Cocharane Review Pharmacotherapy For Hypertension in The Elderly PDF

Pharmacotherapy for hypertension in the elderly (Review)
Musini VM, Tejani AM, Bassett K, Wright JM
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 12
http://www.thecochranelibrary.com

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure 14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Figure 15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 16. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Figure 18. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Figure 19. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Figure 20. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Figure 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Figure 22. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Figure 23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Figure 24. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Figure 25. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 29
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Analysis 1.1. Comparison 1 Antihypertensive drug therapy vs control in elderly 60 years or older, Outcome 1 Total
mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Analysis 1.2. Comparison 1 Antihypertensive drug therapy vs control in elderly 60 years or older, Outcome 2 Cardiovascular
mortality and morbidity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Analysis 1.3. Comparison 1 Antihypertensive drug therapy vs control in elderly 60 years or older, Outcome 3 Withdrawal
due to adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Analysis 2.1. Comparison 2 Antihypertensive drug therapy vs control in very elderly 80 years or older, Outcome 1 Total
mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Analysis 2.2. Comparison 2 Antihypertensive drug therapy vs control in very elderly 80 years or older, Outcome 2
Cardiovascular mortality and morbidity. . . . . . . . . . . . . . . . . . . . . . . . . . 71
Analysis 3.1. Comparison 3 Antihypertensive drug therapy vs control in elderly with ISH, Outcome 1 Total mortality. 72
Pharmacotherapy for hypertension in the elderly (Review) i
Analysis 3.2. Comparison 3 Antihypertensive drug therapy vs control in elderly with ISH, Outcome 2 Cardiovascular
morbidity and mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Analysis 3.3. Comparison 3 Antihypertensive drug therapy vs control in elderly with ISH, Outcome 3 Withdrawal due to
adverse effects 60 years or older. . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 77
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Pharmacotherapy for hypertension in the elderly (Review) ii

[Intervention Review]
Pharmacotherapy for hypertension in the elderly
Vijaya M Musini1 , Aaron M Tejani2 , Ken Bassett1 , James M Wright1

1 Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada. 2 Pharmacy
Services, Fraser Health Authority, Burnaby, Canada
Contact address: Vijaya M Musini, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia,
2176 Health Science Mall, Vancouver, BC, V6T 1Z3, Canada. vijaya@ti.ubc.ca.
Editorial group: Cochrane Hypertension Group.

Publication status and date: Edited (no change to conclusions), published in Issue 12, 2010.
Review content assessed as up-to-date: 31 May 2009.
Citation: Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database of
Systematic Reviews 2009, Issue 4. Art. No.: CD000028. DOI: 10.1002/14651858.CD000028.pub2.
ABSTRACT
Background
Elevated blood pressure (known as hypertension) increases with age, and most rapidly over age 60. Systolic hypertension is more
strongly associated with cardiovascular disease than diastolic hypertension, and occurs more commonly in older people. It is important
to know the benefits and harms of antihypertensive treatment of hypertension in this age group.
Objectives
To quantify antihypertensive drug effect on overall mortality, cardiovascular mortality and morbidity and withdrawal due to adverse
effects in people 60 years and older with mild to moderate systolic or diastolic hypertension.
Search strategy
Updated search of electronic database of EMBASE, CENTRAL, MEDLINE until Dec 2008; previous search of two Japanese databases
(1973-1995) and WHO-ISH Collaboration register (August 1997); references from reviews, trials and previously published meta-
analyses; and experts.
Selection criteria
Randomized controlled trials of at least one year duration in hypertensive elders (at least 60 years old) comparing antihypertensive drug
therapy with placebo or no treatment and providing morbidity and mortality data.
Data collection and analysis
Outcomes assessed were total mortality (including cardiovascular, coronary heart disease and cerebrovascular mortality); total cardio-
vascular morbidity and mortality (representing combined coronary heart disease and cerebrovascular morbidity and mortality); and
withdrawal due to adverse events.
Main results
Fifteen trials (24,055 subjects 60 years) with moderate to severe hypertension were identified. These trials mostly evaluated first-line
thiazide diuretic therapy for a mean duration of treatment of 4.5 years. Treatment reduced total mortality, RR 0.90 (0.84, 0.97); event
rates per 1000 participants reduced from 116 to 104. Treatment also reduced total cardiovascular morbidity and mortality, RR 0.72
(0.68, 0.77); event rates per 1000 participants reduced from 149 to 106. In the three trials restricted to persons with isolated systolic
hypertension the benefit was similar. In very elderly patients 80 years the reduction in total cardiovascular mortality and morbidity
Pharmacotherapy for hypertension in the elderly (Review) 1
was similar RR 0.75 [0.65, 0.87] however, there was no reduction in total mortality, RR 1.01 [0.90, 1.13]. Withdrawals due to adverse
effects were increased with treatment, RR 1.71 [1.45, 2.00].
Authors conclusions
Treating healthy persons (60 years or older) with moderate to severe systolic and/or diastolic hypertension reduces all cause mortality
and cardiovascular morbidity and mortality. The decrease in all cause mortality was limited to persons 60 to 80 years of age.
PLAIN LANGUAGE SUMMARY

Blood pressure lowering drugs reduce stroke and heart attack in elderly people with hypertension
Hypertension (high blood pressure) is common among elderly people and increases the risk of heart attack and stroke. An assessment
of all the trials of blood pressure lowering therapy in people with hypertension 60 years and over showed that treatment reduced death,
strokes and heart attacks. The benefit was similar if both the upper and lower number was elevated or only the upper number. In people
80 and over treatment did not reduce death but did reduce stroke.

Pharmacotherapy for hypertension in the elderly (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Antihypertensive drug therapy compared to control in elderly (60 years or older) for hypertension in the elderly
Patient or population: patients with hypertension in the elderly

Settings:
Intervention: Antihypertensive drug therapy
Comparison: control in elderly (60 years or older)
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
control in elderly (60 Antihypertensive drug

years or older) therapy
Total mortality - Elderly Study population RR 0.9 23119

60 years or older (0.84 to 0.97) (12 studies) low1
116 per 1000 104 per 1000
(97 to 113)
Low risk population
100 per 1000 90 per 1000

(84 to 97)
High risk population
300 per 1000 270 per 1000

(252 to 291)
Cardiovascular mortal- Study population RR 0.72 23094

ity and morbidity - El- (0.68 to 0.77) (13 studies) high
derly 60 years or older
3
153 per 1000 110 per 1000

(104 to 118)
Low risk population
150 per 1000 108 per 1000

(102 to 115)
400 per 1000 288 per 1000

(272 to 308)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 The upper confidence interval is approaching no effect.
4
BACKGROUND
Types of studies
Blood pressure increases with age, and the rate of rise is greater over
Only randomized controlled trials of at least one year duration
age 60. As a result the number of people with elevated blood pres-
were included. Trials must have included a control group that
sure (known as hypertension) increases with age. Systolic blood
either received a placebo or received no anti-hypertensive therapy.
pressure is more strongly associated with cardiovascular disease
Trials that compared two specific antihypertensive therapies were
than diastolic blood pressure particularly in older people. Iso-
excluded.
lated systolic hypertension occurs more commonly in older peo-
ple. Older people also accumulate higher rates of other risk factors
for cardiovascular disease including obesity, left ventricular hyper- Types of participants
trophy, sedentary life style, hyperlipidemia, and diabetes. Trials must include only people 60 or older or separately report
Most of the early trials evaluating antihypertensive drug therapy outcomes for people 60 or older. Participants must have a systolic
were conducted in lower risk people under age 60. The first blood pressure of at least 140 mmHg and/or a diastolic blood
definitive clinical trial evidence supporting blood pressure lower- pressure of at least 90 mmHg at baseline.
ing treatment was produced in the mid-1980s. Before that time,
policymakers and clinicians were reluctant to recommend treat-
Types of interventions
ment particularly in the elderly; some regarded systolic hyperten-
sion as a natural feature of aging, while others feared excessive Acceptable anti-hypertensive drug therapies include: angiotensin
harm from blood pressure lowering in this age group. converting enzyme inhibitors, angiotensin receptor antagonists,
beta adrenergic blockers, combined alpha and beta blockers, cal-
Since 1985, several large trials have been conducted, and several cium-channel blockers, diuretics, alpha adrenergic blockers, cen-
meta-analyses have summarized their results (Davidson 1987, tral sympatholytics, direct vasodilators or peripheral adrenergic
Staessen 1988, Staessen 1990a, Staessen 1990b, Leonetti 1992, antagonists. Drugs could have been administered alone or in com-
Thijs 1992, Celis 1993, MacMahon 1993, Thijs 1994, Insua bination or in fixed or stepped up regimens.
1994, Pearce 1995, Wright JM 1999, Gueyffier F 1999, HYVET
P 2003, HYVET 2008, Musini VM 2008). The purpose of this
systematic review is to summarize all the available evidence for the Types of outcome measures
benefits and harms of antihypertensive treatment for people aged Morbidity and mortality were defined as follows:
60 and above. Total mortality means deaths from all causes.
Coronary heart disease (CHD) mortality includes fatal
myocardial infarctions and sudden or rapid cardiac death.
OBJECTIVES Cerebrovascular mortality includes fatal strokes.
Cardiovascular mortality sums coronary heart disease
Primary: mortality and cerebrovascular mortality.
CHD morbidity and mortality includes fatal and non fatal
1. To quantify antihypertensive drug effect on overall mortality
myocardial infarctions and sudden or rapid cardiac death.
in people 60 years and older with mild to moderate systolic or
Cerebrovascular morbidity and mortality includes fatal and
diastolic hypertension.
nonfatal strokes.
Secondary: Cardiovascular morbidity and mortality includes CHD
plus cerebrovascular morbidity and mortality plus aneurysms,
2. To quantify antihypertensive drug effect on cardiovascular spe-
congestive heart failure and transient ischemic attacks.
cific morbidity and mortality in people 60 years and older with
mild to moderate systolic or diastolic hypertension.
Withdrawal due to adverse effects
3. To quantify withdrawal due adverse events.
When the primary trials did not report outcomes with exact defi-
Planned subgroup analyses included patients with isolated systolic nitions as listed above, the review authors categorized data to mini-
hypertension and the very elderly people 80 years or older. mize missing data while maintaining the intended study measures.
For example, the Medical Research Council Trial of Treatment of
Hypertension in Older Adults (MRCOA) includes deaths due
METHODS to hypertension in its definition of cardiovascular events. The
broad label deaths due to hypertension is not included in the
standard definition for cardiovascular morbidity and mortality
Criteria for considering studies for this review listed above. We include MRCOAs results in the cardiovascular
morbidity and mortality outcome measure because deaths due

to hypertension was congruous with the concept of cardiovascu- / at the end of a term indicates that it is a Medical Subject Head-
lar morbidity and mortality. The alternative, omitting MRCOAs ing (MeSH) term; exp indicates that the term is exploded mean-
data, would result in a more reliable measure but at the expense ing that all MeSH terms nested under the exploded MeSH term
of accuracy of the effect estimate. The number of differences in are included in the search; tw indicates that the term is a text
definitions was small and is unlikely to affect results. Supporting word meaning the title, abstract and MeSH terms are searched for
this assumption, previous meta-analyses found homogeneity of the term; hypertension/dt returns references coded as Drug Treat-
risk reduction among outcome measures suggesting differences in ment for hypertension; pt indicates a publication type; ti.ab
outcome definition were unlikely causes of bias. indicates a search for the text word in the title and abstract but not
One of the new trials included in the update (HYVET P 2003) the MeSH terms; the symbols $ and ? are wildcard characters
was not conducted according to the standards of Good Clinical used to search for multiple forms of a word; the search modifier
Practice Guidelines and did not collect data on serious adverse adj plus a number between any two terms returns records which
events, non-fatal MI or heart failure (personal communication contain the two terms within the specified number of words of
with the author). However, data on cardiovascular mortality and each other.)
morbidity was reported in the trial and is included in the meta- The updated search of Medline up to December 2008 identified
analysis. 162 citations. The titles and abstracts of this list were screened in-
The actual endpoints represented by each outcome measure for dependently by two reviewers (VM and AT) for inclusion which re-
each study are listed under the Outcomes heading of the sulted in the retreival of 31 full papers. One reviewer then screened
Characteristics of included studies table. Within each study the the 31 full papers and a further 3 RCTS were considered for po-
definition of endpoints for each outcome measure are identical tential inclusion into the review (Jikei 2007, ADVANCE 2007,
between the treatment and control groups. The individual non- SCOPE 2003). Three reviewers discussed and reached consensus
fatal outcomes included in the composite endpoint were included that the 3 RCTS did not meet the inclusion criteria and were ex-
as counted by the trialist of each study. Many trials did not report cluded. A search of CENTRAL up to June 2009 identified only
on how events were counted after patients were censored. Refer 1 additional citation (HYVET-Cog 2008) that was not identi-
to personal communication with author of HYVET 2008 trial in fied in the Medline search. The HYVET-Cog 2008 was retrieved
the risk of bias table to find out how events were counted in that however it was concluded that this substudy of the HYVET 2008
trial. trial did not provide any additional data for analysis. A search of
EMBASE was conducted up to December 2008 which identified
6 new citations however none of these met inclusion criteria based
Search methods for identification of studies on a review of titles and abstracts.
Bibliographies of newly identified meta-analyses, reviews and trials
The following sources were searched:
were examined for references to other trials.
Updated search of MEDLINE up to Dec. 2008, EMBASE (up
to Dec. 2008), CENTRAL (up to Dec. 2008, issue 4). The
previous version of this review included search of two Japanese
databases: JMEDICINE was searched in the previous review
Data collection and analysis
from 1981-1995 and JAPIC-DOC from 1973-1995 with the Data abstraction
keywords Hikaku-Shiken (comparative studies), Nijuu-Mouken- This review is based on five previously published meta-analyses on
Ho (double-blind method) and Hontaisei-Koketsuatsu (hyperten- the same topic (Mulrow 1994, Mulrow 1998, Wright JM 1999,
sion). This search produced 46 articles of which 34 were reports Gueyffier F 1999, Musini VM 2008). Data was abstracted using
of randomized controlled trials. Titles of the 34 RCTs were trans- a standard data abstraction form; dual abstraction of data from
lated into English by S Lee-Borges. The abstracts of three possibly the original reports of trial results by two independent reviewers;
relevant trials were translated into English. None met the inclu- and disagreements were resolved by discussion. The published
sion criteria of this review. results of these meta-analyses as well as data from additional trials
Thirteen other meta-analyses on antihypertensive drug therapy included in the updated review were compared by two reviewers
in the elderly have also been published (Davidson 1987, Staessen (VM and AT). Any disagreements were resolved by consensus
1988, Staessen 1990a, Staessen 1990b, Leonetti 1992, Thijs 1992, (JMW and KB) .
Celis 1993, MacMahon 1993, Thijs 1994, Pearce 1995, Wright Risk of Bias table
JM 1999, Gueyffier F 1999, Musini VM 2008). A review of the A quality scoring scheme was not used, but instead key trial charac-
reference lists in these review did not identify any additional studies teristics are detailed in the table Characteristics of included studies.
which met the inclusion criteria for this review. Potential parameters of methodological quality listed in the table
The MEDLINE search has been updated by searching from 1994 include: whether randomization was completed in an appropriate
through December 2008. The search strategy (Appendix 1) is de- and blinded manner; whether patients, providers and/or outcome
signed to identify pharmacological treatment of hypertension. (A assessors were blinded to assigned therapy; whether the control

group received a placebo; percent of participants who did not com- Two new randomised controlled trials met the inclusion criteria
plete follow-up (dropouts); and the percent of participants not (HYVET 2008 and HYVET P 2003). Two RCTs included in the
on assigned active or placebo therapy at study completion (cross- previous version were excluded in the update since the control
over). group was not an untreated or placebo control group. The HDFP
The updated review uses the Risk of Bias tool to assess each trial 1982 study was excluded since it is a multifactorial intervention
according to the Cochrane Handbook guidelines. (Ebrahim 2006). CASTEL 1994 was excluded since the control
Analyses group was receiving non-specific anti-hypertensive therapy from
Quantitative analyses of outcomes are based on intention-to-treat their personal physician.
results. Our measure of effect for each study was the Relative- Fifteen trials including 24,005 people age 60 or over were identi-
Risk (RR) with 95% CI. Chi-square tests for heterogeneity were fied. For most subjects included in this review the mean age ranged
used to assess outcome data for compatibility with the assumption from 63 to 84 years. Three trials (Carter 1970, HTN Coop 1974,
of a uniform relative risk (P>0.10). Pooled risk differences are VA Coop 1970) did not report mean age. Most trials were con-
converted to numbers needed to treat (NNTs) with the formula ducted in Western, industrialized countries and evaluated first-
NNT = 1/risk difference. NNTs are the number of patients who line diuretics (ANBP 1981, Carter 1970, EWPHE 1989, HYVET
must be treated to prevent one adverse outcome. 2008, HYVET P 2003, Kuramoto 1981, MRCOA 1992, SHEP
To test for robustness of results, several sensitivity analyses were 1991, SHEP-PS 1986, VA Coop 1970). Two trials evaluated beta-
performed. Data were analysed using both fixed effect and ran- blocker therapies (HEP 1986, STOP 1991). Four of these trials
dom effects models. As further tests of sensitivity, trials that were (Carter 1970, VA Coop 1970, HTN Coop 1974, ANBP 1981)
not blinded and placebo controlled were analysed separately from originally included both younger and older persons. Only data
blinded (subject and/or provider), placebo controlled trials. Re- on those older than 60 is reported. The average age across trials
sults were also analysed with and without those trials restricted was 73.8 years. The Swedish Trial in Old Patients with Hyperten-
to persons who had previously suffered a stroke. Results of tri- sion (STOP 1991) specifically evaluated people over age 70. The
als restricted to persons with isolated systolic hypertension were HYVET P 2003 and HYVET 2008 trials included patients 80
analysed both as a separate group and combined with trials also years or older.
assessing persons with both systolic and diastolic hypertension. Participants were recruited from industrialized countries: USA
Analyses in the very elderly (80 year or older) were planned be- (36%), UK (25%), European multi-site trials (25%), Sweden
cause a subgroup meta-analysis from earlier trials by Gueyffier F (7%), Italy (3%), Australia (3%) and Japan (<1%). HYVET P
1999 showed a trend towards increased mortality. Furthermore, 2003 trial recruited patients from Bulgaria (88%), Spain (3%),
two recent randomised trials HYVET P 2003 and HYVET 2008 Romania (3%), UK (2.5%) and Poland (1.5%) and from other
were specifically done in the very elderly group of patients. countries in smaller numbers (Finland, Lithuania, Ireland, Greece
Individual differences in patient characteristics or disease severity and Serbia). HYVET 2008 trial recruited patients from Western
are associated with different levels of risk to experience an adverse Europe (2.2%), Eastern Europe (55.8%), China (39.6%), Aus-
event. In the aggregate, these individual differences contribute to tralasia (0.5%) and Tunisia (1.9%).
the proportion of patients we expect to experience an event within 14,663 (59.5%) percent of the subjects were female. The four tri-
a population. Variation in level of risk in different patient popu- als based in the USA reported ethnicity African-American: SHEP
lations, both within and between clinical trials, is often associated 1991 (14%), SHEP-PS 1986 (18% non-white), VA Coop 1970
with variability in treatment outcomes (Ioannidis 1997, Schmid (41%), HTN Coop 1974 (78%). The ethnicity data from VA
1998). This average population risk is unknown, but contributes Coop 1970 and HTN Coop 1974 refer to the entire study pop-
to the proportion of events experienced by a placebo control group ulation, not the >60 year old sub-group. All subjects in ANBP
in a randomised trial. We use the term control rate to describe the 1981 and STOP 1991 were white. Nine trials including HYVET
probability that a member within the control group experiences P 2003 and HYVET 2008 did not report ethnicity.
the adverse event, and we use this sample value to estimate the Study populations predominantly consisted of ambulatory pa-
aggregate population risk for patients enrolled in a clinical trial. tients recruited from the community or primary care facilities. A
small proportion (6%) were recruited from hospitals or homes for
the aged. Studies did not consistently report data on pre-existing
conditions for subjects; available data follows. Two small studies
RESULTS were limited to stroke survivors (Carter 1970, HTN Coop 1974).
Six other trials reported the baseline prevalence of stroke. The sam-
ple-size-based weighted average prevalence across those six trials
Description of studies was 3.6%: SHEP-PS 1986 (1%), SHEP 1991 (1.4%), Syst-Eur
1991 (3.5%), Sprackling 1981 (11.3%), HYVET P 2003 (4.5%)
See: Characteristics of included studies; Characteristics of excluded
and HYVET 2008 (6.8%). Six trials reported the baseline preva-
studies.

lence of myocardial infarctions. The average prevalence across trials Syst-Eur 1991 started the treatment group on a calcium chan-
was 2.3%: ANBP 1981 (0.5%), Syst-Eur 1991 (1.2%), SHEP-PS nel blocker. HYVET P 2003 started one treatment arm on a di-
1986 (4%), SHEP 1991 (4.9%), HYVET P 2003 (3.0%), and uretic and other treatment arm with an ACE inhibitor. Second and
HYVET 2008 (3.1%). Two studies excluded patients with diabetes third line drugs included diuretics, beta-blockers, central acting
(ANBP 1981, MRCOA 1992), while three other trials reported anti adrenergic agents, peripheral acting anti adrenergic agents,
the baseline prevalence. The average prevalence across trials was vasodilators, converting-enzyme inhibitors and calcium channel
9.2%: HYVET 2008 (6.8%), SHEP 1991 (10.1%), HTN Coop blockers. See the Interventions heading in the Characteristics of
1974 (36%). Two trials reported the baseline prevalence of hyper- included studies table for a complete description of each studys
lipidemia: HTN Coop 1974 (22%) and ANBP 1981 (62.2%). drug treatment protocol.
Ten trials reported the baseline prevalence of smoking. The aver- Three trials maintained subjects on a particular therapeutic regi-
age prevalence across trials was 12.1%: HYVET P 2003 (4.2%), men (i.e. not stepped care) throughout the study. VA Coop 1970
HYVET 2008 (6.6%), Syst-Eur 1991(7.3%), SHEP-PS 1986 treated subjects with a combination diuretic - central acting anti
(11%), SHEP 1991(12.7%), EWPHE 1989 (16.4%), ANBP adrenergic agent (hydrochlorothiazide/reserpine) plus a vasodila-
1981 (17.5%), MRCOA 1992 (17.5%), HEP 1986 (24%), and tor (hydralazine). HTN Coop 1974 treated subjects with a di-
HTN Coop 1974 (60%). Only HTN Coop 1974 reported data uretic (methyclothiazide) and peripheral acting anti adrenergic
on prevalence of obesity (29%). agent (deserpidine). Sprackling 1981 treated subjects with a cen-
Entry diastolic blood pressure criteria also have varied somewhat tral acting anti adrenergic agent (methyldopa).
from trial to trial. However, trials in older persons have not rou- HYVET P 2003 trial randomized patients to three groups:
tinely included patients with higher diastolic blood pressures than no treatment, diuretic based treatment (usually bendrofluazide
trials in younger persons. 2.5mg) and an ACE-inhibitor based regimen (usually lisinopril
All trials except Carter 1970 reported the mean SBP and DBP 2.5mg). To attain target blood pressure (sitting SBP < 150 mmHg
at baseline. SHEP-PS 1986, SHEP 1991 and Syst-Eur 1991 re- and sitting DBP < 80 mmHg) in the actively treated groups, the
stricted recruitment to persons with isolated systolic hyperten- dose of diuretic or ACEI could be doubled (step 2), diltiazem slow
sion; defined as SBP 160-219 mm Hg and DBP <90 mm Hg release 120 mg could be added (step 3) and diltiazem slow release
(SHEP 1991, SHEP-PS 1986) or DBP < 95 mm Hg (Syst-Eur 240mg could be added as (Step 4).
1991). Mean blood pressure at entry in the 3 isolated systolic hy- HYVET 2008 trial randomized patients to either indapamide sus-
pertension trials was 172/81 mmHg. Two studies (Carter 1970, tained release 1.5 mg or matching placebo. In order to reach tar-
HEP 1986) recruited persons with isolated systolic hypertension, get blood pressure (SBP < 150 mmHg and DBP < 80 mmHg)
diastolic hypertension or systo-diastolic hypertension. Kuramoto perindropil 2 mg or 4 mg or matching placebo could be added.
1981 and MRCOA 1992 recruited patients with either isolated Length of study follow up ranged from relatively short: 1 year
systolic hypertension or systo-diastolic hypertension. HYVET P (HYVET P 2003) or 2 years (STOP 1991, Syst-Eur 1991, HYVET
2003 recruited patients with systolic and/or diastolic hypertension 2008), to relatively long: the rest of the trials lasting 3 to 6 years.
(SBP > 140 mmHg and DBP 90-109 mmHg). HYVET 2008 All of the trials were multi site studies except for Carter 1970 and
recruited patients with persistent hypertension defined as SBP of Kuramoto 1981. The mean duration of treatment was 4.5 years
160-199 mmHg and a DBP < 110mmHg. 32.5% of patients in in elderly (60 years or older) and 2.2 years in very elderly patients
HYVET 2008 had isolated systolic hypertension. The remainder (80 years or older) and 3.2 years in trials with isolated systolic
of the studies required that subjects DBP be at least 90 mm Hg. hypertension in the elderly.
Mean BP at entry in these 11 other trials was 182/95 mmHg.
See the Participants heading in the Characteristics of included
studies table for a complete description of each studys blood pres- Risk of bias in included studies
sure inclusion criteria. The mean sitting SBP/DBP in HYVET P
Twelve of the 15 trials employed some method of blinding.
2003 was 182/99.6 mmHg and in HYVET 2008 was 173/90.8
Twelve blinded subjects to therapy (VA Coop 1970, HTN Coop
mmHg.
1974, ANBP 1981, Kuramoto 1981, HEP 1986, SHEP-PS
Twelve of the 15 trials instituted a stepped care approach to hyper-
1986, EWPHE 1989, SHEP 1991, STOP 1991, MRCOA 1992,
tension treatment. In over 70% of trials a thiazide diuretic was the
Syst-Eur 1991, HYVET 2008). Of these, eleven (all but MRCOA
first line drug in the treatment group. Seven trials (Carter 1970,
1992) also blinded providers to therapy. Eight trials specifi-
ANBP 1981, Kuramoto 1981, SHEP-PS 1986, EWPHE 1989,
cally reported blinding outcome assessors (HEP 1986, SHEP-PS
SHEP 1991, HYVET 2008) started the treatment group exclu-
1986, EWPHE 1989, SHEP 1991, STOP 1991, MRCOA 1992,
sively on a thiazide diuretic. HEP 1986 and STOP 1991 started
Syst-Eur 1991, HYVET 2008).
the treatment group on either a diuretic or beta-blocker. MRCOA
Eleven trials were placebo controlled (VA Coop 1970, HTN Coop
1992 randomized the treatment group to two arms, one initially
1974, ANBP 1981, Kuramoto 1981, SHEP-PS 1986, EWPHE
receiving diuretics and the other initially receiving a beta-blocker.
1989, SHEP 1991, STOP 1991, MRCOA 1992, Syst-Eur 1991,

HYVET 2008). Four trials were no treatment controlled without medication because of adverse drug effects or because they achieved
placebo (Carter 1970, Sprackling 1981, HEP 1986, HYVET P normal blood pressures. The degree to which subjects cross over
2003). from one group to the other dilutes the results of the study. The
In nine of the trials the method of randomization is described percent of patients assigned to the control group which were re-
while in the remaining six trials randomization is mentioned, but ceiving antihypertensive medication by the end of the trial were
not described. See the Method heading in the Characteristics of as follows: HEP 1986 (9%), Kuramoto 1981 (17%), STOP 1991
included studies table for a description of each studys method of (23%), Syst-Eur 1991 (27%), ANBP 1981 (35%), SHEP-PS 1986
randomization and stratification, if any. (40%), SHEP 1991 (44%), MRCOA 1992 (53%), and EWPHE
Nine studies reported loss to follow-up figures of less than 5% 1989 (>35%), HYVET P 2003 (0.8%) and HYVET 2008 (0.6%).
(Carter 1970, ANBP 1981, Sprackling 1981, SHEP-PS 1986, The remaining four trials did not report such data. The percent of
SHEP 1991, STOP 1991, Syst-Eur 1991, HYVET P 2003, patients assigned to the treatment group which had ceased taking
HYVET 2008). Three studies reported loss to follow-up figures antihypertensive medication by the end of the trial were: HYVET
of 13-15% (VA Coop 1970, Kuramoto 1981, EWPHE 1989). P 2003 (4%), HYVET 2008 (0.5%), HEP 1986 (5%), SHEP
MRCOA 1992 experienced a loss to follow-up of 25%. The re- 1991 (10%), STOP 1991 (16%), Syst-Eur 1991 (18%), SHEP-PS
mainder (HTN Coop 1974, HEP 1986) did not report data on 1986 (30%), ANBP 1981 (33%), MRCOA 1992 - diuretic arm
numbers lost to follow-up. (48%), MRCOA 1992 - beta-blocker arm (63%), and EWPHE
Studies included in this review allowed subjects in the control 1989 (>35%). The remaining five trials did not report such data.
group to receive antihypertensive therapy because their blood pres- Figure 1 and Figure 2 show a summary of the Risk of Bias assess-
sure exceeded pre-set escape criteria. Also, a portion of the sub- ment.
jects assigned to the treatment group stopped taking their assigned

Figure 1. Methodological quality summary of each included trial

Figure 2. Methodological quality graph: Each methodological quality item presented as percentages across
all included studies.
Effects of interventions were restricted to stroke survivors (Carter 1970, HTN Coop
See: Summary of findings for the main comparison 1974). Removing these two trials from the analysis did not ap-
Antihypertensive drug therapy compared to control in elderly preciably affect the results. The relative risk point estimates and
(60 years or older) for hypertension in the elderly; Summary of confidence intervals did not shift by more than 0.01. Thus, all
findings 2 Antihypertensive drug therapy compared to control in results reported below include these two trials.
very elderly 80 years or older for hypertension There was homogeneity across studies with respect to all outcomes
Analyses were performed on the combined results of all 15 studies. except cardiovascular morbidity and mortality. Point estimates for
The three trials that included only people with isolated systolic the pooled log relative risk ratios were nearly identical between
hypertension (SHEP-PS 1986, SHEP 1991, Syst-Eur 1991) were the random and fixed effect analyses. Thus, all results are reported
included in the overall analyses and were also analysed separately. using the fixed effects model. In the very elderly patients there was
EWPHE 1989 reported intention-to-treat data for mortality only; homogeneity across studies for all outcomes except total mortality.
the morbidity data reported from EWPHE 1989 is not intention- Total mortality: The combined results of the 12 trials reporting
to-treat and is not included in the analysis. The occurrence of any total mortality data in people 60 years or older show a significant
trial endpoint in ANBP 1981 participants terminated their partic- benefit (RR=0.90, 95% CI 0.84 to 0.97; NNT=84) with event
ipation in the study. Thus, true intention-to-treat data for ANBP rates per 1000 participants reduced from 116 to 104 events with
1981 is only available for combined cardiovascular morbidity and 95% CI of the difference (3 to 19) for a mean duration of treat-
mortality. ment of 4.5 years, see Figure 3. STOP 1991 and HYVET 2008
Results were analysed with and without the two small trials that independently reached a statistically significant mortality benefit.

Figure 3. Forest plot of comparison: 1 Antihypertensive drug therapy vs control in elderly 60 years or older,
outcome: 1.1 Total mortality.
Analysis of trials in very elderly (80 years or older) showed no

reduction in total mortality for a mean duration of treatment of
2.2 years (RR = 0.98 95% CI 0.87 to 1.10; p = 0.72), see Figure
4 . There was significant heterogeneity between trials (RR = 1.06
95% CI 0.88 to 1.28 using random effects model).
Figure 4. Forest plot of comparison: 2 Antihypertensive drug therapy vs control in very elderly 80 years or
older, outcome: 2.1 Total mortality.

The three trials with isolated systolic hypertension did not achieve
a statistically significant reduction in mortality for a mean duration
of treatment of 3.2 years (RR=0.88, 95% CI 0.77 to 1.01; p =
0.07), see Figure 5.
Figure 5. Forest plot of comparison: 3 Antihypertensive drug therapy vs control in elderly with ISH,
outcome: 3.1 Total mortality.
Cardiovascular mortality: The combined results of the 10 trials

reporting cardiovascular mortality data in people 60 years or older
indicated a significant reduction (RR=0.77, 95% CI 0.68 to 0.86;
ARR= 1.5%, NNT = 67), see Figure 6. EWPHE 1989 and STOP
1991 independently reached statistical significance. Non-cardio-
vascular mortality was not affected, RR with 95% CI 1.02(0.92,
1.14 p = 0.65), see Figure 7.

Figure 6. Cardiovascular mortality in elderly patients with hypertension
Figure 7. Non-cardiovascular mortality in elderly patients with hypertension

Combined results of the three trials with isolated systolic hyper-
tension showed a significant reduction in cardiovascular mortality
(RR=0.77, 95% CI 0.63 to 0.95), see Figure 8. Analysis of trials
in very elderly (80 years or older) showed no significant difference
(RR = 0.98 95% CI 0.81 to 1.19; p = 0.86), see Figure 9.
Figure 8. Cardiovascular mortality in elderly patients with ISH

Figure 9. Cardiovascular mortality in the very elderly patients
Cerebrovascular mortality: In people 60 years or older there was a

significant reduction (RR=0.66, 95% CI 0.53 to 0.82), see Figure
10. STOP 1991 and HEP 1986 independently reached statistical
significance.

Figure 10. Cerebrovascular mortality in elderly patients with hypertension
In the three trials with isolated systolic hypertension the reduction

was not statistically significant (RR=0.68 95% CI 0.42 to 1.11; p
= 0.13), see Figure 11.

Figure 11. cerebrovascular mortality in elderly patients with isolated systolic hypertension
In the very elderly (80 years or older) there was also no significant
difference (RR = 0.80 95% CI 0.58 to 1.11; p = 0.18), see Figure
12.

Figure 12. Cerebrovascular mortality in the very elderly patients with hypertension
Coronary heart disease (CHD) mortality: In the 9 trials report-

ing CHD mortality in people 60 years or older treatment reduced
CHD mortality (RR=0.77, 95% CI 0.65 to 0.90), see Figure 13.
EWPHE 1989 independently reached statistical significance.

Figure 13. Coronary heart disease mortality in elderly patients with hypertension
In the very elderly (80 years or older) there was no reduction (RR
= 0.98 95% CI 0.69 to 1.40; p = 0.93), see Figure 14.

Figure 14. Coronary heart disease mortality in the very elderly
In the three trials with isolated systolic hypertension the reduction

was not statistically significant (RR=0.78, 95% CI 0.60 to 1.02;
p = 0.06), see Figure 15.

Figure 15. CHD mortality in elderly patients with isolated systolic hypertension
Cardiovascular mortality and morbidity (M&M): In the 13

trials reporting cardiovascular mortality and morbidity data in
people 60 years or older, treatment caused a significant reduction
(RR=0.72, 95% CI 0.68 to 0.77), see Figure 16. HEP 1986,
HYVET 2008, MRCOA 1992, SHEP 1991, STOP 1991, Syst-
Eur 1991 and VA Coop 1962 independently reached statistical
significance. The significant heterogeneity between trials was no
longer evident when the unblinded HEP 1986 and Sprackling
1981 trials were excluded from the analysis (RR = 0.71 95% CI
0.66 to 0.78 with I2 reduced from 70% with p < 0.0001 to I2 =
32% with p = 0.14).

Figure 16. Forest plot of comparison: 1 Antihypertensive drug therapy vs control in elderly 60 years or
older, outcome: 1.2 Cardiovascular mortality and morbidity.
Excluding MRCOA 1992 because it used a different definition

for the cardiovascular morbidity and mortality outcome did not
affect the estimate (RR=0.69, 95% CI 0.65 to 0.75).
Cardiovascular mortality and morbidity was significantly reduced
in elderly patients due to reduction in both cerebrovascular as well
as CHD mortality and morbidity, see Figure 17 and Figure 18
respectively.

Figure 17. Cerebrovascular mortality and morbidity in elderly patients with hypertension
Figure 18. Coronary heart disease mortality and morbidity in elderly patients with hypertension

In the very elderly patients (80 years or older) and in elderly pa-
tients with isolated systolic hypertension, treatment caused a sig-
nificant reduction in cardiovascular mortality and morbidity (RR
= 0.75 95% CI 0.65 to 0.87 p = 0.0001), see Figure 19, and (RR=
0.68, 95% CI 0.61 to 0.75) see Figure 20 respectively.
Figure 19. Forest plot of comparison: 2 Antihypertensive drug therapy vs control in very elderly 80 years or
older, outcome: 2.2 Cardiovascular mortality and morbidity.
Figure 20. Forest plot of comparison: 3 Antihypertensive drug therapy vs control in elderly with ISH,
outcome: 3.2 Cardiovascular morbidity and mortality.

Cerebrovascular mortality and morbidity was significantly reduced
in the very elderly Figure 21 but there was no significant difference
observed in coronary heart disease mortality and morbidity (Figure
22).
Figure 21. Cerebrovascular mortality and morbidity in the very elderly patients with hypertension

Figure 22. Coronary heart disease mortality and morbidity in the very elderly with hypertension
Cerebrovascular mortality and morbidity (Figure 23) as well as

coronary heart disease mortality and morbidity (Figure 24) were
significantly reduced in the elderly patients with isolated systolic
hypertension.

Figure 23. Cerebrovascular mortality and morbidity in elderly patients with ISH
Figure 24. CHD mortality and morbidity in elderly patients with ISH

Withdrawals due to adverse effects: Numbers of participants
who dropped out of trials due to adverse drug effects were often
not reported. The three trials that did report this data showed
a significant increase in withdrawals due to adverse effects, RR=
1.71, 95% CI 1.45 to 2.00, see Figure 25, with event rates per
1000 participants increased from 65 to 111 events, absolute risk
increase of 46 (95% CI 29 to 65).
Figure 25. Forest plot of comparison: 1 Antihypertensive drug therapy vs control in elderly 60 years or
older, outcome: 1.3 Withdrawal due to adverse effects.
The number of people withdrawing from therapy due to adverse

effects varied significantly from study to study. On average, treat-
ing 17 subjects in SHEP 1991 resulted in one withdrawal, whereas
in MRCOA 1992 treating 9 subjects with a diuretic and 4 sub-
jects with a beta-blocker resulted in one withdrawal in each treat-
ment arm. In MRCOA 1992, un-blinded physicians made deci-
sions regarding severity of side effects and continuation of therapy;
176 subjects in the beta-blocker group were withdrawn because
of bradycardia.

Pharmacotherapy for hypertension in the elderly (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Antihypertensive drug therapy compared to control in very elderly 80 years or older for hypertension
Patient or population: patients with Elderly patients with primary hypertension

Settings: Ambulatory
Intervention: Antihypertensive drug therapy
Comparison: Control
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Control Antihypertensive drug

therapy
Total mortality - Very el- Study population RR 0.98 6701

derly 80 years or older (0.87 to 1.1) (8 studies3 ) low1,2
Follow-up: mean 2 years 142 per 1000 139 per 1000
(124 to 156)
Low risk population
60 per 1000 59 per 1000

(52 to 66)
160 per 1000 157 per 1000

(139 to 176)
Cardiovascular mortal- Study population3 RR 0.75 6546

ity and morbidity - Very (0.65 to 0.87) (7 studies3 ) moderate4
elderly 80 years or older
Follow-up: mean 2 years
30
115 per 1000 86 per 1000

(75 to 100)
Low risk population3
100 per 1000 75 per 1000

(65 to 87)
High risk population3
250 per 1000 188 per 1000

(162 to 218)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Significant heterogeneity I square = 83%
2
Confidence intervals are wide and include 10% benefit or harm.
3 Please note that the duration of the trials is only 2 years and not 4.5 years as in the 60 years or older patients
4 confidence interval is wide
31
DISCUSSION
people at high risk. The subgroup analysis of treatment in the very
This systematic review provides the best available evidence for
elderly patients (80 years or older) showed no significant bene-
antihypertensive treatment for people with elevated blood pressure
fit in terms of all cause mortality including cardiovascular, coro-
who are at least 60 years of age. It is important to appreciate that
nary heart disease or cerebrovascular disease mortality. However,
this represents a group of people with relatively high systolic blood
a higher absolute risk reduction was observed in cardiovascular
pressures: an average of 172/81 mmHg in the isolated systolic
mortality and morbidity from 115 to 86 (75 to 100) events per
hypertension trials and an average of 182/95 mmHg in the 11
1000 participants, which was mostly due to a decrease in cere-
other trials. The reason that the diastolic pressure is lower than
brovascular mortality and morbidity for a mean duration of 2.0
expected is because only 6 of these trials ensured the presence of
years, see Summary of findings 2.
diastolic hypertension, i.e. > 90 mmHg diastolic (ANBP 1981,
EWPHE 1989, HTN Coop 1974, Sprackling 1981, STOP 1991, Trials involving older people could have varied systematically from
VA Coop 1970). In these trials the average diastolic BP was >100 those in younger people. Except for TOMHS 1995, trials that
mmHg. included younger people were published before 1987(VA Coop
1962, Wolf 1966, VA Coop 1970, Barraclough 1973, HTN Coop
In this population antihypertensive drug treatment was associated
1974, USPHS Coop 1977, VA/NHLBI 1978, ANBP 1981, Oslo
with a modest reduction in total mortality, RR 0.90 (0.84 - 0.97).
1986). Six large trials involving older people were published after
This represents an absolute reduction in deaths of 12, from 116 to
1990 (SHEP 1991, STOP 1991, MRCOA 1992, Syst-Eur 1991,
104 events per 1000 participants, over an average duration of 4.5
HYVET P 2003, HYVET 2008). While first-line beta-blockers
years, see Summary of findings for the main comparison. However,
and thiazide diuretics were used in most trials, the recent large trials
the 95% CI range from 3 to 19 deaths per 1000 participants, so
in older people have usually used either lower doses of thiazides or
we cannot be very confident in this result. This absolute reduction
combinations with potassium sparing agents. As a result they may
is explained by 6 less deaths due to stroke and 6 less deaths due
be associated with less toxic adverse effects. The most recent trial
to coronary heart disease. Most importantly when we limited the
in very elderly (HYVET 2008) used indapamide sustained release
analysis to people 80 years old and over there was no reduction
1.5 mg or matching placebo. If blood pressure remained above
in total mortality, RR 0.98 (0.87 - 1.10). Thus trials with longer
SBP=150 mmHg and DBP=80 mmHg, perindopril 2 mg or 4
duration of treatment in the very elderly are warranted.
mg or matching placebo could be added. Thus, this trial showed
Cardiovascular mortality and morbidity was significantly reduced, a significant reduction in mortality, RR 0.82 (0.69 - 0.99), ARR
RR 0.72 (0.68 - 0.77). This represents an absolute reduction of = 2.2%, NNT= 48 for 2 years, and in total cardiovascular events,
43 (35 - 49), from 153 to 110 events per 1000 participants for a RR 0.71 (0.57 - 0.87) with low doses of two antihypertensive
mean duration of treatment of 4.5 years, see Summary of findings drugs. The other trials in the very elderly used higher doses of more
for the main comparison. This was due to a reduction of 20 cere- antihypertensive drugs and showed a trend towards increased total
brovascular disease mortality and morbidity events as well as 10 mortality. These observations suggest that less aggressive treatment
coronary heart disease mortality and morbidity events. In the very is probably a good approach in the very elderly, but this needs to
elderly a similar reduction of 18 cerebrovascular mortality and be validated with RCTs testing different approaches to BP control
morbidity events per 1000 participants was present, but there was in this patient population.
no significant reduction in coronary heart disease mortality and
morbidity. Numbers of participants who dropped out of trials due to adverse
drug effects were often not reported. The three trials that did
The magnitude of benefit depends on multiple factors including report this data showed a significant increase in withdrawals due
their baseline risk of cardiovascular complications of hypertension to adverse effects from 65 to 111 events per 1000 participants,
(Gueyffier 1997). People with more cardiovascular risk factors absolute increase of 46 (29 - 65) per 1000 patients. Separate data
(e.g. diabetes, family history of heart disease, left ventricular hy- for withdrawals due to adverse effects was not available in the very
pertrophy, etc.) have greater likelihood of a reduction in cardio- elderly patients.
vascular events by antihypertensive therapy.
Control rates
The five-year absolute morbidity and mortality benefit of an-
tihypertensive therapy is greater for older than younger adults Control rates provide insight regarding baseline risk of study
(Collins 1990, Mulrow 1994). Several reasons could explain this populations and can explain the differences in outcomes be-
greater absolute benefit. First, older people are at higher imme- tween individual trials. Total mortality rates in the control groups
diate absolute risk of a cardiovascular event than younger people ranged from 3 to 71%. Trials with relatively low rates included
(Alderman 1981, Browner 1989, Alderman 1993). The risk fac- ANBP 1981 (3%), HYVET P 2003 (5.2%), Syst-Eur 1991
tors include pre-existing cardiovascular disease and systolic hyper- (6%), SHEP-PS 1986 (6.5%), STOP 1991 (7.7%), and SHEP
tension (Applegate 1992, Mann 1992). Lowering of blood pres- 1991 (10.2%). Trials with moderate rates included HYVET 2008
sure results in similar relative but higher absolute effect in these (12.3%), MRCOA 1992 (14.2%), HEP 1986 (14.8%), and

Kuramoto 1981 (14.9%). Trials with relatively high rates included results only refer to generally expected benefits for elderly hyper-
Carter 1970 (34.6%), EWPHE 1989 (35.1%), and Sprackling tensive patients, and are not tailored specifically to patients with
1981 (71%). VA Coop 1970 and HTN Coop 1974 did not report particular risk factors. Our average results refer primarily to a pri-
total mortality, but reported the second and third highest event mary prevention population with moderate to severe systolic or
rates (behind Sprackling 1981) in cardiovascular morbidity and systodiastolic hypertension treated with a first-line thiazide. Data
mortality (VA Coop 1970 58.1%, HTN Coop 1974 34.3% and for other first-line drugs is insufficient, and the objective of this
Sprackling 1981 83.9%). review was not to compare different first-line drugs, which has
been done by other systematic reviews (Psaty 1997, Wright JM
The 95% CI of the RR of total mortality for Sprackling 1981, 1.11
1999, Psaty 2003, Wright JM 2009).
(0.90 to 1.36), did not overlap with the 95% CI of the STOP 1991
trial, 0.57 (0.39 to 0.85). Differences in control rates may in part
be due to differing baseline characteristics in recruited subjects. For Actual estimates of benefits and harms of treating elderly persons
example, the subjects in Carter 1970 and HTN Coop 1974 were with hypertension derived from trials with highly selected subjects
all stroke survivors. Subjects in Sprackling 1981 and Kuramoto are not readily generalizable to clinical practice. Many patients ei-
1981 resided in a home for the aged. Subjects in Carter 1970 and ther would not meet eligibility criteria or, if offered the chance,
VA Coop 1962 were recruited from hospitals (though followed would not have enrolled in a clinical trial. Strictly speaking, trial re-
up in clinics) and subjects in EWPHE 1989 were recruited from sults cannot be generalized to such patients. In practice, clinicians
geriatric hospitals, physicians offices and homes for the aged. are of course willing to offer treatment to patients who may not
have been eligible for a trial or who, if eligible, would have refused
Additional explanations of differing control rates include varia- participation; but we should approach these generalizations with
tions in definitions of trial end-points, cross-over rates and follow- forethought. Without extra care and visits provided in many trials,
up durations. Although we attempted to standardize outcome def- even our eligible patients may be less compliant than trial par-
initions as much as possible (see Methods section), truly uniform ticipants. Patients with significant competing comorbidities and
definitions between trials were not possible. Trials had cross-over complicated medical regimens may also have poorer compliance,
rates ranging from 9% to 62% (see Characteristics of included less benefit, and more adverse effects compared to participants in
studies) and follow-up durations ranging from 1 to 6 years. trials. For example in an octagenarian with orthostasis and recur-
Since most data is based on a small percentage of randomized ring falls related to antihypertensive therapy, the harms likely ex-
patients with stroke or MI at baseline, patients with significant ceed benefits. On the other hand, clinicians should not always as-
competing comorbidity and complicated medical regimens may sume that less benefit would be seen in real life clinical settings.
also have poorer compliance, less benefit, and more adverse effects A person who is at high immediate risk of suffering a cardiovas-
compared to participants in trials. cular event and does not have other competing illnesses may have
a higher benefit-to-harm ratio than the average trial participant.
Risk of Bias
Risk of bias was assessed using the Cochrane Risk of Bias tool and
demonstrated that approximately 40% of trials had evidence of
selective reporting bias and approximately 30% of trials did not
deal with missing or incomplete outcome data appropriately. In
AUTHORS CONCLUSIONS
other words, 40% of trials could have censored outcome data for
Implications for practice
patients after they had had their first event. In addition, in 30% Antihypertensive treatment of people aged 60 and older with mod-
of the trials, when outcome data wasnt available it appeared the erate to severe systolic and/or diastolic hypertension reduces total
assumption was that an event did not occur in that patient. See mortality and total cardiovascular morbidity and mortality. The
Figure 1; and Figure 2. The implications are that the available absolute risk reduction in cerebrovascular mortality and morbidity
outcome data used in the meta-analyses may be incomplete. It is over 4.5 years was greater (2.0% and NNT=50) than for coronary
difficult to determine whether this bias would favour treatment or heart disease mortality and morbidity (1.0% with NNT=100).
control. What can be said is that reported event rates are under- The evidence of benefit pertains mostly to a primary prevention
estimates and the calculated effect sizes for outcomes (other than population and first-line treatment with a thiazide. This compre-
death as the first event) may be inaccurate. hensive systematic review provides additional evidence in people
aged 80 and older where antihypertensive treatment reduced total
Limitations and generalizability
cardiovascular morbidity and mortality, but not total mortality.
The most appropriate way to match expected magnitude of ben- In the very elderly the absolute risk reduction in cerebrovascular
efits to patients with particular constellations of risk factors is to mortality and morbidity over 2.2 years was 1.8% with NNT=56,
perform individual patient based meta-analyses (Gueyffier 1997), but there was no significant reduction in coronary heart disease
which was not possible in this review. Moreover, our aggregate mortality and morbidity.

Implications for research drugs at low dose (as in the HYVET 2008 trial) with traditional
antihypertensive therapy with 3 to 4 drugs in maximal doses.
Individual patient based meta-analyses of data from existing trials
should be used to derive evidence for the treatment of specific sub-
groups of elderly hypertensive patients, such as persons with dia-
betes, functional impairment, recent stroke or persons of African
descent. Further long term RCTs are needed to investigate which ACKNOWLEDGEMENTS
first-line drug is best in elderly patients and to study different We would like to acknowledge the authors of the previous (1998)
approaches to treatment e.g. an RCT comparing the use of two version of this systematic review: Cynthia Mulrow, Joseph Lau,
John Cornell, and M Brand.
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CASTEL 1994 {published data only} Ritchie C, Waldman A, Walton I, Poulter R, Ma S, Comsa
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MRC 1985 {published data only} VA Coop 1962 {published data only}
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Oslo 1986 {published data only} reserpine and hydralazine, and three ganglionic blocking
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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
ANBP 1981
Methods Multisite study.

Randomization: stratified by age and sex; method of randomization not stated.
Patients blinded; providers blinded.
Lost to follow-up: 2.1%
% not on assigned therapy at study end:
placebo group: 35%
treatment group: 33%
Participants Geographic region: Australia

Study setting: community.
n = 582 (45% female)
Age range: 60-69 mean: 63.6
Race: White.
Mean blood pressure at entry: 165/101 mmHg
Pre-existing risk factors:
myocardial infarction: excluded if in last three months; 0.5% before 3 months
diabetes: excluded
smoking: 17.5%
hyperlipidemia: 62.2% (cholesterol >220 mg/dL)
Blood pressure (BP) entry criteria: systolic BP < 200 mm Hg and diastolic BP 95 - 110
mm Hg.
Interventions Control: matching placebo.

Treatment: Step 1 - chlorothiazide 500mg daily; Step 2 - chlorothiazide 500mg twice
daily or methyldopa or propranolol or pindolol; Step 3 - hydralazine or clonidine.
Average follow-up: 3.9 years.
Difference in blood pressure at end of study (Treatment - Control) diastolic: -6.7 (systolic
not stated)
Outcomes Total mortality - death from any cause.

CHD (Coronary Heart Disease mortality) mortality - fatal ischemic heart disease
CHD M&M (morbidity and mortality) - CHD mortality; non-fatal myocardial infarc-
tion.
Cerebrovascular mortality
Cerebrovascular M&M - non-fatal cerebrovascular hemorrhage or thrombosis
Cardiovascular mortality -CHD mortality; cerebrovascular mortality
Cardiovascular M&M - CHD M&M; cerebrovascular M&M; transitory cerebral is-
chemic attacks; aortic aneurysms.
Dropouts due to side effects: not stated.
Quality of life or functional status outcomes: not reported.
Notes Exclusions: on treatment for hypertension in past 3 months; history of myocardial in-
farction in past 3 months; history of stroke; pregnancy; taking estrogen and progesterone
in combination; asthma; diabetes; gout; secondary hypertension; evidence of cerebrovas-
cular disease, transient cerebral vascular attacks, acute coronary insufficiency, angina pec-

ANBP 1981 (Continued)
toris, plasma creatinine >2mg/dL; other serious complications of hypertension; ECG

evidence of myocardial ischemia; any potentially fatal disease; taking tricyclic antide-
pressants.
Risk of bias
Item Authors judgement Description
Adequate sequence generation? Unclear unclear
Allocation concealment? Unclear Unclear
Blinding? Yes Clinicians blinded

All outcomes
Incomplete outcome data addressed? No in 504 (of the randomized population)

All outcomes , pressures fell before tablets were due to
be dispensed and never reached again the
threshold to qualify them to start tablets...
Thus, in subjects who prematurely
stopped their regimen, the match between
active and placebo groups in respect to en-
try charatceristics, time of stopping, end-
point rates, end point rates, and reasons for
stopping makes it unlikely that factors asso-
ciated with premature stopping biased the
results of the trial in favour of the active
group.
Free of selective reporting? No The occurence of any trial endpoint ter-

minated the subjects participation in the
study.
For subjects who prematurely stopped
their trial regimen, the withdrawal date was
taken as their exact date of cessation where
known, or, if not, 4 months from the date
of last contact.
Carter 1970
Methods Single site study.

Random allocation: method not described.
Patients and providers not blinded.
Lost to follow-up: 2.8%.
% not on assigned therapy at study end: not reported.
Participants Geographic area: England

Study setting: recruited in hospital, treatment group followed up in clinic.
n = 71 (47.9% female)
Carter 1970 (Continued)
Age range: 60 - 79 mean: not reported.

Race: not reported.
Mean blood pressure (BP) at entry: not reported (entry criteria were systolic BP >160
mmHg and/or diastolic BP > 110 mmHg.
Pre-existing factors:
stroke: 100%
Blood pressure (BP) entry criteria: (systolic BP > 160 mm Hg and diastolic BP < 110
mm Hg) or (diastolic BP >= 110 mm Hg irrespective of systolic BP).
Interventions Control: observation without placebo.

Treatment: first choice - thiazide diuretic; second choice - methyldopa; third choice -
bethanidine, debrisoquine or guanethidine.
Average follow-up: 4.0 years
Difference in blood pressure at study end: not reported.
Outcomes Total mortality: death from all causes.

Dropouts due to side effects: not reported.
Notes Exclusions: cerebral hemorrhage, embolism, tumor, accelerated hypertension, those

with an obvious need for hypotensive therapy, left ventricular failure, congestive cardiac
failure, gross radiological cardiac enlargement, various cardiac arrhythmias, evidence of
renal failure.
Risk of bias
Allocation concealment? Unclear unclear
Blinding? No No
All outcomes
Incomplete outcome data addressed? Yes Of the 99 patients in the trial, 2 have been
All outcomes lost to follow up...
Free of selective reporting? Unclear unclear

EWPHE 1989

Random allocation; method not stated; stratified by age, sex, presence or absence of
cardiovascular complications and site.
Patients blinded; providers blinded; outcomes assessors blinded.
placebo group: >35%
treatment group: >35%
Participants Geographic region: Europe (Belgium (25%), United Kingdom (19%), Finland (17%),
France (14%), Italy (7%), The Netherlands (7%), Ireland (6%), Portugal (3%), Norway
(2%), West-Germany (1%))
Study setting: Hospitals (geriatric); physician offices; nursing home.
n = 840 (69.8% female)
Race: not stated.
smoking: 16.4%
Blood pressure (BP) entry criteria: systolic BP 160 - 239 mm Hg and diastolic BP 90 -
119 mm Hg.

Treatment: Step 1 - hydrochlorothiazide 25-50mg + triamterene 50-100mg daily; Step
2 - methyldopa 250-2000mg daily.
Average follow-up: placebo 4.63 years; treatment 4.69 years
Difference in blood pressure at study end (Treatment - Control) systolic/diastolic: -22/-
10 mmHg

CHD (Coronary Heart Disease mortality) mortality - fatal myocardial infarction and
ischemic heart disease, sudden death and fatal arrhythmia, fatal heart failure.
Cerebrovascular mortality - fatal stroke
Cardiovascular mortality - CHD mortality plus cerebrovascular mortality.
Quality of life or functional outcomes: not stated.
Notes Exclusions: curable causes of high blood pressure; certain complications of hypertension
(ie, retinopathy grade III or IV, congestive heart failure, history of cerebral or subarach-
noid hemorrhage); concurrent diseases such as hepatitis or cirrhosis, gout, malignancy
and diabetes mellitus requiring insulin treatment.
Risk of bias
Allocation concealment? Unclear Unclear

EWPHE 1989 (Continued)
Blinding? Yes Triple blinded

All outcomes
Incomplete outcome data addressed? Unclear unclear

All outcomes
Free of selective reporting? No Patients were censored if they had one of

the specific study terminating events,
including death, non-fatal cerebral or sub-
arachnoid haemorrhage,
development of hypertensive retinopathy
grade III or IV, dissecting
aneurysm, congestive heart failure not con-
trollable without
diuretics or antihypertensive drugs, hyper-
tensive encephalopathy,
severe increase in left ventricular hypertro-
phy, and a rise in blood
pressure exceeding the defined limits.
HEP 1986

Randomization: random number table used and allocation assignment distributed in
opaque envelopes; not stratified by site.
Patients and providers not blinded; assessors of morbidity and mortality outcomes were
blinded.
% lost to follow-up: not stated.
control group: 9%
treatment group: 5%
Participants Geographic region: England and Wales

Study setting: primary care (physicians offices)
n = 884 (69.5% female)
Race: not stated.
smoking: 24%
Blood pressure (BP) entry criteria: systolic BP 170 - 280 mm Hg and /or diastolic BP
105 - 120 mm Hg.
Interventions Control: observation without placebo

Treatment: Step 1 - atenolol 100mg daily; Step 2 - bendrofluazide 5mg daily; Step 3 -
methyldopa 500mg daily; Step 4 - any recognized therapy.
Difference in blood pressure at end of study (Treatment - Control) systolic/diastolic: -

HEP 1986 (Continued)
18/-11
Outcomes Total mortality - death from all causes.

CHD (Coronary Heart Disease) mortality - fatal myocardial infarctions; sudden death.
CHD M&M (morbidity and mortality) - fatal and non-fatal myocardial infarctions.
Cerebrovascular mortality - fatal strokes.
Cerebrovascular M&M - fatal strokes; major strokes and minor strokes.
Cardiovascular mortality - fatal coronary artery attacks; fatal strokes and fatal ruptured
aneurysms.
Cardiovascular M&M - CHD M&M; cerebrovascular M&M; transient ischemic attacks,
ventricular failure.
Quality of life or functional status outcomes: symptom questionnaires showed no sig-
nificant differences between groups.
Notes Exclusions: atrial fibrillation, A-V heart block, ventricular failure, bronchial asthma,
diabetes mellitus (needing pharmacological treatment), any serious concomitant disease
limiting the prospect of fruitful living, untreated hypertension with levels persistently
above 280 mm Hg systolic or 120 mm Hg diastolic, patients already being treated for
hypertension (within three months), dementia.
Risk of bias
Adequate sequence generation? Unclear Random number table used
Allocation concealment? Yes allocation assignment distributed in

opaque envelopes; not stratified by site
Blinding? Yes Patients and providers not blinded; asses-

All outcomes sors of morbidity and mortality outcomes
were blinded

All outcomes
Free of selective reporting? No Once the patients reached the age of 80

and had been in the study for 5 years they
were excluded from further analyses. Pa-
tients who left the practices were excluded
at that time. For this paper, however, no
events that occurred to the patient after
leaving the practices were included in the
analysis. A fatal event cancelled out non-
fatal events of the same kind. In the case
of stroke, the most serious, major, minor,
or transient ischemic attack, was counted.

HTN Coop 1974

Randomization: patients randomly allocated by biostatisticians at central register; strat-
ified by sex, race and diastolic blood pressure.
Patients blinded. Providers blinded.
% lost to follow-up: not reported.
Participants Geographic region: United States of America

Study setting: outpatient clinics.
n = 200 (39.5% female)
Age range:60-75 mean: not reported
Race: Black (77.5%); non-Black (22.5%)
Mean blood pressure at entry: 167/100 mmHg for entire study group (ie, this data not
reported for >60 age sub-group).
Pre-existing risk factors: all patients had history of stroke and/or TIA.
stroke only: 80%
transient ischemic attack (TIA) only: 4%
both stroke and TIA: 16%
diabetes: 36%
smoking: 60%
obesity: 29%
hyperlipidemia: 22%
Blood pressure (BP) entry criteria: systolic BP 140 - 220 mm Hg and diastolic BP 90 -
115 mm Hg.
Interventions Control: placebo.

Treatment: deserpidine 0.5mg and methyclothiazide 5mg in one tablet twice daily.
Difference in blood pressure at study end (Treatment - Control) systolic/diastolic: -27
/ -12 mmHg; estimated from graphical presentation of data and for entire study group
(ie, this data not reported for >60 age sub-group).
Outcomes Cerebrovascular morbidity and mortality (M&M) - fatal and non-fatal stroke
Dropouts due to side effects: for entire study group (ie, this data not reported for >60
age sub-group).
during 6-week pre-trial run-in phase with treatment drugs: 1.4%
during post-randomization period on treatment drugs: 3%
Notes Exclusions: non-ambulatory subjects, >= 75 years old, concomitant disease that might
be influenced adversely by prolonged treatment with drug or placebo, development of
intolerable side effects during 6-week pre-trial run in on deserpidine and methycloth-
iazide.
Risk of bias

HTN Coop 1974 (Continued)
Adequate sequence generation? Yes patients randomly allocated by biostatisti-

cians at central register
Blinding? Yes Stated that neither patient nor the clinician

All outcomes was aware of assigned treatment
Incomplete outcome data addressed? Yes The high degree of cooperation over the
All outcomes long period of the observation is worthy of
comment. Only 30 patients (7%) of those
randomized were unreliable.
HYVET 2008

Randomization: Sequence generation not reported. Randomization was stratified ac-
cording to age (80 to 89 years and 90 years or older) and sex; permuted blocks of 4 and
6 of any 10 patients were used to ensure roughly equal assignment to each of the two
groups within large centers.
Patients and providers were blinded
% lost to follow-up: active treatment 0.3%, placebo 0.6%
% not on assigned therapy at study end: active treatment 0.8%, placebo 0.6%
Participants Geographic region: Western Europe (86 patients), Eastern Europe (2144), China (1526)
, Australasia (19),
and Tunisia (70).
Study setting: Outpatient
n =3845 (61% women)
Age range: 80-105 mean age = 84 years
Race: not stated.
Mean blood pressure at entry: sitting active treatment 1738.4/90.88.5 and sitting
placebo 173.08.6/90.88.5; standing active treatment 168.011.0/88.79.3, sitting
placebo 167.911.1/88.69.3
Cardiovascular disease =12.0%
Hypertension = 89.9%
Antihypertensive treatment = 64%
Stroke = 6.8%
Myocardial infarction = 3.1%
Diabetes = 6.8%
Heart failure = 2.9%
smoking: 6.5%
Blood pressure (BP) entry criteria: mean of the four systolic blood-pressure measurements
taken at the second and third visits (two at each visit) was between 160 and 199mm Hg

HYVET 2008 (Continued)
Interventions Control: placebo.

Treatment: indapamide alone, indapamide plus perindopril 2mg, or indapamide plus
perindopril 4mg
Average follow-up: 2.1 years (median 1.8 years)
Difference in blood pressure at study end (Treatment - Control) systolic/diastolic: sitting
-15.0/-6.1 mmHg, standing -14.7/-5.4 mmHg
Outcomes Fatal/non-fatal stroke

All-cause mortality
Non-cardiovascular /unknown cause mortality
Cardiovascular mortality
Cardiac mortality
Heart failure mortality
Any cardiovascular event
Myocardial infarction
Heart failure
Quality of life
Dropouts due to side effects: not reported
Quality of life or functional status outcomes: not reported (yet)
Notes
Risk of bias
Allocation concealment? Yes An interactive voice response system

(IVRS) is employed to tell the investigator
which
6-month drug pack to prescribe.
Blinding? Yes The main trial is a randomised, double-

All outcomes blind,
placebo-controlled trial.
Incomplete outcome data addressed? Yes Reported on the number of patients lost to
All outcomes follow-up (16 patients)
...vital status was unknown in 17 pa-
tients...
Free of selective reporting? No Cannot extract the number of patients in

each group that had a non-fatal myocardial
infarctions.
Correspondence with the author:
The serious adverse events noted in the
publication...are the numbers the total se-

HYVET 2008 (Continued)
rious adverse events OR was the first event

counted and analyzed? Answer:It is the to-
tal number of SAEs. Patients could con-
tribute more than one SAE.
Correspondence with the author:
If a patient had an event after being cen-
sored were those events counted? If not, is it
possible to see that data? Answer: It would
depend on the event. If it was a recurrent
endpoint then it was not counted (e.g. a
further non-fatal stoke). If the event was
a new endpoint (e.g. a fatal MI in some-
one who had previously had a non-fatal
stroke) then it was.
HYVET P 2003

Randomization: SAS Random Allocation of Treatments Balanced in Blocks Program was
used to generate the schedule. Restricted random allocation to groups was used to ensure
equal allocation per group within each centre and allocation to groups was performed
centrally. Stratified into four groups on the basis of
sex and age (80-89 years and . 90 years).
Patients and providers were not blinded
% lost to follow-up: diuretic 2%, ACEI 2%, no treatment 2%
% not on assigned therapy at study end: diuretic 97%, ACEI 96%, no treatment 99.2%
Participants Geographic region: 1130 (88%) in Bulgaria, 39 (3%) in Spain, 39 (3%) in Romania,
32 (2.5%) in the UK, 20
(1.5%) in Poland and smaller numbers in Finland, Lithuania, Ireland, Greece and Serbia.
Study setting: both primary and secondary care
n =1283 (63% women)
Age range: 79.5-96.1 mean: mean age = 84 years
Race: not stated.
Mean blood pressure at entry: systolic blood pressure averaged 181.5 + 11.3 mmHg
(range 160-217 mmHg) and entry diastolic pressure averaged 99.6 + 3.4 mmHg (range
90-114 mmHg)
Pre-existing factors: patients were not obese, with an average body mass index of 25 kg/
m2; 48% had been previously treated, 3.0% had had a previous myocardial infarction,
4.5% a previous stroke, and 20.7% drank more than 1 unit of alcohol per day.
smoking: 4.2%
Blood pressure (BP) entry criteria: systolic blood pressure (average of four readings)
160-219 mmHg, diastolic blood pressure 95-109 mmHg (later changed to 90-109
mmHg), standing
systolic blood pressure >140 mmHg (average of two readings)
Interventions Control: no treatment

Treatment: Diuretic usually bendroflumethiazide (bendrofluazide) 2.5 mg and ACEI
usually lisinopril 2.5 mg.

HYVET P 2003 (Continued)
To attain target blood pressure in the actively treatedg groups, the procedure allowed for
the dose of diureticor ACE inhibitor to be doubled (step 2), diltiazem slow-release 120
mg to be added (step 3) and diltiazem slow-release 240 mg to be added (step 4). The
target blood pressures were a sitting systolic pressure less than 150 mmHg plus a sitting
diastolic pressure less than 80 mmHg
Average follow-up: 13 months
Difference in blood pressure at study end (Treatment - Control):sitting BP difference
between diuretic/ACEI and no treatment -23/-11 mmHg;standing BP difference be-
tween duiretic and no treatment -23/-11 mmHg and difference between ACEI and no
treatment -24/-12 mmHg
Outcomes Stroke events

total mortality
cardiovascular mortality
cardiac mortality
stroke mortality.
Dropouts due to side effects: not reported
Quality of life or functional status outcomes: not reported
Notes
Risk of bias
Adequate sequence generation? Yes The unit of randomization was the in-
dividual and the SAS Random Allocation
of Treatments Balanced in Blocks Program
was used to generate the schedule.
Blinding? No The trial recruited individuals from both

All outcomes primary and secondary care and was of an
open design.
Incomplete outcome data addressed? No Of the 1283 patients who were assigned
All outcomes to groups, only 27 (2.1%) were lost
to follow-up (had no end-of-trial informa-
tion).
Of the 426 patients allocated randomly
to a diuretic-based treatment, 385 (88.5%)
were alive and provided information at the
end of the trial. The corresponding num-
bers were 397 (89.8%) for ACE based treat-
ment and 394 (90.1%) for no treatment.

HYVET P 2003 (Continued)
Free of selective reporting? No As this was an open study, the randomized

treatment could be continued after a non-
fatal event.
Kuramoto 1981
Methods Single site study.

Allocation of individuals within matched pairs to treatment and control groups made
by a blinded statistical coordinator; thought to be randomized, but not entirely clear
(unpublished information as per personal conversation with author).
placebo group: 17% (withdrawn due to elevated blood pressure)
treatment group: not clear.
Participants Geographic area: Tokyo, Japan.

Study setting: home for the aged.
n = 91 (45% female)
Age range: > 60 mean: 76.1
Race: not stated.
Mean blood pressure at entry: 169/86 mmHg (isolated systolic hypertension in 44% of
subjects).
Pre-existing factors: not reported.
Blood pressure (BP) entry criteria: not clearly stated
Interventions Control: placebo

Treatment: Step 1 - trichlormethiazide 1-4mg/day; Step 2 - reserpine 0.3 mg/day or
methyldopa 125-500mg/day or hydralazine 50-100mg/day.
Difference in blood pressure at study end (based on only 29 patients) (Treatment -
Control) systolic/diastolic: 0.8 / 1.3 mmHg

Coronary heart disease (CHD) mortality - fatal myocardial infarction and sudden death.
CHD morbidity and mortality (M&M) - CHD mortality plus non-fatal myocardial
infarctions.
Cerebrovascular morbidity - fatal cerebral infarction or cerebral hemorrhage.
Cerebrovascular M&M - fatal and non-fatal cerebral infarction or cerebral hemorrhage.
Cardiovascular mortality - CHD mortality plus cerebrovascular mortality.
Cardiovascular M&M - CHD M&M plus cerebrovascular M&M plus congestive heart
failure with arrhythmia.
Dropout due to side effects: not reported.
Notes Exclusions: not reported.
Risk of bias

Kuramoto 1981 (Continued)
Allocation concealment? Yes A - Adequate
Blinding? Unclear unclear

All outcomes
Incomplete outcome data addressed? No unclear

All outcomes
MRCOA 1992

Randomization: stratified by gender and site; at each site subjects were assigned to therapy
based on computer generated lists.
Patients blinded; providers not blinded; mortality outcome assessors blinded.
Lost to follow-up: 25%
% not on assigned therapy at study end (including withdrawals and lost to follow-up):
placebo group: 53%
diuretic arm: 48%
beta-blocker arm: 63%
Participants Geographic region: UK

Study setting: general practice
n = 4396 (58% female)
Age range: 60-74 mean: 70.3 years
Race: not reported
myocardial infarction: excluded if within last 3 months
stroke: excluded if within last 3 months
diabetes: excluded
smoking: 17.5%
Blood pressure (BP) entry criteria: systolic BP 160 - 209 mm Hg and diastolic BP < 115
mm Hg.
Interventions Control: matching placebo

Diuretic Arm: Step 1 - hydrochlorothiazide 25mg or 50mg + amiloride 2.5mg or 5 mg
daily; Step 2 - atenolol 50mg daily; Step 3 - nifedipine up to 20mg daily; Step 4 - other
drugs
Beta-blocker Arm: Step 1 - atenolol 50mg daily; Step 2 - hydrochlorothiazide 25mg or
50mg + amiloride 2.5mg or 5 mg daily; Step 3 - nifedipine up to 20mg daily; Step 4 -
other drugs

MRCOA 1992 (Continued)
Difference in blood pressure at study end (Treatment - Control) systolic/diastolic: -6.3/

-5.9 mmHg

CHD (Coronary Heart Disease mortality) mortality - sudden death thought to be due
to a coronary cause; death known to be due to a myocardial infarction.
tion.
Cerebrovascular mortality - fatal stroke.
Cerebrovascular M&M - fatal or non-fatal stroke.
Cardiovascular mortality -CHD mortality and fatal stroke.
Cardiovascular M&M - CHD M&M plus cerebrovascular M&M plus deaths due to
hypertension and to rupture or dissection of an aortic aneurysm.
Dropouts due to side effects:
Control group: 82 (3.7%)
Diuretic Arm: 160 (14.8%)
Beta-blocker Arm: 333 (30.2%)
Quality of life or functional outcomes: no perceptible negative effect of treatment com-
pared to control on measures of cognitive function.
Notes Exclusions: known or suspected secondary hypertension; taking antihypertensive drugs;

cardiac failure or any other accepted indication for antihypertensive treatment; receiving
treatment for angina pectoris; history of myocardial infarction or stroke within preceding
three months; impaired renal function; diabetic; asthma; serious intercurrent disease,
including malignancy known to be present at time of examination; serum potassium
concentration <= 3.4 mmol/L or > 5.0 mmol/L.
Risk of bias
Allocation concealment? Unclear B - Unclear
Blinding? Yes Patients were blinded

All outcomes
Incomplete outcome data addressed? No Overall the beta-blocker group had signif-
All outcomes icantly more drop outs than the diuretic
group both for major side effects and inad-
equate blood pressure control...
Over the five and a half years 25% of peo-
ple were lost to follow up...48% in the
duiretic group and 68% in the beta blocker
group...

MRCOA 1992 (Continued)
Free of selective reporting? No A patients participation in a trial ended

with a stroke, whether non-fatal or fa-
tal; coronary events...;other cardiovascular
events, and death from any cause.
If a patient had a non-fatal event followed
by a fatal event in the same category, only
the fatal event was included in the analy-
ses. If a patient had two events in different
categories, for example, a non-fatal stroke
then a coronary event (fatal or non-fatal),
then both were included.
SHEP 1991

Randomization: stratified by site and by antihypertensive medication status at initial
contact; patients randomly allocated by coordinating center.
Patients blinded; providers blinded; morbidity and mortality outcomes assessors were
blinded.
% lost to follow-up: <1%.
placebo group: 44%

Study setting: community
n = 4736 (55.8% female)
Age range 60 to >80 mean: 71.6 years
Race: White non-Hispanic (79.2%), Black (13.8%), Hispanic (1.8%), Asian (4.3%),
other (0.9%)
myocardial infarction: 4.9%
stroke: 1.4%
diabetes: 10.1%
smoking: 12.7%
mm Hg.

Treatment: Step 1 - chlorthalidone 12.5 or 25 mg daily; Step 2 - atenolol 25 or 50mg
or reserpine 0.05 or 0.10mg daily.
Average length of follow-up: 4.5 years
-3.4 mmHg

SHEP 1991 (Continued)

CHD (Coronary Heart Disease mortality) mortality - fatal myocardial infarction; sudden
(<1h) or rapid (1-24h) cardiac death.
tion.
Cardiovascular mortality - CHD mortality plus fatal stroke plus fatal left ventricular
failure, fatal presumed myocardial infarction..
Cardiovascular M&M - CHD M&M plus cerebrovascular M&M plus left ventricular
failure, transient ischemic attacks, presumed myocardial infarction.
Control group: 7%
Treatment group: 13%
Quality of life or functional outcomes: no perceptible negative effect of treatment com-
pared to control on measures of cognitive, physical, and emotional function.
Notes Exclusions: history and/or signs of major cardiovascular diseases likely to require pharma-
cologic and other treatment (eg, previous myocardial infarction, coronary artery surgery,
major arrhythmias, conduction defect, recent stroke, carotid artery disease, history of
transient ischemic attack (TIA) with bruit matched with TIA localization, two or more
TIAs and signs or symptoms in a single neurological distribution); other major diseases
(eg, cancer, alcoholic liver disease, established renal dysfunction) with competing risk
factors for the primary endpoint - stroke; presence of medical management problems (eg,
insulin dependent diabetes, history of dementia, evidence of alcohol abuse); bradycardia;
people maintained on beta-blockers, diuretics, other antihypertensive drugs, anticoagu-
lants, or experimental drugs on recommendation of their physicians.
Risk of bias
Allocation concealment? Yes Each randomization was carried out by

telephone
Blinding? Yes Described as double-blind

All outcomes
Incomplete outcome data addressed? Yes We specified an intention to treat rule

All outcomes (with
study groups divided by the randomized
assignment regardless
of subsequent crossovers) and a plan for
replacing any
missing annual visit BP with the last avail-
able value.

SHEP 1991 (Continued)
SHEP-PS 1986

Randomization: patients randomly allocated by coordinating center. Randomization
adapted for race, sex, age and systolic blood pressure.
Patients blinded. Providers blinded. Outcomes assessors blinded.
No loss to follow-up.
placebo group: 40%

Study setting: community
n = 551 (63% female)
Age range: > 60 (15% >80) mean: 72
Race: White (82%); non-White (18%)
myocardial infarction: 4%
stroke: 1%
smoking: 11%
mm Hg.

Treatment: Step 1 - chlorthalidone 25; Step 1 dose 2 - 50mg daily; Step 2 - randomized
to either reserpine 0.05mg twice daily or metoprolol 50mg twice daily or hydralazine
25mg twice daily or matching placebo twice daily; Step 2 dose 2 - double dose of Step
2.
Average length of follow-up: 2.8 years.
Difference in blood pressure at study end (Treatment - Control) systolic/diastolic: -17/-
5 mmHg

CHD (coronary heart disease) mortality - fatal myocardial infarction and sudden death.
CHD morbidity and mortality (M&M) - CHD mortality plus non-fatal myocardial
infarctions.
Cerebrovascular M&M - fatal and non-fatal strokes.
Cardiovascular mortality - CHD mortality plus cerebrovascular mortality plus left ven-
tricular failure.
Cardiovascular M&M - CHD M&M plus cerebrovascular M&M plus left ventricular
failure and transient ischemic attacks.
Dropouts due to side effects (at 12 months; data not reported for end of study):
Treatment group: 7 (1.6%)

SHEP-PS 1986 (Continued)
Notes Exclusions: coronary bypass surgery within 2 years; heart attack within 6 months; stroke
with residua; current treatment with antihypertensive drugs, insulin or anticoagulants;
allergy to study medications; specified arrhythmias or a pacemaker; uncontrolled conges-
tive heart failure; serum creatinine level of 2.0 mg/dL or more; alcohol abuse; cancer or
other life-threatening disease; chronic obstructive pulmonary disease; peripheral vascular
disease with tissue injury; senile dementia; residence in a nursing home; carotid bruit
with history of transient ischemic attacks; history of malignant hypertension.
Risk of bias
Blinding? Yes Triple blinded

All outcomes

All outcomes
Free of selective reporting? No For any participant who had two or more
events, one was designated the study event
based on a hierarchical classification headed
by death followed by four categories of non-
fatal events in rank order of stroke, other
hypertensive events, atherosclerotic events,
and noncardiovascular events. When there
were two events in one category, the event
that occurred first was used.
Sprackling 1981

Randomization: random numbers generated by computer and allocation assignment
distributed in sealed envelopes; stratified by site.
Patients not blinded; providers not blinded.
Lost to follow-up: 2%
% not on assigned therapy at study end: not clear.
Participants Geographic region: Nottinghamshire, England

Study setting: welfare homes for the elderly.
n = 123 (74% female)
Age range: not reported; mean age: 80.7
Race: not stated.

Sprackling 1981 (Continued)

stroke: 11.3%
Blood pressure (BP) entry criteria: diastolic BP > 100 mm Hg.
Interventions Control: observation without placebo.

Treatment: methyldopa 250mg twice daily
Average follow up: not clearly stated, approximately 4 - 5 years
-7.8

Cardiovascular morbidity and mortality: myocardial infarction, stroke, heart failure, or
the deterioration of pre-existing heart failure.
control group: not stated (implied 0%)
treatment group: 9 (15%)
Notes Exclusions: not reported (implied none)
Risk of bias
Adequate sequence generation? Yes Stated that a computer program was used
Allocation concealment? Yes a block of 24 sealed envelopes was pre-

pared for each of the seven homes
Blinding? No Open label study

All outcomes
Incomplete outcome data addressed? No 60 patients were randomized to each group

All outcomes but the blood pressures at the first rou-
tine visit after 6 months from the entry
to the trial were available in 36 surviving
treated patients and 39 surviving observed
patients.

STOP 1991
Methods Multisite study

Randomization: method of randomization and allocation not described.
Patients blinded; providers blinded; outcomes assessors blinded.
No loss to follow-up.
placebo group: 23%
Participants Geographic region: Sweden

Study setting: primary care.
n = 1627 (63% female)
Race: White
Pre-existing risk factors: not reported.
Blood pressure (BP) entry criteria: (systolic BP 180 - 230 mm Hg and diastolic BP >=
90 mm Hg) or (diastolic BP 105 - 120 mm Hg irrespective of systolic BP).
Interventions Control: matching placebo

Treatment: Step 1 - atenolol 50mg daily, or hydrochlorothiazide 25mg + amiloride 2.5mg
daily, or metoprolol 100mg daily, or pindolol 5mg daily; Step 2 - patients on a beta-
blocker received the diuretics and patients on the diuretics received a beta-blocker.
Average follow up: 2.1 years
-10.0 mmHg

CHD (Coronary Heart Disease mortality) mortality - fatal myocardial infarction.
CHD M&M (morbidity and mortality) - fatal or non-fatal myocardial infarction.
Cardiovascular mortality - fatal myocardial infarction; fatal stroke; sudden death; fatal
congestive heart failure and fatal cardiovascular events not covered by above definitions
(eg, ruptured aortic aneurysm).
Treatment group: 58 (7.1%)
Notes Exclusions: isolated systolic hypertension (180 mmHg or higher with diastolic below 90
mmHg); orthosatic hypotension (more than 30 mmHg fall in systolic blood pressure
on standing); contraindications to any of the drugs; myocardial infarction or stroke in
previous 12 months; angina pectoris requiring treatment with drugs other than glyceryl
trinitrate; other severe or incapacitating illnesses; or unwillingness to take part.
Risk of bias

STOP 1991 (Continued)

All outcomes

All outcomes
Syst-Eur 1991

Randomization: stratified by center, sex and previous cardiovascular complications.
Group allocation determined by computerized random function.
Patients blinded; providers blinded; outcome assessors blinded.
Lost to follow-up: 2% at 2 years
% not on assigned therapy at study end (2 years) including open follow-up and lost to
follow-up:
placebo group: 27%
Participants Geographic region: 23 countries across western and eastern Europe, mainly from Finland,
Bulgaria, the Russian Federation, Belgium, Italy, Israel, UK, France, Estonia, Lithuania,
Spain, Poland and Romania.
Study setting: community based and referral clinic.
n = 4695 (66.8% female)
Age range: 60+ mean: 70.3
Race: not reported
Mean blood pressure at entry:174/86 mm Hg
myocardial infarction: 1.2%
stroke: 3.5%
smoking: 7.3%
mm Hg.
Interventions Control: matching placebos with stepped therapy schedule similar to treatment groups.
Treatment: Step 1 - nitrendipine 10 - 40 mg/day; Step 2 - enalapril 5 - 20 mg/day and/
or hydrochlorothiazide 12.5 - 25 mg/day.
Average follow-up: 2 years (median)
Difference in blood pressure at end of study (Treatment - Control) systolic/diastolic: -
10.1 / -4.5 mm Hg at 2 years.

Syst-Eur 1991 (Continued)

CHD (Coronary Heart Disease) mortality - fatal myocardial infarctions and sudden
death.
CHD M&M (morbidity and mortality) - CHD mortality plus non-fatal myocardial
infarctions.
Cerebrovascular M&M - fatal and non-fatal strokes.
Cardiovascular mortality - CHD mortality plus cerebrovascular mortality plus deaths
from dissecting aortic aneurysms or heart failure.
Cardiovascular M&M - CHD M&M plus cerebrovascular M&M plus dissecting aortic
aneurysms, heart failure, pulmonary embolism, or peripheral arterial disease.
Dropouts due to side effects (no significant difference between groups):
placebo: <7.3%
treatment: <7.8%
Notes Exclusions: hypertension secondary to a disorder that needed specific medical or surgical
treatment; retinal hemorrhage or papilledema; congestive heart failure; dissecting aortic
aneurysm; serum creatinine concentration at presentation of 180 micromols/L or more;
history of severe nose bleeds, stroke, or myocardial infarction in the year before the study;
dementia; substance abuse; any disorder prohibiting a sitting or standing position; any
severe concomitant cardiovascular or non-cardiovascular disease.
Risk of bias
Adequate sequence generation? Yes randomized to double-blind treatment

with active medication or placebo by means
of a computerized random function
Blinding? Yes randomized to double-blind treatment

All outcomes with active medication or placebo by means
of a computerized random function
Incomplete outcome data addressed? Yes For patients who withdrew from
All outcomes treatment for whom regular follow-up was
not possible, we
annually collected information on vital sta-
tus, occurrence of major
endpoints and other events, and the use of
antihypertensive
medications (non-supervised open follow-
up). Patients without
any report within the year before the trial
stopped were counted as

Syst-Eur 1991 (Continued)
lost to follow-up.
VA Coop 1970

Randomization: stratified by diastolic blood pressure (ie, 90-114 mm Hg and 115-
129 mmHg); group allocation determined by sealed envelope containing randomized
assignment. Assignment was determined by a statistician utilizing a random number
table.
% lost to follow-up: 14.7% for entire study group (ie, this data not reported for >60 age
sub-group).

Study setting: recruited from Veterans Affairs hospitals and seen in outpatient clinics
n = 81 (0% female)
Age range: 60-75 mean: not reported.
Race: White (57.6%), Black (41.3%), Asian (1.1%); for entire study group (ie, this data
not reported for >60 age sub-group).
Pre-existing factors: not reported.
Blood pressure (BP) entry criteria: diastolic BP 90 - 114 mm Hg.
Interventions Control: placebo

Treatment: hydrochlorothiazide 50mg and reserpine 0.1mg twice daily plus hydralazine
25mg three time daily.
Difference in blood pressure at study end (Treatment - Control) diastolic: -18.6 mmHg
(systolic not reported).
Outcomes Coronary heart disease (CHD) morbidity and mortality (M&M) - myocardial infarction
or sudden death.
Cerebrovascular M&M - cerebrovascular accidents.
Cardiovascular M&M - CHD M&M plus cerebrovascular M&M plus congestive heart
failure and aneurysms.
Dropouts due to side effects: for entire study group (ie, this data not reported for >60
age sub-group)
Control group: 3.1%
Treatment group: 5.9%
Notes Exclusions: severe hypertension; surgically curable hypertension; uremia; concomitant

fatal diseases such as carcinoma; hemorrhages, exudates, or papilledema in the optic
fundi; history of cerebral or subarachnoid hemorrhage; dissecting aneurysm; congestive
heart failure resistant to digitalis and mercurial diuretics; patients who wished to return

VA Coop 1970 (Continued)
to the care of their private physicians; patients unable to attend clinic regularly; patients
of dubious reliability such as alcoholics, vagrants and poorly motivated patients.
Risk of bias

All outcomes

All outcomes
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
ADVANCE 2007 Control group included non-specific antihypertensive therapy
ALLHAT 1996 Head-to-head comparison of different drug therapies without a non-drug control group.
Barraclough 1973 Not a trial in elderly persons.
BMJ 1973 Did not report results separately for elderly subjects.
CASTEL 1994 Control group included non-specific antihypertensive therapy
GLANT 1995 Employed alternate allocation (ie, not random allocation). Head-to-head comparison of different drug therapies
without a non-drug control group.
HAPPHY 1987 Did not report results separately for elderly subjects (age range 40 - 64).
HDFP 1982 Based on the comments received regarding improper inclusion of this trial in the previous systematic review
we excluded this trial since the intervention was multifactorial. It has also been included as multifactorial
intervention trial in another Cochrane systematic review.
HOT 1995 Evaluates the effects of achieving pre-specified levels of diastolic blood pressure control with all patients
receiving antihypertensive treatment.

(Continued)
HYVET-Cog 2008 this publication is a substudy of the HYVET 2008 trial and did not provide any additional data for analysis.
IPPPSH 1985 Did not report results separately for elderly subjects (age range 40 - 64).
Jikei 2007 Did not truly randomize subjets to treatment arms and control group included non-specific antihypertensive
therapy
Kuramoto 1994 Head-to-head comparison of different drug therapies (nicardipine vs trichlormethiazide) without a non-drug
control group.
MAPHY 1988 Did not report results separately for elderly subjects (age range 40 - 64).
Materson 1993 Morbidity and mortality were not assessed. Blood pressure control and incidence of termination of treatment
were the main outcomes.
MIDAS 1996 Evaluated two antihypertensives (isradipine vs hydrochlorothiazide) directly without a control group.
Morgan 1980 Allocation to the four study groups (no treatment, reduced salt intake, thiazide diuretic, beta-blocker) was
non-random (ie, based on their week of presentation at the clinic).
MRC 1985 Did not report results separately for elderly subjects (age range 35 - 64).
Oslo 1986 Not a trial in elderly persons.
PATS 1995 Not all patients were hypertensive.
SCOPE 2003 Control group included non-specific antihypertensive therapy
SHELL 1994 Head-to-head comparison of different drug therapies without a non-drug control group.
STONE 1996 Employed alternate allocation (ie, not random allocation). Four weeks after group assignment, attending
physicians were allowed to reallocate participants from the placebo group to the treatment group if their
diastolic blood pressure was at least 110 mm Hg.
STOP-2 1993 Head-to-head comparison of different drug therapies without a non-drug control group.
Syst-China 1993 Allocation to treatment and control groups not random (ie, alternate allocation was employed).
TOMHS 1995 Morbidity and mortality data not reported separately for elderly subjects.
USPHS Coop 1977 Not a trial in elderly persons.
VA Coop 1962 Did not report results separately for elderly subjects.
VA/NHLBI 1978 Not a trial in elderly persons.
White 1995 Head-to-head comparison of different drug therapies without a non-drug control group.

(Continued)
Wolf 1966 Did not report results separately for elderly subjects.

DATA AND ANALYSES
Comparison 1. Antihypertensive drug therapy vs control in elderly 60 years or older
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Total mortality 12 23119 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.84, 0.97]
1.1 Elderly 60 years or older 12 23119 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.84, 0.97]
2 Cardiovascular mortality and 13 23094 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.68, 0.77]
morbidity
3 Withdrawal due to adverse 3 6914 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [1.45, 2.00]
effects
Comparison 2. Antihypertensive drug therapy vs control in very elderly 80 years or older
No. of No. of
1.1 Very elderly 80 years or 8 6701 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.87, 1.10]
older
2 Cardiovascular mortality and 7 6546 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.65, 0.87]
morbidity
2.1 Very elderly 80 years or 7 6546 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.65, 0.87]
older
Comparison 3. Antihypertensive drug therapy vs control in elderly with ISH
No. of No. of
2 Cardiovascular morbidity and 3 9982 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.61, 0.75]
mortality
3 Withdrawal due to adverse 3 6914 Risk Ratio (M-H, Fixed, 95% CI) 1.71 [1.45, 2.00]
effects 60 years or older

Analysis 1.1. Comparison 1 Antihypertensive drug therapy vs control in elderly 60 years or older, Outcome
1 Total mortality.
Review: Pharmacotherapy for hypertension in the elderly
Comparison: 1 Antihypertensive drug therapy vs control in elderly 60 years or older
Outcome: 1 Total mortality
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Elderly 60 years or older

STOP 1991 36/812 63/815 4.8 % 0.57 [ 0.39, 0.85 ]
HYVET 2008 196/1933 235/1912 18.1 % 0.82 [ 0.69, 0.99 ]
Syst-Eur 1991 123/2398 137/2297 10.7 % 0.86 [ 0.68, 1.09 ]
SHEP 1991 213/2365 242/2371 18.5 % 0.88 [ 0.74, 1.05 ]
Carter 1970 7/22 9/26 0.6 % 0.92 [ 0.41, 2.06 ]
EWPHE 1989 135/416 149/424 11.3 % 0.92 [ 0.76, 1.12 ]
HEP 1986 60/419 69/465 5.0 % 0.97 [ 0.70, 1.33 ]
MRCOA 1992 301/2183 315/2213 24.0 % 0.97 [ 0.84, 1.12 ]
Kuramoto 1981 7/44 7/47 0.5 % 1.07 [ 0.41, 2.80 ]
Sprackling 1981 48/61 44/62 3.3 % 1.11 [ 0.90, 1.36 ]
SHEP-PS 1986 32/443 7/108 0.9 % 1.11 [ 0.51, 2.46 ]
HYVET P 2003 57/857 22/426 2.3 % 1.29 [ 0.80, 2.08 ]
Total (95% CI) 11953 11166 100.0 % 0.90 [ 0.84, 0.97 ]

Total events: 1215 (Treatment), 1299 (Control)
Heterogeneity: Chi2 = 13.61, df = 11 (P = 0.26); I2 =19%
Test for overall effect: Z = 2.74 (P = 0.0062)
0.1 0.2 0.5 1 2 5 10

Favors treatment Favors control

2 Cardiovascular mortality and morbidity.
Outcome: 2 Cardiovascular mortality and morbidity


ANBP 1981 31/293 40/289 2.3 % 0.76 [ 0.49, 1.19 ]
HEP 1986 82/419 120/465 6.6 % 0.76 [ 0.59, 0.97 ]
HTN Coop 1974 28/101 34/99 2.0 % 0.81 [ 0.53, 1.22 ]
HYVET 2008 138/1933 193/1912 11.3 % 0.71 [ 0.57, 0.87 ]
HYVET P 2003 50/857 26/426 2.0 % 0.96 [ 0.60, 1.51 ]
Kuramoto 1981 4/44 9/47 0.5 % 0.47 [ 0.16, 1.43 ]
MRCOA 1992 258/2183 309/2213 17.8 % 0.85 [ 0.73, 0.99 ]
SHEP 1991 346/2365 519/2371 30.1 % 0.67 [ 0.59, 0.76 ]
SHEP-PS 1986 33/443 14/108 1.3 % 0.57 [ 0.32, 1.04 ]
Sprackling 1981 53/61 52/62 3.0 % 1.04 [ 0.89, 1.20 ]
STOP 1991 84/812 152/815 8.8 % 0.55 [ 0.43, 0.71 ]
Syst-Eur 1991 160/2398 216/2297 12.8 % 0.71 [ 0.58, 0.86 ]
VA Coop 1970 9/38 25/43 1.4 % 0.41 [ 0.22, 0.76 ]
Total (95% CI) 11947 11147 100.0 % 0.72 [ 0.68, 0.77 ]

Test for overall effect: Z = 9.60 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10


3 Withdrawal due to adverse effects.
Outcome: 3 Withdrawal due to adverse effects

SHEP 1991 307/2365 166/2371 76.8 % 1.85 [ 1.55, 2.22 ]
SHEP-PS 1986 7/443 2/108 1.5 % 0.85 [ 0.18, 4.05 ]
STOP 1991 58/812 47/815 21.7 % 1.24 [ 0.85, 1.80 ]
Total (95% CI) 3620 3294 100.0 % 1.71 [ 1.45, 2.00 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.1. Comparison 2 Antihypertensive drug therapy vs control in very elderly 80 years or older,
Outcome 1 Total mortality.
Comparison: 2 Antihypertensive drug therapy vs control in very elderly 80 years or older
Study or subgroup Treatment Control Risk Ratio Risk Ratio

1 Very elderly 80 years or older

EWPHE 1989 58/70 60/85 1.17 [ 0.99, 1.40 ]
HEP 1986 0/3 0/4 0.0 [ 0.0, 0.0 ]
HYVET 2008 196/1933 235/1912 0.82 [ 0.69, 0.99 ]
HYVET P 2003 57/857 22/426 1.29 [ 0.80, 2.08 ]
SHEP 1991 57/331 59/319 0.93 [ 0.67, 1.30 ]
SHEP-PS 1986 10/70 0/15 4.73 [ 0.29, 76.64 ]
STOP 1991 11/122 8/113 1.27 [ 0.53, 3.05 ]
Syst-Eur 1991 72/231 53/210 1.23 [ 0.91, 1.67 ]
Total (95% CI) 3617 3084 0.98 [ 0.87, 1.10 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.2. Comparison 2 Antihypertensive drug therapy vs control in very elderly 80 years or older,
Outcome 2 Cardiovascular mortality and morbidity.
Comparison: 2 Antihypertensive drug therapy vs control in very elderly 80 years or older
Outcome: 2 Cardiovascular mortality and morbidity

1 Very elderly 80 years or older

HEP 1986 0/3 1/4 0.4 % 0.42 [ 0.02, 7.71 ]
HYVET 2008 138/1933 193/1912 53.9 % 0.71 [ 0.57, 0.87 ]
HYVET P 2003 50/857 26/426 9.7 % 0.96 [ 0.60, 1.51 ]
SHEP 1991 45/331 65/319 18.4 % 0.67 [ 0.47, 0.94 ]
SHEP-PS 1986 9/70 3/15 1.4 % 0.64 [ 0.20, 2.10 ]
STOP 1991 12/122 16/113 4.6 % 0.69 [ 0.34, 1.40 ]
Syst-Eur 1991 42/231 40/210 11.6 % 0.95 [ 0.65, 1.41 ]
Total (95% CI) 3547 2999 100.0 % 0.75 [ 0.65, 0.87 ]

Heterogeneity: Chi2 = 3.54, df = 6 (P = 0.74); I2 =0.0%
0.1 0.2 0.5 1 2 5 10


Analysis 3.1. Comparison 3 Antihypertensive drug therapy vs control in elderly with ISH, Outcome 1 Total
mortality.
Comparison: 3 Antihypertensive drug therapy vs control in elderly with ISH


SHEP 1991 213/2365 242/2371 61.5 % 0.88 [ 0.74, 1.05 ]
SHEP-PS 1986 32/443 7/108 2.9 % 1.11 [ 0.51, 2.46 ]
Syst-Eur 1991 123/2398 137/2297 35.6 % 0.86 [ 0.68, 1.09 ]
Total (95% CI) 5206 4776 100.0 % 0.88 [ 0.77, 1.01 ]

0.1 0.2 0.5 1 2 5 10

Analysis 3.2. Comparison 3 Antihypertensive drug therapy vs control in elderly with ISH, Outcome 2
Cardiovascular morbidity and mortality.
Outcome: 2 Cardiovascular morbidity and mortality


SHEP 1991 346/2365 519/2371 68.1 % 0.67 [ 0.59, 0.76 ]
SHEP-PS 1986 33/443 14/108 3.0 % 0.57 [ 0.32, 1.04 ]
Syst-Eur 1991 160/2398 216/2297 29.0 % 0.71 [ 0.58, 0.86 ]
Total (95% CI) 5206 4776 100.0 % 0.68 [ 0.61, 0.75 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.3. Comparison 3 Antihypertensive drug therapy vs control in elderly with ISH, Outcome 3
Withdrawal due to adverse effects 60 years or older.
Outcome: 3 Withdrawal due to adverse effects 60 years or older

SHEP 1991 307/2365 166/2371 76.8 % 1.85 [ 1.55, 2.22 ]
SHEP-PS 1986 7/443 2/108 1.5 % 0.85 [ 0.18, 4.05 ]
STOP 1991 58/812 47/815 21.7 % 1.24 [ 0.85, 1.80 ]
Total (95% CI) 3620 3294 100.0 % 1.71 [ 1.45, 2.00 ]

0.1 0.2 0.5 1 2 5 10

APPENDICES
Appendix 1. MEDLINE search strategy
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 randomized controlled trials/
4 random allocation/
5 double blind method/
6 single-blind method/
7 or/1-6
8 animal/ not human/
9 7 not 8
10 clinical trial.pt.
11 exp clinical trials/
12 (clin$ adj25 trial$).ti,ab.
13 ((singl$ or doubl$ or treb$) adj25 (blind$ or mask$)).ti,ab.
14 placebos/
15 placebo$.ti,ab.
16 random$.ti,ab.
17 research design/
18 or/10-17
19 18 not 8
20 19 not 9
21 comparative study/
22 exp evaluation studies/
23 follow up studies/
24 prospective studies/
25 (control$ or prospectiv$ or volunteer$).ti,ab.
26 or/21-25
27 26 not 8
28 27 not (9 or 20)
29 9 or 20 or 28
30 exp antihypertensive agents/
31 exp diuretics/
32 exp adrenergic alpha-antagonists/
33 exp adrenergic beta-antagonists/
34 exp ace inhibitors/
35 exp calcium channel blockers/
36 exp vasodilator agents/
37 losartan.tw.
39 or/30-37
40 39 and hypertension/
41 40 or hypertension/dt
42 41 and 29
FEEDBACK
Comment on the conclusion
Summary
While reading your interesting review in the Cochrane Library: Pharmacotherapy for hypertension in the elderly, we were particularly
interested in a statement made in the Main results of the abstract: The average prevalence of cardiovascular risk factors, cardiovascular
disease, and competing co-morbid diseases was lower among trial participants than the general population of hypertensive elderly
persons. We would very much like to know how you came to that conclusion. After carefully reading the full review, we were not able
to find this statement mentioned in any other part of the review. Could you please provide how you validated this statement and what
references were used to validate this statement?
Reply
We have deleted that statement in the current/updated version of this review.
Contributors
Saba T.A. and Berger Ch.
Fifth year Pharmacy Students
Department of pharmacology
University of Lausanne
Switzerland
We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject
matter of our criticisms.
Conclusions are flawed, 28 October 2008
Summary
As stated in the title and objectives: The purpose of this SR was to provide a comprehensive overview of trial evidence regarding benefits
of anti-hypertensive drug therapy in elders.
This systematic review can be criticized mainly because it includes the HDFP trial (in which patients were randomized to two different
treatment strategies, i.e. stepped care vs. referred care. In other words, in this trial not only the type of pharmacological agents were
different in both groups, but also non-pharmacological interventions. Thus, it is not possible to be certain if the difference in outcomes
was due to pharmacological or to non-pharmacological interventions) and CASTEL trial (similar design as that of HDFP) and pooled
these trials along with true placebo control trials. Thus, when calculating total mortality, the weight given to those two trials in
combination is even greater than that given to the biggest placebo-control trial, SHEP trial. If those two trials were removed the benefit
disappears. Therefore, the conclusions of this systematic review are flawed.
Reply
We have excluded HDFP 1982 trial in the current/updated version of this review.
Contributors
Marco Perez
Occupation MD/research
Department of Anesthesiology, Pharmacology & Therapeutics
University of British Columbia
Vancouver, BC Canada
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of
my feedback.
WHATS NEW
Last assessed as up-to-date: 31 May 2009.
Date Event Description
1 November 2010 Amended Added links to Figures in the result section (to the Forest plots of the primary and secondary
outcome measures) which were initially refered to as links in the Data and Analysis section.
27 October 2009 Amended Corrected denominator of the STOP trial for total mortality from 22 to 122 in the hypertension
in very elderly subgroup

HISTORY
Protocol first published: Issue 3, 1998
Review first published: Issue 3, 1998
Date Event Description
11 August 2009 Feedback has been incorporated Excluded HDFP trial since it is a multi-interventional
study.
11 August 2009 New citation required and conclusions have changed substantive update, authors and conclusions have
changed
28 October 2008 Feedback has been incorporated New feedback received 28 October 2008.
13 August 2008 Amended Converted to new review format.
5 June 2006 Amended Minor update.
17 November 2004 Feedback has been incorporated Feedback added.
CONTRIBUTIONS OF AUTHORS
Vijaya Musini and Aaron Tejani did an updated literature search, data abstraction, data entry, verification and data analysis. James
Wright and Ken Bassett verified data and resolved differences. All authors contributed in writing the results and discussion section.
DECLARATIONS OF INTEREST
None.
SOURCES OF SUPPORT
Internal sources
Department of Anesthesiology, Pharmacology & Therapeutics, University of BC, Canada.
Office space

External sources
CIHR grant to the Hypertension Review Group, Canada.
Infrastructure
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

None.
NOTES
This systematic review has been substantially updated by a new team of authors. The updated review includes two additional trials
identified (HYVET P 2003 and HYVET 2008) and excludes HDFP 1982 and CASTEL 1994 trials that were included in the previous
review. Also meta-analysis of data in the very elderly (80 years or older) has been added to the updated review.
INDEX TERMS
Medical Subject Headings (MeSH)

Age Factors; Antihypertensive Agents [adverse effects; therapeutic use]; Cause of Death; Hypertension [ drug therapy; mortality];
Myocardial Infarction [prevention & control]; Randomized Controlled Trials as Topic; Stroke [prevention & control]; Withholding
Treatment
MeSH check words

Aged; Aged, 80 and over; Humans; Middle Aged


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Pharmacotherapy for hypertension in the elderly (Review)

Musini VM, Tejani AM, Bassett K, Wright JM

Pharmacotherapy for hypertension in the elderly (Review)

Pharmacotherapy for hypertension in the elderly (Review) ii

Pharmacotherapy for hypertension in the elderly

Vijaya M Musini1 , Aaron M Tejani2 , Ken Bassett1 , James M Wright1

Editorial group: Cochrane Hypertension Group.

PLAIN LANGUAGE SUMMARY

Pharmacotherapy for hypertension in the elderly (Review) 2

Patient or population: patients with hypertension in the elderly

Assumed risk Corresponding risk

control in elderly (60 Antihypertensive drug

Total mortality - Elderly Study population RR 0.9 23119

Low risk population

100 per 1000 90 per 1000

High risk population

300 per 1000 270 per 1000

Cardiovascular mortal- Study population RR 0.72 23094

153 per 1000 110 per 1000

Low risk population

150 per 1000 108 per 1000

High risk population

400 per 1000 288 per 1000

GRADE Working Group grades of evidence

Pharmacotherapy for hypertension in the elderly (Review) 5

Pharmacotherapy for hypertension in the elderly (Review) 6

Pharmacotherapy for hypertension in the elderly (Review) 7

Pharmacotherapy for hypertension in the elderly (Review) 8

Pharmacotherapy for hypertension in the elderly (Review) 9

Pharmacotherapy for hypertension in the elderly (Review) 10

Pharmacotherapy for hypertension in the elderly (Review) 11

Analysis of trials in very elderly (80 years or older) showed no

Pharmacotherapy for hypertension in the elderly (Review) 12

Cardiovascular mortality: The combined results of the 10 trials

Pharmacotherapy for hypertension in the elderly (Review) 13

Figure 7. Non-cardiovascular mortality in elderly patients with hypertension

Pharmacotherapy for hypertension in the elderly (Review) 14

Figure 8. Cardiovascular mortality in elderly patients with ISH

Pharmacotherapy for hypertension in the elderly (Review) 15

Cerebrovascular mortality: In people 60 years or older there was a

Pharmacotherapy for hypertension in the elderly (Review) 16

In the three trials with isolated systolic hypertension the reduction

Pharmacotherapy for hypertension in the elderly (Review) 17

Pharmacotherapy for hypertension in the elderly (Review) 18

Coronary heart disease (CHD) mortality: In the 9 trials report-

Pharmacotherapy for hypertension in the elderly (Review) 19

Pharmacotherapy for hypertension in the elderly (Review) 20

In the three trials with isolated systolic hypertension the reduction

Pharmacotherapy for hypertension in the elderly (Review) 21

Cardiovascular mortality and morbidity (M&M): In the 13

Pharmacotherapy for hypertension in the elderly (Review) 22

Excluding MRCOA 1992 because it used a different definition

Pharmacotherapy for hypertension in the elderly (Review) 23

Pharmacotherapy for hypertension in the elderly (Review) 24

Pharmacotherapy for hypertension in the elderly (Review) 25

Pharmacotherapy for hypertension in the elderly (Review) 26

Cerebrovascular mortality and morbidity (Figure 23) as well as

Pharmacotherapy for hypertension in the elderly (Review) 27

Pharmacotherapy for hypertension in the elderly (Review) 28

The number of people withdrawing from therapy due to adverse

Pharmacotherapy for hypertension in the elderly (Review) 29

Patient or population: patients with Elderly patients with primary hypertension

Assumed risk Corresponding risk