pharmacotherapy for hypertension in the elderly · beta adrenergic blockers, combined alpha and...

Dear all,

Welcome to the workshop on Systematic Review!

During our workshop I’ll try to give you an introduction on how to interpret and evaluate a systematic review and how to perform your own SR.

To get started I would like to give you a small reading assignment.

Below you’ll find a Cochrane review on ‘Pharmacotherapy for hypertension in the elderly’. I invite you to read the SR, not to go into details on the results and clinical implications, but really on the methodology.

Therefore, I would like to ask you to look at the following aspects of the review:

- is the objective clearly defined?

- which search strategy was used?

- how were papers selected?

- how was the quality of the different studies evaluated?

- how was the data extraction done?

- was a meta-analysis performed, and do you understand what is presented?

See you!

Kind regards,

Bert Vaes

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

2009, Issue 4

http://www.thecochranelibrary.com

Pharmacotherapy for hypertension in the elderly (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

29ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

32DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

iPharmacotherapy for hypertension in the elderly (Review)


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

morbidity and mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

74APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

78NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiPharmacotherapy for hypertension in the elderly (Review)


[Intervention Review]

Pharmacotherapy for hypertension in the elderly

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

1Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada. 2Pharmacy

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. [email protected].

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.


A B S T R A C T

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 methods

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

1Pharmacotherapy for hypertension in the elderly (Review)


mailto:[email protected]

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.

P L A I N L A N G U A G E S U M M A R Y

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.



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

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

control in elderly (60

years or older)

Antihypertensive drug

therapy

Total mortality - Elderly

60 years or older

Study population RR 0.9

(0.84 to 0.97)

23119

(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-

ity and morbidity - El-

derly 60 years or older


(0.68 to 0.77)

23094

(13 studies)

⊕⊕⊕⊕

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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.

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B A C K G R O U N D

Blood pressure increases with age, and the rate of rise is greater over

age 60. As a result the number of people with elevated blood pres-

sure (known as hypertension) increases with age. Systolic blood

pressure is more strongly associated with cardiovascular disease

than diastolic blood pressure particularly in older people. Iso-

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-

trophy, sedentary life style, hyperlipidemia, and diabetes.

Most of the early trials evaluating antihypertensive drug therapy

were conducted in lower risk people under age 60. The first

definitive clinical trial evidence supporting blood pressure lower-

ing treatment was produced in the mid-1980s. Before that time,

policymakers and clinicians were reluctant to recommend treat-

ment particularly in the elderly; some regarded systolic hyperten-

sion as a natural feature of aging, while others feared excessive

harm from blood pressure lowering in this age group.

Since 1985, several large trials have been conducted, and several

meta-analyses have summarized their results (Davidson 1987,

Staessen 1988, Staessen 1990a, Staessen 1990b, Leonetti 1992,

Thijs 1992, Celis 1993, MacMahon 1993, Thijs 1994, Insua

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

benefits and harms of antihypertensive treatment for people aged

60 and above.

O B J E C T I V E S

Primary:

1. To quantify antihypertensive drug effect on overall mortality

in people 60 years and older with mild to moderate systolic or

diastolic hypertension.

Secondary:

2. To quantify antihypertensive drug effect on cardiovascular spe-

cific morbidity and mortality in people 60 years and older with

mild to moderate systolic or diastolic hypertension.

3. To quantify withdrawal due adverse events.

Planned subgroup analyses included patients with isolated systolic

hypertension and the very elderly people 80 years or older.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Only randomized controlled trials of at least one year duration

were included. Trials must have included a control group that

either received a placebo or received no anti-hypertensive therapy.

Trials that compared two specific antihypertensive therapies were

excluded.

Types of participants

Trials must include only people 60 or older or separately report

outcomes for people 60 or older. Participants must have a systolic

blood pressure of at least 140 mmHg and/or a diastolic blood

pressure of at least 90 mmHg at baseline.

Types of interventions

Acceptable anti-hypertensive drug therapies include: angiotensin

converting enzyme inhibitors, angiotensin receptor antagonists,

beta adrenergic blockers, combined alpha and beta blockers, cal-

cium-channel blockers, diuretics, alpha adrenergic blockers, cen-

tral sympatholytics, direct vasodilators or peripheral adrenergic

antagonists. Drugs could have been administered alone or in com-

bination or in fixed or stepped up regimens.

Types of outcome measures

Morbidity and mortality were defined as follows:

• Total mortality means deaths from all causes.

• Coronary heart disease (CHD) mortality includes fatal

myocardial infarctions and sudden or rapid cardiac death.

• Cerebrovascular mortality includes fatal strokes.

• Cardiovascular mortality sums coronary heart disease

mortality and cerebrovascular mortality.

• CHD morbidity and mortality includes fatal and non fatal

myocardial infarctions and sudden or rapid cardiac death.

• Cerebrovascular morbidity and mortality includes fatal and

nonfatal strokes.

• Cardiovascular morbidity and mortality includes CHD

plus cerebrovascular morbidity and mortality plus aneurysms,

congestive heart failure and transient ischemic attacks.

Withdrawal due to adverse effects

When the primary trials did not report outcomes with exact defi-

nitions as listed above, the review authors categorized data to mini-

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

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”

listed above. We include MRCOA’s results in the cardiovascular

morbidity and mortality outcome measure because “deaths due



to hypertension” was congruous with the concept of cardiovascu-

lar morbidity and mortality. The alternative, omitting MRCOA’s

data, would result in a more reliable measure but at the expense

of accuracy of the effect estimate. The number of differences in

definitions was small and is unlikely to affect results. Supporting

this assumption, previous meta-analyses found homogeneity of

risk reduction among outcome measures suggesting differences in

outcome definition were unlikely causes of bias.

One of the new trials included in the update (HYVET P 2003)

was not conducted according to the standards of Good Clinical

Practice Guidelines and did not collect data on serious adverse

events, non-fatal MI or heart failure (personal communication

with the author). However, data on cardiovascular mortality and

morbidity was reported in the trial and is included in the meta-

analysis.

The actual endpoints represented by each outcome measure for

each study are listed under the “Outcomes” heading of the

Characteristics of included studies table. Within each study the

definition of endpoints for each outcome measure are identical

between the treatment and control groups. The individual non-

fatal outcomes included in the composite endpoint were included

as counted by the trialist of each study. Many trials did not report

on how events were counted after patients were censored. Refer

to personal communication with author of HYVET 2008 trial in

the risk of bias table to find out how events were counted in that

trial.

Search methods for identification of studies

The following sources were searched:

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

from 1981-1995 and JAPIC-DOC from 1973-1995 with the

keywords Hikaku-Shiken (comparative studies), Nijuu-Mouken-

Ho (double-blind method) and Hontaisei-Koketsuatsu (hyperten-

sion). This search produced 46 articles of which 34 were reports

of randomized controlled trials. Titles of the 34 RCTs were trans-

lated into English by S Lee-Borges. The abstracts of three possibly

relevant trials were translated into English. None met the inclu-

sion criteria of this review.

Thirteen other meta-analyses on antihypertensive drug therapy

in the elderly have also been published (Davidson 1987, Staessen

1988, Staessen 1990a, Staessen 1990b, Leonetti 1992, Thijs 1992,

Celis 1993, MacMahon 1993, Thijs 1994, Pearce 1995, Wright

JM 1999, Gueyffier F 1999, Musini VM 2008). A review of the

reference lists in these review did not identify any additional studies

which met the inclusion criteria for this review.

The MEDLINE search has been updated by searching from 1994

through December 2008. The search strategy (Appendix 1) is de-

signed to identify pharmacological treatment of hypertension. (A

“/” at the end of a term indicates that it is a Medical Subject Head-

ing (MeSH) term; “exp” indicates that the term is exploded mean-

ing that all MeSH terms nested under the exploded MeSH term

are included in the search; “tw” indicates that the term is a text

word meaning the title, abstract and MeSH terms are searched for

the term; hypertension/dt returns references coded as Drug Treat-

ment for hypertension; “pt” indicates a publication type; “ti.ab”

indicates a search for the text word in the title and abstract but not

the MeSH terms; the symbols “$” and “?” are wildcard characters

used to search for multiple forms of a word; the search modifier

“adj” plus a number between any two terms returns records which

contain the two terms within the specified number of words of

each other.)

The updated search of Medline up to December 2008 identified

162 citations. The titles and abstracts of this list were screened in-

dependently by two reviewers (VM and AT) for inclusion which re-

sulted in the retreival of 31 full papers. One reviewer then screened

the 31 full papers and a further 3 RCTS were considered for po-

tential inclusion into the review (Jikei 2007, ADVANCE 2007,

SCOPE 2003). Three reviewers discussed and reached consensus

that the 3 RCTS did not meet the inclusion criteria and were ex-

cluded. A search of CENTRAL up to June 2009 identified only

1 additional citation (HYVET-Cog 2008) that was not identi-

fied in the Medline search. The HYVET-Cog 2008 was retrieved

however it was concluded that this substudy of the HYVET 2008

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

on a review of titles and abstracts.

Bibliographies of newly identified meta-analyses, reviews and trials

were examined for references to other trials.

Data collection and analysis

Data abstraction

This review is based on five previously published meta-analyses on

the same topic (Mulrow 1994, Mulrow 1998, Wright JM 1999,

Gueyffier F 1999, Musini VM 2008). Data was abstracted using

a standard data abstraction form; dual abstraction of data from

the original reports of trial results by two independent reviewers;

and disagreements were resolved by discussion. The published

results of these meta-analyses as well as data from additional trials

included in the updated review were compared by two reviewers

(VM and AT). Any disagreements were resolved by consensus

(JMW and KB) .

Risk of Bias table

A quality scoring scheme was not used, but instead key trial charac-

teristics are detailed in the table Characteristics of included studies.

Potential parameters of methodological quality listed in the table

include: whether randomization was completed in an appropriate

and blinded manner; whether patients, providers and/or outcome

assessors were blinded to assigned therapy; whether the control



group received a placebo; percent of participants who did not com-

plete follow-up (dropouts); and the percent of participants not

on assigned active or placebo therapy at study completion (cross-

over).

The updated review uses the Risk of Bias tool to assess each trial

according to the Cochrane Handbook guidelines.

Analyses

Quantitative analyses of outcomes are based on intention-to-treat

results. Our measure of effect for each study was the Relative-

Risk (RR) with 95% CI. Chi-square tests for heterogeneity were

used to assess outcome data for compatibility with the assumption

of a uniform relative risk (P>0.10). Pooled risk differences are

converted to numbers needed to treat (NNTs) with the formula

NNT = 1/risk difference. NNTs are the number of patients who

must be treated to prevent one adverse outcome.

To test for robustness of results, several sensitivity analyses were

performed. Data were analysed using both fixed effect and ran-

dom effects models. As further tests of sensitivity, trials that were

not blinded and placebo controlled were analysed separately from

blinded (subject and/or provider), placebo controlled trials. Re-

sults were also analysed with and without those trials restricted

to persons who had previously suffered a stroke. Results of tri-

als restricted to persons with isolated systolic hypertension were

analysed both as a separate group and combined with trials also

assessing persons with both systolic and diastolic hypertension.

Analyses in the very elderly (80 year or older) were planned be-

cause a subgroup meta-analysis from earlier trials by Gueyffier F

1999 showed a trend towards increased mortality. Furthermore,

two recent randomised trials HYVET P 2003 and HYVET 2008

were specifically done in the very elderly group of patients.

Individual differences in patient characteristics or disease severity

are associated with different levels of risk to experience an adverse

event. In the aggregate, these individual differences contribute to

the proportion of patients we expect to experience an event within

a population. Variation in level of risk in different patient popu-

lations, both within and between clinical trials, is often associated

with variability in treatment outcomes (Ioannidis 1997, Schmid

1998). This average population risk is unknown, but contributes

to the proportion of events experienced by a placebo control group

in a randomised trial. We use the term control rate to describe the

probability that a member within the control group experiences

the adverse event, and we use this sample value to estimate the

aggregate population risk for patients enrolled in a clinical trial.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Two new randomised controlled trials met the inclusion criteria

(HYVET 2008 and HYVET P 2003). Two RCTs included in the

previous version were excluded in the update since the control

group was not an untreated or placebo control group. The HDFP

1982 study was excluded since it is a multifactorial intervention

(Ebrahim 2006). CASTEL 1994 was excluded since the control

group was receiving non-specific anti-hypertensive therapy from

their personal physician.

Fifteen trials including 24,005 people age 60 or over were identi-

fied. For most subjects included in this review the mean age ranged

from 63 to 84 years. Three trials (Carter 1970, HTN Coop 1974,

VA Coop 1970) did not report mean age. Most trials were con-

ducted in Western, industrialized countries and evaluated first-

line diuretics (ANBP 1981, Carter 1970, EWPHE 1989, HYVET

2008, HYVET P 2003, Kuramoto 1981, MRCOA 1992, SHEP

1991, SHEP-PS 1986, VA Coop 1970). Two trials evaluated beta-

blocker therapies (HEP 1986, STOP 1991). Four of these trials

(Carter 1970, VA Coop 1970, HTN Coop 1974, ANBP 1981)

originally included both younger and older persons. Only data

on those older than 60 is reported. The average age across trials

was 73.8 years. The Swedish Trial in Old Patients with Hyperten-

sion (STOP 1991) specifically evaluated people over age 70. The

HYVET P 2003 and HYVET 2008 trials included patients 80

years or older.

Participants were recruited from industrialized countries: USA

(36%), UK (25%), European multi-site trials (25%), Sweden

(7%), Italy (3%), Australia (3%) and Japan (<1%). HYVET P

2003 trial recruited patients from Bulgaria (88%), Spain (3%),

Romania (3%), UK (2.5%) and Poland (1.5%) and from other

countries in smaller numbers (Finland, Lithuania, Ireland, Greece

and Serbia). HYVET 2008 trial recruited patients from Western

Europe (2.2%), Eastern Europe (55.8%), China (39.6%), Aus-

tralasia (0.5%) and Tunisia (1.9%).

14,663 (59.5%) percent of the subjects were female. The four tri-

als based in the USA reported ethnicity African-American: SHEP

1991 (14%), SHEP-PS 1986 (18% non-white), VA Coop 1970

(41%), HTN Coop 1974 (78%). The ethnicity data from VA

Coop 1970 and HTN Coop 1974 refer to the entire study pop-

ulation, not the >60 year old sub-group. All subjects in ANBP

1981 and STOP 1991 were white. Nine trials including HYVET

P 2003 and HYVET 2008 did not report ethnicity.

Study populations predominantly consisted of ambulatory pa-

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

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

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%)

and HYVET 2008 (6.8%). Six trials reported the baseline preva-



lence of myocardial infarctions. The average prevalence across trials

was 2.3%: ANBP 1981 (0.5%), Syst-Eur 1991 (1.2%), SHEP-PS

1986 (4%), SHEP 1991 (4.9%), HYVET P 2003 (3.0%), and

HYVET 2008 (3.1%). Two studies excluded patients with diabetes

(ANBP 1981, MRCOA 1992), while three other trials reported

the baseline prevalence. The average prevalence across trials was

9.2%: HYVET 2008 (6.8%), SHEP 1991 (10.1%), HTN Coop

1974 (36%). Two trials reported the baseline prevalence of hyper-

lipidemia: HTN Coop 1974 (22%) and ANBP 1981 (62.2%).

Ten trials reported the baseline prevalence of smoking. The aver-

age prevalence across trials was 12.1%: HYVET P 2003 (4.2%),

HYVET 2008 (6.6%), Syst-Eur 1991(7.3%), SHEP-PS 1986

(11%), SHEP 1991(12.7%), EWPHE 1989 (16.4%), ANBP

1981 (17.5%), MRCOA 1992 (17.5%), HEP 1986 (24%), and

HTN Coop 1974 (60%). Only HTN Coop 1974 reported data

on prevalence of obesity (29%).

Entry diastolic blood pressure criteria also have varied somewhat

from trial to trial. However, trials in older persons have not rou-

tinely included patients with higher diastolic blood pressures than

trials in younger persons.

All trials except Carter 1970 reported the mean SBP and DBP

at baseline. SHEP-PS 1986, SHEP 1991 and Syst-Eur 1991 re-

stricted recruitment to persons with isolated systolic hyperten-

sion; defined as SBP 160-219 mm Hg and DBP <90 mm Hg

(SHEP 1991, SHEP-PS 1986) or DBP < 95 mm Hg (Syst-Eur

1991). Mean blood pressure at entry in the 3 isolated systolic hy-

pertension trials was 172/81 mmHg. Two studies (Carter 1970,

HEP 1986) recruited persons with isolated systolic hypertension,

diastolic hypertension or systo-diastolic hypertension. Kuramoto

1981 and MRCOA 1992 recruited patients with either isolated

systolic hypertension or systo-diastolic hypertension. HYVET P

2003 recruited patients with systolic and/or diastolic hypertension

(SBP > 140 mmHg and DBP 90-109 mmHg). HYVET 2008

recruited patients with persistent hypertension defined as SBP of

160-199 mmHg and a DBP < 110mmHg. 32.5% of patients in

HYVET 2008 had isolated systolic hypertension. The remainder

of the studies required that subjects’ DBP be at least 90 mm Hg.

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 study’s blood pres-

sure inclusion criteria. The mean sitting SBP/DBP in HYVET P

2003 was 182/99.6 mmHg and in HYVET 2008 was 173/90.8

mmHg.

Twelve of the 15 trials instituted a stepped care approach to hyper-

tension treatment. In over 70% of trials a thiazide diuretic was the

first line drug in the treatment group. Seven trials (Carter 1970,

ANBP 1981, Kuramoto 1981, SHEP-PS 1986, EWPHE 1989,

SHEP 1991, HYVET 2008) started the treatment group exclu-

sively on a thiazide diuretic. HEP 1986 and STOP 1991 started

the treatment group on either a diuretic or beta-blocker. MRCOA

1992 randomized the treatment group to two arms, one initially

receiving diuretics and the other initially receiving a beta-blocker.

Syst-Eur 1991 started the treatment group on a calcium chan-

nel blocker. HYVET P 2003 started one treatment arm on a di-

uretic and other treatment arm with an ACE inhibitor. Second and

third line drugs included diuretics, beta-blockers, central acting

anti adrenergic agents, peripheral acting anti adrenergic agents,

vasodilators, converting-enzyme inhibitors and calcium channel

blockers. See the “Interventions” heading in the Characteristics of

included studies table for a complete description of each study’s

drug treatment protocol.

Three trials maintained subjects on a particular therapeutic regi-

men (i.e. not stepped care) throughout the study. VA Coop 1970

treated subjects with a combination diuretic - central acting anti

adrenergic agent (hydrochlorothiazide/reserpine) plus a vasodila-

tor (hydralazine). HTN Coop 1974 treated subjects with a di-

uretic (methyclothiazide) and peripheral acting anti adrenergic

agent (deserpidine). Sprackling 1981 treated subjects with a cen-

tral acting anti adrenergic agent (methyldopa).

HYVET P 2003 trial randomized patients to three groups:

no treatment, diuretic based treatment (usually bendrofluazide

2.5mg) and an ACE-inhibitor based regimen (usually lisinopril

2.5mg). To attain target blood pressure (sitting SBP < 150 mmHg

and sitting DBP < 80 mmHg) in the actively treated groups, the

dose of diuretic or ACEI could be doubled (step 2), diltiazem slow

release 120 mg could be added (step 3) and diltiazem slow release

240mg could be added as (Step 4).

HYVET 2008 trial randomized patients to either indapamide sus-

tained release 1.5 mg or matching placebo. In order to reach tar-

get blood pressure (SBP < 150 mmHg and DBP < 80 mmHg)

perindropil 2 mg or 4 mg or matching placebo could be added.

Length of study follow up ranged from relatively short: 1 year

(HYVET P 2003) or 2 years (STOP 1991, Syst-Eur 1991, HYVET

2008), to relatively long: the rest of the trials lasting 3 to 6 years.

All of the trials were multi site studies except for Carter 1970 and

Kuramoto 1981. The mean duration of treatment was 4.5 years

in elderly (60 years or older) and 2.2 years in very elderly patients

(80 years or older) and 3.2 years in trials with isolated systolic

hypertension in the elderly.

Risk of bias in included studies

Twelve of the 15 trials employed some method of blinding.

Twelve blinded subjects to therapy (VA Coop 1970, HTN Coop

1974, ANBP 1981, Kuramoto 1981, HEP 1986, SHEP-PS

1986, EWPHE 1989, SHEP 1991, STOP 1991, MRCOA 1992,

Syst-Eur 1991, HYVET 2008). Of these, eleven (all but MRCOA

1992) also blinded providers to therapy. Eight trials specifi-

cally reported blinding outcome assessors (HEP 1986, SHEP-PS

1986, EWPHE 1989, SHEP 1991, STOP 1991, MRCOA 1992,

Syst-Eur 1991, HYVET 2008).

Eleven trials were placebo controlled (VA Coop 1970, HTN Coop

1974, ANBP 1981, Kuramoto 1981, SHEP-PS 1986, EWPHE

1989, SHEP 1991, STOP 1991, MRCOA 1992, Syst-Eur 1991,



HYVET 2008). Four trials were no treatment controlled without

placebo (Carter 1970, Sprackling 1981, HEP 1986, HYVET P

2003).

In nine of the trials the method of randomization is described

while in the remaining six trials randomization is mentioned, but

not described. See the “Method” heading in the Characteristics of

included studies table for a description of each study’s method of

randomization and stratification, if any.

Nine studies reported loss to follow-up figures of less than 5%

(Carter 1970, ANBP 1981, Sprackling 1981, SHEP-PS 1986,

SHEP 1991, STOP 1991, Syst-Eur 1991, HYVET P 2003,

HYVET 2008). Three studies reported loss to follow-up figures

of 13-15% (VA Coop 1970, Kuramoto 1981, EWPHE 1989).

MRCOA 1992 experienced a loss to follow-up of 25%. The re-

mainder (HTN Coop 1974, HEP 1986) did not report data on

numbers lost to follow-up.

Studies included in this review allowed subjects in the control

group to receive antihypertensive therapy because their blood pres-

sure exceeded pre-set “escape” criteria. Also, a portion of the sub-

jects assigned to the treatment group stopped taking their assigned

medication because of adverse drug effects or because they achieved

normal blood pressures. The degree to which subjects cross over

from one group to the other dilutes the results of the study. The

percent of patients assigned to the control group which were re-

ceiving antihypertensive medication by the end of the trial were

as follows: HEP 1986 (9%), Kuramoto 1981 (17%), STOP 1991

(23%), Syst-Eur 1991 (27%), ANBP 1981 (35%), SHEP-PS 1986

(40%), SHEP 1991 (44%), MRCOA 1992 (53%), and EWPHE

1989 (>35%), HYVET P 2003 (0.8%) and HYVET 2008 (0.6%).

The remaining four trials did not report such data. The percent of

patients assigned to the treatment group which had ceased taking

antihypertensive medication by the end of the trial were: HYVET

P 2003 (4%), HYVET 2008 (0.5%), HEP 1986 (5%), SHEP

1991 (10%), STOP 1991 (16%), Syst-Eur 1991 (18%), SHEP-PS

1986 (30%), ANBP 1981 (33%), MRCOA 1992 - diuretic arm

(48%), MRCOA 1992 - beta-blocker arm (63%), and EWPHE

1989 (>35%). The remaining five trials did not report such data.

Figure 1 and Figure 2 show a summary of the Risk of Bias assess-

ment.



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

See: Summary of findings for the main comparison

Antihypertensive drug therapy compared to control in elderly

(60 years or older) for hypertension in the elderly; Summary of

findings 2 Antihypertensive drug therapy compared to control in

very elderly 80 years or older for hypertension

Analyses were performed on the combined results of all 15 studies.

The three trials that included only people with isolated systolic

hypertension (SHEP-PS 1986, SHEP 1991, Syst-Eur 1991) were

included in the overall analyses and were also analysed separately.

EWPHE 1989 reported intention-to-treat data for mortality only;

the morbidity data reported from EWPHE 1989 is not intention-

to-treat and is not included in the analysis. The occurrence of any

trial endpoint in ANBP 1981 participants terminated their partic-

ipation in the study. Thus, true intention-to-treat data for ANBP

1981 is only available for combined cardiovascular morbidity and

mortality.

Results were analysed with and without the two small trials that

were restricted to stroke survivors (Carter 1970, HTN Coop

1974). Removing these two trials from the analysis did not ap-

preciably affect the results. The relative risk point estimates and

confidence intervals did not shift by more than 0.01. Thus, all

results reported below include these two trials.

There was homogeneity across studies with respect to all outcomes

except cardiovascular morbidity and mortality. Point estimates for

the pooled log relative risk ratios were nearly identical between

the random and fixed effect analyses. Thus, all results are reported

using the fixed effects model. In the very elderly patients there was

homogeneity across studies for all outcomes except total mortality.

Total mortality: The combined results of the 12 trials reporting

total mortality data in people 60 years or older show a significant

benefit (RR=0.90, 95% CI 0.84 to 0.97; NNT=84) with event

rates per 1000 participants reduced from 116 to 104 events with

95% CI of the difference (3 to 19) for a mean duration of treat-

ment of 4.5 years, see Figure 3. STOP 1991 and HYVET 2008

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.



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

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

Control Antihypertensive drug

therapy

Total mortality - Very el-

derly 80 years or older

Follow-up: mean 2 years


(0.87 to 1.1)

6701

(8 studies3)

⊕⊕©©

low1,2

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-

ity and morbidity - Very

elderly 80 years or older

Follow-up: mean 2 years

Study population3 RR 0.75

(0.65 to 0.87)

6546

(7 studies3)

⊕⊕⊕©

moderate4

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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 patients4 confidence interval is wide

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D I S C U S S I O N

This systematic review provides the best available evidence for

antihypertensive treatment for people with elevated blood pressure

who are at least 60 years of age. It is important to appreciate that

this represents a group of people with relatively high systolic blood

pressures: an average of 172/81 mmHg in the isolated systolic

hypertension trials and an average of 182/95 mmHg in the 11

other trials. The reason that the diastolic pressure is lower than

expected is because only 6 of these trials ensured the presence of

diastolic hypertension, i.e. > 90 mmHg diastolic (ANBP 1981,

EWPHE 1989, HTN Coop 1974, Sprackling 1981, STOP 1991,

VA Coop 1970). In these trials the average diastolic BP was >100

mmHg.

In this population antihypertensive drug treatment was associated

with a modest reduction in total mortality, RR 0.90 (0.84 - 0.97).

This represents an absolute reduction in deaths of 12, from 116 to

104 events per 1000 participants, over an average duration of 4.5

years, see Summary of findings for the main comparison. However,

the 95% CI range from 3 to 19 deaths per 1000 participants, so

we cannot be very confident in this result. This absolute reduction

is explained by 6 less deaths due to stroke and 6 less deaths due

to coronary heart disease. Most importantly when we limited the

analysis to people 80 years old and over there was no reduction

in total mortality, RR 0.98 (0.87 - 1.10). Thus trials with longer

duration of treatment in the very elderly are warranted.

Cardiovascular mortality and morbidity was significantly reduced,

RR 0.72 (0.68 - 0.77). This represents an absolute reduction of

43 (35 - 49), from 153 to 110 events per 1000 participants for a

mean duration of treatment of 4.5 years, see Summary of findings

for the main comparison. This was due to a reduction of 20 cere-

brovascular disease mortality and morbidity events as well as 10

coronary heart disease mortality and morbidity events. In the very

elderly a similar reduction of 18 cerebrovascular mortality and

morbidity events per 1000 participants was present, but there was

no significant reduction in coronary heart disease mortality and

morbidity.

The magnitude of benefit depends on multiple factors including

their baseline risk of cardiovascular complications of hypertension

(Gueyffier 1997). People with more cardiovascular risk factors

(e.g. diabetes, family history of heart disease, left ventricular hy-

pertrophy, etc.) have greater likelihood of a reduction in cardio-

vascular events by antihypertensive therapy.

The five-year absolute morbidity and mortality benefit of an-

tihypertensive therapy is greater for older than younger adults

(Collins 1990, Mulrow 1994). Several reasons could explain this

greater absolute benefit. First, older people are at higher imme-

diate absolute risk of a cardiovascular event than younger people

(Alderman 1981, Browner 1989, Alderman 1993). The risk fac-

tors include pre-existing cardiovascular disease and systolic hyper-

tension (Applegate 1992, Mann 1992). Lowering of blood pres-

sure results in similar relative but higher absolute effect in these

people at high risk. The subgroup analysis of treatment in the very

elderly patients (80 years or older) showed no significant bene-

fit in terms of all cause mortality including cardiovascular, coro-

nary heart disease or cerebrovascular disease mortality. However,

a higher absolute risk reduction was observed in cardiovascular

mortality and morbidity from 115 to 86 (75 to 100) events per

1000 participants, which was mostly due to a decrease in cere-

brovascular mortality and morbidity for a mean duration of 2.0

years, see Summary of findings 2.

Trials involving older people could have varied systematically from

those in younger people. Except for TOMHS 1995, trials that

included younger people were published before 1987(VA Coop

1962, Wolf 1966, VA Coop 1970, Barraclough 1973, HTN Coop

1974, USPHS Coop 1977, VA/NHLBI 1978, ANBP 1981, Oslo

1986). Six large trials involving older people were published after

1990 (SHEP 1991, STOP 1991, MRCOA 1992, Syst-Eur 1991,

HYVET P 2003, HYVET 2008). While first-line beta-blockers

and thiazide diuretics were used in most trials, the recent large trials

in older people have usually used either lower doses of thiazides or

combinations with potassium sparing agents. As a result they may

be associated with less toxic adverse effects. The most recent trial

in very elderly (HYVET 2008) used indapamide sustained release

1.5 mg or matching placebo. If blood pressure remained above

SBP=150 mmHg and DBP=80 mmHg, perindopril 2 mg or 4

mg or matching placebo could be added. Thus, this trial showed

a significant reduction in mortality, RR 0.82 (0.69 - 0.99), ARR

= 2.2%, NNT= 48 for 2 years, and in total cardiovascular events,

RR 0.71 (0.57 - 0.87) with low doses of two antihypertensive

drugs. The other trials in the very elderly used higher doses of more

antihypertensive drugs and showed a trend towards increased total

mortality. These observations suggest that less aggressive treatment

is probably a good approach in the very elderly, but this needs to

be validated with RCTs testing different approaches to BP control

in this patient population.

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 from 65 to 111 events per 1000 participants,

absolute increase of 46 (29 - 65) per 1000 patients. Separate data

for withdrawals due to adverse effects was not available in the very

elderly patients.

Control rates

Control rates provide insight regarding baseline risk of study

populations and can explain the differences in outcomes be-

tween individual trials. Total mortality rates in the control groups

ranged from 3 to 71%. Trials with relatively low rates included

ANBP 1981 (3%), HYVET P 2003 (5.2%), Syst-Eur 1991

(6%), SHEP-PS 1986 (6.5%), STOP 1991 (7.7%), and SHEP

1991 (10.2%). Trials with moderate rates included HYVET 2008



(12.3%), MRCOA 1992 (14.2%), HEP 1986 (14.8%), and

Kuramoto 1981 (14.9%). Trials with relatively high rates included

Carter 1970 (34.6%), EWPHE 1989 (35.1%), and Sprackling

1981 (71%). VA Coop 1970 and HTN Coop 1974 did not report

total mortality, but reported the second and third highest event

rates (behind Sprackling 1981) in cardiovascular morbidity and

mortality (VA Coop 1970 58.1%, HTN Coop 1974 34.3% and

Sprackling 1981 83.9%).

The 95% CI of the RR of total mortality for Sprackling 1981, 1.11

(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

example, the subjects in Carter 1970 and HTN Coop 1974 were

all stroke survivors. Subjects in Sprackling 1981 and Kuramoto

1981 resided in a home for the aged. Subjects in Carter 1970 and

VA Coop 1962 were recruited from hospitals (though followed

up in clinics) and subjects in EWPHE 1989 were recruited from

geriatric hospitals, physician’s offices and homes for the aged.

Additional explanations of differing control rates include varia-

tions in definitions of trial end-points, cross-over rates and follow-

up durations. Although we attempted to standardize outcome def-

initions as much as possible (see Methods section), truly uniform

definitions between trials were not possible. Trials had cross-over

rates ranging from 9% to 62% (see Characteristics of included

studies) and follow-up durations ranging from 1 to 6 years.

Since most data is based on a small percentage of randomized

patients with stroke or MI at baseline, patients with significant

competing comorbidity and complicated medical regimens may

also have poorer compliance, less benefit, and more adverse effects

compared to participants in trials.

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

other words, 40% of trials could have censored outcome data for

patients after they had had their first event. In addition, in 30%

of the trials, when outcome data wasn’t available it appeared the

assumption was that an event did not occur in that patient. See

Figure 1; and Figure 2. The implications are that the available

outcome data used in the meta-analyses may be incomplete. It is

difficult to determine whether this bias would favour treatment or

control. What can be said is that reported event rates are under-

estimates and the calculated effect sizes for outcomes (other than

death as the first event) may be inaccurate.

Limitations and generalizability

The most appropriate way to match expected magnitude of ben-

efits to patients with particular constellations of risk factors is to

perform individual patient based meta-analyses (Gueyffier 1997),

which was not possible in this review. Moreover, our aggregate

results only refer to generally expected benefits for elderly hyper-

tensive patients, and are not tailored specifically to patients with

particular risk factors. Our average results refer primarily to a pri-

mary prevention population with moderate to severe systolic or

systodiastolic hypertension treated with a first-line thiazide. Data

for other first-line drugs is insufficient, and the objective of this

review was not to compare different first-line drugs, which has

been done by other systematic reviews (Psaty 1997, Wright JM

1999, Psaty 2003, Wright JM 2009).

Actual estimates of benefits and harms of treating elderly persons

with hypertension derived from trials with highly selected subjects

are not readily generalizable to clinical practice. Many patients ei-

ther would not meet eligibility criteria or, if offered the chance,

would not have enrolled in a clinical trial. Strictly speaking, trial re-

sults cannot be generalized to such patients. In practice, clinicians

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

participation; but we should approach these generalizations with

forethought. Without extra care and visits provided in many trials,

even our “eligible” patients may be less compliant than trial par-

ticipants. Patients with significant competing comorbidities and

complicated medical regimens may also have poorer compliance,

less benefit, and more adverse effects compared to participants in

trials. For example in an octagenarian with orthostasis and recur-

ring falls related to antihypertensive therapy, the harms likely ex-

ceed benefits. On the other hand, clinicians should not always as-

sume that less benefit would be seen in “real life” clinical settings.

A person who is at high immediate risk of suffering a cardiovas-

cular event and does not have other competing illnesses may have

a higher benefit-to-harm ratio than the average trial participant.

A U T H O R S ’ C O N C L U S I O N SImplications for practice

Antihypertensive treatment of people aged 60 and older with mod-

erate to severe systolic and/or diastolic hypertension reduces total

mortality and total cardiovascular morbidity and mortality. The

absolute risk reduction in cerebrovascular mortality and morbidity

over 4.5 years was greater (2.0% and NNT=50) than for coronary

heart disease mortality and morbidity (1.0% with NNT=100).

The evidence of benefit pertains mostly to a primary prevention

population and first-line treatment with a thiazide. This compre-

hensive systematic review provides additional evidence in people

aged 80 and older where antihypertensive treatment reduced total

cardiovascular morbidity and mortality, but not total mortality.

In the very elderly the absolute risk reduction in cerebrovascular

mortality and morbidity over 2.2 years was 1.8% with NNT=56,

but there was no significant reduction in coronary heart disease

mortality and morbidity.



Implications for research

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

first-line drug is best in elderly patients and to study different

approaches to treatment e.g. an RCT comparing the use of two

drugs at low dose (as in the HYVET 2008 trial) with traditional

antihypertensive therapy with 3 to 4 drugs in maximal doses.

A C K N O W L E D G E M E N T S

We would like to acknowledge the authors of the previous (1998)

version of this systematic review: Cynthia Mulrow, Joseph Lau,

John Cornell, and M Brand.

R E F E R E N C E S

References to studies included in this review

ANBP 1981 {published data only}

Australian National Blood Pressure Management

Committee. The Australian Therapeutic Trial in Mild

Hypertension. Lancet 1980;1:1261–67.

The Management Committee. Treatment of mild

hypertension in the elderly. A study initiated and

administered by the National Heart Foundation of Australia.

Med J Aust 1981;2:398–402.

Carter 1970 {published data only}

Carter AB. Hypotensive therapy in stroke survivors. Lancet

1970;1:485–89.

EWPHE 1989 {published data only}

Amery A, Bixko P, Clement D, de Schaepdryver A, Fagard

R, Forte J. Mortality and morbidity results from the

European Working Party on High Blood Pressure in the

Elderly Trial. Lancet 1985;1(8442):1349–54.


Elderly (EWPHE). An international trial of antihypertensive

therapy in elderly patients. Objectives, protocol and

organization. Arch Int Pharmacodyn 1985;275:300–34.

O’Malley KO, McCormack P, O’Brien ET. Isolated systolic

hypertension: data from the European Working Party on

High Blood Pressure in the Elderly. J Hypertens 1988;6

(suppl 1):S105–8.

Staessen J, Bulpitt C, Clement D, De Leeuw P, Fagard R,

Fletcher A. Relation between mortality and treated blood

pressure in elderly patients with hypertension: report of the


Elderly. BMJ 1989;298:1552–6.

HEP 1986 {published data only}

Coope J, Warrender TS. Randomized trial of treatment of

hypertension in elderly patients in primary care. BMJ 1986;

293:1145–52.

HTN Coop 1974 {published data only}

Hypertension-Stroke Cooperative Study Group on Agents.

Effect of antihypertensive treatment on stroke recurrence.

JAMA 1974;229:409–18.

HYVET 2008 {published data only}

Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L,

Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y,

Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L,

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80 Yearsof Age or Older. New England Journal of Medicine

2008;358(18):1887–1898.

HYVET P 2003 {published data only}

Bulpitt CJ, Beckett NS, Cooke J, Dumiktrascu DL, Gil-

Extremera B, Nachev C, Nunes M, Peters R, Staessen JA,

Thijs L. Results of the pilot study for the Hypertension

in the VeryElderly Trial. Journal of Hypertension 2003;21:

2409–2417.

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Kuramoto K, Matsushita S, Kuwajima T, Murakami M.

Prospective study on the treatment of mild hypertension in

the aged. Jpn Heart J 1981;22(1):75–85.

MRCOA 1992 {published data only}

MRC Working Party. Medical Research Council Trial of

Treatment of Hypertension in Older Adults: principal

results. BMJ 1992;304(6824):405–412.

SHEP 1991 {published data only}

Applegate WB, Pressel S, Wittes J, Luhr J, Shekelle RB,

Camel GH, et al.al. Impact of the treatment of isolated

systolic hypertension on behavioral variables: results from

the Systolic Hypertension in the Elderly Program. Arch

Intern Med 1994;154:2154–60.

Hulley SB, Furberg CD, Gurland B, McDonald R, Perry

HM, Schnaper HW, et al.Systolic Hypertension in the

Elderly Program (SHEP): antihypertensive efficacy of

chlorthalidone. Am J Cardiol 1985;56(15):913–20.

SHEP Cooperative Research Group. Prevention of stroke

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265(24):3255–64.

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of a randomized clinical trial on prevention of stroke in

isolated systolic hypertension. J Clin Epidemiol 1988;41

(12):1197–1208.

SHEP-PS 1986 {published data only}

Black DM, Brand RJ, Greenlick M, Hughes G, Smith

J. Compliance to treatment for hypertension in elderly



patients: the SHEP pilot study. J Gerentol 1987;42(5):

552–7.

Hulley SB, Furberg CD, Gurland B, McDonald R, Perry

HM, Schnaper HW, et al.for the SHEP Research Group.

Systolic Hypertension in the Elderly Program (SHEP):

antihypertensive efficacy of chlorthalidone. Am J Cardiol

1985;56:913–20.

Perry HM, McDonald RH, Hulley SB, Smith WM, Furberg

CD, Greenlick MR. Systolic Hypertension in the Elderly

Program, Pilot Study (SHEP-PS): morbidity and mortality

experience. J Hypertens 1986;4(6):S21–3.

Perry HM, Smith WM, McDonald RH, Black D, Cutler

JA, Furberg CD, et al.Morbidity and mortality in the

Systolic Hypertension in the Elderly Program (SHEP) Pilot

Study. Stroke 1989;20(1):4–13.

Sprackling 1981 {published data only}

Sprackling ME, Mitchell JRA, Short AH, Watt G. Blood

pressure reduction in the elderly: a randomised controlled

trial of methyldopa. BMJ 1981;283:1151–3.

STOP 1991 {published data only}

Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom

T, Wester P-O. Morbidity and mortality in the Swedish Trial

in Old Patients With Hypertension (STOP-Hypertension).

Lancet 1991;338:1281–5.

Syst-Eur 1991 {published data only}

Amery A, Birkenhager W, Bulpitt CJ, et al.Syst-Eur: a

multicenter trial on the treatment of isolated systolic

hypertension in the elderly; objectives, protocol and

organisation. Aging 1991;3:287–302.

Celis H, Yodfat Y, Thijs L, Clement D, Cozic J, De Cort P,

Forette F, Gregoire M, Heyrman J, Stibbe G, Van den Haute

M, Staessen J, Fagard R. Antihypertensive therapy in older

patients with isolated systolic hypertension: the Syst-Eur

experience in general practice. The Syst-Eur Investigators.

Fam Pract 1996;13(2):138–43.

Girerd X, Amery A, Birkenhager W, Bulpitt C, Cox J, De

Leeuw P. [SYST-EUR: a multicenter trial of treatment of

systolic hypertension in aged subjects. An initial report].

[French] Archives des Maladies du Coeur et des Vaisseaux

1992;85(8):1243–7.

Slovick D, Staessen J, Bert P, Bulpitt C, de Cort P, Fagard

R, et al.Nitrendipine in older patients with isolated systolic

hypertension: second progress report on the Syst-Eur trial.

J Hum Hypertens 1993;7(4):411–2.

Slovick DI, Amery A, Birkenhager W, Bulpitt CJ, Cox J, de

Leeuw P, et al.Syst-Eur multicenter trial on the treatment of

isolated hypertension in the elderly: first interim report. J

Hum Hypertens 1993;7(2):201–3.

Slovick DI, Amery A, Birkenhager W, Bulpitt CJ, Cox J, de

Leeuw P, et al.Syst-Eur multicenter trial on the treatment of

isolated hypertension in the elderly: first interim report. J

Hum Hypertens 1993;7(2):201–3.

Staessen J, Bert P, Bulpitt C. de Cort P, Fagard R, Fletcher

A, et al. Nitrendipine in older patients with isolated systolic

hypertension: second progress report on the Syst-Eur trial.

J Hum Hypertens 1993;7(3):265–71.

Staessen JA, Fagard R, Thijs Lutgarde, Celis H, Arabidze

GG, et al for the Systolic Hypertension in Euorpose

(Syst-Eur) Trial Investigators. Randomised double-blind

comparison of placebo and active treatment for older

patients with isolated systolic hypertension. Lancet 1997;

350:757–64.

Staessen JA, Thijs L, Clement D, Davidson C, Fagard R,

Lehtonen A, Mancia G, Palatini P, O’Brien ET, Parati

G, et al.Ambulatory pressure decreases on long-term

placebo treatment in older patients with isolated systolic

hypertension. Syst-Eur Investigators. J Hypertens 1994;12

(9):1035–9.

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Clinical trials with ambulatory blood pressure monitoring:

fewer patients needed? Syst-Eur Investigators. Lancet 1994;

344(8936):1552–6.

Staessen JA, Thijs L, Mancia G, Parati G, O’Brien ET.

Clinical trials with ambulatory blood pressure monitoring:

fewer patients needed? Syst-Eur Investigators. Lancet 1994;

344(8936):1552–6.

Staessen JA, Tijs L, Bieniaszewski L, O’Brien ET, Palatini

P, Davidson C, Dobovisek J, Jaaskivi M, Laks T, Lehtonen

A, Vanhanen H, Webster J, Fagard R. Ambulatory

monitoring uncorrected for placebo overestimates long-term

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(SYST-EUR) Trial Investigators. Hypertension 1996;27(3

Pt 1):414–20.

Thijs L, Dabrowska E, Clement D, Fagard R, Laks T,

Mancia G, O’Brien E, Omboni S, Parati G, Staessen

J, et al.Diurnal blood pressure profile in older patients

with isolated systolic hypertension. The SYST-EUR

Investigators. J Hum Hypertens 1995;9(11):917–24.

VA Coop 1970 {published data only}

Veterans Administration Cooperative Study Group on

Antihypertensive Agents. Effects of treatment on morbidity

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pressure averaging 90 through 114 mm Hg. JAMA 1970;

213(7):1143–1152.

References to studies excluded from this review

ADVANCE 2007 {published data only}

The ADVACNCE Collaborative Group. Eff ects of a

fi xed combination of perindopril and indapamideon

macrovascular and microvascular outcomes in patientswith

type 2 diabetes mellitus (the ADVANCE trial):a randomised

controlled trial.. The Lancet 2007;370:829–840. [DOI:

10.1016/S0140-6736(07)61303-8]

ALLHAT 1996 {published data only}

Davis BR, Cutler JA, Gordon DJ, et al.for the

ALLHAT Research Group. Rationale and design for the

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342–60.

Barraclough 1973 {published data only}

Barraclough M, Bainton D, Cochrane AL, et al.Control of

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randomized controlled trial. BMJ 1973;3:434–6.



BMJ 1973 {published data only}

Anonymous. Control of moderately raised blood pressure.

Report of a co-operative randomized controlled trial. Br

Med J 1973;3:434–6.

CASTEL 1994 {published data only}

Casiglia E, Spolaore P, Mazza A, Ginocchio G, Colangeli

G, Onesto C, et al.Effect of two different therapeutic

approaches on total and cardiovascular mortality in a

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G, Celegon L. The CASTEL project (CArdiovascular STudy

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Study Group on Long-term Antihypertensive Therapy. A

12-month comparison of ACE inhibitor and CA antagonist

therapy in mild to moderate essential hypertension - the

GLANT Study. Hypertens Res 1995;18:235–44.

HAPPHY 1987 {published data only}

Wilhelmsen L, Berglund G, Elmfeldt D, Fitzsimons

T, Holzgreve H, Hosie J, Hornkvist PE, Pennert K,

Tuomilehto J, Wedel H. Beta-blockers versus diuretics in

hypertensive men: main results from the HAPPHY trial. J

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HDFP 1982 {published data only}

Curb JD, Borhani NO, Schnaper H, Kass E, Entwisle

G, Williams W, Berman R. Detection and treatment of

hypertension in older individuals.. Am J Epidemiol 1985;

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Cardiovasc Pharmacol 1985;7(2):S5–9.

HOT 1995 {published data only}

Hansson L, Zanchetti A. The Hypertension Optimal

Treatment (HOT) Study: 12-month data on blood pressure

and tolerability. With special reference to age and gender.

Blood Pressure 1995;4:313–9.

HYVET-Cog 2008 {published data only}

Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R,

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factors in a randomized trial of treatment based on the beta-

blocker oxprenolol: the International Prospective Primary

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1985;3(4):379–92.

Jikei 2007 {published data only}∗ Mochizuki S, Dahlof B, Shimizu M, Ikewaki K,

Yoshikawa M, Taniguchi I, Ohta M, Yamada T, Ogawa

K, Kanae K, Kawai M, Seki S, Okazaki F, Taniguchi M,

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D, Berglund G. Primary prevention with metoprolol in

patients with hypertension. Mortality results from the

MAPHY study. JAMA 1988;259(13):1976–82.

Materson 1993 {published data only}

Materson BJ, Reda DJ, Cushman WC. Department of

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ED, Kochar MS, et al.Single-drug therapy for hypertension

in men: a comparison of six antihypertensive agents with

placebo. N Engl J Med 1993;328(13):914–21.

MIDAS 1996 {published data only}

Borhani NO, Mercuri M, Borhani PA, Buckalew VM,

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the Multicenter Isradipine Diuretic Atherosclerosis Study

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Morgan 1980 {published data only}

Morgan TO, Adams WR, Hodgson M, Gibberd RW.

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1985;291(6488):97–104.

Oslo 1986 {published data only}

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1986;31(1):41–5.

PATS 1995 {published data only}

PATS Collaborating Group. Post-stroke antihypertensive

treatment study. A preliminary result. Chinese Medical

Journal 1995;108(9):710–7.

SCOPE 2003 {published data only}

Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A,

Olofsson B, Trenkwalder P, Zanchetti A. The Study on

Cognition and Prognosis in the Elderly(SCOPE): principal

results of a randomized double-blindintervention trial.

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C H A R A C T E R I S T I C S O F S T U D I E S

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?

All outcomes

Yes Clinicians blinded

Incomplete outcome data addressed?

All outcomes

No “in 504 (of the randomized population)

, 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 subject’s 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.



Carter 1970 (Continued)

Participants Geographic area: England

Study setting: recruited in hospital, treatment group followed up in clinic.

n = 71 (47.9% female)

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?

All outcomes

No No


All outcomes

Yes “Of the 99 patients in the trial, 2 have been

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?

All outcomes

Yes Triple blinded


All outcomes

Unclear unclear

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 (physician’s 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?

All outcomes

Yes Patients and providers not blinded; asses-

sors of morbidity and mortality outcomes

were blinded


All outcomes

Unclear unclear

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?

All outcomes

Yes Stated that neither patient nor the clinician

was aware of assigned treatment


All outcomes

Yes “The high degree of cooperation over the

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 173±8.4/90.8±8.5 and sitting

placebo 173.0±8.6/90.8±8.5; standing active treatment 168.0±11.0/88.7±9.3, sitting

placebo 167.9±11.1/88.6±9.3


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?

All outcomes

Yes The main trial is a randomised, double-

blind,

placebo-controlled trial.


All outcomes

Yes Reported on the number of patients lost to

follow-up (16 patients)

“...vital status was unknown in 17 patients.

..”

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?

All outcomes

No “The trial recruited individuals from both

primary and secondary care and was of an

open design.”


All outcomes

No “Of the 1283 patients who were assigned

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?

All outcomes

Unclear unclear


All outcomes

No unclear


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?

All outcomes

Yes Patients were blinded


All outcomes

No ”Overall the beta-blocker group had signif-

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 people

were lost to follow up...48% in the duiretic

group and 68% in the beta blocker group.

..”

Free of selective reporting? No “A patient’s participation in a trial ended

with a stroke, whether non-fatal or fa-



MRCOA 1992 (Continued)

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

Difference in blood pressure at study end (Treatment - Control) systolic/diastolic: -11.

1/-3.4 mmHg


CHD (Coronary Heart Disease mortality) mortality - fatal myocardial infarction; sudden

(<1h) or rapid (1-24h) cardiac death.


tion.



SHEP 1991 (Continued)



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?

All outcomes

Yes Described as double-blind


All outcomes

Yes “We specified an “intention to treat” rule

(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-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%)


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-



SHEP-PS 1986 (Continued)

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?

All outcomes

Yes Triple blinded


All outcomes

Unclear unclear

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.



stroke: 11.3%

Blood pressure (BP) entry criteria: diastolic BP > 100 mm Hg



Sprackling 1981 (Continued)

Interventions Control: observation without placebo.

Treatment: methyldopa 250mg twice daily

Average follow up: not clearly stated, approximately 4 - 5 years


4/-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?

All outcomes

No Open label study


All outcomes

No 60 patients were randomized to each group

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


0/-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)



Blinding?

All outcomes



All outcomes

Unclear unclear


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?

All outcomes

Yes “randomized to double-blind treatment

with active medication or placebo by means

of a computerized random function”


All outcomes

Yes “For patients who withdrew from

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




Blinding?

All outcomes



All outcomes

Unclear unclear


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.



D A T A A N D A N A L Y S E S

Comparison 1. Antihypertensive drug therapy vs control in elderly 60 years or older

Outcome or subgroup titleNo. of

studies

No. of

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

morbidity

13 23094 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.68, 0.77]


3 Withdrawal due to adverse

effects


Comparison 2. Antihypertensive drug therapy vs control in very elderly 80 years or older


studies

No. of



1.1 Very elderly 80 years or

older


2 Cardiovascular mortality and

morbidity


2.1 Very elderly 80 years or

older


Comparison 3. Antihypertensive drug therapy vs control in elderly with ISH


studies

No. of




2 Cardiovascular morbidity and

mortality



3 Withdrawal due to adverse

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




1 Very elderly 80 years or older

EWPHE 1989 58/70 60/85 12.2 % 1.17 [ 0.99, 1.40 ]

HEP 1986 0/3 0/4 Not estimable

HYVET 2008 196/1933 235/1912 53.1 % 0.82 [ 0.69, 0.99 ]

HYVET P 2003 57/857 22/426 6.6 % 1.29 [ 0.80, 2.08 ]

SHEP 1991 57/331 59/319 13.5 % 0.93 [ 0.67, 1.30 ]

SHEP-PS 1986 10/70 0/15 0.2 % 4.73 [ 0.29, 76.64 ]

STOP 1991 11/122 8/113 1.9 % 1.27 [ 0.53, 3.05 ]

Syst-Eur 1991 72/231 53/210 12.5 % 1.23 [ 0.91, 1.67 ]

Total (95% CI) 3617 3084 100.0 % 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


A P P E N D I C E S

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

F E E D B A C K

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.

W H A T ’ S N E W

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



H I S T O R Y

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.

C O N T R I B U T I O N S O F A U T H O R S

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.

D E C L A R A T I O N S O F I N T E R E S T

None.

S O U R C E S O F S U P P O R T

Internal sources

• Department of Anesthesiology, Pharmacology & Therapeutics, University of BC, Canada.

Office space



External sources

• CIHR grant to the Hypertension Review Group, Canada.

Infrastructure

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

None.

N O T E S

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.

I N D E X T E R M S

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



pharmacotherapy for hypertension in the elderly · beta adrenergic blockers, combined alpha and...

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