Professional Documents
Culture Documents
ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garca
(Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France),
Jaap Deckers (The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl
(Sweden), Gianfranco Mazzotta (Italy), Keith McGregor (France), Joa ~o Morais (Portugal), Ali Oto (Turkey),
Otto A. Smiseth (Norway)
Document Reviewers, Maria Angeles Alonso Garca (CPG Review Coordinator) (Spain), Diego Ardissino (Italy),
Cristina Avendano (Spain), Carina Blomstro m-Lundqvist (Sweden), Denis Cle ment (Belgium), Helmut Drexler
(Germany), Roberto Ferrari (Italy), Keith A. Fox (UK), Desmond Julian (UK), Peter Kearney (Ireland), Werner Klein
ber (Denmark), Giuseppe Mancia (Italy), Markku Nieminen (Finland), Witold Ruzyllo (Poland),
(Austria), Lars Ko
Maarten Simoons (The Netherlands) Kristian Thygesen (Denmark), Gianni Tognoni (Italy), Isabella Tritto (Italy),
Lars Wallentin (Sweden)
0195-668X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ehj.2004.06.003
ESC Expert consensus document 1455
clinical judgement. This consensus document does not, competitively inhibited by ACE-I. The major effects of
however, override the individual responsibility of health angiotensin-II are summarized in Table 1.
professionals to make appropriate decisions in the cir-
cumstances of the individual patient, in consultation
ACE-Inhibitor classification
with that patient, and where appropriate and necessary
the patients guardian or carer.
ACE-I are classified in three categories according to the
group that binds the zinc atom of the ACE molecule into
those containing a sulfhydril, a carboxyl or a phosphoryl
Pharmacology group as zinc ligand (Table 2).4
Angiotensin converting enzyme inhibitors (ACE-I) com- The absorption is highly variable among ACE-I (2575%)
petitively inhibit the angiotensin converting enzyme.13 and food either has no effect or reduces the rate, but not
ACE is a non-specific enzyme involved in the metabolism the extent of absorption. Some ACE-I are pro-drugs and
of many small peptides, including the conversion of an- they remain inactive until they are converted into active
giotensin I, an inactive octapeptide, into angiotensin II. metabolites by hydrolysis in the liver or in the gastroin-
Kininase, an enzyme that catalyses the degradation of testinal tissue.13 The peak plasma drug concentrations
bradykinin and other potent vasodilator peptides, is also are reached 14 h after ingestion. Pro-drugs are more
Carboxyl-containing inhibitors
Cilazapril 10 80 1.255 daily 0.52.5 daily
Enalapril 11 88 2.520 b.i.d. 2.520 b.i.d.
Lisinopril 12 70 2.510 daily 2.55 daily
Perindopril >24 75 48 daily 2 daily
Quinapril 24 75 1040 daily 2.55 daily
Ramipril 814 85 2.510 daily 1.255 daily
Spirapril 1.6 50 36 daily 36 daily
Trandolapril 1624 15 14 daily 0.51 daily
Phosphinyl-containing inhibitors
Fosinopril 12 50 1040 daily 1040 daily
lipophylic and they have a better access to the target Inhibition of plasma ACE appears to be less important
tissue where they are converted to the active compound. during chronic administration. At this time, inhibition of
Most ACE-I and their metabolites are mainly excreted by ACE in different tissues (i.e., vessels, kidney, heart) may
the renal route, whereas fosinopril, zofenopril, trando- be more important in determining their pharmacological
lapril and spirapril display balanced elimination through effects.10
hepatic and renal routes.5 Captopril is eliminated more Since the mechanism of action of ACE-I is the same,
rapidly from the body, which accounts for its brief du- their effects are attributed to the class as a whole.
ration of action (<6 h), whereas ramiprilat (the active Nevertheless, there are important differences in the
metabolite of ramipril) and specially tandrolaprilat are binding affinity to tissue ACE and individual pharmaco-
eliminated more slowly than other ACE-I (Table 2). kinetic properties of individual drugs, which may result in
In patients with congestive heart failure reduced ab- marked differences in tissue concentration and in dif-
sorption and biotransformation may delay the onset of ferential clinical effects. However, the clinical relevance
effect. Due to diminished renal perfusion, renal excre- of such differences has never been demonstrated. In
tion may be reduced, leading to elevated maximum drug fact, all currently available ACE-I can be considered
plasma levels and prolonged duration of action. Thus, equally effective at lowering blood pressure. Therefore,
dose reductions are required in the presence of impaired the choice and dose of the ACE-I should be based on the
renal function (when creatinine clearance falls to 6 30 results of clinical trials where the benefit has been
ml/min).5 Fosinopril, spirapril, trandolapril and zofe- demonstrated.
nopril are excreted in both the urine and bile, so that
their clearance is not significantly altered by renal im- Effects of ACE-inhibitors
pairment (Table 2).
Haemodynamic effects
Mechanism of action ACE-I decrease total peripheral vascular resistances,
promote natriuresis but cause little change in heart
ACE-I competitively block the conversion of angiotensin-I rate.14 Local inhibition of ACE and angiotensin-II for-
into angiotensin-II reducing the circulating and local mation in specific target organs, such as the vascular
levels of angiotensin-II. ACE-I also reduce aldosterone and wall, is involved in these responses.
vasopressin secretion and decrease sympathetic nerve In normotensive and hypertensive patients without
activity as well as the trophic effects of angiotensin-II. congestive heart failure, ACE-I have little effect on car-
However, they do not inhibit the actions of angiotensin-II diac output or capillary wedge pressure. In contrast to
mediated via the activation of AT1 and AT2 receptors and other vasodilators, no reflex tachycardia is observed,
they do not interact directly with other components of possibly due to an effect on baroreceptor sensitivity,
the reninangiotensin system.14;6;7 In addition, ACE-I vagal stimulation and/or reduced stimulation of sympa-
may also inhibit kininase II and increase bradykinin levels, thetic nerve activity. Changes in heart rate during ex-
which in turn stimulates the B2 receptors leading to the ercise or postural changes are not impaired.11 ACE-I
release of nitric oxide NO, and vasoactive prostaglandins reverse cardiac hypertrophy in hypertensive patients12
(prostacyclin and prostaglandin E2).8;9 and reduce endothelial dysfunction in normotensive
1458 ESC Expert consensus document
patients with coronary artery disease, hypertension, effect in dilating postglomerular efferent than afferent
non-insulin-dependent diabetes mellitus and heart fail- arterioles, leading to a reduction in glomerular capillary
ure.6;1315 Improvement in endothelial function is related hydrostatic pressure and GFR.25 Natriuresis is due to the
to attenuation of vasoconstriction and to the increased improvement of renal haemodynamics, a decreased re-
bradykinin-induced production of endothelium-derived lease of aldosterone and bradykinin that exert direct
NO.14;15 tubular effects and inhibition of the direct renal effects
In patients with congestive heart failure ACE-I induce of angiotensin-II. ACE-I prevent progression of microal-
venous and arterial vasodilatation.14 Venous vasodilata- buminuria to overt proteinuria,26 attenuate the pro-
tion increases peripheral venous capacitance, reduces gression of renal insufficiency in patients with a variety
right atrial pressure, pulmonary arterial pressure, capil- of non-diabetic nephropathies27 and prevent or delay the
lary wedge pressures and left ventricular filling volumes progression of nephropathy in patients with insulin-
and pressures, producing a rapid relief of pulmonary con- dependent diabetes mellitus.28
gestion. The arterial vasodilator effect reduces peripheral
vascular resistances and increases cardiac output. Other effects
ACE-I improve cardiac relaxation and distensibility The renin-angiotensin system plays an important role in
acutely and their long-term use reduces hypertrophy and the pathogenesis and progression of atherosclerosis.6 In
blood pressure in hypertension.3;4;6 animal models, ACE-I can retard the development of
atherosclerosis.29;30 These antiatherogenic properties
Neurohormonal effects can be related to the inhibition of angiotensin-II forma-
Antiproliferative effects
Effects on fibrinolytic balance
ACE-I also exhibit antiproliferative effects (reduction of
ACE-I also modulate vascular fibrinolytic balance by de-
vascular and cardiac hypertrophy and extracellular matrix
creasing angiotensin-II, a potent stimulus for plasmino-
proliferation) and reduce ventricular remodelling after
gen activator inhibitor type 1 (PAI-1) synthesis and by
myocardial infarction.23;24 They reverse ventricular re-
increasing bradykinin levels a potent stimulus for tissue
modelling by reducing ventricular preload/afterload,
plasminogen activator.36 Thus, ACE-I lower plasminogen
preventing the proliferative effects of AII and sympathetic
activator inhibitor type 1 (PAI-1) concentrations and the
nerve activity and by inhibiting the aldosterone-induced
molar ratio of PAI-1 to tissue plasminogen activator.
cardiac hypertrophy and interstitial and perivascular fi-
ACE-I also counteract the platelet aggregation induced
brosis.11;12 In the hypertrophied heart ACE-I reduce car-
by angiotensin-II since they increased the production of
diac hypertrophy and improve diastolic function. ACE-I
NO and prostacyclin.
also prevent apoptosis of cardiac myocytes in pressure-
overloaded hearts.
Side-effects
Renal effects
ACE-I decrease renal vascular resistances and increase In most patients ACE-I are well tolerated, however,
renal blood flow and promote Na and water excretion. several adverse reactions may occur.1;2;37
Nevertheless, the Glomerular Filtration Rate (GFR) re- Hypotension. Symptomatic hypotension due to the
mains unchanged or falls slightly, and thus, filtration withdrawal of angiotensin-II mediated vasoconstrictor
fraction is decreased. This is due to the relatively greater tone can occur, especially after the first dose of an ACE-I,
ESC Expert consensus document 1459
particularly in patients with high plasma renin activity foetal abnormalities (i.e., oligohydramnios, pulmonary
(e.g., salt-depleted patients due to high doses of di- hypoplasia, foetal growth retardation, renal dysgenesis
uretics or with congestive heart failure). neonatal anuria and neonatal death).46
Dry cough appears in 5% to 10% of patients3840 and it Other side-effects, not related to ACE inhibition in-
is not always easy to distinguish that resulting from clude ageusia and other taste disturbances (especially in
pulmonary congestion or concomitant diseases, e.g., the elderly); neutropenia; and maculopapular rash.
respiratory disease.41 The aetiology is unknown, but it Neutropenia is rare and occurs more frequently in pa-
may be related to increased levels of bradykinin and/or tients with renal or collagen vascular disease.
substance P in the lungs. Cough is not dose-dependent, is
more frequent among women and in Asian populations, it Contraindications
usually develop between 1 week and a few months of
treatment and sometimes requires treatment discontin- History of angioneurotic oedema, allergy and bilateral
uation, even if some patients may tolerate re-institution renal artery stenosis are absolute contraindications for
of the ACE-I after a drug-free period. Once therapy is initiation of ACE-I treatment. Although ACE-I are not
stopped, cough usually disappears within 3-5 days. There contraindicated in women of reproductive age, they
are no differences in the propensity of cough among the should be discontinued as soon as pregnancy is suspected
different ACE-I. or diagnosed.4;4648 Low blood pressures (systolic blood
Hyperkalemia due to a decrease in aldosterone se- pressure <90 mmHg) during ACE-I treatment are accept-
cretion is rarely found in patients with normal renal able if the patient is asymptomatic. If potassium rises to
daily doses of different agents and Table 4 the initial and compared to 35.2% in the active treatment group. This
target doses in patients with chronic heart failure. equates to 45 fewer deaths per 1000 patients treated or a
number needed to treat for one year to save one life
(NNT) of 22 for 3.5 years to prevent or postpone one
Clinical efficacy and practical use
premature death. In the large trials, ACE-I clearly re-
duced hospital admission rates (admissions for all causes
The benefits of and clinical indications to the ACE-I have
but particularly those related to worsening heart fail-
been clearly defined in many cardiovascular conditions
ure). For example, in SOLVD, the NNT was 4.5 for 3.5
and agreement as to their potential usefulness has been
years to prevent one hospitalisation for heart failure and
established in chronic heart failure, asymptomatic left
3.0 for all-cause hospitalisation.
ventricular dysfunction, acute myocardial infarction,
In the second Vasodilator Heart Failure Trial (VheFT-
hypertension and in patients with high risk for cardio-
II)56 the effect of enalapril was compared with that of a
vascular events. The presence of diabetes in the afore-
combination of hydralazine and isosorbide dinitrate in
mentioned conditions identifies a subgroup of particular
men with heart failure. Mortality after two years was
benefit. General recommendations for the use of ACE-I
significantly lower in the enalapril arm than in the hy-
include the control of blood pressure, renal function and
dralazine-isosorbide dinitrate arm (18% vs. 25%). The
serum K ; the starting dose should be low and progres-
lower mortality in the enalapril arm was attributable to a
sively increased, especially in patients with hypotension
reduction in the incidence of sudden death, and this
or heart failure.
beneficial effect was more prominent in patients with
ferent in the two treatment groups, but the combined However, no relationship was found between the dose of
end-point of all-cause death and all-cause hospitalisation enalapril and the clinical outcome during 24 weeks fol-
was significantly less common in patients receiving high low-up. Deaths in each group were 4.2%, 3.3% and 2.9%,
dose treatment, as was the overall number of hospitali- respectively (ns). The combined end-point of death,
sations (24% reduction). For this reason, the higher tar- heart failure related hospitalisation or worsening heart
get doses of ACE-I selected in the key clinical trials are failure was also similar (12.3%, 12.9% and 14.7%, re-
also recommended in clinical practice, although there is spectively; ns) in each group.
probably only a small benefit when comparing interme- It is notable that neither the ACE-I ATLAS or NETWORK
diate and high doses of ACE-I. trials showed differences in end-points between inter-
In the NETWORK trial63 patients with NYHA class II-IV mediate and high dose. In conclusion, clinicians should
heart failure were randomised to receive enalapril 2.5 aim to achieve the targed dose defined in the relevant
mg twice daily, 5 mg twice daily, or 10 mg twice daily. clinical trials, providing the dose is well tolerated.
1462 ESC Expert consensus document
Practical guidance on using ACE-I in heart failure is given failure, to placebo or enalapril. Most patients had coro-
in Table 4.64 nary heart disease and prior MI. After an average of 3.12
years of follow-up, active therapy reduced the risk of
ACE-I compared with angiotensin receptor blockers death or hospitalisation for new or worsening heart
failure from 24.5% to 20.6%. There were approximately
The clinical efficacy of ACE-I has been compared with
70 fewer hospitalisations for worsening heart failure per
that of direct angiotensin-II receptor antagonists in
1000 patients treated (NNT for 3 years 14). The risk of
several trials. In most of the studies, the angiotensin-II
developing heart failure was reduced from 38.6% to
inhibitors were not superior to the comparator ACE-I. In
29.8% and the median length of time to the development
the second losartan in heart failure survival study
of heart failure increased from 8.3 months in the placebo
(ELITE-2)65 mortality in 3152 patients with chronic heart
group to 22.3 months in the ACE-I group. Neither all
failure was similar in losartan and captopril allocated
cause death nor hospitalisations from any cause were
groups, after a follow-up of 555 days (11.7% vs. 10.4%,
reduced significantly by ACE-I treatment in SOLVD-P
respectively). In the Optimal Trial in Myocardial Infarc-
original follow-up of 3.2 years. However Jong et al.71
tion with the Angiotensin II Antagonist Losartan (OPTI-
recently reported a significant decrease in mortality
MAAL)66 5447 patients with heart failure after infarction
(50.9% vs. 56.4%) during an 11.3 years extension of fol-
were randomly allocated to receive losartan or cap-
low-up of the SOLVD-P. Interestingly, enalapril signifi-
topril. Mortality after 2.7 years of follow-up was similar
cantly reduced the incidence of diabetes in patients with
in both treatment groups (18% and 16% respectively). In
left ventricular dysfunction, especially those with im-
the Valsartan in Acute Myocardial Infarction (VALIANT)
Two types of large outcome trials have been carried reinfarction, post infarction angina, cardiogenic shock
out with ACE-I in patients with AMI: early and late in- and stroke did not differ between lisinopril patients and
tervention trials. A number of short term treatment trials controls.
with early interventions enrolled relatively unselected In the CCS-1 study87 13,634 patients with AMI were
patients: the 2nd Cooperative New Scandinavian Enala- randomised to received captopril or placebo. A trend
pril Survival Study (CONSENSUS-2),84 the 4th Interna- toward 35-day mortality reduction (9.1% vs. 9.6%; ns)
tional Study of Infarct Survival (ISIS 4),85 the 3rd Study of was observed.
These data suggest that ACE-I may have a role in early approximately 2.5 years, to prevent or postpone 1 pre-
management as well as in the convalescence phase of mature death). These trials also showed that ACE-I reduce
acute MI but only in high risk groups. If treatment is the risk of developing heart failure and requiring hospi-
initiated early, i.v. enalapril should be avoided; the ini- talisation for heart failure. With ACE-I treatment, the risk
tial dose should be low and increased progressively of reinfarction was reduced from 13.2% to 10.8% and the
within 48 h with monitoring of blood pressure and renal risk of heart failure hospitalisation from 15.5% to 11.9%.
function. As a result of these trials there was debate about how
Late intervention trials. The trials including selected ACE-I should be used in MI. One approach advocated the
high risk patients with treatment initiated later (>48) treatment of all patients initially, with continued treat-
after AMI and continued long term demonstrated a ment only in those with clinical evidence of heart failure
greater benefit obtained from the treatment with ACE-I. or left ventricular systolic dysfunction. Others argued
In the SAVE study31 2230 patients with a LVEF <40% that the small benefit of acute therapy in unselected
were randomised 3 to 16 days after infarction to receive patients was actually concentrated in high risk patients
captopril or placebo. Mortality at an average follow-up of and that only these should be treated, though treatment
42 months was lower in the captopril group (20% vs. 25%). should be given indefinitely. This debate has been su-
In addition, the incidence of fatal or non-fatal major perseded following completion of the Heart Outcomes
cardiovascular events was also reduced in the captopril Protection Evaluation (HOPE) study34 and the EURopean
group, including the risk for developing heart failure, trial On reduction of cardiac events with Perindopril in
hospitalisation and reinfarction. These benefits were stable coronary Artery disease EUROPA trial,90 both
heart failure, reduced systolic left ventricular ejection In the Perindopril Protection against Recurrent Stroke
fraction or diabetes, previous myocardial infarction or Study (PROGRESS)99 6,105 hypertensive and non-hyper-
stroke and patients with high coronary disease risk, tensive patients with a history of stroke or transient is-
based on the efficacy of these drugs in these patient chaemic attack, were randomly assigned active
populations9193 (Table 6). treatment (perindopril, with the addition of indapamide
In the second Swedish Trial in Old Patients with hy- at the discretion of treating physicians) or placebo. The
pertension (STOP-2)94 6,614 patients aged 7084 years primary outcome was total stroke. After a follow-up of 4
with hypertension were randomly assigned conventional years active treatment reduced the incidence of stroke
antihypertensive drugs (atenolol, metoprolol, pindolol, (10% vs. 14%) and also the risk of total major vascular
or hydrochlorothiazide plus amiloride) or newer drugs events. The reduction of stroke was similar in hyper-
(enalapril or lisinopril, or felodipine or isradipine). Blood tensives and normotensives. Combination therapy with
pressure was decreased similarly in all treatment groups. perindopril and indapamide produced larger blood pres-
The primary combined end-point of fatal stroke, fatal sure reductions and larger risk reductions (43%) than did
myocardial infarction, and other fatal cardiovascular single drug-therapy with perindopril alone. Single-drug
disease was similar in the different treatment groups. therapy produced a clinically relevant reduction in the
The combined end-point of fatal and non-fatal stroke, risk of stroke.
fatal and non-fatal myocardial infarction, and other In a meta-analysis by the blood pressure lowering
cardiovascular mortality was also similar. treatment trialists collaboration,100 the overview of
One of the secondary objectives of the Appropriate placebo-controlled trials of ACE-I (four trials, 12,124
33,357 hypertensives with at least one other cardiovas- patients. Enalapril failed to reduce the severity of coro-
cular risk factor. Patients were divided into 3 groups to nary lesions as compared with placebo.
receive chlorthalidone, amlodipine or lisinopril. The Several large multicenter trials were designed to test
primary outcome was cardiovascular death or non-fatal whether an ACE-I reduces major cardiovascular events in
myocardial infarction. Secondary outcomes included all- populations selected for coronary or other vascular dis-
cause mortality, stroke, and different combined cardio- eases, including the Heart Outcomes Prevention Evalua-
vascular outcomes including coronary revascularisation, tion Study (HOPE), the EURopean trial On reduction of
angina with hospitalisation, heart failure and peripheral cardiac events with Perindopril in stable coronary Artery
vascular disease). The follow-up period was 4.9 years. disease (EUROPA), the Prevention of Events with Angio-
Although the primary outcome failed to demonstrate a tensin-Converting Enzyme Inhibition (PEACE) and the
difference between treatments, and all cause mortality telmisartan alone and in combination with ramipril glo-
was also similar for lisinopril vs. chlorthalidone. Lisino- bal endpoint trial (ONTARGET) trials.
pril had higher 6-year rates of combined cardiovascular The HOPE trial34;107109 enrolled 9297 men and women
disease (33.3% vs. 30.9%); stroke (6.3% vs. 5.6%); and HF with either confirmed arterial disease (known coronary
(8.7% vs. 7.7%), and this brings into question use of ACE-I heart disease, peripheral arterial disease, stroke) or di-
as first line therapy in hypertensive patients without high abetes and one other risk factor (hypertension, cigarette
risk profile or heart failure. smoking, microalbuminuria or dyslipidaemia). Of note,
In summary, it seems that the level or blood pressure 80% of patients had coronary heart disease, 55% had a
reduction is more important than the specific treatment, history of angina, 52% prior MI, 43% peripheral arterial
tective effect of ACE-I in patients with coronary and 11. Giannettasio C, Grassi G, Seravalle G et al. Investigation of reflexes
other forms of atherosclerotic arterial disease. from volume and baroreceptors during converting-enzyme inhibition
in humans. Am Heart J 1989;117:7405.
Along the same lines of HOPE and EUROPA, the PEACE 12. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular
trial is testing the efficacy of ACE-I (trandolapril) in the hypertrophy in essential hypertension: A meta-analysis of random-
prevention of cardiovascular events in patients with ized double-blind studies. JAMA 1996;275:150713.
documented coronary artery disease with preserved 13. Thadei S, Virdis A, Ghiadoni L et al. Effects of angiotensin converting
enzyme inhibition on endothelium-dependent vasodilation in pa-
systolic function. Ongoing research also includes the
tients with essential hypertension. J Hypertens 1998;16:44756.
comparison and combination of ACE-I with angiotensin-II 14. Hornig B, Landmesser U, Kohler C et al. Comparative effect of ace
receptor blockers (telmisartan alone and in combination inhibition and angiotensin II type 1 receptor antagonism on bioavail-
with ramipril global end-point trial (ONTARGET).111 ) The ability of nitric oxide in patients with coronary artery disease: role of
after myocardial infarction. Results of the survival and ventricular 52. Shekelle PG, Rich MW, Morton SC et al. Efficacy of angiotensin-
enlargement trial. The SAVE Investigators. N Engl J Med converting enzyme inhibitors and beta-blockers in the management
1992;327:66977. of left ventricular systolic dysfunction according to race, gender,
32. Yusuf S, Pepine CJ, Garces C et al. Effect of enalapril on myocardial and diabetic status. A meta-analysis of major clinical trials. J Am
infarction and unstable angina in patients with low ejection fraction. Coll Cardiol 2003;41:152938.
Lancet 1993;340:11738. 53. Flather M, Yusuf S, Kber L, Pfeffer M, Hall A, Murria G et al. for the
33. Teo KK, Yusuf S, Pfeffer M et al. for the ACE Inhibitors Collaborative ACE-Inhibitor Myocardial Infarction Collaborative Group. Long-term
Group. Effects of long-term treatment with angiotensin-converting ACE-inhibitor therapy in patients with heart failure or left-ventric-
enzyme inhibitors in the presence or absence of aspirin: a systematic ular dysfunction: a systematic overview of data from individual
review. Lancet 2002;360:103743. patients. Lancet 2000;355:1575781.
34. The Heart Outcomes Prevention Evaluation Study Investigators 54. The Consensus Trial Study Group. Effects of enalapril on mortality in
(HOPE). Effects of angiotensin-converting-enzyme inhibitor, ramip- severe congestive heart failure. N Engl J Med 1987;316:142935.
ril, on cardiovascular events in high-risk patients. N Engl J Med 55. The SOLVD Investigators. Effect of enalapril on survival in patients
2000;342:14553. with reduced left ventricular ejection fractions and congestive heart
35. Lonn EM, Yusuf S, Dzavik V et al. Effects of ramipril and vitamin E on failure. N Engl J Med 1991;325:293302.
atherosclerosis: the study to evaluate carotid ultrasound changes in 56. Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with
patients treated with ramipril and vitamin E (SECURE). Circulation hydralazine-isosorbide dinitrate in the treatment of chronic conges-
2001;103:91925. tive heart failure. N Engl J Med 1991;325:30310.
36. Vaughan D. The reninangiotensin system and fibrinolysis. Am J 57. Study Investigators. Effect of ramipril on mortality and morbidity of
Cardiol 1997;79(Suppl. 5):126. survivors of acute myocardial infarction with clinical evidence of
37. DiBianco R. Adverse reactions with angiotensin converting enzyme heart failure. The Acute Infarction Ramipril Efficacy. Lancet
inhibitors. Med Toxicol 1986;1:12241. 1993;342:8218.
38. Visser LE, Stricker BH, van der Velden J et al. Angiotensin converting 58. Narang R, Swedberg K, Cleland JG. What is the ideal study design for
71. Jong P, Yusuf S, Rousseau MF et al. Effect of nealapril on 12 year 88. Ambrosioni E, Borghi C, Magnani B for the survival of myocardial
survival and life expectancy in patients with left ventricular systolic infarction long term evaluation (SMILE) Study Investigators. The
dysfunction: a follow-up study. Lancet 2003;361:18438. effect of the angiotensin-converting-enzyme inhibitor on mortality
72. Vermes E, Ducharme A, Bourassa MG et al. Enalapril reduces the and morbidity after anterior myocardial infarction. N Engl J Med
incidence of diabetes in patients with chronic heart failure. Insight 1995;332:805.
from the studies of left ventricular dysfunction (SOLVD). Circulation 89. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications
2003;107:12916. for ACE inhibitors in the early treatment of acute myocardial
73. Kober L, Torp-Pedersen C, Carlsen JE et al. for the trandolapril infarction: systematic overview of individual data from 100 000
cardiac evaluation (TRACE) study group: a clinical trial of the patients in randomized trials. Circulation 1998;97:220212.
angiotensin converting enzyme inhibitor trandolapril in patients with 90. The EURopean trial On reduction of cardiac events with Perindopril
left ventricular dysfunction after myocardial infarction. N Engl J in stable coronary Artery disease Investigators. Efficacy of perin-
Med 1995;33:167076. dopril in reduction of cardiovascular events among patients with
74. Torp-Pedersen C, Kober L. Effect of ACE inhibitor trandolapril on life stable coronary artery disease: randomised, double-blind, placebo-
expectancy of patients with reduced left-ventricular function after controlled, multicentre trial (the EUROPA study). Lancet 2003;362:
acute myocardial infarction. TRACE Study Group. Trandolapril 7828.
Cardiac Evaluation. Lancet 1999;354:912. 91. Wood D, De Backer G, Faergeman O, Graham I, Mancia G and Pyo ra
la
75. Philbin EF, Rocco TA, Lindenmuth NW et al. Systolic versus diastolic K et al. for the Second Joint Task Force of European and other
heart failure in community practice: clinical features, outcomes, Societiesyon Coronary Prevention: European Society of Cardiology,
and the use of angiotensin-converting enzyme inhibitors. Am J Med European Atherosclerosis Society, European Society of Hypertension,
2000;109:60513. International Society of Behavioural Medicine, European Society of
76. Cleland JG. ACE inhibitors for diastolic heart failure? reasons not to General Practice/Family Medicine, European Network. Prevention of
jump to premature conclusions about the efficacy of ACE inhibitors coronary heart disease in clinical practice. Eur Heart J 1998;19:
among older patients with heart failure. Eur J Heart Fail 1434503.
atherosclerosis: the Simvastatin/enalapril Coronary Atherosclerosis 110. Sleight P, Yusuf S, Pogue J et al. Blood-pressure reduction and
Trial (SCAT). Circulation 2000;102:174854. cardiovascular risk in HOPE study. Lancet 2001;358:21301.
107. Arnold JMO, Yusuf S, Young J et al. on behalf of the HOPE 111. Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND
Investigators. Prevention of heart failure in patients in the Heart studies: challenges in improving prognosis. Am J Cardiol
Outcomes Prevention Evaluation (HOPE) study. Circulation 2002;89:18A25A.
2003;107:128490. m-Lundqvist C et al. for the Task Force on
112. Priori SG, Aliot E, Blomstro
108. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Sudden Cardiac Death of the European Society of Cardiology. Eur
Effects of ramipril on cardiovascular and microvascular outcomes in Heart J 2001;22:1374450.
people with diabetes mellitus: results of the HOPE study and MICRO- m-Lundqvist C et al. for the Task Force on
113. Priori SG, Aliot E, Blomstro
HOPE substudy. Lancet 2000;355:2539. Sudden Cardiac Death of the European Society of Cardiology. Update
109. Bosch J, Yusuf S, Pogue J et al. Use of ramipril in preventing stroke: on the guidelines for sudden cardiac death of the European Society
double blind randomised trial. Br Med J 2002;324;699702. of Cardiology. Eur Heart J 2003;24:135.