (figure 2).
Tolerability data on the combined use of
Patients receiving combined therapy with

amlodipine/valsartan are available from two large,
amlodipine/valsartan had a significantly lower inci-
randomized, factorial trials in patients with mild to
dence of peripheral oedema than those treated with
moderate hypertension (studies 1 and 2)
[27]
and a
amlodipine monotherapy (5.4% vs 8.7%; p < 0.05),
phase IIIbIV trial involving switch therapy (see
but a higher incidence than those receiving valsartan
section 3 for study design details),
[29]
as well as from
monotherapy (2.1%; p < 0.001); the incidence in
two smaller trials whose primary aim was to evalu-
placebo recipients (3.0%) did not differ significantly
ate safety variables.
[30,31]
from that in combination recipients.
[27]
The lower
One of the tolerability studies compared the ef-
incidence of peripheral oedema in combination ver-
fects of amlodipine/valsartan 10 mg/160 mg on an-
sus amlodipine monotherapy recipients was thought
kle oedema with those of amlodipine or valsartan
to result from a decrease in both arteriolar and
monotherapy at the same once-daily dosage for
venous resistance associated with the combination,
6 weeks.
[30]
Ankle foot volume (AFV) and pretibial
whereas amlodipine would be expected to reduce
subcutaneous tissue pressure (PSTP) were blinded
arteriolar resistance only.
endpoints used as objective measures of ankle oede-
The incidence of headache was significantly

ma. The open-label crossover study included 80 pa-
lower in patients receiving amlodipine/valsartan
tients with grade 1 or 2 hypertension who were
therapy than amlodipine monotherapy (4.3% vs
randomized to receive the three treatment regimens.
7.6%; p < 0.01), but no different to that seen with
Each crossover period was separated by a 2-week
valsartan monotherapy (4.8%) or placebo (5.9%).
[27]
placebo period.
The overall incidence of adverse events reported The other tolerability study compared the overall
with amlodipine/valsartan was similar to that report- safety profile of amlodipine/valsartan 510 mg/
ed for amlodipine (44.1% vs 45.7%), but signifi- 160 mg with that of lisinopril/HCTZ 1020 mg/
cantly higher than that reported for valsartan (44.1% 12.5 mg once daily in 130 patients with stage 2
vs 39.8%; p < 0.05).
[27]
The incidence of adverse hypertension.
[31]
The randomized, double-blind trial
events leading to discontinuation of study drug was included a washout period of 37 days followed by a
p < 0.01) and PSTP (+23.2% vs +75.5%; p < 0.001)
than amlodipine monotherapy.
[30]
These data also
support the concept of reduced peripheral oedema
with the dual mechanism of action of amlodipine/
valsartan affecting arteries and veins. As expected,
valsartan monotherapy did not affect AFV or PSTP.
Amlodipine/valsartan 510 mg/160 mg or lisi-

nopril/HCTZ 1020 mg/12.5 mg once daily for
6 weeks were both generally well tolerated in
130 patients with stage 2 hypertension (DBP
110 mmHg and <120 mmHg) who participated in a
randomized, double-blind trial.
[31]
Overall, adverse
events were reported in 40.6% of patients treated
with amlodipine/valsartan and 31.8% of those who
received lisinopril/HCTZ. Most adverse events were
mild to moderate in severity. Headache (10.9%) and
peripheral oedema (7.8%) were the most frequently
reported adverse events among amlodipine/val-
sartan recipients, whereas diarrhoea and pharyngitis
(both 6.1%) were the most frequently reported ad-
verse events with lisinopril/HCTZ.
5. Dosage and Administration
The recommended dose of amlodipine/valsartan
for patients with hypertension in the EU is one tablet
(5 mg/80 mg, 5 mg/160 mg or 10 mg/160 mg) once
AML/VAL (n = 1437)
AML (n = 460)
VAL (n = 921)
Placebo (n = 337)
0.9
2.1
1.8
5.9
3
2.4
1.4
4
4.8
2.1
1.5
2.4
3.5
7.6
8.7
2.1
2.9
4.3
4.3
5.4
0 1 2 3 4 5 6 7 8 9 10
Dizziness
URTI
Nasopharyngitis
Headache
Peripheral
oedema
Percentage of patients
Fig. 2. Tolerability data from 3155 patients with mild to moderate

hypertension. Pooled data from two randomized, double-blind,
8-week, factorial trials comparing combinations of amlodipine/val-
sartan (AML/VAL) vs monotherapy with either drug or placebo.
[27]
Adverse events are those reported in at least 2% of patients treated
with AML/VAL. URTI = upper respiratory tract infection; * p < 0.05
vs placebo; p < 0.05 vs VAL; p < 0.05 vs AML.
daily, taken with or without food.
[4]
In the US,
commercially available dosages of amlodipine/val-
1.8% with amlodipine/valsartan, which was similar
sartan include 5 mg/160 mg, 10 mg/160 mg, 5 mg/
to that reported with placebo (2.1%).
320 mg and 10 mg/320 mg, which are administered
In the phase IIIbIV trial in which patients with

once daily.
[5]
Although a direct switch from mono-
inadequate control of BP were switched (without
therapy to the fixed-dose combination may be ap-
washout) to amlodipine/valsartan 5 mg/160 mg or
propriate for some patients, individual dose titration
10 mg/160 mg once daily for 16 weeks (with or
with amlodipine and valsartan is generally recom-
without the addition of HCTZ at week 8 or 12), the
mended before changing to the fixed-dose combina-
most frequently reported treatment-related adverse
tion.
[4,5]
event was peripheral oedema, which occurred in
Caution is advised when prescribing the fixed-
8.1% and 25.1% of patients in the respective dosage
dose combination to patients with hepatic impair-
groups.
[29]
Peripheral oedema led to discontinuation
ment or biliary obstructive disorders and when in-
of therapy in 2.3% and 9.1% of patients, respective-
creasing the dosage of amlodipine/valsartan in eld-
ly.
erly patients (>65 years of age).
[4,5]
The maximum
In the study evaluating ankle oedema in 80 pa- recommended dose of valsartan is 80 mg in patients
tients, amlodipine/valsartan 10 mg/160 mg once with mild to moderate hepatic impairment without
daily for 6 weeks was associated with smaller in- cholestasis (EU prescribing information).
[4]
Dosage
creases from baseline in AFV (+6.8% vs +23%; adjustments are not required for patients with mild
to moderate renal impairment, although potassium Acknowledgements and Disclosures
levels and serum creatinine should be monitored in
those with moderate renal impairment.
[4]
The manuscript was reviewed by: J.P. Baguet, Depart-
ment of Cardiology and Hypertension, Grenoble University
No specific drug interaction studies have been
Hospital, Grenoble, France; L. Frost, Department of Medi-
conducted with the fixed-dose combination of am-
cine and Clinical Institute, Silkeborg Hospital, Aarhus
University Hospital, Silkeborg, Denmark; M.F. ORourke,
lodipine/valsartan and other drugs, although interac-
St Vincents Clinic, Carlinghurst, New South Wales, Austra-
tions between the individual components (amlodip-
lia; D. Poldermans, Erasmus Medisch Centrum Rotterdam,
ine or valsartan) and other drugs also apply to the
Rotterdam, The Netherlands.
fixed-dose combination.
[4]
Local prescribing infor-
external funding. During the peer review process, the manu- mation should be consulted for detailed information
facturer of the agent under review was also offered an oppor-
on drug interactions, contraindications, precautions
tunity to comment on this article. Changes resulting from any
and use in special patient populations.
comments received were made on the basis of scientific and
editorial merit.
6. Amlodipine/Valsartan: Current Status
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Drugs 2008; 68 (3): 383-397
ADIS DRUG EVALUATION 0012-6667/08/0003-0383/$53.45/0
Sildenafil
A Review of its Use in Pulmonary Arterial Hypertension
Katherine F. Croom and Monique P. Curran
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Various sections of the manuscript reviewed by:
S.H. Abman, Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of
Medicine, Aurora, Colorado, USA; R.N. Channick, University of California San Diego Medical Center, La
Jolla, California, USA; G.A. Heresi, Department of Pulmonary, Allergy and Critical Care Medicine, The
Cleveland Clinic, Cleveland, Ohio, USA; L.J. Rubin, Division of Pulmonary and Critical Care Medicine,
University of California at San Diego, La Jolla, California, USA; A. Torbicki, Department of Chest Medicine,
National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
Data Selection
Sources: Medical literature published in any language since 1980 on sildenafil, identified using MEDLINE and EMBASE, supplemented by
AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published
articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were sildenafil and (PAH or pulmonary arterial hypertension or
hypertension pulmonary). Searches were last updated 29 January 2008.
Selection: Studies in patients with pulmonary arterial hypertension who received sildenafil. Inclusion of studies was based mainly on the
methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant
pharmacodynamic and pharmacokinetic data are also included.
Index terms: Sildenafil, pulmonary arterial hypertension, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
3.1 Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
3.2 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
4.1 SUPER-1 and -2 Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
4.1.1 SUPER-1 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
4.1.2 SUPER-2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
4.2 Active-Comparator Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
4.3 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
7. Place of Sildenafil in the Management of Pulmonary Arterial Hypertension. . . . . . . . . . . . . . . . . . . . . 392
384 Croom & Curran
Summary
Sildenafil citrate (Revatio
), an inhibitor of phosphodiesterase type 5 (PDE5), is

Abstract
approved for use in the US, Europe and other countries for the treatment of
pulmonary arterial hypertension (PAH). Oral sildenafil 20 mg three times daily
added to conventional background therapy was significantly more effective than
placebo at increasing exercise capacity in patients with idiopathic PAH or PAH
associated with connective tissue diseases or repaired congenital systemic-to-
pulmonary shunts. Sildenafil was also associated with improvements in WHO
functional class and haemodynamic parameters, and was generally well tolerated.
Sildenafil provides benefits in terms of exercise capacity when added to epopros-
tenol; however, these findings come from a trial that did not use the approved
dosage of sildenafil. In conclusion, sildenafil is an effective oral treatment option
for patients with PAH.
Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate-
Pharmacological
specific PDE5, and causes relaxation of smooth muscle, in particular, in the
Properties
pulmonary vasculature and corpus cavernosum. It causes pulmonary vasodilation
in patients with pulmonary hypertension and is associated with improvements in
mean pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR)
and, in some studies, cardiac index. At the approved dosage of 20 mg three times
daily, sildenafil does not affect systemic blood pressure. Sildenafil potentiates the
hypotensive effect of nitrates and these drugs should not be coadministered.
Oral sildenafil is absorbed rapidly, reaching peak plasma concentrations after
1 hour. It is metabolized principally by cytochrome P450 (CYP) 3A4 and to a
lesser extent by CYP2C9, and inducers or inhibitors of these isozymes can affect
the clearance of sildenafil. It should not be coadministered with potent CYP3A4
inhibitors. Caution should be exercised when administering sildenafil with bosen-
tan (a CYP3A4 and CYP2C9 inducer), because sildenafil plasma concentrations
decrease and bosentan concentrations increase. Sildenafil is predominantly
excreted as metabolites in the faeces and has a terminal elimination half-life of
35 hours. The major (N-desmethyl) metabolite of sildenafil has an in vitro
potency approximately half that of the parent compound.
The efficacy of sildenafil in adults with idiopathic PAH was demonstrated in a
Therapeutic Efficacy
large, well designed, 12-week trial (SUPER-1). Dosages included 20 (the
approved dosage), 40 and 80 mg three times daily. At baseline, most patients were
in WHO functional class II or III and had a mean 6-minute walking distance of
344 m. All dosages of sildenafil significantly increased the placebo-corrected
6-minute walking distance (the primary endpoint) by 4550 m after 12 weeks, but
there was no significant difference in efficacy between the three dosages. At the
approved dosage, sildenafil also led to significant increases in the proportion of
patients improving by at least one functional class and exhibiting significant
improvements in haemodynamic parameters, including mean PAP and PVR.
Health-related quality of life (all dosages combined) significantly improved with
sildenafil compared with placebo for domains addressing the physical impact of
PAH and general health. In an open-label extension study of SUPER-1
(SUPER-2) in which all patients received sildenafil 80 mg three times daily
(higher than the approved dosage), efficacy was maintained to 1 year and, among
141 patients with idiopathic PAH, 1-year survival was 96% compared with a
predicted survival of 71%.
Studies comparing sildenafil with other specific PAH therapies, or evaluating
combination therapy, all used dosages higher than the approved dosage. In a
Sildenafil: A Review 385
small, 16-week study in patients with PAH (functional class III), there was no
significant difference between sildenafil and bosentan for change in right ventric-
ular mass (primary endpoint) or 6-minute walking distance. The combination of
sildenafil with intravenous epoprostenol was evaluated in a large, well designed,
16-week trial in patients with PAH. The addition of sildenafil to epoprostenol
significantly increased 6-minute walking distance (placebo-corrected increase of
26 m; p = 0.0009) and improved most haemodynamic parameters compared with
placebo.
Sildenafil was generally well tolerated by patients with PAH. Based on placebo-
Tolerability
subtracted incidences, the most common adverse events with sildenafil 20 mg
three times daily in SUPER-1 were epistaxis, headache, dyspepsia, flushing,
insomnia and erythema. Retinal haemorrhage occurred in 1.4% of the sildenafil
20 mg three times daily group (vs 0% for placebo); most patients had risk factors
for bleeding. Epistaxis was more common among patients with connective tissue
disorders than in those with idiopathic PAH, and concomitant use of vitamin K
antagonists also increased the risk of epistaxis.
Adverse events reported during combination therapy with sildenafil and
epoprostenol were consistent with events reported during SUPER-1.
1. Introduction agonists, increased the treatment options.
[7]
How-
ever, some of these agents require continuous intra-
Pulmonary arterial hypertension (PAH) is a rare
venous or subcutaneous infusion or frequent nebu-
disease, characterized by increased pulmonary vas-
lized inhalation.
[8]
In addition, PAH is a progressive
cular resistance, which, if left untreated, leads to
condition and treatment will fail in some patients,
right ventricular failure and death.
[1]
PAH can be
and require the use of several agents over time.
idiopathic or associated with other disorders, such as
Consequently, there remains a need for additional
connective tissue diseases.
[2]
Data regarding the in-
therapies, particularly other oral therapies.
cidence of PAH are limited,
[3,4]
but idiopathic PAH
One of the mechanisms underlying PAH is the
accounts for about 50% of registries and reference-
impairment of the nitric oxide pathway.
[9]
The pul-
centre PAH patient populations. Examination of
monary vasodilating effects of nitric oxide are medi-
Scottish population-based hospitalization records
ated by cyclic guanosine monophosphate (cGMP),
from 1986 to 2001 gave an annual incidence of PAH
which is metabolized by phosphodiesterase type 5
of 7.1 cases per million population.
[3]
Data from a
(PDE5), an enzyme present in the smooth muscle of
French PAH registry gave an annual incidence of
the pulmonary vasculature.
[9]
2.4 cases per million population.
[4]
Sildenafil, a selective inhibitor of PDE5, in-
Prior to the advent of specific PAH therapies, the
creases levels of cGMP and therefore nitric oxide- median survival time was 2.8 years from diag-
mediated vasodilation.
[9]
Sildenafil (Revatio
)
1
has nosis.
[5]
Clinical symptoms include dyspnoea, fa-
been approved in various countries, including the tigue, exertion intolerance, syncope and chest pain;
US and Europe, for the treatment of PAH. It is also however, it is often asymptomatic in the early
approved for the treatment of erectile dysfunc- stages.
[2]
In the past, conventional treatment includ-
tion,
[10]
but that indication is outside the scope of ed anticoagulants, diuretics, digoxin, oxygen and, in
this review. This article reviews the pharmacology, some patients, calcium channel antagonists.
[6]
The
therapeutic efficacy and tolerability of oral silde- development of more specific therapies for PAH,
such as prostanoids and endothelin-receptor ant- nafil in the treatment of patients with PAH.
386 Croom & Curran
2. Pharmacodynamic Properties
Sildenafil is a potent and selective inhibitor of
cGMP-specific PDE5. By inhibiting the metabolism
of cGMP by PDE5, sildenafil increases pulmonary
smooth muscle relaxation.
[11]
This can lead to vaso-
dilation of the pulmonary vascular bed in patients
with pulmonary hypertension. In addition to being
found in the pulmonary vascular smooth muscle,
PDE5 is also found in the vascular smooth muscle of
other tissues, the corpus cavernosum and in plate-
lets.
[9]
The half-maximal inhibition (IC
50
) of PDE5 is
3.5 nmol/L.
[11]
By comparison, the IC
50
value for
the inhibition of PDE6 was approximately 10-fold
higher and values for PDE1 to PDE4 were 80- to
>8500-fold higher.
[11]
The pharmacodynamic properties of sildenafil,
which have been reviewed in detail previously, are
summarized in table I.
[9,10,12]
A number of small studies using single doses
of sildenafil 50 mg (or 75
[13]
or 100 mg
[14]
; all
Table I. Pharmacodynamic properties of sildenafil
[9,10,12,20,22]
Effects on the pulmonary vasculature
Mean PAP
a
(see section 4)
Mean PVR
a
(see section 4)
Pulmonary hypertension associated with hypoxia at rest and
during exercise
b
Other effects
Mild and transient in systemic blood pressure
a
,
b
,
c
CI
a
(see section 4)
No clinically relevant effects on ECG
a
,
b
No effect on heart rate
a
,
b
Arteriole endothelial function in patients with chronic congestive
heart failure
Erectile response to sexual stimulation
b
Anti-aggregation effects of sodium nitroprusside on platelets
d
Transient visual disturbances and chromatopsia
a
,
b
a In patients with PAH.
b In healthy volunteers.
c At sildenafil dosages higher than those approved for patients
with PAH.
d In vitro and in vivo.
CI = cardiac index; ECG = echocardiogram; PAH = pulmonary
arterial hypertension; PAP = pulmonary arterial pressure;
PVR = pulmonary vascular resistance; indicates increased;
indicates decreased.
higher than the approved dosage of 20 mg three
times daily), provided initial evidence that sildenafil
causes pulmonary vasodilation in patients with idio- ventilation-perfusion matching, thereby reducing
pathic PAH
[13,15-18]
or PAH associated with oth- the ventilatory requirement for exercise.
[21]
In a
er conditions.
[13,16,18,19]
In these studies, sildenafil
small study (n = 28) in patients with PAH, the
reduced mean pulmonary arterial pressure
addition of sildenafil to other specific PAH therapy
(PAP)
[14,16-19]
and pulmonary vascular resistance
improved ventilation relative to carbon dioxide out-
(PVR), and increased cardiac index.
[13-19]
Haemo-
put, as well as end-tidal carbon dioxide tension,
dynamic data from a large, randomized, placebo-
peak oxygen uptake and peak oxygen pulse, during
controlled clinical trial that included the approved
exercise.
[21]
dosage of 20 mg three times daily are discussed in
Because of its effects on the nitric oxide/cGMP
section 4.
pathway, sildenafil can potentiate the hypotensive
Sildenafil can cause modest and transitory reduc-
effect of nitrates,
[23]
and concomitant use of these
tions in systemic blood pressure. Although chronic
drugs is contraindicated (section 6).
[20,22]
Synergistic
administration of sildenafil 80 mg three times daily
haemodynamic effects were observed when
to patients with systemic hypertension reduced sys-
sildenafil was coadministered with iloprost.
[16,17]
tolic and diastolic blood pressure by 9.4 and
Coadministration of sildenafil and -blockers can
9.1 mmHg, chronic administration of sildenafil at
cause symptomatic hypotension in some patients, as
this dosage had reduced effects on blood pressure in
both are vasodilators; caution is recommended when
patients with PAH (both systolic and diastolic blood
prescribing them together.
[20]
However, amlodipine
pressure reduced by 2 mmHg).
[20]
The dosage of
and alcohol do not potentiate the blood pressure-
sildenafil approved for PAH (20 mg three times
lowering effect of sildenafil.
[20]
daily) had no effect on systemic blood pressure.
[20]
In a recent study, the administration of a single Sildenafil has been associated with improved ex-
dose of sildenafil 25 mg to 40 patients with PAH ercise efficiency, which is likely to result from the
who were receiving long-term bosentan therapy re- improved pulmonary blood flow and more uniform
duced PVR by 15%, total pulmonary resistance by Total clearance of sildenafil is 41 L/h, with a
13% and mean PAP by 9% (all p < 0.0001), and terminal half-life of 35 hours.
[20,25,30]
Sildenafil is
increased cardiac output by 6% (p = 0.0026).
[24]
excreted primarily as metabolites in the faeces
(80% of the administered oral dose), with 13%
Sildenafil did not potentiate bleeding time when
excreted in the urine.
[20]
coadministered with acetylsalicylic acid.
[20]
3.1 Special Patient Populations
3. Pharmacokinetic Properties
In the elderly (aged >65 years), compared with
younger adults, the clearance of sildenafil is re-
Data in this section are primarily from studies in
duced, C
max
is 6070% higher, AUC is approxi-
healthy adult volunteers.
[25-31]
Some data from pa-
mately 100% higher and the half-life approximately
tients with PAH have been obtained from the
1 hour longer.
[27]
However, free sildenafil plasma
sildenafil European summary of product character-
concentrations are only 40% higher, because of
istics
[20]
and US prescribing information.
[22]
differences in protein binding in this age group.
[27]
Oral sildenafil is absorbed rapidly, with maxi-
In general, dosage adjustments are not required in
mum plasma concentrations (C
max
) observed after
elderly patients (section 6).
[20,22]
1 hour in the fasted state.
[20,25]
Sildenafil undergoes
The pharmacokinetics of sildenafil are not altered
first-pass metabolism
[30]
and the mean absolute bio-
significantly in patients with mild to moderate renal
availability is 41%.
[20,26]
When taken with food, the
insufficiency (creatinine clearance 3080 mL/min);
rate of absorption is slowed, with time to C
max
however, in those with severe renal impairment
delayed by 1 hour and C
max
reduced by 29%.
[20]
In
(creatinine clearance <30 mL/min), AUC and C
max
the fed state, the area under the plasma concentra-
increase by 100% and 88% for sildenafil and by
tion-time curve (AUC) is reduced by 11%; however,
200% and 79% for the N-desmethyl metabolite.
[20,27]
this effect is not considered clinically signif-
However, dosage adjustments are generally not ne-
icant.
[20,26]
C
max
and AUC increase in a dose propor-
cessary (section 6).
tional manner over the range of 2040 mg three
In patients with mild to moderate liver cirrhosis
times daily, but increase in more than a dose propor-
(Child-Pugh classes A and B), compared with
tional manner at higher doses.
[20]
healthy volunteers, AUC and C
max
increase by 85%
In patients with PAH, oral bioavailability was
and 47% for sildenafil and by 154% and 87% for the
43% higher with 80 mg three times daily than with
N-desmethyl metabolite;
[20,27]
however, dosage ad-
lower doses.
[20]
Mean C
max
at steady state for
justments are generally not required (section 6).
sildenafil 20 mg three times daily is 113 ng/mL.
[20]
Sildenafil pharmacokinetics have not been evalu-
Based on population pharmacokinetics in patients
ated in patients with severe hepatic impairment.
with PAH receiving 2080 mg sildenafil three times
daily, mean steady-state concentrations are 2050%
3.2 Drug Interactions
higher and minimum concentrations are doubled
compared to healthy volunteers.
[20]
Mean volume of
Since sildenafil is metabolized by CYP3A4 and
distribution at steady state is 105 L.
[20]
Sildenafil and
CYP2C9, inhibitors and inducers of these isozymes
its major metabolite (N-desmethyl) are 96% bound
can alter the clearance of this agent.
[20,32]
In a popu-
to plasma proteins.
lation pharmacokinetic analysis of patients with
PAH, coadministration with CYP3A4 substrates or Sildenafil is metabolized principally by cyto-
CYP3A4 substrates plus -adrenoceptor antagonists chrome P450 (CYP) 3A4 and to a lesser extent by
(-blockers) increased the bioavailability of CYP2C9 isozymes. The N-desmethyl metabolite
sildenafil by 43% and 66%.
[20]
has an in vitro potency for PDE5 of around half that
of sildenafil.
[20]
After administration with sildenafil In healthy volunteers, coadministration of a sin-
20 mg three times daily in patients with PAH, plas- gle dose of sildenafil 100 mg with the CYP3A4
ma concentrations of the N-desmethyl metabolite inhibitors ritonavir (500 mg twice daily), saquinavir
are 72% of those for sildenafil.
[20]
(1200 mg three times daily) or erythromycin
388 Croom & Curran
(500 mg twice daily) increased sildenafil exposure therapy,
[38]
did not use the approved dosage of
by 1000%, 210% and 182%, respectively.
[20]
sildenafil and so are only briefly discussed.
Grapefruit juice is a weak inhibitor of intestinal wall In trials discussed in this section,
[36-38]
patients
CYP3A4 and can increase sildenafil exposure by generally had PAH that was idiopathic, associated
23%.
[28]
with connective tissue disease or anorexigen use, or
occurred after surgical repair of congenital sys-
Coadministration of sildenafil with bosentan, a
temic-to-pulmonary shunts. Patients generally had
CYP3A4 and CYP2C9 inducer, leads to decreased
to have a 6-minute walking distance between 100
sildenafil plasma concentrations and increased bo-
and 450 m to be eligible for inclusion.
[36-38]
Unless
sentan concentrations.
[29,31]
In healthy volunteers
indicated otherwise, patients could have any WHO
who were given sildenafil 80 mg three times daily
functional class of PAH. Sildenafil, either alone or
(titrated up from 20 mg) and bosentan 125 mg twice
in combination, was added to conventional back-
daily, sildenafil dose-interval AUC decreased by
ground therapy (e.g. calcium channel antagonists,
63%, and bosentan dose-interval AUC increased
digoxin, diuretics, oxygen and anticoagulants). With
50%.
[31]
In ten patients with PAH who were given a
the exception of the study involving combination
single dose of sildenafil 100 mg in conjunction with
therapy,
[38]
concomitant treatment with specific
bosentan 62.5 mg twice daily, sildenafil exposure
PAH therapies (e.g. epoprostenol, bosentan, ilo-
decreased by 50% in association with a 2-fold in-
prost, treprostinil or L-arginine) was not permitted.
crease in sildenafil clearance.
[29]
Few data are avail-
The primary endpoint in the two larger studies
able on treatment with combined sildenafil and bo-
was the change in exercise capacity.
[36,38]
This was
sentan in the clinical setting (section 4), and dose
measured as the total distance walked in 6 minutes.
recommendations are not available, but caution is
Common secondary endpoints included the change
advised.
[20]
in haemodynamic parameters (e.g. mean PAP),
There are no significant pharmacokinetic interac-
dyspnoea (usually assessed using the Borg scale,
tions between sildenafil and antacids, oral contra-
where 0 = none and 10 = maximal dyspnoea), WHO
ceptives, tolbutamide, warfarin, atorvastatin, ace-
functional classification of PAH and time to clinical
nocoumarol, or acetylsalicylic acid.
[20]
worsening (defined as death, transplantation, hospi-
talization for PAH or initiation of additional therapy
4. Therapeutic Efficacy
for PAH [or initiation of bosentan or change in
epoprostenol dose by >10%
[38]
]).
[36,38]
Health-relat-
ed quality of life (HR-QOL) was also assessed in
Although a number of small, noncomparative
these two studies
[36,38]
(data for SUPER-1 presented
trials have evaluated the efficacy of sildenafil in
in separate publication
[39]
), using the Short-Form 36
PAH, only data from randomized, placebo- or ac-
(SF-36) and the EuroQoL (EQ-5D) questionnaires.
tive-controlled trials are included in this review.
Primary analyses were performed on the inten-
Data from several small, crossover, placebo-control-
tion-to-treat (ITT) population, which was defined
led studies
[33-35]
provided initial evidence of the clin-
for the two largest studies as patients who received
ical efficacy of sildenafil added to conventional
study drug, and had baseline and at least one other
background therapy in the treatment of patients with
measurement of an efficacy endpoint (except for
PAH; however, these trials did not use the approved
clinical worsening, when it included all patients who
dosage of sildenafil and will not be discussed fur-
had received study drug), and used last-observation-
ther.
carried forward methodology.
[36-38]
The main focus of this section is the approved
dosage of 20 mg three times daily. However, only
4.1 SUPER-1 and -2 Trials one placebo-controlled trial of sildenafil evaluated
this dosage (SUPER-1; Sildenafil Use in Pulmonary
Arterial Hypertension).
[36]
The long-term extension SUPER-1 was a large, randomized, double-blind,
of the SUPER-1 trial (SUPER-2),
[36]
as well as trials parallel-group, placebo-controlled, multicentre trial
involving an active comparator
[37]
or combination of 12 weeks duration.
[36]
Patients (n = 278) were
randomized to receive oral sildenafil 20 (approved [figure 1]. The sensitivity analysis, which took into
dosage), 40 or 80 mg, or placebo, three times daily, account missing data, supported the main analysis
in addition to background therapy. Patients in the (p < 0.001 for all three dosage groups); the placebo-
80 mg group received 40 mg three times daily for corrected treatment effect in the 20 mg group was
the first week, after which the dose was increased; 38 m in this analysis. A per-protocol analysis also
dummy-dose escalation was performed in the other supported the ITT analysis (p < 0.001 for all three
dose groups. Randomization was stratified accord- dosage groups).
[36]
ing to the cause of pulmonary hypertension and
When the 20 mg group data were analysed ac-
baseline walking distance (<325 m or 325 m). A
cording to baseline characteristics, placebo-sub-
sequential step-down, closed testing procedure was
tracted improvements were seen for all subgroups
used to evaluate endpoints, whereby the response in
baseline 6-minute walking distance (<325 m or
each sildenafil group was compared with placebo,
325 m), cause of PAH, functional class (I/II or III/
starting with the highest dose group and with subse-
IV), sex, age (<median or median) and mean PAP
quent groups tested only if significant efficacy was
(<median or median).
[36]
For functional class, pla-
demonstrated in the previous group.
[36]
cebo-corrected increases in 6-minute walking dis-
Three-quarters of the patients were female and
tance of 50 and 48 m were seen for class I/II and
the mean age was 49 years. Patients had PAH (de-
class III/IV patients (both p < 0.05).
[36]
fined as mean PAP 25 mmHg and pulmonary-
The proportion of patients with an improvement
capillary wedge pressure 15 mmHg at rest) that
of at least one functional class after 12 weeks was
was idiopathic (63% of patients), associated with
significantly greater with sildenafil than with place-
connective tissue disease (30%) or followed surgical
bo in all dosage groups; in the 20 mg group the pla-
repair of a congenital systemic-to-pulmonary shunt
cebo-corrected difference was 21% (p = 0.003).
[36]
5 years prior to the study (7%). The most common
Among haemodynamic parameters, mean PAP
WHO functional classes at baseline were classes II
and PVR decreased significantly with sildenafil
(39%) and III (58%). The mean 6-minute walking
compared with placebo in all groups (e.g.
2.1
distance across all patients at baseline was 344 m.
[36]
vs 0.6 mmHg [p = 0.04] and
122 vs
After completing the SUPER-1 trial, 259 patients
49 dyn sec cm
5
[p = 0.01] for the 20 mg group).
entered a 1-year noncomparative extension study
Cardiac index did not differ significantly from pla-
(SUPER-2);
[36]
however, the dosage used in the
extension study (80 mg three times daily) was
higher than the final approved dosage for sildenafil.
Patients from the original 20 and 40 mg groups were
given sildenafil 40 mg three times daily for the first
6 weeks of the extension, after which the dosage was
increased. Patients who had been receiving placebo
were titrated up to 80 mg over 12 weeks. Dummy-
dose escalation was performed in patients from the
original 80 mg dose group.
[40]
4.1.1 SUPER-1 Results
Sildenafil increased exercise capacity signifi-
cantly compared with placebo,
[36]
with no difference
in efficacy between the three sildenafil dosage
groups.
[20,22]
Improvements in walking distance
were apparent from week 4. After 12 weeks, the
placebo-corrected increase in the mean 6-minute
walking distance (primary endpoint) was 45 m in the
sildenafil 20 mg group (99% CI 21, 70; p < 0.001)
0
10
20
30
40
50
60
20 mg 40 mg 80 mg
M
e
a
n

p
l
a
c
e
b
o
-
c
o
r
r
e
c
t
e
d

c
h
a
n
g
e

i
n
6
-
m
i
n
u
t
e

w
a
l
k
i
n
g

d
i
s
t
a
n
c
e

(
m
)
*
*
*
Sildenafil
Fig. 1. Effect of sildenafil on exercise capacity in patients with
pulmonary arterial hypertension. Mean change from baseline in
6-minute walking distance for 266 patients with outcome data from
a 12-week, randomized, double-blind, placebo-controlled trial in
which patients received sildenafil 20, 40 or 80 mg, or placebo, three
times daily, in addition to conventional background therapy.
[36]
The
approved dosage of sildenafil is 20 mg three times daily. * p < 0.001
vs placebo.
390 Croom & Curran
cebo for the 20 mg group (although it did increase walking distance increased from baseline by 42 m
significantly [p < 0.03] at higher sildenafil dosages), (95% CI 27, 57) after 12 weeks.
and there was also no significant between-group Observed and predicted survival were compared
difference for change in right atrial pressure or heart for 141 of 175 patients who had idiopathic PAH.
rate. There was no significant difference between One-year observed survival (Kaplan-Meier esti-
sildenafil and placebo for change in Borg dyspnoea mate) was 96% compared with a predicted survival
score or for time to clinical worsening.
[36]
of 71% (estimated using the prognostic index based
on the National Institute of Health [NIH] idiopathic A post hoc subgroup analysis found that
PAH registry, using baseline values for cardiac in- sildenafil improved exercise capacity, functional
dex, mean PAP and mean right atrial pressure).
[40]
class and (in the 20 mg group only) haemodynamic
parameters in patients who had PAH associated with
4.2 Active-Comparator Trial
connective tissue disease. Of the 84 patients in this
analysis, 45% had scleroderma, 23% had systemic
Only one randomized, multiple-dose trial com-
lupus erythematosus and 32% had other diagno-
paring sildenafil with another specific PAH therapy
ses.
[41]
In the 20 mg group (n = 20), the mean
(bosentan) has been published.
[37]
In this small
placebo-corrected increase in 6-minute walking dis-
(n = 26), 16-week, double-blind trial, patients with
tance at 12 weeks was 55 m (p < 0.01) and an
PAH of functional class III received either sildenafil
improvement of at least one functional class was
(50 mg twice daily for 4 weeks then 50 mg three
seen in six patients (29%) compared with one pa-
times daily for 12 weeks) or bosentan (62.5 mg
tient (5%) in the placebo group (p < 0.003). Signif-
twice daily for 4 weeks then 125 mg twice daily,
icant improvements were also seen in mean PAP
plus a third daily dose of placebo). Patients were
and PVR with 20 mg sildenafil compared with pla-
symptomatic despite conventional background ther-
cebo (
4.6 vs 1.4 mmHg [p < 0.01] and
243 vs
apy and had a mean 6-minute walking distance of
19 dyn sec cm
5
[p < 0.05]), but not for right
297 m at baseline.
atrial pressure or cardiac output.
[41]
There was no significant difference between
HR-QOL was reported for all sildenafil-treated
sildenafil and bosentan for the primary endpoint,
patients combined.
[39]
Compared with placebo, sig-
right ventricular mass (as measured by cardio-
nificant improvements were seen for the physical
vascular magnetic resonance), or for any secondary
functioning, general health and vitality domains of
endpoint (change in 6-minute walking distance, car-
the SF-36 and for the current health state score and
diac index, Borg dyspnoea scale, quality of life
utility index of the EQ-5D (all p < 0.05).
[QOL] and plasma B-type natriuretic peptide levels)
in an ITT analysis. Compared with baseline, right
4.1.2 SUPER-2 Results
ventricular mass decreased significantly after
All of the 259 patients who entered the extension
16 weeks in the sildenafil group (
8.1 g from base-

study received sildenafil 80 mg three times daily
line 159.8 g; p = 0.016; value of no change as-
(not the approved dosage: for further discussion see
sumed for one patient who died), while no signif-
section 7).
[36]
The efficacy of sildenafil in terms of
icant change was seen with bosentan (
3 g from
exercise capacity was maintained to 1 year. Among
baseline 134.4 g; p = 0.172).
[37]
222 patients who had received sildenafil for at least
12 months at the time of reporting (and had not
4.3 Combination Therapy
received prostanoids or endothelin-receptor ant-
agonists in addition during this period), the mean The addition of sildenafil to epoprostenol was
increase from baseline in 6-minute walking distance evaluated in a randomized, double-blind, placebo-
was 51 m (95% CI 41, 60) after 12 months (com- controlled, multicentre 16-week study involving
pared with 48 m [95% CI 40, 55] after 12 weeks).
[36]
267 patients with PAH who had been stabilized on
Among 58 patients who had received placebo in intravenous epoprostenol (data presented in an ab-
SUPER-1 and were then titrated to 80 mg three stract
[38]
and the European summary of product
times daily during the extension, mean 6-minute characteristics
[20]
). Patients continued on epopros-
tenol (3181 ng/kg/min) and were randomized to worsening was significantly longer in those patients
treated with sildenafil (p = 0.012).
[38]
receive, in addition, either sildenafil 20 mg three
times daily, titrated at 4-weekly intervals to 40 mg
and then 80 mg three times daily, or placebo with 5. Tolerability
dummy-dose escalation.
Data in this section are primarily derived from
The most common type of PAH among partici-
the large, placebo-controlled SUPER-1 trial that in-
pants was idiopathic (79%), and most patients were
cluded the approved sildenafil dosage of 20 mg
WHO functional class II (26%) or III (66%).
[20]
three times daily (section 4.1),
[36]
the manufacturers
The addition of sildenafil to long-term epopros-
US prescribing information
[22]
and the European
tenol treatment significantly increased exercise ca-
summary of product characteristics.
[20]
There are a
pacity. At 16 weeks, the placebo-adjusted increase
lack of data comparing the tolerability of sildenafil
in 6-minute walking distance was 26 m (p = 0.0009).
with other specific therapies for PAH.
The effect was evident among patients with a base-
In patients (n = 69) treated with 12 weeks of
line 6-minute walking distance 325 m (treatment
sildenafil 20 mg three times daily (SUPER-1), most
effect 38.4 m in favour of sildenafil, compared with
adverse events were mild or moderate in severi-
2.3 m in favour of placebo for those with a baseline
ty.
[22,36]
A similar proportion of recipients of
walking distance <325 m). The treatment effects for
sildenafil 20 mg three times daily discontinued treat-
patients with idiopathic PAH and for those with
ment as in the placebo group (both 3%).
[22]
Based on
PAH associated with other etiologies were 31.1 and
placebo-subtracted incidences, the most frequent ad-
7.7 m in favour of sildenafil.
[20,38]
verse events with sildenafil 20 mg three times daily
included epistaxis (8%), headache (7%), dyspepsia, The addition of sildenafil led to significantly
flushing, insomnia (each 6%) and erythema (5%); greater improvements than those that occurred with
see figure 2. There were no clinically significant epoprostenol monotherapy for haemodynamic end-
changes in laboratory parameters.
[36]
points, including mean PAP (mean placebo-
corrected treatment effect of
3.9 mmHg in favour In SUPER-1, when sildenafil was administered at

of sildenafil; p = 0.00003).
[20]
The time to clinical dosages above the recommended 20 mg three times
0
5
10
15
20
25
30
35
40
45
50
H
e
a
d
a
c
h
e
D
y
s
p
e
p
s
i
a
B
a
c
k

p
a
i
n
F
l
u
s
h
i
n
g
D
i
a
r
r
h
o
e
a
E
p
i
s
t
a
x
i
s
L
i
m
b

p
a
i
n
M
y
a
l
g
i
a
C
o
u
g
h
I
n
s
o
m
n
i
a
P
y
r
e
x
i
a
I
n
f
l
u
e
n
z
a
P
e
r
c
e
n
t
a
g
e

o
f

p
a
t
i
e
n
t
s
Placebo (n = 70)
Sildenafil 20 mg (n = 69)
Fig. 2. Tolerability of sildenafil in patients with pulmonary arterial hypertension. Adverse events reported by at least 3% of patients and more
frequently with sildenafil than placebo in a 12-week, randomized, double-blind, placebo-controlled trial (SUPER-1) in which patients also
received conventional background therapy.
[36]
Events are ordered from largest to smallest placebo-subtracted incidence.
[22]
The study
evaluated sildenafil 20, 40 and 80 mg three times daily; however, only data from patients treated with sildenafil 20 mg or placebo three times
daily (approved dosage) are shown.
392 Croom & Curran
daily, the incidence of flushing, diarrhoea, myalgia coadministered with potent CYP3A4 inhibitors
and visual disturbances (colour-tinged vision, sensi- (section 3.2).
[20,22]
Dosage adjustment are recom-
tivity to light, blurred vision) increased; for exam- mended when administering CYP3A4 inhibitors of
ple, placebo-subtracted incidences were 11%, 4%, intermediate potency. Coadministration of sildenafil
10% and 7%, respectively, in the 80 mg group.
[36]
with CYP3A4 inducers (including bosentan, barbi-
turates, carbamazepine, phenytoin, efavirenz, nevi- During SUPER-1, retinal haemorrhage occurred
rapine, rifampicin and rifabutin) may alter plasma in 1.4% of the sildenafil 20 mg group (1.9% of all
levels of either or both medications, and dosage dose groups) compared with 0% on placebo. Eye
adjustment may be necessary.
[20,22]
haemorrhage occurred in 1.4% of both sildenafil-
and placebo-treated patients.
[22]
Most of these pa- Prior to initiating sildenafil therapy, physicians
tients had risk factors for bleeding, such as being on should carefully consider whether patients with cer-
anticoagulant therapy. There was a higher incidence tain underlying conditions could be adversely af-
of epistaxis among patients with connective tissue fected by this agents mild to moderate vasodilatory
disease (13% on sildenafil vs 0% on placebo) than effects, for example, patients with resting hypoten-
among those with idiopathic PAH (sildenafil 3% vs sion (blood pressure <90/50 mmHg), or with fluid
placebo 2%).
[22]
In addition, concomitant use of depletion, severe left ventricular outflow obstruc-
vitamin K antagonists appeared to increase the risk tion or autonomic dysfunction.
[20,22]
of epistaxis (9% vs 2% in those not receiving such No specific dosage adjustments are needed in
agents).
[22]
elderly patients or in those with renal impairment. In
Adverse events reported during combination patients with hepatic impairment (Child-Pugh class
therapy with sildenafil 80 mg three times daily and A and B), initial dose adjustments are not required,
epoprostenol were consistent with those reported for but sildenafil is not recommended for use in patients
the SUPER studies, with headache, flushing, dys- with severe hepatic impairment (Child-Pugh class
pepsia, diarrhoea and limb pain being more com- C).
[20]
monly reported in sildenafil plus epoprostenol recip- Local prescribing information should be con-
ients than placebo plus epoprostenol recipients.
[20]
sulted for detailed information, including other con-
When used to treat erectile dysfunction, silde- traindications, warnings, precautions, drug interac-
nafil (25100 mg once daily) has been associated tions and use in special patient populations.
with serious cardiovascular, cerebrovascular and
vascular events and, rarely, with non-arteritic anteri-
7. Place of Sildenafil in the Management
or ischaemic optic neuropathy.
[20,22]
Most patients
of Pulmonary Arterial Hypertension
had pre-existing risk factors for these events.
PAH forms one of the categories within the over-
6. Dosage and Administration all clinical classification of pulmonary hypertension
(table II). The PAH category includes idiopathic
Sildenafil is indicated in the US, Europe and PAH, familial PAH and PAH associated with other
other countries for the treatment of adults with PAH conditions or risk factors, which may share common
to improve exercise capacity.
[20,22]
In the US, pathological mechanisms.
[42]
The European Society
sildenafil is approved for PAH WHO diagnostic of Cardiology (ESC) guidelines define PAH by a
classification group 1 (regardless of functional mean PAP >25 mmHg at rest (or >30 mmHg during
class) [see table II].
[20]
In Europe, this agent is exercise), by a pulmonary capillary wedge pressure
approved for patients with PAH who have WHO of 15 mmHg and by a PVR > 3 mmHg/L/min
functional class III. In both Europe and the US, the (Woods units).
[43]
approved dosage is 20 mg three times daily.
[20,22]
PAH is characterized by endothelial cell dysfunc-
The tablets should be taken orally, with or without tion and vascular remodelling of the pulmonary
food. arteries.
[6]
The endothelial cell dysfunction causes
Sildenafil is contraindicated in patients taking impaired production of vasodilators, such as nitric
nitrates or nitric oxide donors, and should not be oxide and prostacyclins, and overproduction of va-
Table II. Venice (2003) clinical classification of pulmonary hypertension
[44]a
Group 1 Pulmonary arterial hypertension (PAH)
idiopathic PAH
familial PAH
associated with connective tissues disease, congenital systemic-to-pulmonary shunts, portal hypertension, HIV,
infection, drugs and toxins (e.g. anorexigens), other disorders (thyroid disease, glycogen storage disease
Gauchers disease, hereditary haemorrhagic telangiectasia, haemoglobinopathies, myeloproliferative disorders,
splenectomy)
associated with significant venous or capillary involvement (pulmonary veno-occlusive disease, pulmonary
capillary haemangiomatosis)
persistent pulmonary hypertension of the newborn
Group 2 Pulmonary venous hypertension associated with left heart disease
Group 3 Pulmonary hypertension associated with hypoxia or respiratory disease
Group 4 Pulmonary hypertension due to chronic thromboembolic disease
Group 5 Miscellaneous
a Updated version of the classification developed at a WHO meeting at Evian in 1998.
soconstrictors, such as endothelin-1. These factors capacity and haemodynamics; however, this costly
present targets for specific PAH therapies.
[1,6]
therapy is complicated by the need to administer it
as a continuous intravenous infusion through a cen-
Patients with PAH can be classified according to
tral venous catheter. Acute tachyphylaxis can be a
their functional status (table III), which can affect
common event and frequent dose titrations are re-
treatment recommendations. Overall, most random-
quire with this agent.
[8,42]
Interruption of the infusion
ized clinical trials of PAH therapies have involved
can result in rapid deterioration of the patients
patients in functional classes III and IV; there are
condition.
[8]
Treprostinil, another prostacyclin ana-
limited data for patients in functional class II and
logue, is longer acting than epoprostenol and can be
very few data for functional class I.
[43,45]
Guidelines
administered by continuous subcutaneous infusion
[8]
on the treatment of PAH produced in 2004 by the
or intravenously.
[45]
Iloprost is a prostacyclin ana-
ESC
[43]
and ACCP
[46]
were generally in agreement;
logue available in an aerolized formulation, which is
however, an update to the ACCP guidelines was
inhaled via a nebulizer 69 times daily; however,
published in 2007,
[45]
which took into account new
therapeutic concentrations may not be maintained
data, and this update now includes recommenda-
overnight when there is a prolonged interval be-
tions for patients in functional class II (table IV).
Historically, conventional treatment of PAH
(anticoagulation, digoxin, diuretics and oxygen) was
largely supportive.
[6]
Later, calcium channel ant-
agonists were found to provide benefit in a limited
number of patients with idiopathic PAH who have a
positive response to acute vasodilatory testing.
[7]
More recently, specific therapies for PAH have been
developed, targeting the three main pathobiological
pathways implicated in PAH: (i) the prostacyclin
pathway (prostanoids such as epoprostenol, trepros-
tinil, iloprost); (ii) the endothelin pathway (endothe-
lin-receptor antagonists such as bosentan); and (iii)
the nitric oxide pathway (PDE5 inhibitors such as
sildenafil).
[7]
Epoprostenol was the first specific PAH therapy
to be approved. Long-term therapy with epopros-
tenol improves survival and QOL as well as exercise
Table III. WHO functional classification of pulmonary arterial
hypertension
[44]a
Class I Without limitation of physical activity. Ordinary
activity does not cause undue dyspnoea,
fatigue, chest pain or near syncope
Class II Slight limitation of physical activity. Comfortable
at rest, but ordinary activity causes undue
dyspnoea or fatigue, chest pain, or near
syncope
Class III Marked limitation of physical activity.
Comfortable at rest, but less than ordinary
activity causes undue dyspnoea or fatigue,
chest pain, or near syncope
Class IV Inability to carry out any physical activity without
symptoms. Signs of right heart failure, dyspnoea
and/or fatigue may be present at rest, and
discomfort is increased by any activity
a Modified from the New York Heart Association functional
classification.
394 Croom & Curran
Table IV. Drug treatment recommendations for patients with pulmonary arterial hypertension (PAH) from major guidelines
[43,45]
Step Patients ACCP (2007) ESC (2004)
1 FC II-IV (ACCP), or III and IV (ESC) Anticoagulants, diuretics, oxygen Anticoagulants, diuretics, oxygen,
digoxin
2 FC II-IV (ACCP), or III and IV (ESC) Calcium channel antagonist trial in Calcium channel antagonist in suitable
suitable patients
a
,
b
patients
a
3 FC II Sildenafil (PO) or treprostinil (SC or IV)
3 FC III Sildenafil (PO) or bosentan (PO) or Sildenafil (PO) or bosentan (PO) or
epoprostenol (IV) or iloprost (INH) or epoprostenol (IV) or iloprost (INH) or
treprostinil (SC or IV) treprostinil (SC)
c
or beraprost
c
3 FC IV Epoprostenol (IV) or bosentan (PO) or Epoprostenol (IV)
d
or bosentan or
iloprost (INH) or sildenafil (PO) or treprostinil (SC)
c
or iloprost (IV)
c
treprostinil (SC or IV)
d
4 FC III or IV with no improvement after Combination therapy (with two out of Combination therapy
monotherapy with a specific PAH prostanoid, bosentan, sildenafil)
therapy
a Patients with positive acute vasodilator response (decrease in mean pulmonary artery pressure of 10 to 40 mmHg with an
increased or unchanged cardiac output). If a sustained response is not achieved with treatment, follow recommendations for specific
PAH therapies for individual FC classes.
b If patient does not have idiopathic PAH or PAH associated with anorexigen use, or has an advanced functional class, consider
using a specific PAH therapy.
c Not available in Europe.
d Unstable patients in FC IV should receive epoprostenol.
ACCP = American College of Chest Physicians; ESC = European Society of Cardiology; FC = functional class; INH = inhaled;
IV = intravenous; PO = oral; SC = subcutaneous.
tween doses.
[8]
The routes of administration required Sildenafil, the first PDE5 inhibitor approved for
for prostanoids means treatment can be complex for the treatment of PAH, is also administered orally. At
the patient. the approved dosage of 20 mg three times daily, this
agent has demonstrated efficacy in terms of exercise Bosentan, an endothelin-receptor antagonist, was
capacity (in both functional class II and class III the first specific PAH therapy approved by the US
PAH patients) and haemodynamics and improved FDA that could be administered orally. It improves
functional class in a trial of 12 weeks in duration exercise capacity, haemodynamics and functional
(section 4.1.1). Data from an extension trial (up to class.
[8]
A comparison of outcomes from the open-
1 year) demonstrate continued efficacy over the long label extension trials of the BREATH (Bosentan:
term and suggest a positive effect on survival; how- Randomized Trial of Endothelin Receptor Ant-
agonist THErapy for Pulmonary Hypertension) trial ever, these data are only available for a dosage
with those of the NIH PAH registry demonstrated a higher than that approved for this indication (section
survival benefit for bosentan,
[47]
and a prospective 4.1.2) and require confirmation in comparative trials
study with a historical control has also indicated a using the approved dosage of 20 mg three times
possible survival advantage with bosentan.
[48]
How- daily. Sildenafil is generally well tolerated (section
ever, well controlled prospective clinical trials are 5). Because sildenafil is not associated with abnor-
needed to confirm these results. Bosentan can be mal liver function, recipients of this agent are not
associated with elevated hepatic enzymes. In recipi- subject to the monthly liver function tests associated
ents of this agent, the FDA requires that liver func- with bosentan treatment. Unlike bosentan, sildenafil
tion tests are performed at least once monthly, with is also not associated with a teratogenic potential.
the European Medicines Agency recommending Sildenafil recipients are also not subject to the injec-
monthly administration of these tests.
[43]
Two selection-related events seen with infused prostanoids.
[8]
tive endothelin-A receptor antagonists, sitaxsentan Like bosentan, sildenafil has the potential for a
(Canada, Australia and Europe)
[49,50]
and am- number of significant drug interactions (section
brisentan (US)
[49,51,52]
are also approved for PAH. 3.2).
There are limited data comparing sildenafil with recommended as first-line therapy for critically ill
other drugs used to treat PAH. In a small trial in patients.
[45]
In the US, the prescribing information
26 patients with functional class III PAH, sildenafil for sildenafil does not specify a particular functional
reduced right ventricular mass to a similar extent as class of PAH, although it notes that most data was
bosentan; however, the dosage of sildenafil evalu- obtained from trials in patients in classes IIIV.
[22]
ated was higher than the approved dosage. Larger In Europe, sildenafil is approved specifically for use
trials comparing the approved dosage of sildenafil in patients with functional class III PAH,
[20]
which is
with bosentan and with other PAH therapies would consistent with the treatment recommendations in
be valuable. Trials with sildenafil have largely en- the 2004 ESC guidelines (which were published
rolled patients with idiopathic PAH or PAH asso- prior to the approval of sildenafil) [table IV].
[43]
ciated with connective tissue diseases, and well de-
Combination therapy using drugs with different
signed studies of sildenafil in patients with other
mechanisms of action may appear to be an attractive
types of PAH (e.g. associated with HIV infection,
option for some patients with PAH, particularly if
portal hypertension or uncorrected congenital shunt)
they are not responding adequately to a single
would be helpful to establish its potential role in
agent.
[45]
The ACCP guideline suggests using com-
these patients.
bination therapy (two out of sildenafil, bosentan and
a prostanoid) in class III or IV patients who have not Oral medications, such as sildenafil and bosen-
responded to treatment.
[45]
However, at present there tan, are more convenient for patients than intrave-
is a lack of data from well designed trials on combi- nous, subcutaneous or inhaled preparations, and
nation therapy. The addition of bosentan to epopros- avoid the risk of injection-related adverse effects. In
tenol did not provide significant benefit in terms of addition, they do not need expensive equipment or
total pulmonary resistance compared with the addi- special training, which could help limit the costs
tion of placebo in one small trial.
[53]
In another associated with treatment.
[8]
However, care should
placebo-controlled trial, the addition of inhaled ilo- be taken to ensure that patients on this oral med-
prost to bosentan improved exercise capacity.
[54]
ication are getting a complete work-up and that they
The addition of sildenafil to epoprostenol has been are referred to a PAH centre for further manage-
shown to significantly increase exercise capacity in ment. Pharmacoeconomic data on the use of
patients with PAH; however, the sildenafil dosages sildenafil in the treatment of PAH would be of
evaluated were higher than the approved dosage interest.
(section 4.3). In relation to combination therapy, it is
The 2007 updated guideline from the ACCP sug-
possible that the mutual pharmacokinetic interaction
gests that sildenafil may be the preferred choice of
between sildenafil and bosentan (section 3.2) could
therapy for most PAH patients in functional class II,
have an effect on the dosages that should be used
because of its efficacy and the ability to administer
with this combination; however, the clinical effect
this agent orally.
[45]
The guideline indicates that
of this interaction has not yet been established.
sildenafil or bosentan should be first-choice therapy
Other studies of combination therapy are ongoing,
for patients with early functional class III PAH, and
including evaluations of sildenafil with bosentan or
the choice between these agents may depend on
with iloprost.
[55]
their adverse event profiles. For example, physi-
Other PDE5 inhibitors, such as tadalafil, are cur-
cians might decide to give bosentan to patients who
rently being evaluated for PAH.
[49]
The position of
are at risk of epistaxis or have eye disease, while
sildenafil relative to the selective endothelin-A re-
patients with liver disease or who cannot have
ceptor antagonists, sitaxsentan and ambrisentan,
monthly liver function tests might be given
will also need to be established in the future.
sildenafil.
[45]
The guideline notes that patients with
advanced class III disease may need to be given a In conclusion, sildenafil is an effective oral treat-
prostanoid. According to the ACCP guideline, ment for adults with PAH. It improves exercise
sildenafil can be considered for class IV patients; capacity in patients with idiopathic PAH or PAH
however, generally intravenous therapy is preferred associated with connective tissue disease or repaired
for these patients and, in particular, epoprostenol is congenital systemic-to-pulmonary shunts, and is
396 Croom & Curran
primary pulmonary hypertension. Chest 2004 Feb; 125 (2):
generally well tolerated in these patients. Sildenafil
580-6
also provides benefits in terms of exercise capacity
15. Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on the
acute pulmonary vasodilator response to inhaled nitric oxide in
when added to epoprostenol; however, this finding
adults with primary pulmonary hypertension. Am J Cardiol
needs to be confirmed in trials that use the approved
2002 Sep 15; 90 (6): 677-80
dosage of sildenafil. Thus, sildenafil is an effective
16. Ghofrani HA, Wiedemann R, Rose F, et al. Combination ther-
apy with oral sildenafil and inhaled iloprost for severe pulmon-
oral agent for use in the treatment of patients with
ary hypertension. Ann Intern Med 2002 Apr 2; 136 (7): 515-22
PAH.
17. Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus
oral sildenafil in patients with primary pulmonary hyperten-
sion. Circulation 2001 Sep 11; 104 (11): 1218-22
Disclosure
18. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differ-
ences in hemodynamic and oxygenation responses to three
different phosphodiesterase-5 inhibitors in patients with pul-
external funding. During the peer review process, the manu-
monary arterial hypertension: a randomized prospective study.
J Am Coll Cardiol 2004 Oct 6; 44 (7): 1488-96 facturer of the agent under review was offered an opportunity
19. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for to comment on this article. Changes resulting from comments
treatment of lung fibrosis and pulmonary hypertension: a ran-
received were made on the basis of scientific and editorial
domised controlled trial. Lancet 2002 Sep 21; 360 (9337): 895-
merit.
900
20. Pfizer Ltd. Summary of product characteristics: Revatio
20 mg
film-coated tablets. Aug 2007 [online]. Available from URL:
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6 months for a 50-mg implant. There

(nicardipine HCI) prescribing

(nifedipine) prescribing information

Complete seroconversion was evident after the

At all timepoints from months 2 to 48, anti-V5

Anti-HPV 16 and and anti-HPV 18 neutralizing

This sustained antibody response was associated

At month 7, peak GMTs were 313-fold (HPV 16)

In another bridging study, anti-HPV 16 and anti-

In both studies, seroconversion rates of 100% for

Anti-HPV antibodies must be present within the

Additional analysis with these three cases ex-

Women who had evidence of previous infection

The AS04-adjuvanted HPV 16/18 vaccine was

Cross-protection against incident

In the phase II trial, the vaccine demonstrated

In addition, the HPV 16/18 vaccine demonstrated

The HPV 16/18 vaccine also affords cross-pro-

In placebo recipients who were HPV 16/18 ser-

The AS04-adjuvanted HPV 16/18 vaccine show-

The AS04-adjuvanted HPV 16/18 vaccine was

The safety and tolerability profile of the HPV 16/

Combined data from clinical trials showed that

Results from individual phase II or III trials were

). Drugs contribution of cross-protection [abstract no. O-1472]. 46th

in healthy females 18-45

Plasma noradrenaline levels in patients with mild

As well as significantly reducing BP, the addi-

Peak plasma concentrations of amlodipine and

When administered as individual components,

Amlodipine is extensively (90%) metabolized

Both amlodipine and valsartan are associated

24.1 mmHg) or val-

20 mmHg for both 160 and

15.9 mmHg) were

Subgroup analyses of studies 1 and 2, conducted doses of amlodipine (

11.5 mmHg) or valsartan

9.7 to 13.4 mmHg) monotherapy, or with place-

Reductions from baseline in mean sitting SBP

22.7 mmHg with

15.1 mmHg) or valsartan (

15.7 mmHg) monotherapy, or with placebo

More than 80% of patients treated with

In study 2, reductions from baseline in mean

28 mmHg with either dose of HCTZ could be increased to 25 mg/day. The

BP control was achieved in 76.4% and 71.1% of

At week 8, reductions in mean sitting SBP/DBP

11.3 mmHg with amlodipine/valsartan

9.3 mmHg with the lower

Week 8 data for reductions in mean sitting SBP

17.6 mmHg, from 149.5 mmHg at baseline to

21.0 mmHg, from 150.8 mmHg at base-

Amlodipine/valsartan was associated with signif-

35.8 mmHg), and in

43.0 mmHg) in a 6-week trial comparing the

Another 6-week study focusing on tolerability

The combined safety population from studies 1

Patients receiving combined therapy with

The incidence of headache was significantly

Amlodipine/valsartan 510 mg/160 mg or lisi-

Fig. 2. Tolerability data from 3155 patients with mild to moderate

In the phase IIIbIV trial in which patients with