4

Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program

Benefits and Harms of 

Treating Blood Pressure 

in Older Adults: A 

Systematic Review and 

Meta-analysis 

April 2016

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420 

Prepared by:

Evidence-based Synthesis Program (ESP) 

Portland VA Health Care System

Portland, OR 

Devan Kansagara, MD, MCR, Director 

Investigators:

Principal Investigators: 

Jessica Weiss, MD

Devan Kansagara, MD, MCR

Co-Investigators: 

Amy Kerfoot, MD

Michele Freeman, MPH

Makalapua Motu’apuaka, BS

Rochelle Fu, PhD

Allison Low, BA

Robin Paynter, MLIS

Karli Kondo, PhD
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

i

PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and 

policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding 

for four ESP Centers, and each Center has an active University affiliation. Center Directors are 

recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based 

Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA 

Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as 

designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help: 

Develop clinical policies informed by evidence;

Implement effective services to improve patient outcomes and to support VA clinical practice

guidelines and performance measures; and

Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence 

syntheses have informed the clinical guidelines of large professional organizations. 

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the 

capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program 

development and evaluation, and dissemination efforts. The ESP CC establishes standard operating 

procedures for the production of evidence synthesis reports; facilitates a national topic nomination, 

prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial 

review processes; ensures methodological consistency and quality of products; produces “rapid response 

evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for 

Information Dissemination and Education Resources (CIDER) to develop a national dissemination 

strategy for all ESP products; and interfaces with stakeholders to effectively engage the program. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program 

Manager, at Nicole.Floyd@va.gov. 

Recommended citation: Weiss J, Kerfoot A, Freeman M, Motu’apuaka M, Fu R, Low A, Paynter R, 

Kondo K, Kansagara D. Benefits and harms of treating blood pressure in older adults: a systematic 

review and meta-analysis. VA ESP Project #05-225; 2015. 

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Center located at 

the VA Portland Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans 

Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. The 

findings and conclusions in this document are those of the author(s) who are responsible for its contents; the 

findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the 

United States government. Therefore, no statement in this article should be construed as an official position of the 

Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, 

consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or 

royalties) that conflict with material presented in the report.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

ii

TABLE OF CONTENTS 

PREFACE ....................................................................................................................................... I

TABLE OF CONTENTS ............................................................................................................ II

EXECUTIVE SUMMARY .......................................................................................................... 1

Introduction ................................................................................................................................ 1

Methods ...................................................................................................................................... 1

Data Sources and Searches .................................................................................................... 1

Study Selection ...................................................................................................................... 1

Data Abstraction and Quality Assessment ............................................................................ 1

Data Synthesis and Analysis ................................................................................................. 2

Results ........................................................................................................................................ 2

Results of Literature Search .................................................................................................. 2

Results for Key Questions ..................................................................................................... 2

Summary of Evidence and Discussion ....................................................................................... 4

Key Findings and Strength of Evidence ................................................................................ 4

Applicability .......................................................................................................................... 5

Conclusions ........................................................................................................................... 5

Summary of the Evidence on More vs Less Intensive Treatment for Hypertension in the 

Elderly ........................................................................................................................................ 6

ABBREVIATIONS ....................................................................................................................... 8

INTRODUCTION....................................................................................................................... 10

METHODS .................................................................................................................................. 10

Topic Development .................................................................................................................. 10

Search Strategy......................................................................................................................... 11

Study Selection ........................................................................................................................ 11

Data Abstraction....................................................................................................................... 14

Quality Assessment .................................................................................................................. 14

Data Synthesis .......................................................................................................................... 14

Study-level Meta-analysis ................................................................................................... 15

Individual Patient Data Meta-analysis ................................................................................ 15

Rating the Body of Evidence ................................................................................................... 16

Peer Review ............................................................................................................................. 16

RESULTS .................................................................................................................................... 17

Literature Flow ......................................................................................................................... 17

Key Question 1: In adults over age 60, what are the health outcome effects of differing blood 

pressure targets? ....................................................................................................................... 19

Overview of Results ............................................................................................................ 19

Trial Characteristics ............................................................................................................ 19

Detailed Study Results ........................................................................................................ 27

Key Question 1b: In patients who have suffered a TIA or stroke, does treatment of blood 

pressure to specific targets affect outcomes? ........................................................................... 39

Key Question 2: How does age modify the benefits of differing blood pressure targets?....... 40

Overview of Results ............................................................................................................ 40
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

iii

Detailed Results ................................................................................................................... 40

Key Question 3: How does the patient burden of comorbidities modify the benefits of 

differing blood pressure targets? .............................................................................................. 44

Comorbidity Burden ............................................................................................................ 44

Cardiovascular Risk ............................................................................................................ 44

Key Question 4: What are the harms of targeting lower blood pressure in older patients? Do 

the harms vary with age?.......................................................................................................... 49

General Adverse Effects ...................................................................................................... 49

Medication Burden .............................................................................................................. 49

Renal Outcomes .................................................................................................................. 49

Cognitive Outcomes ............................................................................................................ 53

Quality of Life and Functional Status ................................................................................. 58

Falls and Fractures .............................................................................................................. 59

Effects of Age ...................................................................................................................... 59

Harms according to DBP ..................................................................................................... 60

Key Question 5: Do the harms of targeting lower blood pressure vary with patient burden of 

comorbidities? .......................................................................................................................... 61

SUMMARY AND DISCUSSION .............................................................................................. 62

Limitations ............................................................................................................................... 67

Future Research ........................................................................................................................ 67

Conclusions .............................................................................................................................. 67

REFERENCES ............................................................................................................................ 69

TABLES

Table 1. Key Questions, Inclusion Criteria, and Scope Parameters......................................... 13

Table 2. Characteristics of Trials that Compared Blood Pressure Target Goals ..................... 21

Table 3. Characteristics of Trials that Compared More vs Less Intensive 

Antihypertensive Treatment ..................................................................................................... 23

Table 4. Effects of Age on Outcomes in Trials that Conducted Age-Stratified Analyses ....... 42

Table 5. Patient characteristics used to determine eligibility or exclusion 

from trial enrollment ................................................................................................................ 45

Table 6. Renal Outcomes and Other Adverse Effects.............................................................. 50

Table 7. Cognitive Outcomes Reported in Trials and Prospective Cohort 

Studies of Hypertension Management in the Elderly .............................................................. 54

Table 8. Summary of the Evidence on More vs Less Intensive Treatment 

for Hypertension in the Elderly ................................................................................................ 64

Table 9. Inclusion Codes, Code Definitions, and Criteria Corresponding 

to the Key Questions ................................................................................................................ 80

Table 10. Exclusion Codes, Code Definitions, and Criteria Corresponding 

to the Key Questions ................................................................................................................ 81

Table 11. Assessment of Randomized Controlled Trials for Potential Risk of Bias ............... 82

Table 12. Detailed Results of Trials that Conducted Age-stratified Analyses ........................ 88

FIGURES

Figure 1. Literature Flow Diagram .......................................................................................... 18

Figure 2. Relative risk of mortality stratified by mean achieved SBP, combining 

trials by achieved mean SBP ≥ 140 or < 140 mm Hg in the intervention group ..................... 28
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

iv

Figure 3. Relative risk of stroke stratified by mean achieved SBP, combining 

trials by achieved mean SBP ≥ 140 or < 140 mm Hg in the intervention group ..................... 29

Figure 4. Relative risk of major cardiac events stratified by mean achieved SBP, 

combining trials by achieved mean SBP ≥ 140 or < 140 mm Hg in the intervention group ... 30

Figure 5. Relative risk of death, stroke, and cardiac events, combining trials 

by mean baseline SBP ≥ 160 or < 160 mm Hg ........................................................................ 32

Figure 6. Relative risk of death, stroke, and cardiac events in trials in which 

the intervention arm had an SBP target < 140 mm Hg or DBP ≤ 85 mm Hg, and the control 

arm had a less strict blood pressure target ............................................................................... 36

Figure 7. Relative risk of stroke in trials of patients with history of stroke ............................. 39

Figure 8. Relative risk of mortality in trials of patients with history of stroke ........................ 92

Figure 9. Relative risk of major cardiac events in trials of patients with history of stroke ..... 93

APPENDIX A. SEARCH STRATEGIES ................................................................................. 75

APPENDIX B. STUDY SELECTION ...................................................................................... 80

APPENDIX C. QUALITY ASSESSMENT .............................................................................. 82

APPENDIX D. DATA SUPPLEMENT .................................................................................... 88

APPENDIX E. PEER REVIEWER COMMENTS AND AUTHOR RESPONSES ............. 94
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

1

EXECUTIVE SUMMARY 

INTRODUCTION 

Hypertension is a very common chronic illness in the United States and among Veterans. Use of 

antihypertensive medications can lower the risk of cardiovascular disease, cerebrovascular 

disease, renal disease, and death. The most beneficial blood pressure targets for patients of 

specific age groups, however, has been a topic of some debate and controversy, stemming from 

concerns that the ratio of benefit to harm of a given blood pressure level may vary with age. In 

2014, the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of 

High Blood Pressure (previously JNC-FG8, referred to in this report as JNC-BP) published new 

guidelines for the treatment of hypertension, as well as a new treatment goal for older individuals 

(over age 60) for systolic blood pressure (SBP) of < 150 mm Hg rather than < 140 mm Hg. The 

new goal for those over 60 years of age has been very controversial; the issue of the appropriate 

(safest and most beneficial) goal for older people has been debated among experts with 

viewpoints supporting both higher and lower treatment goals. The objectives of this review are to 

examine the benefits and harms of differing blood pressure targets among adults over age 60. 

METHODS

Data Sources and Searches

We searched MEDLINE®, Embase®, and Ovid EBM Reviews from database inception through 

January 2015, and updated the MEDLINE® search in September 2016. We additionally 

examined all trials included in the JNC-BP review as well as the Blood Pressure Lowering 

Treatment Trialists Collaborative (BPLTTC) at the full-text level. We also searched

ClinicalTrials.gov to identify in-progress or unpublished studies, and included related 

publications if in-progress trials were completed by December 2015. Using pre-specified 

inclusion/exclusion criteria, we reviewed titles and abstracts and retrieved full-text articles with 

potential relevance to the Key Questions. Two independent reviewers reviewed the full-text

articles to determine a final inclusion/exclusion decision. 

Study Selection 

We only included studies in which the study population had mean age of ≥ 60 years and all 

participants carried a diagnosis of hypertension at the time of enrollment. We included controlled 

trials which examined the health outcome effects of lower versus higher blood pressure targets, 

or which compared more intensive to less intensive treatment strategies in the absence of a 

specific blood pressure goal. We excluded comparative effectiveness trials which directly 

compared the effects of different antihypertensive drugs to one another. We excluded 

observational studies in considering our primary health outcomes (mortality, stroke, cardiac

events), given the risk of confounding and the existence of many controlled trials. We included 

observational studies to assess potential harms of antihypertensive therapy. 

Data Abstraction and Quality Assessment 

Data from published reports were abstracted into a customized database by one reviewer and 

reviewed for accuracy and completeness by a second reviewer. Outcomes of interest for Key 

Questions 1 to 3 of this review included potential benefits of lower versus higher blood pressure 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

2

targets: all-cause mortality, cardiovascular mortality, stroke (fatal or non-fatal), and 

cardiovascular morbidity (myocardial infarction and sudden cardiac death). Outcomes of interest 

related to Key Questions 4 and 5 (potential harms of lower versus higher blood pressure targets) 

included changes in cognition, changes in quality of life, falls and fractures, hypotension, and 

acute kidney injury (defined as doubling of serum creatinine or requiring renal-replacement 

therapy). 

Two reviewers independently assessed the quality of each trial using a tool developed by the 

Cochrane Collaboration. Disagreements were resolved through discussion. Each trial was given 

an overall summary assessment of low, high, or unclear risk of bias. 

Data Synthesis and Analysis 

We conducted meta-analyses using study-level data to get more precise estimates for several 

outcomes including death from all causes, cardiovascular death, fatal and nonfatal stroke, major 

cardiac events, and withdrawal due to adverse events. We used the profile-likelihood randomeffects model to combine risk ratios, while incorporating variation among studies. We assessed 

the presence of statistical heterogeneity among the studies by using the standard Cochran’s chisquare test, and assessed the magnitude of heterogeneity by using the I

2 statistic. We 

qualitatively synthesized results for all other outcomes. 

We classified the overall quality of evidence as high, moderate, low, or insufficient using a 

method which considers the consistency, coherence, and applicability of a body of evidence, as 

well as the internal validity of individual studies. 

RESULTS 

Results of Literature Search 

We reviewed 11,268 titles and abstracts from the combined searches. We selected 330 articles 

for full-text review. We identified 21 randomized controlled trials (RCTs) and 3 cohort studies 

that contained primary data relevant to the Key Questions. 

Results for Key Questions 

The following section briefly describes the findings for each Key Question. The strength of 

evidence and pooled estimates are provided in the Summary of Evidence table below. 

Key Question 1. In adults aged over age 60, what are the health outcome effects of 

differing blood pressure targets?

We found 8 trials comparing blood pressure treatment targets, and 13 trials comparing more 

versus less intensive treatment. Overall, there was clear and consistent evidence that treating 

blood pressure in older adults reduced mortality, cardiac events, and stroke. We found the most 

consistent and largest effects among trials in which participants had higher baseline blood 

pressures (SBP 160 mm Hg) and achieved moderate blood pressure control (< 150/90 mm Hg). 

Six trials compared more aggressive blood pressure treatment targets (SBP < 140 mm Hg or 

diastolic blood pressure [DBP] < 85 mm Hg) to higher targets and found that lower targets were 

associated with a nonsignificant reduction in all-cause mortality (RR 0.86, 95% CI 0.69-1.06; 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

3

ARR 0.80; I2=13.3%), a reduction in stroke (RR 0.79, 95% CI 0.59-0.99; ARR 0.49; I2=16.2%), 

and a marginally significant reduction in cardiac events (RR 0.82, 95% CI 0.64-1.00; ARR 0.94; 

I

2

=15.5%). Most of the evidence supporting the benefit of lower treatment targets came from one 

large trial of non-diabetic patients at high cardiovascular risk which compared an SBP target of 

120 mmHg to an SBP target of 140 mmHg. 

Key Question 1b. In patients who have suffered a transient ischemic attack (TIA) or 

stroke, does treatment of blood pressure to specific targets affect outcomes?

Pooled analyses of 2 trials of participants with mean baseline SBP of 140 to 150 mm Hg and 

known cerebrovascular disease found that treating to SBP < 140 mm Hg compared to slightly 

higher targets reduced recurrent stroke (RR 0.76, 95% CI 0.66 to 0.92, I

2 = 0%), but not cardiac 

events (RR 0.78, 95% CI 0.61 to 1.08) or mortality (RR 0.98, 95% CI 0.85 to 1.19). One of the 

trials targeted SBP < 130 mm Hg and found a non-significant trend towards reduced stroke. The 

other trial found that a more intensive treatment strategy achieving SBP < 140 mm Hg reduced

stroke and cardiac events. 

Key Question 2: How does age modify the benefits of differing blood pressure targets?

We found no evidence that age modifies treatment effects: 12 trials found no age-treatment 

interactions on health outcome effects, and 3 trials found that the rate of harms from more 

intensive treatment was similar in those age ≥ 75 years and < 75 years. 

Key Question 3: How does the patient burden of comorbidities modify the benefits of 

differing blood pressure targets?

We found no studies examining the impact of comorbidity burden on antihypertensive treatment 

effects. 

We found subgroup analyses from 4 trials which examined whether treatment effects varied 

according to cardiovascular risk profile. These studies provide low-strength evidence that there

may be greater absolute treatment effects amongst patients with high cardiovascular risk, though 

relative treatment effects are similar across risk groups. Confidence in these conclusions is 

tempered by the post hoc nature of some of these analyses, the small number of studies, and 

variation in the outcomes contributing to these findings. 

Key Question 4. What are the harms of targeting lower blood pressure in older patients?

Do the harms vary with age?

General Adverse Events 

Four of 10 trials found that more intensive blood pressure treatment was associated with a 

statistically significant increase in withdrawals due to adverse events, with relative risk increases 

ranging from 44 to 100%. Cough and hypotension were among the most frequently reported 

events. Two of 3 trials found more intensive treatment was associated with a higher risk of 

syncope. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

4

Renal Outcomes

We found low-strength evidence from 11 trials that more intensive blood pressure treatment was 

not associated with worsening of renal outcomes. 

Cognitive Outcomes

We found moderate-strength evidence from 7 RCTs that use of antihypertensive treatment to 

achieve moderately strict blood pressure control for up to 5 years does not worsen cognitive 

outcomes compared to less strict blood pressure control. 

Quality of Life and Functional Status 

Overall, we found moderate-strength evidence from prospective substudies of 4 large, low risk of 

bias trials that use of antihypertensive therapy to achieve moderate blood pressure control (SBP 

140 to 150 mm Hg) was not associated with a deterioration in quality of life compared to less 

intensive blood pressure control. We did not find data about quality of life in trials achieving 

lower blood pressures (SBP < 140 mm Hg). 

Falls and Fractures 

We found moderate-strength evidence from 3 large, low risk of bias trials that more intensive 

blood pressure treatment (SBP targets of < 120 mm Hg and < 150 mm Hg, and achieved SBP < 

150 mm Hg in the third trial) did not increase risk of fracture. We found low-strength evidence

that more aggressive blood pressure control did not consistently increase the risk of falls. Two of 

the trials found that very aggressive blood pressure lowering (SBP < 120 mm Hg) did not 

increase the risk of falls, while a third trial found that moderate blood pressure control (SBP < 

150 mm Hg) was associated with a small increase in the risk of fall. 

Effects of Age 

We found limited evidence from 3 studies that differences in rates of adverse events such as 

unsteadiness, dizziness, and renal failure between intervention and control groups were not 

appreciably different in those greater and less than 75 years of age. 

Key Question 5. Do the harms of targeting lower blood pressure vary with patient 

burden of comorbidities? 

We found no trials which examined the impact of participants’ burden of comorbidities on risk 

of adverse events. 

SUMMARY OF EVIDENCE AND DISCUSSION 

Key Findings and Strength of Evidence 

In this systematic review, we examined the benefits and harms of treating hypertension to lower 

compared more moderate blood pressure targets in patients over age 60. The table that follows 

provides a summary of the evidence. Overall, we found high strength evidence that treating 

blood pressure in patients over age 60 to current treatment targets (< 150/90 mmHg) 

substantially reduces mortality, stroke, and cardiac events. Much of this data comes from trials in 

which the mean baseline SBP was > 160 mmHg. We also found evidence, driven mainly by one 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

5

large trial, that lower targets (SBP < 140 mmHg or DBP < 85 mmHg) compared to higher targets 

reduced stroke (moderate strength evidence) and cardiac events (low strength evidence); 

mortality was also reduced though not significantly (low strength evidence). There is little data 

that directly helps distinguish benefits between SBP 140 and 150 mmHg. Most of the trials 

achieving SBP < 140 mmHg were the treat-to-target trials. Only one trial included patients with 

baseline SBP 140-150 mmHg and found an improvement in mortality, but not other outcome. 

We found moderate strength evidence that more aggressive blood pressure control (SBP < 140 

mmHg) in patients with prior stroke substantially reduced rates of recurrent stroke. 

The treat-to-target trials overall support a lower blood pressure treatment target in some patients 

with high cardiovascular risk. Most of the evidence in support of lower treatment targets comes 

from one large trial examining an SBP target of < 120 mmHg in which a substantial proportion 

of intervention patients achieved SBP 120-130 mmHg. Lower targets may prevent (on average, 

across a population) roughly 10-20 events for every 1000 high-risk patients treated over 5 years 

(Table 2), but more aggressive treatment is likely associated with a higher medication burden 

and higher risk of adverse effects such as hypotension and syncope. On the other hand, we found 

that lower targets are unlikely to increase the risk of dementia, fractures, and falls, or reduce 

quality of life. 

Applicability 

The generalizability of our findings to the oldest age groups and the frail elderly is limited. Very 

few patients over age 80 were included in the trials, though one trial exclusively enrolled patients 

over age 80 and found a reduced risk of stroke with moderate blood pressure control (< 150/90 

mm Hg). Patients with serious life-limiting illness, frailty, or dementia were excluded from most 

studies. 

Conclusions 

Lowering blood pressure in adults over age 60 reduces mortality, stroke, and cardiac events. The 

most consistent and largest effects are seen in studies of patients with higher baseline blood 

pressures (SBP ≥ 160 mmHg) achieving moderate blood pressure control (< 150/90 mmHg). 

Lower treatment targets (< 140/85 mmHg) are likely to be beneficial for some patients at high 

cardiovascular risk, but the results across trials are less consistent. Lower treatment targets are 

largely supported by findings from one trial which targeted SBP <120 mmHg and in which most 

intervention patients achieved SBP < 130 mmHg. In patients with cerebrovascular disease, more 

aggressive blood pressure lowering (SBP <140 mmHg) likely reduces recurrent stroke. Lower 

treatment targets are associated with higher medication burden and an increased risk of shortterm harms such as hypotension. On the other hand, evidence that there is not an increased risk 

in cognitive impairment, falls, and reduced quality of life may provide some flexibility for 

providers in crafting an individualized antihypertensive treatment plan. There is little data to 

assess the risks and benefits of antihypertensive treatment among institutionalized elder patients 

or those with multiple comorbidities.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

6

Summary of the Evidence on More vs Less Intensive Treatment for Hypertension in the Elderly

Outcome

N studies

(N = total 

patients 

combined)

Combined estimates:

RR (95% CI)

ARR 

N: events (95% CI) 

prevented per 1000 highrisk patients over 5 yearsa 

Strength of 

Evidenceb Summary of findings

Mortality 9 RCTsc

(N = 46,450) 

RR 0.90 (0.83-0.98)

ARR 1.64 

N: 34 (7-58)

Highd Consistent benefit of treating blood pressure to 

levels < 150/90 mmHg. 

6 RCTse

(N = 41,491)

RR 0.86 (0.69-1.06)

ARR 0.80

N: 18 (n/af

-40)

Low Lower treatment targets (SBP ≤ 140 mmHg or DBP 

≤ 85 mmHg, or lower) associated with nonsignificant mortality reduction compared to higher 

targets. Findings were inconsistent across studies

and estimate was imprecise.

Stroke 9 RCTsc

(N = 46,450) 

RR 0.74 (0.65-0.84)

ARR 1.13

N: 26 (16-35)

Highd Clear, consistent benefit of treating blood pressure to 

levels < 150/90 mmHg. 

6 RCTse

(N = 41,491)

RR 0.79 (0.59-0.99)

ARR 0.49

N: 9 (0-17)

Moderate Lower treatment targets (SBP ≤ 140 mmHg or ≤ 

DBP 85 mmHg, or lower) reduced the risk of stroke 

compared to higher targets; some inconsistency but 

relatively stable effect across analysesf

Cardiac 

events

9 RCTsc

(N = 46,450) 

RR 0.77 (0.68-0.89)

ARR 1.25

N: 65 (31-90)

Highd Clear, consistent benefit of treating blood pressure to 

levels < 150/90 mmHg. 

6 RCTse

(N = 41,491)

RR 0.82 (0.64-1.00)

ARR 0.94

N: 18 (n/af

-36)

Low Lower treatment targets (SBP ≤ 140 mmHg or DBP 

≤ 85 mmHg, or lower) may reduce the risk of 

cardiac events compared to higher targets. Findings 

were inconsistent across studies and estimate was 

imprecise.

Short-term 

adverse 

events

19 RCTs

(N = 98,964) 

--- --- Mixed findings: withdrawal due to adverse events 

was increased in the intervention group by 44-100% 

in 4 of 10 trials reporting this outcome. Cough and 

hypotension were the most frequently reported 

events. The risk of syncope was increased in 2 of 3 

trials reporting this outcome. Excessive 

heterogeneity among trials precluded pooling of 

results.

Renal 

outcomes

13 RCTs

(N = 66,607) 

--- Low More intensive blood pressure treatment did not 

worsen renal outcomes. Outcome definitions varied, 

and event rates for clinically significant outcomes 

such as end stage renal disease were low.

Cognitive 

outcomes

7 RCTs

(N = 25,901)

Incident dementia 

in 4 RCTs of patients 

without prior stroke:

OR 0.89 (0.74-1.07)

Moderate No effect on degree of cognitive decline or incidence 

of dementia. Loss to follow-up ranged across 

studies; patients lost to follow-up may differ in risk 

for dementia.

Falls/

fracture

Fracture:

3 RCTs

(N = 11,680)

--- Moderate 

(fracture)

Mixed findings: 3 trials found no effect of lower 

blood pressure targets on risk of fracture. Two trials 

with SBP target of 120 mmHg found no effect on 

risk of falls, while a 3rd (with achieved SBP < 150 

mmHg) found a small increase in risk of fall. 

Falls: 3 RCTs

(N = 17,196)

--- Low (falls)
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

7

Outcome

N studies

(N = total 

patients 

combined)

Combined estimates:

RR (95% CI)

ARR 

N: events (95% CI) 

prevented per 1000 highrisk patients over 5 yearsa 

Strength of 

Evidenceb Summary of findings

Quality of 

life (QOL)

4 RCTs

(N = 7,154)

--- Moderate 

(QOL)

Low 

(functional 

status)

Moderate BP control (SBP 140-150 mmHg) did not 

affect QOL. One study found no effect on functional 

status.

Effects of 

age

12 RCTs

(N = 76,137) 

--- Low Similar effects across different age groups in agetreatment interaction analyses, but based on studylevel subgroup analyses and dichotomized at a 

younger age in many studies.

Effects of 

comorbidity 

burden

--- --- No evidence No studies reported outcomes based on comorbidity 

burden; most trials excluded patients with dementia, 

serious comorbidities, and life-limiting illness.

Effects in 

the frail 

elderly

2 RCTs

(N = 5,166)

--- Insufficient Treatment effects did not vary with frailty score in 

post-hoc analyses from 2 trials, one of which had 

large amount of missing data. Most trials did not 

assess frailty, and many trials excluded patients who 

were frail, had dementia, or were institutionalized.

Effects in 

stroke 

patients

2 RCTs

(N = 9,125) 

Stroke recurrence:

RR 0.76 (0.66-0.92)

ARR 3.02

Moderate Targeting SBP < 140 mmHg reduced recurrent 

stroke. 

Cardiac events:

RR 0.78 (0.61-1.08)

Mortality:

RR 0.98 (0.85-1.19)

Abbreviations: ARR = absolute risk reduction; BP = blood pressure; CI = confidence interval; DBP = diastolic blood pressure; N = 

population size (N total / n subgroup); OR = odds ratio; QOL = quality of life; RCT = randomized controlled trial; RR = relative risk; 

SBP = systolic blood pressure. a We used observed control group event rates standardized to 5 years. As poorly controlled blood pressure itself contributes to 

cardiovascular risk, we used data from the 2 most contemporary trials for each set of analyses. We used the HYVET study (22) to 

estimate event rates in the higher baseline blood pressure analyses, and data from SPRINT (the older age subgroup since the mean age 

was comparable to that in HYVET) for the treat to target analyses (50). b

The overall quality of evidence for each outcome is based on the consistency, coherence, and applicability of the body of evidence, as 

well as the internal validity of individual studies. The strength of evidence is classified as follows: 

High = Further research is very unlikely to change our confidence on the estimate of effect.

Moderate = Further research is likely to have an important impact on our confidence in the estimate of effect and may change 

the estimate.

Low = 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.

Insufficient = Any estimate of effect is very uncertain. c

The analyses presented here are of trials with baseline SBP 160 mmHg. The achieved SBP in 3 of the trials was < 140 mmHg, but 

these studies contributed relatively few events. Achieved SBP in all the other studies was 140 mmHg. d

Most of the evidence comes from trials in which baseline SBP ≥160 mmHg and achieved SBP was 140-150 mmHg. These are large 

trials providing consistent evidence, and a precise summary estimate.

e

All trials that tested strict versus less strict blood pressure targets in which the target blood pressure in the intervention group was 

SBP < 140 mmHg or DBP < 85 mmHg, or even lower. f The number of prevented events is not applicable because the upper bound of the confidence interval for relative risk was 1.00.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

8

ABBREVIATIONS 

Abbreviation Definition

α-B Alpha-blocker

β-B Beta-blocker

ACCORD Action to Control Cardiovascular Risk in Diabetes

ACE Angiotensin converting enzyme

ADL Activities of daily living

ADVANCE Action in Diabetes and Vascular Disease

AE Adverse effect or event

AHRQ Agency for Healthcare Research and Quality

ARB Angiotensin II receptor blockers

ARR Absolute risk reduction

BENEDICT-B Bergamo Nephrologic Diabetes Complications Trial-B

BioLINCC Biologic Specimen and Data Repository Information Coordinating Center

BP Blood Pressure

BPLTTC Blood Pressure Lowering Treatment Trialists Collaborative

CAD Coronary artery disease

Cardio-Sis Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa 

Sistolica

CCB Calcium channel blocker

CHD Coronary heart disease

CHF Congestive heart failure

CI Confidence interval

CKD Chronic kidney disease

CVA Cerebrovascular accident

CVD Cerebrovascular disease

DBP Diastolic blood pressure

DM Diabetes mellitus

DSST Digit Symbol Substitution Test

ESP Evidence-based Synthesis Program

EuroQOL European Quality of Life scale

EWPHE European Working Party on High Blood Pressure in the Elderly

FEVER Felodipine Event Reduction Study

HOT Hypertension Optimal Treatment

HR Hazard ratio

HYVET Hypertension in the Very Elderly Trial

JATOS Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive 

Patients

JNC-BP Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of 

High Blood Pressure

KQ Key Question(s)

LVH Left Ventricular Hypertrophy

MI Myocardial infarction

mm Hg Millimeters of mercury (unit of pressure)
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

9

MMSE Mini-mental state examination

MRI Magnetic resonance imaging

N Number randomized (N= total, n = subgroup)

NNT Number needed to treat

NR Not reported

ns Not statistically significant

OR Odds ratio

PALT Paired Associate Learning Test

PGWB Psychological General Well-Being

PICOTS Population, intervention, comparator, outcome, timing, study design

PROGRESS Perindopril Protection Against Recurrent Stroke Study

QOL Quality of life

RCT Randomized controlled trial

RENAAL Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

RR Relative risk 

SBP Systolic blood pressure

SCOPE Study on Cognition and Prognosis in the Elderly

SD Standard deviation

SHEP Systolic Hypertension in the Elderly Program

SIP Sickness Impact Profile

SPRINT Systolic Blood Pressure Intervention Trial

SPS3 Secondary Prevention of Small Subcortical Strokes

SSA-P Subjective Symptoms Assessment Profile

STONE Shanghai Trial of Nifedipine in the Elderly

Syst-China Systolic Hypertension in China

Syst-Eur Systolic Hypertension in Europe

TIA Transient ischemic attack

TRANSCEND Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with 

Cardiovascular Disease

VA Veterans Administration

VALISH Valsartan in Elderly Isolated Systolic Hypertension

WHO World Health Organization
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

10

EVIDENCE REPORT

INTRODUCTION

Hypertension is a very common chronic illness in the United States, with an estimated 

prevalence of 27% among adults over age 18 and as much as 67% in adults over age 60, and 

possibly a higher prevalence among Veterans.1 Hypertension management is known to modify 

the risk of cardiovascular disease, renal disease, cerebrovascular disease, and death.2-5 The issue 

is of great relevance to Veterans Affairs (VA) given the very high prevalence of hypertension 

and other vascular risk factors such as diabetes and hyperlipidemia in Veterans generally and the 

aging Veteran population more specifically. The benefit of some versus no blood pressure 

control has been shown to be consistent for older adults (aged ≥ 60 years), even the very elderly 

(aged ≥ 80 years).6-8 The most beneficial blood pressure targets for patients of specific age 

groups, however, has been a topic of some debate and controversy, stemming from concerns that 

the ratio of benefit to harm of a given blood pressure level may vary with age. Further, the 

disease-disease and disease-treatment interactions which can occur when treating hypertension in

older adults with multiple chronic comorbidities remain unclear. This holds particular relevance 

for Veterans over age 65, who experience an average of 5 comorbidities and for whom the most 

common comorbidity clusters in both men and women include hypertension.9

In 2014, the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment 

of High Blood Pressure (previously JNC-FG8, referred to in this report as JNC-BP) published 

new guidelines for the treatment of hypertension as well as a new treatment goal for older 

individuals (age ≥ 60 years) for systolic blood pressure (SBP) of < 150 mm Hg rather than < 140 

mm Hg.

10 The new goal for those ages ≥ 60 years has been very controversial. The recent 

publication of a trial showing a benefit from aggressive blood pressure treatment in older 

individuals has further fueled debate about the safest and most beneficial blood pressure goal for 

older people.11 The objectives of this review are to examine the benefits and harms of differing 

blood pressure targets among older adults (aged ≥ 60 years).

METHODS

TOPIC DEVELOPMENT

This topic was nominated by Dr. Dawn Bravata with the Stroke Quality Enhancement Research 

Initiative. Additional key stakeholders for this project include the directors for the offices of 

Neurology, Clinical Analytics and Reporting, the Evidence-based Practice Program, and 

Preventive Medicine. The research questions for this systematic review were developed after a 

topic refinement process that included a preliminary review of published peer-reviewed 

literature, discussion with internal partners and investigators, and consultation with content 

experts and key stakeholders. A protocol describing the review plan was posted to a publicly 

accessible website before the study was initiated.

12
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

11

In this report we address the following Key Questions which all apply to adults over age 60:

Key Question 1. What are the health outcome effects of differing blood pressure targets? b) What 

are the health outcome effects of differing blood pressure targets in patients who have suffered a 

transient ischemic attack (TIA) or stroke?

Key Question 2. How does age modify the benefits of differing blood pressure targets?

Key Question 3. How does the patient burden of comorbidities modify the benefits of differing 

blood pressure targets?

Key Question 4. What are the harms of targeting lower blood pressure in older patients? Do the 

harms vary with age?

Key Question 5. Do the harms of targeting lower blood pressure vary with patient burden of 

comorbidities?

SEARCH STRATEGY

We developed a literature search strategy in consultation with a research librarian (Appendix A). 

We searched MEDLINE®, Embase®, and Ovid EBM Reviews from database inception through 

January 2015, and updated the MEDLINE® search in September 2016. We also examined all 

trials included in the recent JNC-BP review10 and the Blood Pressure Lowering Treatment 

Trialists Collaborative (BPLTTC)13 at the full-text level. We conducted an additional search 

from January 2012 through January 2015 focused specifically on blood pressure treatment trials 

(because all trials in JNC-BP and BPLTTC were published before 2012). We further evaluated

the bibliographies of included primary studies and recent systematic reviews. We also searched

ClinicalTrials.gov to identify in-progress or unpublished studies, and identified related 

publications if in-progress trials were completed through December 2015.

STUDY SELECTION

The criteria for patient population, intervention, comparator, outcome measures, timeframe for 

outcomes, and study design (PICOTS) vary by Key Question. Table 1 shows how each 

parameter in the PICOTS corresponds to the Key Questions. We applied specific 

inclusion/exclusion codes in screening the literature for relevant studies (Appendix B). We 

reviewed titles and abstracts and retrieved full-text articles with potential relevance to the Key 

Questions. Two independent reviewers reviewed the full-text articles to determine a final 

inclusion/exclusion decision. 

Studies were considered for inclusion if the study population had mean age of ≥ 60 years, all 

participants carried a diagnosis of hypertension at the time of enrollment, and the study design 

either compared higher versus lower blood pressure targets or more versus less intensive 

antihypertensive therapy (ie, compared the addition of an antihypertensive medication to 

placebo). We excluded studies in populations with specific diagnoses in which medications were 

used primarily for effects other than blood pressure lowering (eg, studies of beta-blockade in 

patients with systolic heart failure, or studies of acute myocardial infarction). We also excluded 

studies focused on the management of acute stroke. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

12

We excluded comparative effectiveness trials which directly compared the effects of different 

antihypertensive drugs to one another. We excluded observational studies in considering our 

primary health outcomes (mortality, stroke, cardiac events) given the risk of confounding and the 

existence of many controlled trials. We included observational studies to assess potential harms 

of antihypertensive therapy. Because harms may be relatively infrequent and are not always 

immediate, we surmised the larger patient numbers and longer follow-up of cohort studies may 

be more likely to identify important harms/adverse events of blood pressure management. We 

only included observational studies in which there was some assessment of blood pressure 

change over time and in which patients were receiving antihypertensive therapy. We did not 

include studies examining the relationship between a baseline blood pressure and subsequent 

outcomes. We included trial extension studies and companion studies which reported subgroup 

analyses of interest such as treatment effect modifications based on age. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

13

Table 1. Key Questions, Inclusion Criteria, and Scope Parameters

Key Question

(KQ)

In adults over age 

60 with 

hypertension:

KQ1. What are the health 

outcome effects of differing 

blood pressure targets?

b) What are the health outcome 

effects of differing blood 

pressure targets in patients who 

have suffered a TIA or stroke?

KQ2. How does age 

modify the benefits of 

differing blood pressure 

targets?

KQ3. How does the patient 

burden of comorbidities modify 

the benefits of differing blood 

pressure targets?

KQ4. What are the harms of 

targeting lower blood pressure 

in older patients? Do these 

harms vary with age?

KQ5. Do the harms of 

targeting lower blood 

pressure vary with patient 

burden of comorbidities? 

Population Adults aged ≥ 60 years with hypertension Adults aged ≥ 60 years with 

hypertension and CVA or other 

existing comorbidity

Adults aged ≥ 60 years with 

hypertension

Adults aged ≥ 60 years with 

hypertension and at least one 

comorbidity

Intervention Include: Pharmacologic treatment of hypertension to specified targets; or more versus less 

intensive treatment of hypertension

Exclude: 

Interventions for which hypertension management was not the primary objective (Example: 

studies conducted in patients with heart failure for which vasoactive medications are being 

used for cardiac remodeling effects.)

Non-pharmacologic interventions for blood pressure control

Include: Pharmacologic treatment of hypertension, not 

necessarily to specified targets 

Exclude: Management of hypertension in patients with acute 

stroke; non-pharmacologic interventions for blood pressure 

control

Comparators Placebo or a higher blood pressure target

Outcomes All-cause mortality

Mortality related to stroke, coronary heart disease, congestive heart failure, and renal 

disease

Morbidity including stroke, coronary heart disease, congestive heart failure, and renal 

disease

Changes in cognition

Falls

Changes to quality of life

Polypharmacy/medication burden

Hypotension

Acute kidney injury (defined as doubling of serum 

creatinine or requiring renal replacement therapy)

Timing Long term (> 6 months) outcomes Any

Study design Include:

Controlled study designs (RCT and non-randomized controlled clinical trials) 

Include:

Controlled study designs (RCT and non-randomized 

controlled clinical trials used for KQs 1-3) 

Cohort extensions of trials that examined specific blood 

pressure targets

Cohort studies that examined the effects of lower blood 

pressure in the context of antihypertensive medication

Cohort studies that reported the effects of lower blood 

pressure despite that hypertension management was not the 

primary objective of the intervention studied. 

Exclude: Case reports; case series; controlled before/after studies, RCTs with less than 6 month follow-up.

Abbreviations: CVA = cerebrovascular accident; KQ = Key Question; RCT = randomized controlled trials; TIA = transient ischemic attack
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

14

DATA ABSTRACTION

Data from published reports were abstracted into a customized database by one reviewer and 

reviewed for accuracy and completeness by a second reviewer. From each study, we abstracted

the following characteristics: 

study design

objectives

setting

demographic variables (including sex and age) 

comorbidities (burden of comorbidity, number of medications/burden at baseline, 

baseline cognitive function)

subject eligibility and exclusion criteria

number of subjects

years of enrollment

duration of follow-up

the study and comparator interventions (including screening intervals, antihypertensive 

agents used, blood pressure targets)

important co-interventions

health outcomes (all-cause mortality, mortality/morbidity related to cerebrovascular 

accident, coronary heart disease, congestive heart failure, renal disease)

adverse events (including changes in cognitive status, falls, changes in quality of life, 

polypharmacy, and acute kidney injury)

Additional study result characteristics of interest included achieved blood pressures (systolic and 

diastolic), documented cognitive changes, and number of antihypertensive medications required.

QUALITY ASSESSMENT

Two reviewers independently assessed the quality of each trial using a tool developed by the 

Cochrane Collaboration.14 Disagreements were resolved through discussion. Each trial was given 

an overall summary assessment of low, high, or unclear risk of bias (Appendix C).

DATA SYNTHESIS

Outcomes of interest for Key Questions 1 to 3 of this review included potential benefits of lower 

versus higher blood pressure targets: all-cause mortality, cardiovascular mortality, stroke (fatal 

or non-fatal), and cardiovascular morbidity (myocardial infarction and sudden cardiac death). 

We do not present cardiovascular mortality data in this report because these data were very 

similar to the all-cause mortality and cardiac events data. Because hypertension therapy is longterm in both nature and benefit, we were interested only in these outcomes when they occurred at 

≥ 6 months of treatment. For each outcome, we abstracted the number of events and total 

participants from each treatment group to obtain a pooled estimate of relative risk (RR).

Outcomes of interest related to Key Questions 4 and 5 (potential harms of lower versus higher 

blood pressure targets) included changes in cognition and changes in quality of life, falls and 

fractures, hypotension, and acute kidney injury (defined as doubling of serum creatinine or 

requiring renal-replacement therapy). From the included trials, we also reported medication 

burden (number of antihypertensive medications required in each group), and withdrawals due to 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

15

adverse events. We did not specifically search for studies reporting well-known drug-specific 

adverse effects such as angiotensin converting enzyme (ACE) inhibitor-induced cough or 

thiazide diuretic-induced hypokalemia, but we described the common adverse events leading to 

withdrawal among the trials.

Study-level Meta-analysis

We conducted meta-analyses using study-level data to get more precise estimates for several 

outcomes including death from all causes, cardiovascular death, fatal and nonfatal stroke, major 

cardiac events and withdrawal due to adverse events. To determine the appropriateness of metaanalysis, we considered clinical and methodological diversity and assessed statistical 

heterogeneity. For each outcome, we abstracted the number of events and total participants from 

each treatment group. We used the profile-likelihood random-effects model15 to combine risk 

ratios, while incorporating variation among studies. We assessed the presence of statistical 

heterogeneity among the studies using the standard Cochran’s chi-square test, and the magnitude 

of heterogeneity using the I

2 statistic.16

We performed a number of sensitivity analyses to help address the heterogeneity of study design 

and patient populations. We stratified analyses by baseline study characteristics (mean age, 

enrollment age, SBP) and achieved SBP level. We conducted analyses of studies whose mean 

population age was ≥ 70 and studies whose inclusion criteria stipulated entry age of ≥ 60 to 

ensure results were consistent among study populations which most definitively met the age 

criteria of interest. We conducted analyses grouping studies in which the intervention group did 

and did not achieve mean SBP < 140 mm Hg to better examine outcomes among patient 

populations whose achieved blood pressure was genuinely lower than that suggested by current 

guidelines (SBP < 150 mm Hg). To examine whether blood pressure treatment affected 

populations with mild to moderate versus more severe hypertension differently, we also 

conducted analyses of studies with mean baseline SBP > 160 mm Hg and ≤ 160 mm Hg.

We conducted subgroup analyses of trials specifically examining blood pressure targets since 

these trials are most directly applicable to the clinical questions of interest guiding this report.

Analyses included evaluation of those studies which stipulated target SBP ≤ 140 mm Hg or 

lower for the more intensive treatment arm. We also included one study which compared 3

diastolic blood pressure (DBP) targets.17 In order to most directly address current guidelines, we 

dichotomized data from this study to DBP ≤ 90 mm Hg versus a combination of the 2 lower 

targets (≤ 85 plus ≤ 80 mm Hg). In an additional sensitivity analysis we incorporated only the 2

more disparate DBP groups from this trial (≤ 80 vs ≤ 90 mm Hg) as this provided the optimal 

difference between achieved SBP and DBP between groups (Appendix D).

Finally, we conducted analyses excluding trials which achieved negligible differences in SBP (≤

3 mm Hg) between study arms. We also conducted analyses excluding methodologically flawed 

studies with a high risk of bias. 

All analyses were performed using Stata/IC 13.1 (StataCorp, College Station, TX).

Individual Patient Data Meta-analysis

In an effort to better understand treatment effects among different age subgroups, we explored 

the possibility of gathering data to conduct analysis based on individual patient data from blood 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

16

pressure treatment trials. We contacted authors from all included RCTs. We received responses 

from 13, and we ultimately received either individual patient data or analyses of outcomes 

according to age subgroups from 4 trials (Valsartan in Elderly Isolated Systolic Hypertension 

[VALISH], Systolic Hypertension in Europe [Syst-Eur], European Working Party on High Blood 

Pressure in the Elderly [EWPHE], Action in Diabetes and Vascular Disease [ADVANCE]). We 

were also able to obtain study data from the Biologic Specimen and Data Repository Information 

Coordinating Center (BioLINCC) of the National Heart, Lung, and Blood Institute on 2 studies: 

the Action to Control Cardiovascular Risk in Diabetes study (ACCORD) and the Systolic 

Hypertension in the Elderly Program (SHEP) trial. We anticipate using data from these 6 trials to 

conduct meta-analyses examining blood pressure treatment benefits and harms in those aged 60

to 69 years, 70 to 79 years, over age 80 years. We will also conduct analyses examining the 

impact of comorbidity burden on outcomes if this data is available. We anticipate these analyses 

will be completed and published at a later date. 

RATING THE BODY OF EVIDENCE

We assessed the overall quality of evidence for each outcome using a method developed by the 

Agency for Healthcare Research and Quality (AHRQ).18 We considered the consistency, 

coherence, and applicability of the body of evidence, as well as the internal validity of individual 

studies, to classify the strength of evidence for each outcome as follows:

High = Further research is very unlikely to change our confidence on the estimate of 

effect.

Moderate = Further research is likely to have an important impact on our confidence in 

the estimate of effect and may change the estimate.

Low = 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.

Insufficient = Any estimate of effect is very uncertain.

PEER REVIEW

A draft version of this report was reviewed by 12 individuals with technical expertise and

clinical leadership. Their comments and our responses are presented in Appendix E.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

17

RESULTS

LITERATURE FLOW

The combined literature searches yielded 11,268 titles and abstracts, including 11,153 from 

electronic database searches, and 115 from reference lists of systematic reviews and other 

relevant articles. We applied pre-specified inclusion criteria (Appendix B) in screening the 

abstracts and selected 330 articles for full-text review. We identified 21 randomized controlled 

trials (RCTs) and 3 cohort studies that contained primary data relevant to the Key Questions

(Figure 1). 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

18

Figure 1. Literature Flow Diagram

11,153 Citations identified from electronic database searches 

 8,483 from Ovid MEDLINE® on 1/30/2015; updated 09/15/2016 

 2,505 from EMBASE on 1/30/2015 

 41 from the Ovid EBM Reviews/Cochrane library on 1/30/2015 

 73 from PubMed publisher status segment on 1/30/2015 

51 from Conference Papers Index on 1/30/2015

115 Citations identified from reference lists of review articles and

manual searches for recent, unpublished or ongoing studies

11,268 Citations compiled for review of titles and abstracts

10,938 Titles and abstracts excluded 

for lack of relevance 

330 Potentially relevant articles retrieved for further review

284 Excluded articles:

 Study population not in scope = 27 

 No primary data or excluded study design = 48 

 Treatment comparison or study objectives not in scope = 106 

 Reported outcomes not in scope = 28 

 Secondary report of an included trial, no applicable data = 27 

Systematic review used for identifying additional studies = 11

Retrieved for background, discussion, or methods = 37

24 primary studies

published in 

46 articles 21 Randomized controlled trials (RCTs)

3 Prospective cohort studies: harms data only

7 RCTs comparing 

BP targets

8 RCTs comparing 

more vs less intensive treatment 

15 RCTs included in meta-analyses of mortality, stroke, cardiac events

6 RCTs excluded from meta-analyses
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

19

KEY QUESTION 1: In adults over age 60, what are the health outcome 

effects of differing blood pressure targets?

Overview of Results

We found 21 trials comparing blood pressure treatment targets, or more versus less intensive 

treatment. Overall, there was clear and consistent evidence that treating blood pressure in older 

adults reduced mortality, cardiac events, and stroke. We found the most consistent and greatest 

absolute benefit among trials in which participants had higher baseline blood pressures (SBP 

160 mm Hg) and achieved moderate blood pressure control (< 150/90 mm Hg). Six trials 

compared more aggressive blood pressure treatment targets (SBP < 140 mm Hg or DBP < 85 

mm Hg) to higher targets and found no significant effect on all-cause mortality. More aggressive 

treatment did reduce the risk of cardiac events and stroke, but the absolute effects were smaller 

than those seen among trials of patients with higher baseline blood pressures achieving moderate 

control. 

Trial Characteristics

The 21 included clinical trials varied significantly in study design and primary outcomes. All 

studies were considered low risk of bias with the exception of 3 studies.

19-21 Eight studies 

randomized patients to different blood pressure targets (Table 2).

11,17,21-26 The remaining 13 trials 

randomized patients to more versus less intensive hypertensive therapy, which often resulted in 

different achieved blood pressures across treatment arms (Table 3).

6,8,19,20,27-35

Target blood pressures varied widely across studies. The SBP treatment target for the more 

intensive treatment arm ranged from 120 to 150 mm Hg; one study targeted DBP.

17 Achieved 

blood pressures also varied widely; SBP in the more intensive arm (either lower target or more 

intensive therapy) ranged from 119 to 149 mm Hg and in half the trials achieved SBP was ≥ 140 

mm Hg. Three studies had ≤ 2 mm Hg difference in achieved SBP between treatment arms.

28,32,35

All but 3 trials

25,34,35 reported DBP at trial end, and 14 of these noted a > 1 mm Hg difference 

between arms in achieved DBP, but only 3 trials8,11,22 reported DBP < 70 mm Hg in the more 

intensive arm and none of the trials reported achieved DBP > 90 mm Hg in the less intensive arm. 

The examined patient populations varied widely across studies, from differences in race to 

differences in burden of comorbid illness. Three studies included only patients with type 2 

diabetes,22,27,32 3 excluded all patients with diabetes,

11,19,23 and 6 excluded patients with type 1 

diabetes or insulin-requiring diabetes.8,17,22,27,29,32 Five studies enrolled patients with history of 

stroke or with high cardiovascular risk.

11,25,27,31,35

Examined outcomes also varied across included trials. Nine of the 21 studies had a composite 

outcome for the primary outcome,

11,17,22,24,26,27,33,35 and 6 had a primary outcome related to 

stroke.

6,8,20,25,30,31 The remaining studies had primary outcomes related to renal disease or 

microalbuminuria28,32 or additional outcomes not specified of interest for this review (left 

ventricular hypertrophy regression).23 Use of antihypertensive agents varied widely across 

studies. Among trials which specified a particular medication as first-line therapy, 7 used ACE 

inhibitor or angiotensin II receptor blockers, 5 used calcium channel blockers, and 6 used 

diuretics (Tables 2 and 3).
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

20

Not surprisingly, differences between study populations and methodologies yielded differences 

in event rates. The proportion of patients experiencing an event varied from 0.36% to 35.1% for 

all-cause mortality, from 0.27% to 13.75% percent for stroke, and from 0.26% to 11.39% for 

major cardiac events. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

21

Table 2. Characteristics of Trials that Compared Blood Pressure Target Goals 

Study

BP goals (mm Hg), T vs C

Mean or median(*) length 

of follow-up

Antihypertensive therapy used to reach 

targets

Sample size, 

T vs C

Mean age (SD)

% Male

Comorbidities

% DM

% CAD

% CVD

Baseline 

SBP/DBP, 

T vs C

Achieved 

SBP/DBP, 

T vs C

Mean number or % 

distribution of antihypertensive 

medications used, T vs C

ACCORD, 201022

SBP < 120 vs < 140

4.7 years

Step 1: a diuretic combined with an ACEI

or β-B.

Medications that could be added to reach 

BP target: dihydropyridine and 

nondihydropyridine CCB, α-B, ARB, 

sympatholytics, α-B/β-B, and the 

following combinations: thiazide diuretic + 

a potassium-sparing diuretic; β-B + 

diuretic; ACEI + diuretic, ARB + a 

diuretic; dihydropyridine CCB + ACEI.

2362 vs 2371

62.2 (6.9) 

52.3% 

100% DM

33.7% CAD

139.0/75.9 vs 

139.4/76.0

119.3/64.4 vs 

133.5/70.5

Mean 3.5 vs 2.2

Cardio-Sis, 200923

SBP < 130 vs < 140

2.0* years

Diuretics (hydrochlorothiazide + ramipril 

or telmisartan, furosemide), β-B 

(bisoprolol), CCB (amlodipine), ACEI 

(ramipril ± hydrochlorothiazide), ARB 

(telmisartan ± hydrochlorothiazide), 

centrally acting sympathetic inhibiting 

drugs (clonidine), plus drugs previously 

taken by subjects.

557 vs 553

67 (7.0)

52.3% 

12% CAD

8.5% CVD

163.3/89.7 vs 

163.3/89.6

131.9/77.4 vs 

135.6/78.7

Mean 2.9 vs 2.9

OR (95% CI) at 2-year followup, T vs C: 

Diuretic: 1.36 (1.08 to 1.71)

ARB: 1.17 (0.90 to 1.52)

β-B, CCB, and ACEI: no 

difference

HOT, 199817

DBP ≤ 80 vs ≤85 vs 

≤ 90

3.8 years

Step 1: low-dose felodipine 

Step 2: + low-dose ACEI or β-B 

Step 3: + high-dose felodipine 

Step 4: + high-dose ACEI or β-B 

Step 5: + other, mainly thiazide

6262 vs 6264 vs 

6264

61.5 (7.5) 

53% 

1.5% MI

1.2% CVD

8% DM

170/105 vs 

170/105 vs 

170/105

By assigned 

DBP, ≤ 80 vs ≤

85 vs 

≤ 90:

139.7/81.1 vs

141.4/83.2 vs 

143.7/85.2

% using drug per DBP target, ≤

80 vs ≤ 85 vs ≤ 90:

Felodipine: 79 vs 78 vs 77

ACEI: 45 vs 42 vs 35

β-B: 32 vs 28 vs 25

Diuretic: 24 vs 22 vs 19

JATOS, 200824

SBP < 140 vs < 160

2.0 years

Efonidipine, 20-40 mg once daily, 

increasing to 60 mg once or twice daily if 

needed. Drugs other than CCB were added 

if needed.

2212 vs 2206

73.6 (5.2) 

38.8% 

11.8% DM

9.1% CVD

9.9% Renal 

disease

171.6/89.1 vs 

171.5/89.0

139.3/76.1 vs 

146.5/ 78.5

N drugs used by % of patients:

1: 47.7 vs 57.8 (P < .001)

2: 31.6 vs 27.3 (P = .002)

3: 15.1 vs 9.3 (P < .001)

4: 2.9 vs 1.9 (P = .05)

5: 0.1 vs 0.14 (P = 1.0) 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

22

Study

BP goals (mm Hg), T vs C

Mean or median(*) length 

of follow-up

Antihypertensive therapy used to reach 

targets

Sample size, 

T vs C

Mean age (SD)

% Male

Comorbidities

% DM

% CAD

% CVD

Baseline 

SBP/DBP, 

T vs C

Achieved 

SBP/DBP, 

T vs C

Mean number or % 

distribution of antihypertensive 

medications used, T vs C

SPS3, 201325

SBP < 130 vs 130-149

3.7 years

At the discretion of the physician; at least 

one drug from each major class was 

available. 

1501 vs 1519

63 (11.0)

63% 

36.5% DM

100% CVD

10.5% CAD

142/78 vs 

144/79

SBP 127

vs 138

DBP NR 

Mean 2.4 vs 1.8 (P < .001)

Drugs used by T vs C (%) at 1 

year:

Thiazides: 58 vs 43

ACEI/ARB: 80 vs 63

CCB: 43 vs 30

β-B: 31 vs 25

Other: 11 vs 9

SPRINT, 201511

SBP < 120 vs < 140 

3.26* years

Thiazide-type diuretic, and/or an ACEI or 

ARB (but not both) and/or a CCB. Titrate 

or add therapy not already in use as 

needed.

4678 vs 4683

67.9 (9.5)

64.4%

0% DM

0% CVD

20.1% CAD

28.3% CKD

139.7/78.2 vs 

139.7/78.0

121.5/66

vs 134.6/74

Mean 2.7 (1.2) vs 1.8 (1.1)

% using N meds:

0: 2.7 vs 11.3

1: 10.5 vs 31.1

2: 30.5 vs 33.3

3: 31.8 vs 17.2

4+: 24.3 vs 6.9

VALISH, 201026

SBP < 140 vs < 150

3.0* years

Step 1: Valsartan, 40-80 mg once daily

Step 2: Increase valsartan up to 160 mg, 

and/or other agents (diuretics, CCBs) 

except other ARBs

1545 vs 1534

76.1 (4.1) 

37.6% 

13.0% DM

6.5% CVD

5.0% CAD

1.4% Renal 

insufficiency

169.5/81.7 vs 

169.6/81.2

136.6/74

vs 142/76.5

% using drug:

Valsartan only: 56.1 vs 57.6 (P = 

ns)

Valsartan dose, mg: 91.2 vs 88.1 

(P =.0236)

CCB: 37.1 vs 36.4 (P = ns)

Diuretic: 13.0 vs 11.9 (P = ns)

β-B: 6.0 vs 5.0 (P = ns)

ACEI: 2.1 vs 2.5 (P = ns)

Wei, 201321

SBP < 140 vs < 150

4.0 years

Step 1: Monotherapy with enalapril 

10mg/d; bisoprolol 2.5-5 mg or metoprolol 

50-100 mg/d; amlodipine 5-10 mg/d; or 

indapamide 1.5-2.5 mg/d

Step 2: Add 1, 2, or 3 anti-hypertension 

drugs stepwise

Step 3: Increase dosage of antihypertension drugs

363 vs 361

76.6 (4.6) 

66% 

23.3% DM

6.6% CVD

158.8/83.7 vs 

160.3/84.8

135.7/76.2 vs

149.7/82.1

% using combination therapy: 

53.7 vs 39.1 (P < .01).

Abbreviations: α-B = alpha-blocker; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blockers; β-B = 

beta-blocker; BP = blood pressure; Cardio-Sis = Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica; C = comparator/control; CAD = coronary artery disease; 

CCB = calcium channel blocker; CI = confidence interval; CKD = chronic kidney disease; CVD = cerebrovascular disease; DBP = diastolic blood pressure; DM = diabetes mellitus; HOT = 

Hypertension Optimal Treatment; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; mg = milligram; MI = myocardial infarction; N/n = population 

size (total/sub); NR = not reported; ns = not statistically significant; OR = odds ratio; SBP = systolic blood pressure; SD = standard deviation; SPRINT = Systolic Blood Pressure Intervention Trial; 

SPS3 = Secondary Prevention of Small Subcortical Strokes; T = treatment; VALISH = Valsartan in Elderly Isolated Systolic Hypertension.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

23

Table 3. Characteristics of Trials that Compared More vs Less Intensive Antihypertensive Treatment

Study

BP goal (mm Hg)

Mean or median*

length of follow-up

Antihypertensive treatment 

strategies

Sample size, 

T vs C 

Age mean (SD) 

% Male

Comorbidities

% DM

% CAD

% CVD

Baseline 

SBP/DBP, 

T vs C 

Achieved 

SBP/DBP, 

T vs C

Mean number or % distribution of 

antihypertensive medications used, T vs C

ADVANCE, 200727

Goal NR

4.3 years

T: Perindopril + indapamide ± 

physician’s discretion

C: Placebo ± physician’s discretion

Not permitted: thiazide diuretics,

other ACEI 

5569 vs 5571

66 (6.5)

57% 

100% DM

12% CAD

9% CVD

145/81 vs

145/81

136/73 vs

140/73

% using drug (at end of follow-up):

Any BP lowering drug: 74 vs 83

Perindopril: 45 vs 55

Other ACEI: 5 vs 5

ARB: 10 vs 13

β-B: 31 vs 35

CCB: 32 vs 43

Thiazides: 3 vs 5

Other diuretics: 14 vs 16

BENEDICT-B, 

201128

≤ 120/80 mm Hg

4.5 years

T: VeraTran (Verapamil + 

trandolapril) ± physician’s 

discretion 

C: Trandolapril ± physician’s 

discretion

138 vs 143

62.3 (8.3) 

62.4% 

100% DM 149.5/86.3 

overall

141.0/81.6 vs

141.8/82.3

% using drug (on follow-up):

Any antihypertensive agent: 94.9 vs 92.3

Diuretic: 87.7 vs 84.6

β-B: 14.5 vs 16.1

CCB: 44.2 vs 50.3

Sympatholytic agent: 66.7 vs 69.9 

P = ns

EWPHE, 198529

≤ 160/90 mm Hg

4.7 years

T: Hydrochlorothiazide + 

triamterene ± methyldopa

C: Placebo

416 vs 424

72 (8.0)

69.8%

3.5% CAD

1.2% CVD

183/101 vs

182/101

148/85 vs

167/90

Used by % of treatment group in addition to 

active study medication: 

Methyldopa: 35%

FEVER, 200530

< 160/95 mm Hg

3.3 years

T: Felodipine ± physician’s 

discretion

C: Placebo ± physician’s discretion

4841 vs 4870

61.5 (7.2) 

61% 

12.8% DM

15.5% CAD

14.9% CVD 

158.7/92.4 vs

158.9/92.7

138.1/82.3 vs

141.6/83.9

Add-on medication used by % of group:

No add-on: 66.1 vs 57.7 (P < .001)

Diuretic: 12.6 vs 19.8 (P < .001)

β-B: 7.3 vs 8.8 (P = .008)

α-B: 0.2 vs 0.6 (P = .004)

ACEI: 16.8 vs 26.0 (P < .001)

ARB: 0.9 vs 1.1 (P = .325)

CCB: 12.1 vs 12.8 (P = .263)

Other antihypertensive medications: 5.5 vs 8.2 

(P < .001)
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

24

Study

BP goal (mm Hg)

Mean or median*

length of follow-up

Antihypertensive treatment 

strategies

Sample size, 

T vs C 

Age mean (SD) 

% Male

Comorbidities

% DM

% CAD

% CVD

Baseline 

SBP/DBP, 

T vs C 

Achieved 

SBP/DBP, 

T vs C

Mean number or % distribution of 

antihypertensive medications used, T vs C

HYVET, 20086

< 150/80 mm Hg

1.8* years

T: Indapamide ± perindopril

C: Placebo

Patients withdrawn from doubleblind follow-up if used additional 

antihypertensive agents for > 3 

months, or had received the 

maximum dose of the study drugs 

yet had SBP ≥ 220 mm Hg or DBP 

≥ 110 mm Hg on at least 2 

consecutive visits ≥ 2 weeks apart.

1933 vs 1912

83.5 (3.2) 

60.5% 

6.9% DM

3.2% CAD

6.8% CVD

173/90.8 vs

173/90.8

143.5/77.9 vs

158.5/84.0

% using drug or corresponding placebo (at 2-

year follow-up): 

Indapamide only: 25.8 vs 14.2 (corresponding 

placebo)

Indapamide + perindopril (2 mg): 23.9 vs 13.4 

(corresponding placebo)

Indapamide + perindopril (4 mg): 49.5 vs 71.8 

(corresponding placebo)

PROGRESS, 200131

Goal NR

3.9 years

T: Perindopril ± indapamide

C: Placebo

3051 vs 3054

64 (10.0)

70%

13% DM

100% CVD

147/86 vs

147/86

138/82 vs

147/86

% of treatment group assigned to use:

Perindopril only = 42%

Perindopril + Indapamide = 58%

RENAAL, 200132

< 140/90 mm Hg

3.4 years

T: Losartan ± physician’s 

discretion

C: Placebo ± physician’s discretion

Not permitted: ACEIs, ARBs

751 vs 762

60 (7.0)

63.2% 

100% DM

11% CAD

0.1% CVD

152/82 vs

153/82

140/74 vs

142/74

A mean of 3.5 different antihypertensive 

medications were used in addition to the 

randomized drug to achieve BP goal of 

< 140/90 mm Hg.

% using drug: 

CCB: 77.9 vs 81.1 

Diuretic: 83.8 vs 84.0

α-B: 40.2 vs 45.7

β-B: 34.1 vs 36.7

Centrally acting agent: 18.0 vs 21.7

SCOPE, 200333

< 160/85 mm Hg 

3.7 years

T: Candesartan ± physician’s 

discretion

C: Placebo ± physician’s discretion

Not permitted: ACEIs, ARBs 

2477 vs 2460

76.4 (NR) 

64.5% 

12% DM

4.5% CAD

3.9% CVD

166.0/90.3 vs

166.5/90.4

145.2/79.9 vs

148.5/81.6

% using drug: 

Study drug only: 25 vs 16

Study drug + hydrochlorothiazide: 26 vs 18

Add-on treatment: 49 vs 66

Diuretic: 33 vs 44

β-B: 17 vs 26

CCB: 18 vs 28

ACEI: 8 vs 11

ARB: 3 vs 4
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

25

Study

BP goal (mm Hg)

Mean or median*

length of follow-up

Antihypertensive treatment 

strategies

Sample size, 

T vs C 

Age mean (SD) 

% Male

Comorbidities

% DM

% CAD

% CVD

Baseline 

SBP/DBP, 

T vs C 

Achieved 

SBP/DBP, 

T vs C

Mean number or % distribution of 

antihypertensive medications used, T vs C

SHEP, 19918

SBP < 160 mm Hg or 

reduction of ≥ 20 mm 

Hga

4.5 years

T: Chlorthalidone ± atenolol or 

reserpine 

C: Placebo

Upper BP threshold above which 

active treatment indicated in 

placebo arm (escape criteria): SBP 

> 240 mm Hg or DBP > 115 mm 

Hg at a single visit, or sustained 

SBP > 220 mm Hg or DBP > 90 

mm Hg.

2365 vs 2371

71.6 (6.7) 

64.5% 

10.1% DM

4.9% CAD

1.4% CVD

170.5/76.7 vs

170.1/76.4

143/68 vs

155/72

0 (No active drug): 9% vs 53%

1: Chlorthalidone: 46% of treatment group

2: Chlorthalidone + atenolol: 23% of 

treatment group

Other active medication: 21% of treatment 

group

% meeting escape criteria: 3 vs 15

% prescribed active hypertensive therapy in 

placebo group: 13% at year 1, 33% at year 3, 

44% at year 5 

STONE, 199619

140-159/< 90 mm Hg 

2.5 years

T: Nifedipene ± captopril ± 

dihydrochlorothiazide C: Placebo

Upper BP threshold above which 

active treatment (captopril ± 

dihydrochlorothiazide) indicated in 

placebo arm: SBP ≥ 200 mm Hg or 

DBP ≥ 110 mm Hg at 2 subsequent 

follow-ups. 

815 vs 817

66.4 (5.3) 

46.8% 

NR 168/99 vs

168/97

146.9/85.0 vs

156.2/89.3

0: 98.8% of placebo

1: Nifedipene only was used by 99.1% of 

treatment group

Syst-China, 200020

SBP < 150 mm Hg 

(reduction of ≥ 20 

mm Hg)

3.0* years

T: Nitrendipine ± captopril ±

hydrochlorothiazide

C: Placebo

1253 vs 1141

66.5 (5.5) 

65.5% 

4.1% DM

11.2% CVD

170.5/86.0 

overall,

T vs C NR

150.5/81 vs

159.5/84

1: Nitrendipine only: 72.3% vs 57.0% 

(corresponding placebo)

2+: Combination of nitrendipine ± captopril ± 

hydrochlorothiazide: 20.0% vs 32.9% 

(corresponding placebo)
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

26

Study

BP goal (mm Hg)

Mean or median*

length of follow-up

Antihypertensive treatment 

strategies

Sample size, 

T vs C 

Age mean (SD) 

% Male

Comorbidities

% DM

% CAD

% CVD

Baseline 

SBP/DBP, 

T vs C 

Achieved 

SBP/DBP, 

T vs C

Mean number or % distribution of 

antihypertensive medications used, T vs C

Syst-Eur, 201434

SBP < 150 mm Hg 

(reduction of ≥ 20 

mm Hg)

2.0* years

T: Nitrendipine ± enalapril ± 

hydrochlorothiazide 

C: Placebo

2297 vs 2398

70.25 (6.7) 

33.2% 

10.5% DM

29.8% CAD

173.8 vs 85.5 

overall,

P = ns for T vs

C 

NR 0: 14.9% of placebo 

1: 55.0% of treatment

2: 26.1% of treatment

3: 16.4% of treatment

% using drug or corresponding placebo (at 2-

year follow-up):

Nitrendipine: 84.4 vs 92.4 (corresponding 

placebo)

Enalapril: 32.6 vs 55.1 (corresponding 

placebo)

Hydrochlorothiazide: 16.2 vs 34.2 

(corresponding placebo)

% of patients started on multiple drug 

treatment or proceeding to open follow-up 

increased faster in the placebo group than 

active treatment group (P < .001)

TRANSCEND, 

200835

Goal NR

4.7* years

T: Telmisartan ± physician’s 

discretion

C: Placebo ± physician’s discretion

2954 vs 2972

66.9 (7.4) 

57% 

35.7% DM

74.5% CAD

22% CVD

140.7/81.8 vs

141.3/82.0

NR % using drug: 

Non-study ARB: 5.8 vs 7.6 (P = NR) 

Diuretic: 33.7 vs 40.0 (P < .0001) 

CCB: 38.0 vs 45.9 (P < .0001)

β-B: 56.6 vs 59.0 (P = .081)

α-B: 5.3 vs 7.5 (P = .002) 

Abbreviations: α-B = alpha-blocker; β-B = beta-blocker; ACEI = Angiotensin converting enzyme inhibitor; ADVANCE = Action in Diabetes and Vascular Disease; ARB = 

Angiotensin II receptor blockers; BENEDICT-B = Bergamo Nephrologic Diabetes Complications Trial-B; BP = blood pressure; C = control/comparator; CAD = Coronary artery 

disease; CCB = calcium channel blocker; CVD = Cerebrovascular disease; DBP = Diastolic blood pressure; DM = diabetes mellitus; EWPHE = European Working Party on High 

Blood Pressure in the Elderly; FEVER = Felodipine Event Reduction Study; HYVET = Hypertension in the Very Elderly Trial; NR = not reported; ns = not statistically significant; 

PROGRESS = Perindopril Protection Against Recurrent Stroke Study; RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; SBP = 

Systolic blood pressure; SCOPE = Study on Cognition and Prognosis in the Elderly; SD = standard deviation; SHEP = Systolic Hypertension in the Elderly Program; STONE = 

Shanghai Trial of Nifedipine in the Elderly; Syst-China = Systolic Hypertension in China; Syst-Eur = Systolic Hypertension in Europe; T = treatment; TRANSCEND = 

Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease.

a

For individuals with SBP ≥180 mm Hg, the goal was < 160 mm Hg; for those with SBP 160-179 mm Hg, the goal was an SBP reduction of ≥ 20 mm Hg.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

27

Detailed Study Results

All Studies

We found varied results across the 21 included studies, but overall more intensive blood pressure 

treatment was associated with significant reductions in mortality, major cardiac events, and 

stroke. However, the marked differences among the studies in their baseline, intended, and 

achieved blood pressures make it difficult to interpret pooled estimates of all results. Rather, we 

present analyses according to achieved blood pressure, baseline blood pressure, and then focus 

on those trials which explicitly compared blood pressure treatment targets. Medication choice 

varied widely among studies but we found no discernible pattern of antihypertensive choice on 

treatment effects.

There were 3 trials with almost no difference in achieved blood pressure between intervention 

and control groups (mean difference SBP < 3 mm Hg).28,32,35 Another 3 trials rated as high risk 

of bias had significant methodologic flaws threatening the validity of their results.

19-21 We 

conducted sensitivity analyses with and without these studies. One of the studies with high risk 

of bias was a treat-to-target trial.21 The exclusion of this study lowered absolute effect sizes 

modestly. Otherwise, these sensitivity analyses did not dramatically alter results, but did reduce 

heterogeneity. In the following sections we present analyses without these 6 studies. Additional 

analyses are summarized in Appendix D.

Of the remaining 15 studies presented in the following analyses, relatively few individual studies 

found statistically significant treatment effects (mortality in 4 studies; stroke in 5 studies; cardiac 

events in 7 studies). 

Studies Grouped by Achieved Blood Pressure

We performed meta-analyses separately grouping studies with achieved SBP ≥ 140 mm Hg and

studies with achieved SBP < 140 mm Hg (Figures 2 to 4). We found similar relative treatment 

effects for mortality (RR 0.91, 95% Confidence Interval [CI] 0.84 to 0.99, number needed to 

treat [NNT] 105; I

2 = 0% for SBP ≥ 140, and RR 0.88, 95% CI 0.81 to 0.96, NNT 91; I2 = 18.4%

for SBP < 140 mm Hg). We found similar relative treatment effects, but slightly larger absolute 

effects on major cardiac outcomes among studies achieving higher blood pressure (RR 0.78, 

95% CI 0.68 to 0.93, NNT 74; I

2 = 35.9% for SBP ≥ 140) than among those achieving lower 

blood pressure (RR 0.82, 95% CI 0.72 to 0.91, NNT 108; I

2 = 2.1%). There was a more 

consistent and slightly larger relative treatment effect on stroke among studies achieving SBP ≥

140 (RR 0.72, 95% CI 0.62 to 0.82, NNT 76; I

2 = 0%) than among studies achieving SBP < 140 

mm Hg (RR 0.80, 95% CI 0.70 to 0.90, NNT 78; I

2 = 36.5%). 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

28

Figure 2. Relative risk of mortality stratified by mean achieved SBP, combining trials by achieved 

mean SBP ≥ 140 or < 140 mm Hg in the intervention group

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular 

Disease; Cardio-Sis = Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica; 

CI = confidence interval; EWPHE = European Working Party on High Blood Pressure in the Elderly; FEVER = 

Felodipine Event Reduction Study; HOT = Hypertension Optimal Treatment; HYVET = Hypertension in the Very 

Elderly Trial; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; 

PROGRESS = Perindopril Protection Against Recurrent Stroke Study; SBP = systolic blood pressure; SCOPE = 

Study on Cognition and Prognosis in the Elderly; SHEP = Systolic Hypertension in the Elderly Program; SPRINT = 

Systolic Blood Pressure Intervention Trial; SPS3 = Secondary Prevention of Small Subcortical Strokes; Syst-Eur = 

Systolic Hypertension in Europe; VALISH = Valsartan in Elderly Isolated Systolic Hypertension
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

29

Figure 3. Relative risk of stroke stratified by mean achieved SBP, combining trials by achieved 

mean SBP ≥ 140 or < 140 mm Hg in the intervention group

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular 

Disease; Cardio-Sis = Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica; 

CI = confidence interval; EWPHE = European Working Party on High Blood Pressure in the Elderly; FEVER = 

Felodipine Event Reduction Study; HOT = Hypertension Optimal Treatment; HYVET = Hypertension in the Very 

Elderly Trial; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; 

PROGRESS = Perindopril Protection Against Recurrent Stroke Study; SBP = systolic blood pressure; SCOPE = 

Study on Cognition and Prognosis in the Elderly; SHEP = Systolic Hypertension in the Elderly Program; SPRINT = 

Systolic Blood Pressure Intervention Trial; SPS3 = Secondary Prevention of Small Subcortical Strokes; Syst-Eur = 

Systolic Hypertension in Europe; VALISH = Valsartan in Elderly Isolated Systolic Hypertension
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

30

Figure 4. Relative risk of major cardiac events stratified by mean achieved SBP, combining trials 

by achieved mean SBP ≥ 140 or < 140 mm Hg in the intervention group

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular 

Disease; Cardio-Sis = Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica; 

CI = confidence interval; EWPHE = European Working Party on High Blood Pressure in the Elderly; FEVER = 

Felodipine Event Reduction Study; HOT = Hypertension Optimal Treatment; HYVET = Hypertension in the Very 

Elderly Trial; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; 

PROGRESS = Perindopril Protection Against Recurrent Stroke Study; SBP = systolic blood pressure; SCOPE = 

Study on Cognition and Prognosis in the Elderly; SHEP = Systolic Hypertension in the Elderly Program; SPRINT = 

Systolic Blood Pressure Intervention Trial; SPS3 = Secondary Prevention of Small Subcortical Strokes; Syst-Eur = 

Systolic Hypertension in Europe; VALISH = Valsartan in Elderly Isolated Systolic Hypertension
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

31

Studies Grouped by Baseline Blood Pressure

To better understand the evidence regarding the thresholds at which to start or intensify blood 

pressure treatment, we analyzed studies according to baseline blood pressure. Nine studies had

higher baseline blood pressures (SBP ≥ 160 mm Hg) including all the studies achieving SBP ≥

140 mm Hg plus 3 studies which achieved lower blood pressures.

23,24,26 Intensive blood pressure 

treatment had a more consistent and greater absolute effect on mortality (RR 0.90, 95% CI 0.83

to 0.98, NNT 61, I

2 = 0%), stroke (RR 0.74, 95% CI 0.65 to 0.84, NNT 89, I2 = 0%), and cardiac

events (RR 0.77, 95% CI 0.68 to 0.89, NNT 80, I

2 = 3.2%) in studies of patients with higher 

baseline blood pressures than in studies of patients with lower baseline blood pressures 

(mortality RR 0.85, 95% CI 0.72 to 0.99, NNT 118, I

2 = 53.1%), stroke (RR 0.80, 95% CI 0.62 

to 1.01, NNT = 159, I

2 =67%), and cardiac events (RR 0.86, 95% CI 0.72 to 0.96, NNT 148, I2 =

40.6%) (Figure 5). The subgroup with lower baseline blood pressures did not include the 2 trials 

of patients with prior stroke.

25,31
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

32

Figure 5. Relative risk of death, stroke, and cardiac events, combining trials by mean baseline SBP 

≥ 160 or < 160 mm Hg 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

33

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular 

Disease; Cardio-Sis = Studio Italiano Sugli Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica; 

CI = confidence interval; EWPHE = European Working Party on High Blood Pressure in the Elderly; FEVER = 

Felodipine Event Reduction Study; HOT = Hypertension Optimal Treatment; HYVET = Hypertension in the Very 

Elderly Trial; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; 

RR = relative risk; SBP = systolic blood pressure; SCOPE = Study on Cognition and Prognosis in the Elderly; SHEP 

= Systolic Hypertension in the Elderly Program; SPRINT = Systolic Blood Pressure Intervention Trial; Syst-Eur = 

Systolic Hypertension in Europe; VALISH = Valsartan in Elderly Isolated Systolic Hypertension.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

34

Studies Comparing Blood Pressure Treatment Targets

The studies that most directly address the controversy of strict versus more moderate blood 

pressure control are those that compared treatment targets. We found 8 trials comparing lower 

and higher blood pressure treatment targets (Table 2). One of these trials, which included only 

patients with prior stroke, is discussed in the next section and is not included in the analyses in 

this section.25 As mentioned previously, another small study with dramatically higher mortality 

rates had high risk of bias;

21 we present the sensitivity analyses without this study here but 

additional analysis results are available in Appendix D. The 6 remaining treat-to-target studies 

evaluated a total of 32,312 patients and were all low risk of bias. 

The largest study, the Hypertension Optimal Treatment (HOT) trial (N = 18,790), evaluated DBP 

targets while the remaining 5 studies examined SBP targets of ≤ 140 mm Hg in the more

intensive control arm. Two of these 5 studies targeted SBP < 140 mm Hg in the more intensive 

treatment arm,

24,26 while the remaining 3 used lower SBP targets (< 120 mm Hg11,22 and < 130 

mm Hg23) for the intensive treatment arm. Among the trials specifying initial therapy, 2 used 

calcium channel blockers,

17,24

one used an angiotensin II receptor blocker,

26 and 2 used a thiazide 

diuretic in combination with another medication.

11,22 All trials allowed use of the same 4 core 

antihypertensive drug classes for additional therapy (renin angiotensin system blockade, thiazide 

diuretics, calcium channel blockers, and beta-blockers). Again, we did not find a consistent 

pattern of effects according to choice of first-line antihypertensive therapy.

Taken together, these studies show that blood pressure treatment targets of SBP ≤ 140 mm Hg or 

lower are associated with a non-significant trend toward lower mortality, and have a marginally 

significant effect on lowering stroke and major cardiac events (Figure 6). These are large trials 

with low risk of bias, and the meta-analyses suggest acceptable levels of statistical heterogeneity.

Nevertheless, the evidence for mortality and cardiac events should be considered low strength 

because there are important inconsistencies in results, substantial variation in results in different 

sensitivity analyses, and because the results are imprecise with relatively wide confidence 

intervals around the summary estimates encompassing both the possibility of marked risk 

reduction and no effect. For the outcome of stroke, the direction and magnitude of effect was 

more consistent across analyses and, therefore, the strength of evidence for this outcome should 

be considered moderate.

We found that the absolute treatment effects varied in our sensitivity analyses. The most 

pronounced differences involved analyses with the HOT trial.17 The HOT trial was by far the 

largest and in some ways the most difficult to assess both because it assessed DBT targets, and 

because it included 3 arms each with over 6,000 patients. In the analyses in Figure 6, we grouped 

the 2 HOT arms with DBP targets of ≤ 85 mm Hg or less together because this was the most 

relevant comparison when considering current guidelines. The numbers needed to treat over 2 to 

5 years to prevent one event were 125 (mortality), 204 (stroke), and 106 (major cardiac events).

However, the achieved SBP in the group assigned to a DBP target of ≤ 85 mm Hg was > 140 

mm Hg (141.4 mm Hg), while the achieved SBP in the group assigned to a target ≤ 80 mm Hg

was 139.7 mm Hg. When we excluded this middle group (DBT target of ≤ 85 mm Hg) from our 

analyses, we found substantially higher NNT (263 for mortality, 286 for stroke, and 238 for 

major cardiac events).

The Systolic Blood Pressure Intervention Trial (SPRINT)

11 and ACCORD22 trials are different 

than the other treat-to-target trials both because of the aggressive intervention group SBP target 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

35

of < 120 mm Hg, and because the mean baseline SBP was just under 140 mm Hg. Both trials 

enrolled patients with high cardiovascular risk, but excluded patients on more than 3 

antihypertensive medications at baseline. There are several important differences between these 

2 studies: 1) ACCORD included only diabetic patients while SPRINT excluded diabetic patients, 

2) ACCORD mostly excluded patients ≥ 80 years, and therefore had a population slightly 

younger than SPRINT (mean age 62 vs 68 years), and 3) the SPRINT trial was stopped early for 

benefit and consequently had a shorter mean duration of follow-up (3.3 vs 4.7 years). Of note, 

the proportion of control group participants experiencing each outcome was higher in ACCORD 

than in SPRINT. As Figure 5 shows, intensive treatment did not reduce mortality or cardiac 

events in ACCORD, but did reduce the risk of stroke. On the other hand, intensive treatment 

reduced both mortality and cardiac events in SPRINT, but not stroke risk. 

When we removed the SPRINT trial in additional sensitivity analyses, effects on mortality (RR 

0.96, 95% CI 0.80 to 1.15, I

2 = 0%) and cardiac events (RR 0.88, 95% CI 0.74 to 1.04, I2 = 4.0%) 

were no longer significant but effects on stroke remained largely unchanged (RR 0.74, 95% CI 

0.56 to 0.99, NNT 182, I

2 = 25.8%).

Of note, there were marked differences in event rates among the studies. The SPRINT and 

ACCORD trials each enrolled patients with higher cardiovascular risk profiles and, not 

surprisingly, had higher mortality and cardiac event rates than the other 4 trials. On the other 

hand, the stroke event rates were more similar among the trials. It is not clear whether 

differences in event rates entirely explain the nonsignificant mortality reduction since the 

inconsistency in findings does not clearly follow event rate patterns. For instance, ACCORD and 

SPRINT have similar event rates but different findings.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

36

Figure 6. Relative risk of death, stroke, and cardiac events in trials in which the intervention arm 

had an SBP target < 140 mm Hg or DBP ≤ 85 mm Hg, and the control arm had a less strict blood 

pressure target

ACCORD = Action to Control Cardiovascular Risk in Diabetes; C = control; Cardio-Sis = Studio Italiano Sugli 

Effetti Cardiovascolari del Controllo della Pressione Arteriosa Sistolica; CI = confidence interval; DBP = diastolic 

blood pressure; HOT = Hypertension Optimal Treatment; JATOS = Japanese Trial to Assess Optimal Systolic 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

37

Blood Pressure in Elderly Hypertensive Patients; RR = relative risk; SBP = systolic blood pressure; T = treatment; 

VALISH = Valsartan in Elderly Isolated Systolic Hypertension
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

38

Treatment Effects According to DBP

It is difficult to determine whether the treatment effects of blood pressure lowering are mediated 

through impact on SBP or DBP, or both. The majority of evidence applies most closely to the 

treatment of SBP. In 15 trials, patients had isolated systolic hypertension (ie, SBP > 140 mm Hg

with DBP 90 mm Hg). There were no trials in which patients had isolated diastolic 

hypertension with mean DBP > 90 mm Hg and mean SBP < 140 mm Hg. 

The HOT trial is most directly relevant as it enrolled patients with high DBP (> 100 mm Hg) and 

compared, as described above, the effects of 3 DBP targets (≤ 80 vs ≤ 85 vs ≤ 90 mm Hg).17

Compared to patients assigned to the ≤ 90 mm Hg target, patients assigned to lower DBP targets 

experienced a reduced risk of cardiac events (RR 0.92, 95% CI 0.42 to 0.92), but not of stroke 

(RR 0.74, 95% CI 0.4 to 1.36) or mortality (RR 0.77, 95% CI 0.48 to 1.21). Of note, the mean 

achieved DBP was substantially less than 90 mm Hg in all 3 groups (81.1, 83.2, and 85.2 mm

Hg, respectively) and patients also had marked systolic hypertension at baseline (mean baseline 

SBP 170 mm Hg). 

There were 6 trials with baseline DBP > 90 mm Hg.

6,17,19,29,30,33 One of the trials had high risk of 

bias.19 In 4 of the other 5 trials, the baseline SBP was ≥ 160 mm Hg and in the other trial the 

mean baseline SBP was 158.8 mm Hg.

30 The achieved DBP was < 90 mm Hg in all trials. In 4 of 

the 5 trials, there was a significant reduction in at least one of our outcomes of interest (in the 

other, there was a nearly significant reduction in stroke risk).33 

Overall, patients with DBP > 90 mm Hg appear to benefit from blood pressure-lowering 

treatment, but these patient populations also had marked moderate to severe systolic 

hypertension at baseline. There was no evidence to assess whether treatment of diastolic 

hypertension in the absence of systolic hypertension is beneficial. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

39

KEY QUESTION 1B: In patients who have suffered a TIA or stroke, 

does treatment of blood pressure to specific targets affect outcomes?

Two trials included in this review limited their patient populations to adults with prior history of 

cerebrovascular accident (stroke or TIA).25,31 The Secondary Prevention of Small Subcortical 

Strokes (SPS3) trial evaluated potential benefit of SBP < 130 mm Hg versus 130 to 149 mm Hg 

as secondary stroke prevention for 3,020 adults over age 30 (mean age 63 years). This study 

included patients with magnetic resonance imaging (MRI)-confirmed lacunar stroke, but 

excluded those with prior intracranial hemorrhage, severely disabling strokes, and cortical 

ischemic stroke.

25 The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) 

included 6,105 adults over age 26 (mean age 64 years) with history of ischemic or hemorrhagic 

stroke, or TIA.

31 Participants were randomized to placebo or active treatment including an ACE 

inhibitor to which a diuretic could be added at the discretion of the treating physician. The 

achieved SBP in the treatment group ranged from 135 to 138 mm Hg (depending on receipt of 

single or dual therapy). 

Pooled analysis of data from these 2 trials showed more intensive versus less intensive blood 

pressure management decreased the risk of recurrent stroke (RR 0.76, 95% CI 0.66 to 0.92, NNT 

33, I

2 = 0%), but not cardiac events (RR 0.78, 95% CI 0.61-1.08) or mortality (RR 0.96, 95% CI 

0.86 to 1.12) (Figure 7 and Appendix D). Of note, the results from these trials do not apply to the 

management of acute stroke. 

Figure 7. Relative risk of stroke in trials of patients with history of stroke 

CI = confidence interval; PROGRESS = Perindopril Protection Against Recurrent Stroke Study; SPS3 = Secondary 

Prevention of Small Subcortical Strokes
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

40

KEY QUESTION 2: How does age modify the benefits of differing 

blood pressure targets?

Overview of Results 

Twelve of the 21 included trials conducted age-stratified analyses (Table 4). We found no 

evidence that age modifies treatment effects: 12 trials found no age-treatment interactions on 

health outcome effects, and 3 trials found that the rate of harms from more intensive treatment 

was similar in those age ≥ 75 years and < 75 years.

Detailed Results

We conducted meta-analyses according to mean age and found similar results in studies with 

mean age 70 and < 70 for mortality (mean age ≥ 70: RR 0.91, 95% CI 0.84 to 0.99, NNT 133, 

I

2 = 0%; mean age < 70: RR 0.86, 95% CI 0.75 to 0.95, NNT 76, I2 = 39.4%); stroke (mean age ≥ 

70: RR 0.75, 95% CI 0.66 to 0.86, NNT 101, I

2 = 0%; mean age < 70: RR 0.76, 95% CI 0.66 to 

0.86, NNT 68, I

2 = 42.6%); and cardiac events (mean age ≥ 70: RR 0.79, 95% CI 0.69 to 0.94, 

NNT 101, I

2 = 0%; mean age < 70: RR 0.82, 95% CI 0.71 to 0.90, NNT 68, I2 = 42.6%). 

However, we mainly did these analyses to ensure that our findings were not disproportionately 

driven by studies with lower mean age populations which may have included substantial 

proportions of patients over age 60. Because of concerns for ecologic fallacy, these analyses 

cannot reliably estimate age-treatment effects. Rather, we summarize analyses from studies 

which specifically examined age-treatment interactions. 

Of the 12 trials that provided analyses by age subgroups, 5 randomized patients to different 

blood pressure targets,17,22,24-26 and 6 randomized patients to more versus less antihypertensive 

therapy.6,8,20,27,34,35 All of these studies were considered low risk of bias with the exception of one 

study that used insufficient methods for randomization and allocation concealment.20 Seven 

studies provided age analyses which differentiated adults over age 70 from their younger peers; 

these analyses were generally for adults ages greater or less than 75 years,

24,26 or by age bands 

which included age ≥ 70 as compared to younger patients.8,35,36 The remaining 5 studies provided 

analyses by age greater or less than 65 years.

20,26,27,37-39 Given that we limited our review to 

studies with mean population over age 60, these analyses could not meaningfully address our 

question about the role that advancing age may play in mitigating or modifying the benefits of 

differing blood pressure targets. 

Results were mixed among the 7 studies which performed age-specific analyses for adults ages ≥

70. The Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive 

Patients (JATOS) described an increased risk of cardiovascular disease, cerebrovascular disease, 

and renal failure when SBP was targeted to be < 140 mm Hg for adults age ≥ 75 but this increase 

in risk was not demonstrated among their younger peers.24 Conversely, in the SHEP trial in 

which the patient population had a mean SBP of 170 mm Hg, the decreased risk of stroke 

associated with achieving SBP was < 150 mm Hg was seen in adults over age 70 but not in their 

younger counterparts.8

In the SPRINT trial, participants assigned to an SBP target of < 120 mm Hg experienced a 

reduction in cardiac events and there was no significant interaction between age and treatment.

11

This reduction was marginally significant in those under age 75, but statistically significant in 

the subgroup over age 75, likely because of the substantially higher event rates in this group. The 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

41

Hypertension in the Very Elderly Trial (HYVET) examined the benefit of blood pressure control 

among adults aged 80 to 84 years versus aged ≥ 85 years, and demonstrated decreased risk of 

cardiovascular mortality and stroke for both age groups, but unclear benefit among those aged ≥

85 on risk of cardiac events and all-cause mortality.36 Similarly, in the VALISH study, there was 

no significant difference in a composite cardiac event outcome for adults older and younger than 

75 years.

26 Age-specific results for the Syst-Eur trial are difficult to interpret because they are 

presented as unadjusted hazard ratios without 95% confidence intervals,40 and the Telmisartan 

Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease

(TRANSCEND) trial reported only a non-significant P-value of 0.8 for interaction by age.35
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

42

Table 4. Effects of Age on Outcomes in Trials that Conducted Age-Stratified Analyses 

Direction of association

Study

Comparison, T vs C 

Age stratification 

Findings

Beneficial effects decrease 

with age

JATOS24

SBP < 140 vs < 160 mm Hg

Age: < 75, ≥ 75

Significant age-treatment interaction: benefit of treatment on stroke, 

cardiac events, and renal failure was limited to those < 75 years old.

SPS339

SBP < 130 vs 130-149 mm Hg

Age: < 75, ≥ 75

Benefit of treatment on recurrent stroke was limited to those < 75 years

old.

Syst-China20

(Nitrendipine ± captopril ± hydrochlorothiazide) vs

placebo

Age: < 65, 65-69, ≥ 70

Benefit of treatment on cardiac events and cardiovascular death was 

limited to those < 65 years old.

Syst-Eur40

(Nitrendipine ± enalapril ± hydrochlorothiazide) vs

placebo

Age: 60-69, 70-79, ≥ 80

Significant age-treatment interaction: benefit of treatment on mortality 

(all-cause and cardiovascular) and stroke was limited to those < 80 years

old.

Beneficial effects increase with 

age

SHEP8

(Chlorthalidone ± atenolol or reserpine) vs placebo

Age: 60-69, 70-79, ≥ 80

Benefit of treatment on stroke was limited to those aged ≥ 70 years old.

SPS339

SBP < 130 vs 130-149 mm Hg

Age: < 75, ≥ 75

Benefit of treatment on vascular death was limited to those aged ≥ 75 

years old. 

No change in effect with age ACCORD37

SBP < 120 vs < 140 mm Hg

Age: < 65, ≥ 65

Effects of treatment were similar across age groups on composite 

endpoint (nonfatal MI, nonfatal stroke, or cardiovascular death).

ADVANCE27

(Perindopril + indapamide) vs placebo

Age: < 65, ≥ 65

Effects of treatment were similar across age groups on combined 

macrovascular and microvascular events: total death, coronary events, 

cerebrovascular events, renal events, and eye events (retinopathy and 

visual deterioration)

HOT38

DBP ≤ 80 vs ≤ 85 vs ≤ 90 mm Hg

Age: < 65, ≥ 65

Effects of treatment on total death, cardiovascular death, MI/cardiac 

events, and stroke were similar across age groups

HYVET36

(Indapamide ± perindopril) vs placebo

Age: 80-84, ≥ 85

Effects of treatment on total death, cardiovascular death, MI/cardiac 

events, and stroke were similar across age groups.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

43

Direction of association

Study

Comparison, T vs C 

Age stratification 

Findings

SPRINT11

SBP < 120 vs 140 mm Hg

Age < 75, ≥ 75 

Benefit of treatment on composite outcome (MI, other acute coronary 

syndromes, stroke, heart failure, or cardiovascular death) increased from 

marginally to statistically significant in aged ≥ 75 years old, but agetreatment interaction was not significant.

SPS339

SBP < 130 vs 130-149 mm Hg

Age: < 75, ≥ 75

Effects of treatment on MI and total mortality were similar across age 

groups. 

TRANSCEND35

Telmisartan vs placebo

Age: < 65, 65-74, ≥ 75

Effects of treatment were similar across age groups on composite 

endpoint (cardiovascular death, MI, or stroke). 

VALISH26

SBP < 140 vs < 150 mm Hg

Age: < 75, ≥ 75

Effects of treatment were similar across age groups on composite 

endpoint: sudden death, fatal and nonfatal stroke, fatal and nonfatal 

myocardial infarction, heart failure death, other cardiovascular death, 

unplanned hospitalization because of cardiovascular diseases, renal 

dysfunction (doubling of serum creatinine and creatinine, or introduction 

of dialysis).

Abbreviations: ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease; C = comparator/control; 

DBP = diastolic blood pressure; HOT = Hypertension Optimal Treatment; HYVET = Hypertension in the Very Elderly Trial; JATOS = Japanese Trial to Assess 

Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MI = myocardial infarction; SBP = systolic blood pressure; SHEP = Systolic Hypertension in 

the Elderly Program; SPRINT = Systolic Blood Pressure Intervention Trial; SPS3 = Secondary Prevention of Small Subcortical Strokes; Syst-China = Systolic 

Hypertension in China; Syst-Eur = Systolic Hypertension in Europe; T = treatment; TRANSCEND = Telmisartan Randomized Assessment Study in ACE 

Intolerant Subjects with Cardiovascular Disease; VALISH = Valsartan in Elderly Isolated Systolic Hypertension.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

44

KEY QUESTION 3: How does the patient burden of comorbidities 

modify the benefits of differing blood pressure targets?

Comorbidity Burden

No studies examined how comorbidity burden modifies blood pressure treatment effects. 

Of note, it is likely that patients with a high burden of comorbidity were not included in the 

overall group of studies. Table 5 details the types of comorbidity that were excluded from each 

trial. Fourteen trials excluded patients with heart failure, 11 excluded patients with recent cardiac 

events, 17 excluded patients based on abnormal renal function criteria, 12 trials excluded patients 

with malignancy or other life-limiting illness, and 15 studies used criteria that would implicitly 

or explicitly exclude patients with dementia and/or diminished functional status.

Cardiovascular Risk 

We found subgroup analyses from 4 trials which examined whether treatment effects varied 

according to cardiovascular risk profile.41-43 These studies provide low-strength evidence that 

there may be greater absolute treatment effects amongst patients with high cardiovascular risk 

though relative treatment effects are similar across risk groups. Confidence in these conclusions 

is tempered by the post hoc nature of some of these analyses, the small number of studies, and 

variation in the outcomes contributing to these findings. 

One substudy of SHEP reported outcomes according to quartiles of cardiovascular risk based on 

the Multiple Risk Factor Assessment Equation.43 The number needed to treat for one year to 

prevent a major cardiac event (myocardial infarction, stroke, or heart failure) ranged from 160 in 

the lowest risk group to 37 in the highest risk group. A reduction in heart failure incidence 

appeared to be the major contributor to these findings, while findings for stroke and myocardial 

infarction were not significant for most of the subgroups.

A substudy grouped participants in the ADVANCE trial into moderate-high and very high 5-year 

cardiovascular risk according to the Framingham Anderson equation.41 Similar to the SHEP 

substudy, these authors found that relative risks remained similar across subgroups (and were 

often non- or marginally significant), but absolute risk reductions were higher in the very high 

cardiovascular risk group. For example, the absolute risk reduction for total coronary events was 

0.5% in the moderate-high risk group but 2.0% in the very high risk group.

An analysis of the HOT trial similarly grouped participants into medium-high and very high 

cardiovascular risk according to a World Health Organization (WHO) risk tool.42 This study did 

not report absolute event rates and found no significant relative risk reduction in either risk group 

for any outcome, except for myocardial infarction in which there was a significant reduction in 

the higher risk group (RR 0.77, 95% CI 0.62 to 0.96) but not in the moderate risk group (RR 

0.99, 95% CI 0.76 to 1.29).

In the SPRINT trial, the cardiac event risk reduction was actually greater in those without a 

history of cardiovascular disease (RR 0.71, 95% CI 0.57 to 0.88 vs RR 0.83, 95% CI 0.62 to 

1.09) or chronic kidney disease (RR 0.70, 95% CI 0.56 to 0.87 vs RR 0.82, 95% CI 0.63 to 1.07), 

though the comorbidity-treatment interactions were not significant.11
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

45

Table 5. Patient characteristics used to determine eligibility or exclusion from trial enrollment 

Trial; Age 

mean (SD) Diabetes status Chronic Kidney Disease Heart failure (HF)

Criteria likely to exclude those 

with dementia or diminished 

functional status*

Comorbidity

ACCORD22

62.2 (6.9) years

T2 DM required for 

inclusion; T1 DM 

excluded

Excluded (Creatinine

 > 1.5 mg/dL)

-Men eGFR no < 45 

-Women eGFR no < 33 

Excluded symptomatic 

HF (NYHA III or IV)

-Excluded for any factors likely to 

limit adherence to intervention

-Excluded those living in SNF

Excluded for: BMI > 45, LFTs > 2 times the 

upper limit normal limit, cardiac 

event/procedure within 3 months, or “any 

condition likely to limit survival to < 3 years or 

malignancy” (exclude non-melanoma skin 

cancer)

ADVANCE27

66 (6) years

T2-DM diagnosis

age ≥ 30 required 

for inclusion. 

Excluded if “definite 

indication for longterm insulin therapy 

at study entry.”

--- --- --- Excluded if definite indication for ACEI not met 

by perindopril 2 mg or 4 mg.

BENEDICTB28

62.3 (8.3) years

--- Excluded for creatinine

 > 1.5; non-DM renal 

disease; or history of 

kidney transplant

-Men no eGFR < 46 

-Women no eGFR < 34 

Excluded for HF 

(NYHA III or IV)

Excluded for “any major clinical 

condition that may jeopardize 

study participation.”

Excluded for: history of CVA, AMI, TIA, 

unstable angina, cancer, “systemic disease,” 

severe hematologic or liver disorder, 

malabsorption, valvular disease or heart block.

CARDIO-SIS23

67 (7) years

DM excluded Excluded (Creatinine > 2 

mg/dL)

-Men eGFR no < 33 

-Women eGFR no < 24 

Unclear 

-LVH and valvular 

heart disease excluded

--- Excluded for: diabetes, atrial fibrillation/flutter, 

“clinically significant hepatic or hematologic 

disorder, alcoholism or drug addiction, valvular 

heart disease, LVH (or other confounders to 

EKG interpretation), or any disease causing 

reduced life expectancy”

EWPHE29

72 (8) years

Excluded DM 

requiring insulin 

therapy

Creatinine ≥ 2.5 mg/dL

-Men eGFR no < 25 

-Women no eGFR < 19

Excluded for HF Inability to achieve a sitting 

position

Excluded for: hypertensive retinopathy, history

of cerebral or subarachnoid hemorrhage, or 

concurrent disease including hepatitis/cirrhosis, 

gout, and malignancy.

FEVER30

61.5 (7.2) years

--- Excluded (Creatinine > 2)

-Men eGFR no < 32 

-Women no eGFR < 24 

Excluded for 

cardiomyopathy

-Excluded for “unwillingness to 

cooperate”

Excluded for: CVA or MI within 6 months, 

unstable angina, gout, uncontrolled DM, 

“Serious pulmonary or hepatic disease.” 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

46

Trial; Age 

mean (SD) Diabetes status Chronic Kidney Disease Heart failure (HF)

Criteria likely to exclude those 

with dementia or diminished 

functional status*

Comorbidity

HOT17

61.5 (7.5) years

Excluded DM 

requiring insulin 

therapy

--- Excluded for HF --- Excluded for CVA or MI within 12 months, 

serious concomitant disease which could affect 

2-3 years survival, or requirement for β-B, 

ACEI or diuretic for reasons other than 

hypertension. 

HYVET6

83.5 (3.2) years

--- Excluded for creatinine >

1.7 

-Men eGFR no < 39 

-Women no eGFR < 29 

Excluded for “overt” 

clinical CHF requiring 

ACEI or diuretics

-Excluded for dementia

-Excluded those living in SNF

-Excluded for inability to stand up 

or walk

Excluded for: any condition expected to 

severely limit survival (terminal illness), 

cerebral or subarachnoid hemorrhage in past 6 

months, gout, hypertensive retinopathy.

JATOS24

73.6 (5.2) years

Excluded for DM if 

HgA1c > 8 

Excluded for creatinine 

> 1.5 

-Men eGFR no < 44 

-Women no eGFR < 33 

Excluded for HF 

(NYHA II or higher) 

-Excluded if “considered 

unsuitable as subjects.” 

Excluded for: history of MI/angioplasty in 6 

months prior, atrial fibrillation, hypertensive 

retinopathy, AST or ALT more than double 

upper limit of normal, malignant disease or 

collagen disease.

PROGRESS31

64 (10) years

--- Unclear. Excluded if had 

“a definite indication for 

ACEI” which would 

include proteinuria.

Unclear. Excluded if 

had “a definite 

indication for ACEI” 

and HF given as 

example.

-Excluded for “disability that is 

likely to prevent regular attendance 

at study clinics.”

---

RENAAL32

60 (7) years

T2 DM required for 

inclusion; T1 DM 

excluded

Excluded relatively severe 

disease (eGFR < 16 for 

women and < 21 for 

men). 

Excluded for HF --- Excluded for: non-diabetic renal disease, history

of MI/CABG within 1 month, CVA within 6 

months, TIA within 12 months

SCOPE33

76.4 years 

(NR)

--- Excluded for creatinine

 > 2 in men and > 1.6 in 

women. 

-Men eGFR no < 32 

-Women no eGFR< 30 

Excluded for 

decompensated HF 

-Excluded for dementia

-Excluded those with conditions 

which preclude MMSE (poor 

vision, aphasia, paralysis, other 

speech disorders, poor literacy)

Excluded for: CVA or MI within 6 months, 

LFTs > 3 times the upper limit of normal limit, 

“serious concomitant disease affecting 

survival,” alcohol/drug abuse, orthostasis, or 

disorders likely to affect cognition (including 

vitamin B12 deficiency, new hypothyroidism, 

neurosyphilis, AIDS, or severe depression). 

SHEP8

71.6 (6.7) years

Excluded DM 

requiring insulin 

therapy

Excluded for “history of 

renal insufficiency” (no 

additional definition 

provided)

--- -Excluded for dementia

-Excluded if “presence of medical 

management problems.” 

Excluded for: atrial fibrillation or flutter, AV

block, bradycardia. Recent MI or CVA, CABG 

within prior 6 months, and history of alcohol

abuse 

SPRINT11

67.9 (9.5)

DM excluded Excluded for eGFR < 20 Excluded

-for symptomatic HF 

within 6 months or 

ejection fraction < 35%

-Excluded for dementia

-Excluded those living in SNF

-Excluded for factors judged likely 

to limit adherence to interventions.

Excluded for history of CVA, or “a medical 

condition likely to limit survival to less than 3 

years or a cancer diagnosed/treated in prior 2 

years likely to limit trial completion.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

47

Trial; Age 

mean (SD) Diabetes status Chronic Kidney Disease Heart failure (HF)

Criteria likely to exclude those 

with dementia or diminished 

functional status*

Comorbidity

SPS325

63 (11)

--- --- --- --- Excluded if ICH from non-trauma, cortical 

ischemic stroke, or severely disabling stroke.

STONE19

66.4 (5.3)

DM excluded Excluded for azotemia 

(BUN > 40)

Excluded for HF --- Excluded for: angina, MI, severe arrhythmia, 

atrial fibrillation, COPD, cirrhosis, cancer, and 

diabetes.

Syst-China20

66.5 (5.5)

--- Excluded for creatinine >

2 

-Men eGFR no < 33 

-Women no eGFR < 24 

Excluded for HF -Excluded for dementia

-Excluded for “lack of 

cooperation.”

Excluded for: heart disease, renal or eye 

manifestations of hypertension, peripheral 

vascular disease, intracranial hemorrhage or sub 

arachnoid hemorrhage, MI within 1 year, 

valvular heart disease, hematologic malignancy 

or cancer, hyperthyroidism, gout, estrogen 

hormonal therapy or clotting disorders.

Syst-Eur34

70.25 (6.7)

Excluded DM if 

blood sugar not 

“adequately 

controlled.”

Excluded for creatinine >

2.

-Men eGFR no < 33

-Women eGFR no < 24

Excluded for other 

diseases that require 

continuous use of BP 

lowering drugs 

including diuretics, 

ACEI, CCBs, or β-B.

-Excluded for dementia

-Excluded for any condition which 

precludes a sitting or standing 

condition.

Excluded for: severe sequelae of hypertension

(retinopathy, dissection), SAH or cerebral 

hypertension, nosebleeds, if MI in the year prior, 

malignancy or hepatic dysfunction, or poorly 

controlled DM.

TRANSCEND35

66.9 (7.4)

--- Excluded for proteinuria Excluded for 

symptomatic CHF

Excluded for significant disability 

precluding regular follow-up visits. 

Excluded for other major non-cardiac illness 

expected to reduce life expectancy. 

VALISH26

76.1 (4.1)

--- Excluded for creatinine >

2 

-Men eGFR no < 32 

-Women no eGFR < 24 

Excluded for HF 

(NYHA III or higher)

-Excluded if “judged to be 

inappropriate” for the study by the 

investigator.

Excluded for: history of CVA or MI within 6 

months, angioplasty within 6 months or planned, 

atrial fibrillation /flutter, severe aortic stenosis 

or valvular disease, or “serious” liver 

dysfunction.

Wei, 201321

76.6 (4.6)

--- Excluded for creatinine >

3 

-Men eGFR no < 20 

-Women no eGFR < 15 

Excluded for HF 

(NYHA III or higher)

or ejection fraction < 

40%

-Excluded for diagnosis of 

Alzheimer’s disease

Excluded for: valvular heart disease, MI or CVA 

in 6 months prior, hepatic dysfunction, 

autoimmune disorders, malignant tumor, and 

“other non-cardiovascular diseases potentially 

causing death before the end of the study.”

Abbreviations: ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACEI = Angiotensin converting enzyme inhibitor; ADVANCE = Action in Diabetes and Vascular 

Disease; AIDS = acquired immune deficiency syndrome; ALT = alanine aminotransferase; AMI = acute myocardial infarction; AST = aspartate aminotransferase; AV = 

atrioventricular; β-B = Beta-blocker; BENEDICT-B = Bergamo Nephrologic Diabetes Complications Trial-B; BMI = body mass index; BP = blood pressure; BUN = blood urea 

nitrogen; CABG = coronary artery bypass grafting; CCB = calcium channel blocker; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; CVA = 

cerebrovascular accident; DM = diabetes mellitus (T2 = type 2, T1= type 1); EKG = electrocardiogram; EWPHE = European Working Party on High Blood Pressure in the 

Elderly; FEVER = Felodipine Event Reduction Study; HF = heart failure; HOT = Hypertension Optimal Treatment; HYVET = Hypertension in the Very Elderly Trial; ICH = 

intracerebral hemorrhage; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; LFT = liver function tests; LVH = left ventricular 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

48

hypertrophy; MI = myocardial infarction; MMSE = mini-mental state examination; NR = not reported; NYHA = New York Heart Association; PROGRESS = Perindopril 

Protection Against Recurrent Stroke Study; RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; SCOPE = Study on Cognition and 

Prognosis in the Elderly; SD = standard deviation; SAH = subarachnoid hemorrhage; TRANSCEND = Telmisartan Randomized Assessment Study in ACE Intolerant Subjects 

with Cardiovascular Disease; SHEP = Systolic Hypertension in the Elderly Program; SNF = skilled nursing facility; SPRINT = Systolic Blood Pressure Intervention Trial; SPS3 = 

Secondary Prevention of Small Subcortical Strokes; STONE = Shanghai Trial of Nifedipine in the Elderly; Syst-China = Systolic Hypertension in China; Syst-Eur = Systolic 

Hypertension in Europe; TIA = transient ischemic attack; VALISH = Valsartan in Elderly Isolated Systolic Hypertension. 

Notes: Specific exclusion criteria related to type of hypertension (ex: excluded based on secondary hypertension) is not noted here. If mean age was provided by treatment group, 

mean age by active treatment is listed in column 1. Estimated glomerular filtration rate (eGFR) is calculated using approximated upper end of age range for a given study via the 4-

variable MDRD equation.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

49

KEY QUESTION 4: What are the harms of targeting lower blood 

pressure in older patients? Do the harms vary with age?

General Adverse Effects

Ten trials compared rates of withdrawal due to adverse events (Table 6). We attempted metaanalysis of these results, but the heterogeneity of treatment effects was excessive (I

2 = 92.1%, 

chi-square P < 0.001), precluding the valid estimation of a summary effect. Four trials found 

more intensive blood pressure treatment was associated with a statistically significant increase in 

withdrawals due to adverse events, with relative risk increases ranging from 44 to 100%.8,27,31,35

Two trials found a trend towards increased adverse events in the intervention group,

26,28 while 4 

trials found the intervention group had the same or lower risk of adverse events.24,29,32,33 One trial 

found a nearly two-fold increase risk of serious adverse events possibly or definitely related to 

the intervention.11 The specific types of adverse events reported varied among trials, though 

cough or hypotension were among the more frequently reported events (Table 5). There was a 

higher rate of syncope among those assigned to more aggressive treatment in 2 trials,8,11 but not 

in a third.

25

Medication Burden

Tables 2 and 3 list the mean number of antihypertensive medications used in each group when 

available, or the proportion of each group taking different antihypertensive medications. It is 

difficult to define the increase in medication burden associated with different treatment targets 

given variation in reporting. In general, the mean number of medications or the proportion of 

participants taking multiple medications was higher in the intervention groups.

Renal Outcomes

We found low-strength evidence from 12 trials that more intensive blood pressure treatment was 

not associated with worsening of renal outcomes (Table 6). Outcome definitions varied among 

trials, and event rates of clinically significant outcomes such as end stage renal disease were 

generally low. Four trials found similar rates of end stage renal disease, need for dialysis, or 

renal failure in intervention and control groups,22,24,29,30 while one trial found that use of an 

angiotensin II receptor blocker was associated with a lower risk of end stage renal disease.

32 One 

trial found an increased risk for acute renal failure with more aggressive blood pressure 

lowering.11
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

50

Table 6. Renal Outcomes and Other Adverse Effects

Study

Comparison, T vs C 

Adverse effects that occurred frequently, or 

differed significantly in frequency, % of T 

vs C

Renal outcomes, % of T vs C 

Trials that compared BP target goals

ACCORD22

SBP < 120 vs < 140

Hypotension: 0.7 vs 0.04 (P < .001)

Hyperkalemia: 0.4 vs 0.04 (P = .01) 

ESRD or need for dialysis: 2.5 vs 2.4 (P

= .93) 

Elevation in serum creatinine: 

> 1.5 mg/dl in men: 12.9 vs 8.4 (P < .001) 

> 1.3 mg/dl in women: 10.9 vs 7.1 (P 

< .001) 

Estimated GFR < 30 ml/min/1.73 m2

: 

4.2 vs 2.2 (P < .001)

Cardio-Sis23

SBP < 130 vs < 140

Peripheral edema: 3.2 vs 4.9 (P = .16)

Asthenia: 2.3 vs 0.9 (P = .06)

Cough: 2.5 vs 1.3 (P = .13) 

Skin reactions: 2.7 vs 1.4 (P = .21)

NR

HOT17

DBP ≤ 80 vs ≤ 85 vs

≤ 90

AEs that exceeded 2%:

Dizziness, headache, leg edema, flushing, and 

coughing. T vs C not reported.

NR

JATOS24

SBP < 140 vs < 160

Withdrawal due to AE: 1.6 vs 1.6 (P = ns)

AEs resulting in discontinuation of treatment: 

Malignant disease: 0.3 vs 0.5 (P = .31)

Psychoneurological symptom: 0.18 vs 0.23 

(P = .74)

Poor blood pressure control: 0.18 vs 0.23 

(P = .74)

Cardiac symptom or arrhythmias: 0.32 vs 0.18

(P = .37)

Respiratory symptom or disease: 0.18 vs 0.09 

(P = .42)

Renal failure: 0.36 vs 0.41 (P = ns)

SPS325

SBP < 130 vs 130-

149

Syncope: 0.7 vs 0.3 (P = .14) NR

SPRINT11

SBP < 120 vs < 140 

Serious AE possibly or definitely related to 

intervention: 4.7 vs 2.5%; HR 1.88 (P < .001)

Hypotension: 2.4 vs 1.4; HR 1.67 (P < .001) 

Syncope: 2.3 vs 1.7; HR 1.33 (P = .05) 

Electrolyte abnormality: 3.1 vs 2.3; HR 1.35 

(P = .02) 

Fall resulting in ER visit/hospitalization: 

2.2 vs 2.3; HR 0.95 (P = .71) 

Acute kidney injury or acute renal failure:

4.1 vs 2.5; HR 1.66 (P < .001) 

VALISH26

SBP < 140 vs < 150

Withdrawal due to AE: 1.9 vs 1.2 (P = ns)

AEs not otherwise specified.

Renal insufficiency: 0.32 vs 0.13 (P = .267)

HR 2.45 (95% CI 0.48 to 12.64), adjusted 

for sex, age, BMI, smoking, dyslipidemia, 

diabetes, and anti-hypertension agents used 

before enrollment.

Wei, 201321

SBP < 140 vs < 150

Femoral fracture: 0.8 vs 1.3 (P = .716)

Vascular dementia: 0.6 vs 0.8 (P = .995)

NR

Trials that compared more vs less intensive antihypertensive treatment

ADVANCE27 Withdrawal due to AE: 5.7 vs 2.9 (P < .01) New or worsening nephropathy: 3.3 vs 3.9 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

51

Study

Comparison, T vs C 

Adverse effects that occurred frequently, or 

differed significantly in frequency, % of T 

vs C

Renal outcomes, % of T vs C 

(Perindopril + 

indapamide) vs

placebo

Cough: 3.3 vs 1.3 (P < .01)

Hypotension or dizziness: 1.2 vs 0.4 (P < .01) 

(P = ns)

RR reduction: 18% (95% CI, -1 to 32)

BENEDICT-B28

VeraTran (verapamil

+ trandolapril) vs

Trandolapril

Withdrawal due to cough: 14.5 vs 9.1 (P = ns) NR

EWPHE29

(Hydrochlorothiazide 

+ Triamterene) vs

placebo

Withdrawal due to AE: 6.0 vs 13.2 (P < .01)

Withdrawal due to severe increase in BP: 

0.5 vs 4.5 (P = .0001) 

Death from renal causes: 1.0 vs 0.2 (P = ns)

Withdrawn due to 100% increase in serum 

creatinine: 1.0 vs 0.2 (P = ns)

Renal disease: 3.1 vs 0.5 (P < .001) 

Pyelonephritis: 1.2 vs 0.5 (P = ns)

Nephrotic syndrome: 0.2 vs 0 (P = ns)

Chronic nephritis: 0.2 vs 0 (P = ns)

Renal disease of undetermined origin: 1.4

vs 0 

(P = ns)

FEVER30

Felodipine vs placebo

AEs reported during treatment:

Flushness: 1.4 vs 0.2 (P < .001) 

Fatigue: 0.64 vs 1.05 (P = .037) 

Ankle edema: 1.0 vs 0.37 (P < .001)

Renal failure: 0.20 vs 0.16 (P = .5)

HR 1.38 (95% CI, 0.54 to 3.52)

HYVET6

Indapamide vs

placebo

Serious AEs occurred in 18.5 vs 23.4 (P =.001)

Types of AEs not specified. 

No significant differences between T vs C 

in changes from baseline in serum 

creatinine: 

3.4 vs 2.3 μmol/L (P =.30)

(0.04 vs 0.03 mg/dL) 

PROGRESS31

(Perindopril ± 

Indapamide) vs

placebo

Withdrawal due to AE: 5.2 vs 3.6 (P < .01)

Reasons for discontinuation; 

Cough: 2.2 vs 0.4 (P < .05) 

Hypotension: 2.1 vs 0.9 (P < .01)

NR

RENAAL32

Losartan vs placebo

Withdrawal due to AE: 17.2 vs 21.7 (P < .05)

AEs leading to discontinuation:

Increased serum creatinine: 1.5 vs 1.2 (P = ns)

Increased serum potassium: 1.1 vs 0.5 (P = ns)

End-stage renal disease: 19.6 vs 25.5 

(P = .002); RR 0.77 (95% CI, 0.63 to 0.93)

Doubling of serum creatinine: 21.6 vs 26.0 

(P = .006) 

RR 0.83 (95% CI, 0.63 to 0.99)

SCOPE33

Candesartan vs

placebo 

Dizziness/vertigo: 20.9 vs 20.0 (P = ns)

Accident/injury: 18.4 vs 18.4 (P = ns) 

Back pain: 9.2 vs 17.1 (P = ns) 

Bronchitis: 15.9 vs 16.0 (P = ns) 

Significant cognitive decline: 13.5 vs 15.2 

(P = ns)

Dementia: 6.8 vs 6.3 (P = ns) 

Withdrawal due to AE: 15.0 vs 17.0 (P = .07)

NR

SHEP8

Chlorthalidone vs

placebo

Chest pain or heaviness: 28.0 vs 21.3 (P < .01)

Trouble with memory/concentration: 26.4 vs

20.4 (P < .01) 

Cold or numb hands: 13.6 vs 9.8 (P < .01) 

Change in bowel habits: 15.4 vs 11.4 (P < .01) 

Unusual joint pain: 36.4 vs 31.4 (P < .01) 

Heart beating unusually slowly: 3.8 vs 2.1 

(P < .01)

Renal dysfunction or death from renal 

disease: 

0.38 vs 0.55 (P = .40)

RR 0.65 (95% CI, 0.30 to 1.62)
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

52

Study

Comparison, T vs C 

Adverse effects that occurred frequently, or 

differed significantly in frequency, % of T 

vs C

Renal outcomes, % of T vs C 

Ankle swelling: 19.5 vs 15.6 (P < .01)

Falls: 12.8 vs 10.4 (P < .05) 

Problems in sexual function: 4.8 vs 3.2 (P

< .05) 

Syncope: 2.2 vs 1.3 

(P < .05) 

Withdrawal due to AE: 13.0 vs 7.0 (P < .05)

STONE19

Nifedipene vs

placebo

NR NR

Syst-China20

(Nitrendipine ± 

Captopril ± 

Hydrochlorothiazide) 

vs placebo

NR NR

Syst-Eur44

Nitrendipine vs

placebo

NR Mild renal dysfunction: 0.22 vs 0.61 (P

= .05)

Active treatment reduced the rate of 

dysfunction by 64% (95% CI, 0 to 87%; P

= .04) from 2.6 to 0.9 events per 1000

patient-years. 

In Cox regression with adjustments for sex, 

age, SBP at entry, previous cardiovascular 

complications and antihypertensive 

treatment, body mass index and smoking 

and alcohol intake at entry, the reduction 

was 64% (95% CI, 0 to 84%; P < .05).

No patient died of renal failure.

TRANSCEND35

Telmisartan vs

placebo

Withdrawal due to AE: 2.6 vs 1.7 (P < .05)

Hypotensive symptoms resulting in 

withdrawal: 

0.98 vs 0.54 (P = .049)

Renal abnormalities that led to study 

withdrawal: 0.81 vs 0.44 (P = .067) 

Abbreviations: ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes 

and Vascular Disease; AE = adverse event; BENEDICT-B = Bergamo Nephrologic Diabetes Complications Trial-B; 

BMI = body mass index; BP = blood pressure; C = comparator/control; Cardio-Sis = Studio Italiano Sugli Effetti 

Cardiovascolari del Controllo della Pressione Arteriosa Sistolica; CI = confidence interval; DBP = diastolic blood 

pressure; ER = emergency room; ESRD = end-stage renal disease; EWPHE = European Working Party on High 

Blood Pressure in the Elderly; FEVER = Felodipine Event Reduction Study; GFR = glomerular filtration rate; HOT 

= Hypertension Optimal Treatment; HR = hazard ratio; HYVET = Hypertension in the Very Elderly Trial; JATOS = 

Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; NR = not reported; ns = 

not statistically significant; PROGRESS = Perindopril Protection Against Recurrent Stroke Study; RENAAL = 

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; RR = relative risk; SBP = systolic 

blood pressure; SCOPE = Study on Cognition and Prognosis in the Elderly; SHEP = Systolic Hypertension in the 

Elderly Program; SPRINT = Systolic Blood Pressure Intervention Trial; SPS3 = Secondary Prevention of Small 

Subcortical Strokes; STONE = Shanghai Trial of Nifedipine in the Elderly; Syst-China = Systolic Hypertension in 

China; Syst-Eur = Systolic Hypertension in Europe; T = treatment; TRANSCEND = Telmisartan Randomized 

Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease; VALISH = Valsartan in Elderly Isolated 

Systolic Hypertension. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

53

Cognitive Outcomes

We found moderate-strength evidence from 7 RCTs that use of antihypertensive treatment to 

achieve moderately strict blood pressure control for up to 5 years does not worsen cognitive 

outcomes compared to less strict blood pressure control (Table 7). The mean age of trial 

participants ranged from 62 to 83 years, and baseline cognitive function was generally normal. In 

most trials, the intervention group achieved SBP in the 140 to 150 mm Hg range, though in one 

study the intervention group achieved an SBP of 119 mm Hg. Three large-scale trials reported 

cognitive outcomes for the entire cohort,45-47 while 3 other trials prospectively collected 

cognitive outcomes data for a subpopulation of patients.8,48,49 In patients without a prior history 

of cerebrovascular disease, 3 trials found no difference in rates of incident dementia,45,47,48 while 

one trial found that more intensive blood pressure control was associated with a lower rate of 

dementia.46 A prior meta-analysis of these 4 trials found no significant difference in development 

of dementia (odds ratio [OR] 0.89, 95% CI 0.74 to 1.07, I

2 = 17%).50 Another trial of patients 

with a prior history of stroke similarly found no difference in rates of incident dementia (RR 

0.88, 95% CI 0.72 to 1.08).48 Six of the trials with serial cognitive assessments found the groups 

did not differ in change in cognitive function over time (Table 6).

Six of the trials had low risk of bias, while an older trial had an unclear risk of bias because of 

poor methods reporting.51 The 4 trials reporting incident dementia used robust diagnostic criteria 

centrally adjudicated by blinded outcomes assessors. Rates of missing data or loss to follow-up 

ranged from 0.5 to 13.8%, but results were consistent across all studies.

We found 2 observational studies that suggested an SBP range of approximately 135 to 150 mm 

Hg was associated with the lowest risk of cognitive decline.52,53 However, in both studies there 

were missing data from a large proportion of patients (13.5 to 37%) who were generally less 

well-educated than those with full data available. A third observational study in patients ≥ 80 

years of age similarly found the lowest rate of cognitive decline among those whose 4 year mean 

SBP was between 140 to 160 mm Hg, while those with lower or higher blood pressures 

experienced steeper rates of cognitive decline.54
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

54

Table 7. Cognitive Outcomes Reported in Trials and Prospective Cohort Studies of Hypertension Management in the Elderly

Study

Setting Study overview Sample 

size

Age at 

baseline

Mean or 

*median 

follow-up

(years)

Baseline cognitive 

function

Mean 

achieved BP 

(mm Hg) 

T vs C

Results, T vs C Comments

Randomized controlled trials (RCTs)

ACCORDMIND47

substudy of 

ACCORD RCT

SBP target < 120 vs

SBP target < 140 mm 

Hg

1439 62 3.3 DSST: 52.28

MMSE: 27.25

SBP: 119 vs

133.2

DBP: 64 vs

70.2

Change from baseline:

DSST: -1.86 vs -1.61 (P = .55)

MMSE: -0.25 vs -0.30 (P = .70)

199 (13.8%) of enrollees had 

one or more missing data 

points, and those with 

missing follow-up data were 

slightly older and had slightly 

lower cognitive function at 

baseline

Bird, 199051

Medical 

Research 

Council 

multisite 

outpatient trial, 

Great Britain

RCT

Treat to SBP target

< 150 mm Hg if 

baseline SBP 160-

179, or < 160 mm Hg

if baseline SBP 180-

209; primary 

intervention 

medications were 

hydrochlorothiazide/ 

amiloride or atenolol

2446 70.3 0.75 PALT:

85% scored 16-18 

(normal).

14.8% scored 8-15. 

25% scored < 8.

Trail making test:

63.6% normal 

(≤ 60 seconds) 

SBP: 149 vs

167

DBP: 79 vs

86

Mean achieved BP atenolol vs

hydrochlorothiazide/amiloride vs

placebo:

156/79 vs 149/79 vs 167/86

% with abnormal PALT atenolol vs

hydrochlorothiazide/amiloride vs

placebo:

19.9 vs 21.2 vs 18.5 (P = ns) 

% with abnormal trail making test (≥ 

90 seconds) atenolol vs

hydrochlorothiazide/amiloride vs

placebo: 

5.9 vs 5.7 vs 6.7 (P = ns)

Unclear risk of 

bias:randomization and 

allocation concealment 

procedures not well 

described; loss to follow-up 

appears low but poorly 

reported; little data 

comparing group baseline 

characteristics 

HYVET-COG45

substudy of 

HYVET RCT

BP target 150/80 vs

placebo

3336 83.5 2.2 MMSE: 26 Mean 

decrease in 

SBP: 29.6 vs

14.6

Mean 

decrease in 

DBP: 13.1 

vs 7.2

Incident dementia: 126/1687 (7.5%) 

vs 137/1649 (8.3%) 

HR 0.86 (95% CI 0.67-1.09)

Cognitive decline (fall in MMSE to < 

24 or decline of > 3 points in one 

year): 485/1687 (28.7%) vs 486/1649 

(29.5%)

HR 0.93 (95% CI 0.82-1.05)

509 (13.2%) of potentially 

eligible patients did not meet 

criteria for inclusion in 

cognitive substudy because 

of missing data. However, 

these patients had similar 

baseline demographic, 

education, and cognitive 

characteristics as included 

patients.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

55

Study

Setting Study overview Sample 

size

Age at 

baseline

Mean or 

*median 

follow-up

(years)

Baseline cognitive 

function

Mean 

achieved BP 

(mm Hg) 

T vs C

Results, T vs C Comments

PROGRESS48

Multisite RCT 

in patients with 

stroke

Perindopril ±

indapamide vs

placebo

6105 64 3.9 MMSE: 29 Reduction in 

SBP/DBP: 

9.0 vs 4.0 

Incident dementia: 

193/3051 (6.3%) vs 217/3054 (7.1%) 

RR 0.88 (95% CI 0.72-1.08)

Change in MMSE: 

-0.05 vs -0.24 (P = .01)

Patients with cognitive decline 

(MMSE decline of 3 or more points): 

276/3051 (9.0%) vs 334/3054 (10.9%)

RR 0.81 (95% CI 0.68-0.96)

Serial cognitive assessments 

were available for most 

patients (96.4%). Dementia 

assessment done by 

interviewers blinded to 

treatment group. 

SCOPE49

Multisite RCT, 

cognitive 

outcomes 

secondary 

outcome of 

parent study

Candesartan vs

placebo to achieve 

BP < 160/90 mm Hg

4937 76.4 3.7 MMSE: 28.5 SBP: 145.2 

vs 148.5

DBP: 79.9 

vs 81.6

Incident dementia: 

62/2477 (6.8%) vs 57/2460 (6.3%) (P 

= ns)

Change in MMSE: 

-0.49 vs -0.64 (P = ns)

Very low loss to follow-up.

99.5% of patients originally 

randomized were included in 

analyses. Most (84%) of the 

control participants also 

received antihypertensive 

treatment. 

SHEP8

Multisite RCT

Thiazide ± atenolol to 

achieve

≥ 20 mm Hg drop in 

SBP vs placebo

4736 71.6 4.5 Cognitive 

impairment score55

≥ 4 (as cited in 

SHEP8

), T vs C: 

0.3% vs 0.5%

SBP: 144.0 

vs 155.1

DBP: 67.7 

vs 71.1

Incident dementia: 

37/2365 (1.6%) vs 44/2371 (1.9%)

RR 0.84 (95% CI 0.54-1.31)

About 4% in each group 

referred for dementia 

evaluation, and about 10% of 

those referred declined 

further evaluation.

Characteristics of these 

patients were not described.

Syst-Eur46

Dementia 

substudy of 

larger multisite 

European RCT

SBP < 150 mm Hg vs

placebo

2902 68 3.9* MMSE: 29 SBP: 149.1 

vs 156.1

DBP: 79.4 

vs 82.5

Incident dementia: 

21/1485 (1.4%) vs 43/1417 (3.0%)

Rate per 1000 patient-years:

3.3 vs 7.4 (P < .001)

Change in MMSE at 3 years:

-0.17 vs -0.14 (P = .73)

326 (10.1%) of eligible 

cohort did not contribute data 

to this analysis, but their 

baseline characteristics are 

not available. 

Prospective cohort studies
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

56

Study

Setting Study overview Sample 

size

Age at 

baseline

Mean or 

*median 

follow-up

(years)

Baseline cognitive 

function

Mean 

achieved BP 

(mm Hg) 

T vs C

Results, T vs C Comments

Liu, 201352

Indianapolis

cohort of the 

IndianapolisIbadan 

Dementia 

Project

Prospective 

cohort study 

African Americans 

aged ≥ 65 years with 

assessment every 2-3 

years from 1992-

2009

2721 76 NR Median 

Community 

Screening 

Interview for 

Dementia score 

(possible score 0-

80): 68 

(interquartile range

62-72)

NR Nonlinear association between BP and 

cognitive function. 

Optimal cognitive function associated 

with SBP of about 135 mm Hg and 

DBP of about 80 mm Hg. 

424 (13.5%) of original 

cohort had missing data and 

were excluded. These 

patients were older and less 

educated. Used a 

semiparametric mixed effects 

model approach in which 

each patient could contribute 

several longitudinal 

observations

Peng, 201454

China

Prospective 

cohort study 

Community-dwelling 

hypertensive 

participants ≥ 80 

years old; no standard 

treatment protocol

294 84.4 85% with 

complete 

4-year 

follow-up 

MMSE: 26 Baseline:

SBP: 176

DBP: 78

4-year mean:

SBP: 153

DBP: 75

% change in MMSE: 

SBP < 140 mm Hg: -7.78 (SD 8.1) 

SBP 140-160 mm Hg: -3.51 (SD 7.75) 

SBP >160 mm Hg: -8.8 (SD 9.27) 

P-value for differences between 

groups < .001

% change in MMSE by SBP decline: 

< 15 mm Hg: -8.94 (SD 9.1) 

15-35 mm Hg: -3.77 (SD 7.33) 

Ø 35 mm Hg: -7.03 (SD 8.75) 

P-value for differences between 

groups < .001

44 participants excluded from 

final analysis due to 

death/stroke/withdrawal.

250/294 (85%) included in 

analysis. 

Sacktor, 199953

Baltimore 

Longitudinal 

Study of Aging

Prospective 

cohort study

Patients ≥ 60 treated 

for hypertension with 

serial BP measures 

and neuropsychologic 

testing; tested 

association between 

maintenance of low 

(SBP < 135), 

intermediate (SBP 

135-150), and high 

(SBP > 150) BP and 

cognitive outcomes

158 74.5 5.1 MMSE: 28.4 % with 

Low: 18 

Intermediate:

30

High: 51

Change in Low vs Intermediate vs

High BP groups:

MMSE: 0.2 vs 0.3 vs 0.2 (P = .77)

Trail making test part B: -0.1 vs 5.4 vs

5.2 (P = .19)

Total free recall: -0.3 vs 0.0 vs 0.6 

(P = .02)

Delayed recall: 0.4 vs 0.0 vs 0.1

(P = .04)

132 (37%) of the original 

cohort of 354 patients did not 

receive longitudinal 

neuropsychologic testing; 

these excluded patients were 

younger and less educated. 

Abbreviations: ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACCORD-MIND = Action to Control Cardiovascular Risk in Diabetes - Memory in Diabetes; BP 

= blood pressure; C = comparator/control; CI = confidence interval; DBP = Diastolic blood pressure; DSST = Digit Symbol Substitution Test; HR = hazard ratio; HYVET = 

Hypertension in the Very Elderly Trial; HYVET-COG = Hypertension in the Very Elderly Trial - Cognitive Function Assessment; MMSE = mini-mental state examination; NR = 

not reported; ns = not statistically significant; PALT = Paired Associate Learning Test; PROGRESS = Perindopril Protection Against Recurrent Stroke Study; RCT = randomized 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

57

controlled trial; RR = relative risk; SBP = systolic blood pressure; SCOPE = Study on Cognition and Prognosis in the Elderly; SD = standard deviation; SHEP = Systolic 

Hypertension in the Elderly Program; Syst-Eur = Systolic Hypertension in Europe; T = treatment.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

58

Quality of Life and Functional Status

Overall, we found moderate-strength evidence from prospective substudies of 4 large low risk of 

bias trials that use of antihypertensive therapy to achieve moderate blood pressure control (SBP 

140 to 150 mm Hg) was not associated with a deterioration in quality of life compared to less 

intensive blood pressure control. We found low-strength evidence from one large low risk of bias 

trial that moderate blood pressure control was not associated with deterioration in functional 

status compared to less intensive control. 

In the SHEP trial, all participants were included in a longitudinal assessment of functional 

status.56 Most participants (intervention group 95.6%, control group 92.8%) completed baseline 

and follow-up questionnaires about deterioration in Activities of Daily Living (ADLs). At a 

mean of 5 years of follow-up, a similar proportion of intervention and control group participants 

reported a deterioration in basic ADLs (18.6 vs 20.1%, P = .20), moderate ADLs (22.1 vs 23.4, P

= .30), and advanced ADLs (46.6 vs 49.1, P = .72). 

A smaller pre-specified subpopulation (N = 2,034) of SHEP trial participants was included in a 

longitudinal behavioral assessment that included 3 questions globally assessing quality of life.

56

Baseline and follow-up questionnaires were completed by 1758/2034 (86.4%) of participants. On 

all 3 measures, quality of life was similar in intervention and control groups at last follow-up. 

For example, a similar proportion rated their health as good or excellent at follow-up (T vs C, 

78.0 vs 76.4%, P = .70). 

A subpopulation of 1,348 of the 4,695 patients in the Syst-Eur trial was recruited for a quality of 

life assessment.

57 Six hundred and ten of these patients completed a baseline and at least one 

follow-up questionnaire which included the Sickness Impact Profile (SIP), a quality of life 

measure examining the effects of poor health on ambulation, social interaction, home work, and 

sleep and rest. There were no differences in SIP score changes over time between intervention 

and control groups, although an age-adjusted model showed slightly more intervention patients 

reported difficulty on the social interaction scale (OR 1.32, 95% CI 1.02 to 1.69). 

In the HOT trial (total N = 19,193), of 922 patients recruited into a quality of life substudy, 610 

(66%) completed questionnaires consisting of the Psychological General Well-Being index 

(PGWB) and the Subjective Symptoms Assessment Profile (SSA-P) at baseline and at the 6 

month follow-up visit.58 There was slightly more improvement in global PGWB scores (potential 

range 22 to 132) in the group randomized to target DBP of ≤ 80 mm Hg than the 2 less intensive 

blood pressure target groups (mean change in scores 2.8 vs 0.6 vs 1.3, P < .001). These small 

improvements are of uncertain clinical significance and were driven by very small changes in the 

anxiety, general well-being, and vitality subscales. 

The SSA-P used 7-point Likert-scale questions to assess various subjective symptoms potentially 

associated with antihypertensive therapy. Headache, dizziness, and cardiac symptoms such as 

palpitations improved slightly in all groups (approximately -0.5, -0.2, and -0.2, respectively, P < 

.01), while sex-life scores deteriorated slightly in males assigned to the 2 more intensive 

treatment groups (0.2 vs 0.0, P < .01). 

The SCOPE trial enrolled 2,850 of its 4,937 in a quality of life substudy.59 The PGWB, SSA-P, 

and European Quality of Life scale (EuroQOL, a 100-point visual analog scale assessing selfrated current health) were completed at baseline and last follow-up by 92.9 and 93.7% of the 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

59

intervention and control groups, respectively. Quality of life deteriorated slightly less in the 

intervention than in the control group, though this difference is likely of little clinical 

significance (-3.1 vs -5.3, mean difference in change -2.19, 95% CI -3.8 vs -0.56). Changes in 

PGWB and SSA-P scores were similar in the 2 groups. 

Falls and Fractures 

We found moderate-strength evidence from 3 large low risk of bias trials that more intensive 

blood pressure treatment (SBP targets < 120 mm Hg and < 150 mm Hg, and achieved SBP < 150 

mm Hg in the third trial) did not increase risk of fracture.60,61 We found low-strength evidence 

that more aggressive blood pressure control did not consistently increase the risk of falls. Two of 

the trials found that very aggressive blood pressure lowering (SBP < 120 mm Hg) did not 

increase the risk of falls,

11,60 while a third trial found that moderate blood pressure control (SBP 

< 150 mm Hg) was associated with a small increase in the risk of falls.8

In meta-analyses of these studies statistical heterogeneity was too high to permit meaningful 

summary estimates of treatment effects. 

In the ACCORD study, 3,099 of the 4,733 participants were enrolled in the ACCORD-BONE 

substudy.60 Participants (mean age 62 years), were asked annually to report falls or non-spine 

fractures over the prior 12 months. Fracture events were centrally adjudicated using radiology 

reports by blinded outcome assessors. Over a mean of 3.5 years of follow-up, the rate of falls 

was similar in the intervention and control groups (62.2/100 person-years vs 74.1/100 personyears, RR 0.84, 95% CI 0.54 to 1.29). A similar proportion of participants in each group had one 

or more falls (20 vs 21%, OR 0.94, 95% CI 0.84 to 1.05). The risk of non-spine fractures was 

non-significantly lower in the intervention group (hazard ratio [HR] 0.79, 95% CI 0.62 to 1.01). 

Interaction terms including age and comorbidities were all P > .05. 

In the SHEP study (N = 4,736) more patients in the intervention group reported one or more falls 

over the 4.5 year follow-up (12.8 vs 10.4%, P < .05), though a similar number in both groups 

experienced a fracture (2.4 vs 2.0%, P > .05).8

All participants (N = 3,845, mean age 83.5) in the HYVET study were included in an analysis of 

hypertension treatment (with a thiazide diuretic ± ACE inhibitor) on risk of fracture.61 Fractures 

were identified if included in routine serious adverse event reporting. Additionally, at each trial 

follow-up investigators were asked to report whether participants had experienced an interim 

fracture. Fracture events were centrally adjudicated by blinded outcome assessors who examined 

relevant radiological and medical reports. Over a mean of 2.1 years of follow-up, one or more 

definite or probable fractures occurred in 38/1933 (2.0%) intervention participants compared to 

52/1912 (2.7%) control participants (HR 0.69, 95% CI 0.46 to 1.05). 

In the SPRINT trial (N = 9,361, mean age 67.9) a similar proportion of participants in the 

intervention and control groups had a fall leading to an emergency room visit or hospitalization 

(2.2 vs 2.3%, HR 0.95, P = .71). However, there was a higher risk of syncope among 

intervention participants (2.3 vs 1.7%; HR 1.33, P = .05). 

Effects of Age 

Three studies reported harms associated with more versus less intensive blood pressure treatment 

according to age. The SPS3 trial compared results in participants ≥ 75 years (N = 494) and < 75 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

60

years (N = 2,526).39 The rates of adverse events related to blood pressure lowering such as 

unsteadiness, dizziness, and orthostatic syncope were similar among patients assigned to a lower 

treatment target (achieved SBP 125 mm Hg) and higher treatment target (achieved SBP 137 mm 

Hg) in both age groups. Fewer participants assigned to the lower treatment target experienced 

one or more episodes of postural hypotension (53 vs 65% and 57 vs 62% in the older and 

younger age groups, respectively; P < .01 in both groups). 

In the JATOS study, rates of renal failure were similar in lower and higher treatment target 

groups in older (≥ 75 years) and younger (< 75 years) participants, though event rates were 

low.24

The SPRINT trial did not directly compare harms in different age groups, but found that the 

pattern of harms in the subgroup of patients over age 75 was similar to overall study findings. 

For example, a similar proportion of older patients in the intervention and control groups 

experienced a fall resulting in an emergency room visit or hospitalization (5.3 vs 6.0%; HR 0.88, 

P = .42).11

Overall, there were very few participants ≥ 80 years included in most of the trials. The major 

exception was the HYVET trial which only included patients over age 80 and found that use of 

medication to achieve moderate blood pressure control (150/80 mm Hg) was not associated with 

an increased risk of adverse events.6

Harms according to DBP

Theoretically, low DBP could also contribute to harms. We found very little data to assess the 

contribution of low DBP to the harms described above. The only 2 studies in which the achieved 

DBP was < 70 mm Hg were ACCORD and SPRINT (mean achieved DBP 64.4 and 66 mm Hg), 

which also examined the effects of aggressive SBP targets of < 120 mm Hg. As described above, 

these studies found that achieved DBP < 70 mm Hg was not associated with an increased risk of 

falls, fractures, or cognitive impairment. However, there was an increased risk of symptomatic 

hypotension in both trials,11,22 and an increased risk of syncope in one trial.11 Whether these 

effects were seen primarily in patients with very low DBP, SBP, or both is unclear. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

61

KEY QUESTION 5: Do the harms of targeting lower blood pressure 

vary with patient burden of comorbidities?

We found no trials which examined the impact of participants’ burden of comorbidities on risk 

of adverse events. As noted in Key Question 3, patients with severe comorbidities or high 

comorbidity burden were not well-represented among these studies (Table 5). There is an 

insufficient body of evidence examining the safety of intensive blood pressure treatment in 

adults with dementia or other serious illness since these patients were excluded from most trials.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

62

SUMMARY AND DISCUSSION

In this systematic review, we examined the benefits and harms of treating hypertension to lower 

compared more moderate blood pressure targets in patients over age 60. Table 8 provides a 

summary of the evidence. Overall, we found high-strength evidence that treating blood pressure 

in patients over age 60 to current treatment targets (< 150/90 mmHg) substantially reduces 

mortality, stroke, and cardiac events. Much of this data comes from trials in which the mean

baseline SBP was > 160 mmHg. We also found evidence, driven mainly by one large trial, that 

lower targets (SBP < 140 mmHg or DBP < 85 mmHg) compared to higher targets reduced stroke 

(moderate strength evidence) and cardiac events (low strength evidence); mortality was also

reduced though not significantly (low strength evidence). There is little data that directly helps

distinguish benefits between SBP 140 and 150 mmHg. Most of the trials achieving SBP < 140 

mmHg were the treat-to-target trials. Only one trial included patients with baseline SBP 140-150 

mmHg and found an improvement in mortality, but not other outcome. We found moderate 

strength evidence that more aggressive blood pressure control (SBP < 140 mmHg) in patients 

with prior stroke substantially reduced rates of recurrent stroke. 

The treat-to-target trials overall support a lower blood pressure treatment target in some patients 

with high cardiovascular risk. Most of the evidence in support of lower treatment targets comes 

from one large trial examining an SBP target of < 120 mmHg in which a substantial proportion 

of intervention patients achieved SBP 120-130 mmHg. Lower targets may prevent (on average, 

across a population) roughly 10-20 events for every 1000 high-risk patients treated over 5 years 

(Table 8), but more aggressive treatment is likely associated with a higher medication burden 

and higher risk of adverse effects such as hypotension and syncope. On the other hand, we 

found that lower targets are unlikely to increase the risk of dementia, fractures, and falls, or 

reduce quality of life. 

Current guidelines suggest aiming for moderate blood pressure control (< 150/90 mm Hg) in 

most adults over age 60. We found strong evidence supporting benefit of moderate blood 

pressure control. The main area of controversy, however, is whether or not there is an additional 

benefit from more aggressive blood pressure control. Taken as a whole, trials examining lower 

blood pressure targets suggest there may be some benefit in more aggressive control, though the 

absolute effect is smaller and there is not a consistent effect on mortality. It is possible that the 

smaller incremental benefit from more aggressive blood pressure control may be related to the 

relatively small number of cardiovascular and mortality events in some of the trials.

24,26 As 

discussed above, 3 studies found that patients with higher baseline cardiovascular risk had higher 

event rates and tended to experience more absolute benefit.41-43 However, the magnitude of these 

effects was modest and was not consistent across outcomes. 

Part of the answer may depend on consideration of the individual trials. The SPRINT and 

ACCORD trials are clearly different than the others in that they included patients with 

reasonable blood pressure control (about 140/90 mm Hg) at baseline and targeted “normal” SBP

of 120 mm Hg. However, these 2 trials provide conflicting results: in SPRINT there was a 

substantial reduction in mortality and cardiac events but not stroke, while in ACCORD there was 

a reduction in stroke but not the other outcomes. Both trials included patients with substantial 

cardiovascular risk (and, in fact, the proportion of patients experiencing events was higher in 

ACCORD), though the mean age was higher in the SPRINT trial. The ACCORD trial included 

only diabetic patients, while SPRINT excluded diabetic patients. However, it is not immediately 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

63

clear why results would differ based on diabetes status alone. Of note, the SPRINT trial was 

stopped early for benefit but it is unclear whether this necessarily accounted for the different 

results. Sensitivity analyses suggest that SPRINT was the main contributor to the non-significant 

trend towards reduced mortality and the significant effects on cardiac events.

There was consistent evidence that more aggressive blood pressure control modestly reduced 

stroke outcomes with or without the inclusion of SPRINT. The modest stroke risk reduction may 

provide rationale for more aggressive treatment in some patients. The main trade-off in 

considering more aggressive treatment would be a higher medication burden, and the increased

risk of adverse effects seen in some studies such as cough and hypotension. Two of 3 trials found 

higher rates of syncope in the intervention group suggesting that hypotension is potentially a 

serious short-term harm. Theoretically, there is also reason to be concerned about more serious 

long-term adverse effects of lowering blood pressure in older adults in whom arterial stiffness, 

subclinical cerebrovascular disease, cognitive impairment, and multiple comorbidities can 

combine to increase risk of falls, fracture, dementia, and poor quality of life. However, we found 

moderate-strength evidence that blood pressure treatment to SBPs as low as 120 mm Hg did not 

increase the risk of dementia, fractures, falls, or reduce quality of life.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

64

Table 8. Summary of the Evidence on More vs Less Intensive Treatment for Hypertension in the Elderly

Outcome

N studies

(N = total 

patients 

combined)

Combined estimates:

RR (95% CI)

ARR 

N: events (95% CI) 

prevented per 1000 highrisk patients over 5 yearsa 

Strength of 

Evidenceb Summary of findings

Mortality 9 RCTsc

(N = 46,450) 

RR 0.90 (0.83-0.98)

ARR 1.64 

N: 34 (7-58)

Highd Consistent benefit of treating blood pressure to levels 

< 150/90 mmHg. 

6 RCTse

(N = 41,491)

RR 0.86 (0.69-1.06)

ARR 0.80

N: 18 (n/af

-40)

Low Lower treatment targets (SBP ≤ 140 mmHg or DBP 

≤ 85 mmHg, or lower) associated with nonsignificant mortality reduction compared to higher 

targets. Findings were inconsistent across studies and 

estimate was imprecise.

Stroke 9 RCTsc

(N = 46,450) 

RR 0.74 (0.65-0.84)

ARR 1.13

N: 26 (16-35)

Highd Clear, consistent benefit of treating blood pressure to 

levels < 150/90 mmHg. 

6 RCTse

(N = 41,491)

RR 0.79 (0.59-0.99)

ARR 0.49

N: 9 (0-17)

Moderate Lower treatment targets (SBP ≤ 140 mmHg or ≤ 

DBP 85 mmHg, or lower) reduced the risk of stroke 

compared to higher targets; some inconsistency but 

relatively stable effect across analysesf

Cardiac 

events

9 RCTsc

(N = 46,450) 

RR 0.77 (0.68-0.89)

ARR 1.25

N: 65 (31-90)

Highd Clear, consistent benefit of treating blood pressure to 

levels < 150/90 mmHg. 

6 RCTse

(N = 41,491)

RR 0.82 (0.64-1.00)

ARR 0.94

N: 18 (n/af

-36)

Low Lower treatment targets (SBP ≤ 140 mmHg or DBP 

≤ 85 mmHg, or lower) may reduce the risk of cardiac 

events compared to higher targets. Findings were 

inconsistent across studies and estimate was 

imprecise.

Short-term 

adverse 

events

19 RCTs

(N = 98,964) 

--- --- Mixed findings: withdrawal due to adverse events 

was increased in the intervention group by 44-100% 

in 4 of 10 trials reporting this outcome. Cough and 

hypotension were the most frequently reported 

events. The risk of syncope was increased in 2 of 3 

trials reporting this outcome. Excessive heterogeneity 

among trials precluded pooling of results.

Renal 

outcomes

13 RCTs

(N = 66,607) 

--- Low More intensive blood pressure treatment did not 

worsen renal outcomes. Outcome definitions varied, 

and event rates for clinically significant outcomes 

such as end stage renal disease were low.

Cognitive 

outcomes

7 RCTs

(N = 25,901)

Incident dementia 

in 4 RCTs of patients 

without prior stroke:

OR 0.89 (0.74-1.07)

Moderate No effect on degree of cognitive decline or incidence 

of dementia. Loss to follow-up ranged across studies; 

patients lost to follow-up may differ in risk for 

dementia.

Falls/

fracture

Fracture:

3 RCTs

(N = 11,680)

--- Moderate 

(fracture)

Mixed findings: 3 trials found no effect of lower 

blood pressure targets on risk of fracture. Two trials 

with SBP target of 120 mmHg found no effect on 

risk of falls, while a 3rd (with achieved SBP < 150 

mmHg) found a small increase in risk of fall. 

Falls: 3 RCTs

(N = 17,196)

--- Low (falls)
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

65

Outcome

N studies

(N = total 

patients 

combined)

Combined estimates:

RR (95% CI)

ARR 

N: events (95% CI)

prevented per 1000 highrisk patients over 5 yearsa 

Strength of 

Evidenceb Summary of findings

Quality of 

life (QOL)

4 RCTs

(N = 7,154)

--- Moderate 

(QOL)

Low 

(functional 

status)

Moderate BP control (SBP 140-150 mmHg) did not 

affect QOL. One study found no effect on functional 

status.

Effects of 

age

12 RCTs

(N = 76,137) 

--- Low Similar effects across different age groups in agetreatment interaction analyses, but based on studylevel subgroup analyses and dichotomized at a 

younger age in many studies.

Effects of 

comorbidity 

burden

--- --- No evidence No studies reported outcomes based on comorbidity 

burden; most trials excluded patients with dementia, 

serious comorbidities, and life-limiting illness.

Effects in 

the frail 

elderly

2 RCTs

(N = 5,166)

--- Insufficient Treatment effects did not vary with frailty score in 

post-hoc analyses from 2 trials, one of which had 

large amount of missing data. Most trials did not 

assess frailty, and many trials excluded patients who 

were frail, had dementia, or were institutionalized.

Effects in 

stroke 

patients

2 RCTs

(N = 9,125) 

Stroke recurrence:

RR 0.76 (0.66-0.92)

ARR 3.02

Moderate Targeting SBP < 140 mmHg reduced recurrent 

stroke. 

Cardiac events:

RR 0.78 (0.61-1.08)

Mortality:

RR 0.98 (0.85-1.19)

Abbreviations: ARR = absolute risk reduction; BP = blood pressure; CI = confidence interval; DBP = diastolic blood pressure; N = 

population size (N total / n subgroup); OR = odds ratio; QOL = quality of life; RCT = randomized controlled trial; RR = relative risk; 

SBP = systolic blood pressure. a We used observed control group event rates standardized to 5 years. As poorly controlled blood pressure itself contributes to 

cardiovascular risk, we used data from the 2 most contemporary trials for each set of analyses. We used the HYVET study (22) to 

estimate event rates in the higher baseline blood pressure analyses, and data from SPRINT (the older age subgroup since the mean age 

was comparable to that in HYVET) for the treat to target analyses (50). b

The overall quality of evidence for each outcome is based on the consistency, coherence, and applicability of the body of evidence, as 

well as the internal validity of individual studies. The strength of evidence is classified as follows: 

High = Further research is very unlikely to change our confidence on the estimate of effect.

Moderate = Further research is likely to have an important impact on our confidence in the estimate of effect and may change

the estimate.

Low = 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.

Insufficient = Any estimate of effect is very uncertain. c

The analyses presented here are of trials with baseline SBP 160 mmHg. The achieved SBP in 3 of the trials was < 140 mmHg, but 

these studies contributed relatively few events. Achieved SBP in all the other studies was 140 mmHg. d

Most of the evidence comes from trials in which baseline SBP ≥160 mmHg and achieved SBP was 140-150 mmHg. These are large 

trials providing consistent evidence, and a precise summary estimate.

e

All trials that tested strict versus less strict blood pressure targets in which the target blood pressure in the intervention group was 

SBP < 140 mmHg or DBP < 85 mmHg, or even lower. f The number of prevented events is not applicable because the upper bound of the confidence interval for relative risk was 1.00.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

66

We found no data about the role of comorbidity burden in the relationship between blood 

pressure targets and the identified outcomes of interest, or between burden of comorbidity and 

potential harm of differing blood pressure targets. The importance of multimorbidity and the 

disease-disease and disease-treatment interaction which occurs when multiple chronic conditions 

co-exist is of critical importance to older adults. Co-existence of multiple comorbidities may lead 

to burdensome therapy regimens and adverse therapy interactions based on combinations of 

clinical practice guidelines built around a single focus of disease.62-64 Further, particularly among 

Veterans, hypertension is the most common comorbidity occurring in over 80% of adults over 

age 80, and the number of comorbidities for adults is known to increase with advancing age.9,65

The importance of multimorbidity in older adults makes the relationship between hypertension, 

common comorbidities, and patient-important outcomes an invaluable target for future research. 

As noted above, exclusion criteria specified by these trials often decreased the relative 

comorbidity burden in study populations. In particular, patients with renal disease, heart failure, 

and cancer or comorbid illness likely to limit life expectancy were frequently excluded. 

Importantly, the generalizability of our findings to the oldest age groups is limited. Fewer than 

half of these studies included adults over age 80. The primary exception is HYVET, which 

included only adults over age 80 and described a decreased risk of stroke with moderate blood 

pressure reduction (< 150/90 mm Hg).6 The HYVET trial was like most of the other trials in 

implicitly or explicitly excluding patients with dementia or in long-term care, thus limiting the 

population to relatively high functioning older adults. Given the absence of data on comorbidity 

burden, the applicability of these data to the most elderly patients is questionable, particularly in 

adults over age 80 with significant frailty or poor functional status. This limitation may have 

heightened importance when relevance of these data are considered for the aging Veteran 

population, which experiences a significant burden of comorbidity and frailty.9

A number of recent reviews have also attempted to address the question of optimal blood 

pressure targets in older adults. Dr. Neal and colleagues with BPLTTC recently presented a 

patient-level meta-analysis of adults with mild hypertension (baseline SBP 140 to 159 mm Hg).66

This review was not limited to older adults, however, and the majority of included patients in the 

individual-level analysis also had diabetes. A recent meta-analysis found that a drop in SBP of 

10 mm Hg was associated with reduced mortality, cardiac events, and stroke in patients with 

diabetes.67 This study also found that most of the benefit was limited to studies in which the 

baseline blood pressure was ≥ 140 mm Hg. However, the studies included in this meta-analysis 

were clinically very heterogeneous and included studies of younger patients, trials of 

normotensive patients with conditions such as heart failure, and comparative effectiveness 

studies. The most recently published systematic review concluded that more intensive blood 

pressure treatment was associated with improvements in stroke and cardiovascular outcomes, but 

not mortality.

68 However, this review did not focus on older patients, did not include SPRINT, 

and also did not include several other large trials included in our review. 

Our review contributes further to the literature on hypertension management in older adults by 

specifically limiting study inclusion to populations with mean age over 60 and hypertension, and 

by focusing on studies that used a treat-to-target strategy for blood pressure goals most 

commensurate with the controversy of strict versus moderate blood pressure control in older 

patients. By focusing on treat-to-target studies in addition to studies comparing more versus less 

intensive therapy we hoped to mitigate potential drug-specific effects which could affect 

outcomes (eg, more versus less renin angiotensin system blockade) as well as potentially larger 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

67

and more definitive differences in achieved blood pressures between treatment arms. For similar 

reasons, we did not include comparative effectiveness studies which might speak more to 

optimal medication choice in a particular population as opposed to the true benefits or harms of a 

given level of blood pressure. Finally, our review adds to the existing knowledge base by 

including a broad examination of potential longer-term harms of blood pressure treatment. 

LIMITATIONS

This review has several potential limitations. We could not determine if any specific medication, 

medication class, or combination of medications may have played a role in influencing clinical 

outcomes. The wide variety of medications used across studies and the absence of any pattern 

between medication types and relative risk provides some reassurance that medication-specific 

effects are likely minimal. Moreover, we focused on pharmacologic therapy and, therefore, may 

have missed important effects of nonpharmacological therapy of hypertension. 

The populations and study design varied considerably across included trials. We incorporated a 

number of sensitivity analyses to better understand how different trial characteristics contributed 

to results. While the relative treatment effects remained fairly consistent across different 

analyses, the variation in numbers needed to treat were probably clinically important. We 

therefore strived to remain transparent about the analyses which contributed to the chosen 

summary estimates, and present a range of numbers needed to treat for outcomes in which there 

were significant findings. 

We report study-level data here, but recognize there may be individuals within a study 

population who benefit more or less from treatment. We found fairly consistent results across 

many subgroup analyses. We also are in the process of conducting analyses from 6 trials to see if 

the results reported here remain consistent in patient-level analyses. We focused on comorbidity 

burden rather than specific comorbidities such as diabetes, but it is possible that results might be 

different among certain condition-specific subgroups. 

FUTURE RESEARCH 

There is a need for more research examining how the severity of comorbidity and the presence of 

multiple comorbidities modifies the effects of more intensive blood pressure treatment. Though 

there have been more recent trials which have included patients over age 80, there is a need for 

more research in this age group. Moreover, future studies should enroll patients who have not yet 

been represented in the evidence, including those with cognitive impairment and other causes of 

frailty. Finally, future reviews using individual patient-level data on medication use could clarify 

whether or not the findings in this report apply equally across antihypertensive drug class. 

CONCLUSIONS

Lowering blood pressure in adults over age 60 reduces mortality, stroke, and cardiac events. The 

most consistent and largest effects are seen in studies of patients with higher baseline blood 

pressures (SBP ≥ 160 mmHg) achieving moderate blood pressure control (< 150/90 mmHg). 

Lower treatment targets (< 140/85 mmHg) are likely to be beneficial for some patients at high 

cardiovascular risk, but the results across trials are less consistent. Lower treatment targets are 

largely supported by findings from one trial which targeted SBP <120 mmHg and in which most 

intervention patients achieved SBP < 130 mmHg. In patients with cerebrovascular disease, more 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

68

aggressive blood pressure lowering (SBP <140 mmHg) likely reduces recurrent stroke. Lower 

treatment targets are associated with higher medication burden and an increased risk of shortterm harms such as hypotension. On the other hand, evidence that there is not an increased risk 

in cognitive impairment, falls, and reduced quality of life may provide some flexibility for 

providers in crafting an individualized antihypertensive treatment plan. There is little data to 

assess the risks and benefits of antihypertensive treatment among institutionalized elder patients 

or those with multiple comorbidities.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

69

REFERENCES 

1. Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States:

National Health and Nutrition Examination Survey, 2011-2012. NCHS data brief. Oct

2013(133):1-8.

2. Anonymous. Effects of treatment on morbidity in hypertension. Results in patients with

diastolic blood pressures averaging 115 through 129 mm Hg. Jama. Dec 11

1967;202(11):1028-1034.

3. Anonymous. Medical Research Council trial of treatment of hypertension in older adults:

principal results. MRC Working Party. Bmj. Feb 15 1992;304(6824):405-412.

4. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic

blood pressure averaging 90 through 114 mm Hg. Jama. Aug 17 1970;213(7):1143-1152.

5. The Australian therapeutic trial in mild hypertension. Report by the Management

Committee. Lancet. Jun 14 1980;1(8181):1261-1267.

6. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years

of age or older. N Engl J Med. May 1 2008;358(18):1887-1898.

7. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo

and active treatment for older patients with isolated systolic hypertension. The Systolic

Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. Sep 13

1997;350(9080):757-764.

8. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug

treatment in older persons with isolated systolic hypertension. Final results of the Systolic

Hypertension in the Elderly Program (SHEP). Jama. Jun 26 1991;265(24):3255-3264.

9. Steinman MA, Lee SJ, John Boscardin W, et al. Patterns of multimorbidity in elderly

veterans. J Am Geriatr Soc. Oct 2012;60(10):1872-1880.

10. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management

of high blood pressure in adults: report from the panel members appointed to the Eighth

Joint National Committee (JNC 8).[Erratum appears in JAMA. 2014 May

7;311(17):1809]. Jama. Feb 5 2014;311(5):507-520.

11. Wright JT, Jr., Williamson JD, Whelton PK, et al. A Randomized Trial of Intensive

versus Standard Blood-Pressure Control. N Engl J Med. Nov 26 2015;373(22):2103-2116.

12. Weiss J, Kerfoot A, Freeman M, et al. Benefits and harms of treating blood pressure in

older adults. PROSPERO 2015:CRD42015017677 Available from

http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015017677 .

Accessed August 18, 2015.

13. Sundstrom J, Arima H, Woodward M, et al. Blood pressure-lowering treatment based on

cardiovascular risk: a meta-analysis of individual patient data. Lancet. Aug 16

2014;384(9943):591-598.

14. Higgins JPT, Altman DG, editors. Chapter 8: Assessing risk of bias in included studies.

In: Cochrane Handbook for Systematic Reviews of Interventions. 2008;Version 5.0.1.

The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org

Accessed Dec 5, 2014.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

70

15. Hardy RJ, Thompson SG. A likelihood approach to meta-analysis with random effects.

Stat Med. Mar 30 1996;15(6):619-629.

16. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. Bmj. Sep 6 2003;327(7414):557-560.

17. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure

lowering and low-dose aspirin in patients with hypertension: principal results of the

Hypertension Optimal Treatment (HOT) randomised trial. The Lancet.

1998;351(9118):1755-1762.

18. Berkman ND, Lohr KN, Ansari M, et al. Grading the Strength of a Body of Evidence

When Assessing Health Care Interventions for the Effective Health Care Program of the

Agency for Healthcare Research and Quality: An Update. Methods Guide for

Comparative Effectiveness Reviews (Prepared by the RTI-UNC Evidence-based Practice

Center under Contract No. 290-2007-10056-I). AHRQ Publication No. 13(14)-EHC130-

EF. Rockville, MD: Agency for Healthcare Research and Quality. November 2013.

http://www.effectivehealthcare.ahrq.gov/ehc/products/457/1752/methods-guidancegrading-evidence-131118.pdf Accessed on August 19, 2015

19. Gong L, Zhang W, Zhu Y, et al. Shanghai trial of nifedipine in the elderly (STONE). J

Hypertens. Oct 1996;14(10):1237-1245.

20. Wang JG, Staessen JA, Gong L, Liu L. Chinese trial on isolated systolic hypertension in

the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group. Arch

Intern Med. Jan 24 2000;160(2):211-220.

21. Wei Y, Jin Z, Shen G, et al. Effects of intensive antihypertensive treatment on Chinese

hypertensive patients older than 70 years. J Clin Hypertens (Greenwich). Jun

2013;15(6):420-427.

22. ACCORD Study Group. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes

Mellitus. N Engl J Med. 2010;362(17):1575-1585.

23. Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood

pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label

randomised trial. Lancet. 2009;374(9689):525-533.

24. Goto Y, Ishii M, Saruta T, et al. Principal results of the Japanese trial to assess optimal

systolic blood pressure in elderly hypertensive patients (JATOS). Hypertension research:

official journal of the Japanese Society of Hypertension. 2008;31(12):2115-2127.

25. SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients

with recent lacunar stroke: the SPS3 randomised trial.[Erratum appears in Lancet. 2013

Aug 10;382(9891):506 Note: Coffey, C S [aded]]. Lancet. Aug 10 2013;382(9891):507-

515. 

26. Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated

systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension

study. Hypertension. Aug 2010;56(2):196-202.

27. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and

indapamide on macrovascular and microvascular outcomes in patients with type 2

diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet.

2007;370(9590):829-840.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

71

28. Ruggenenti P, Fassi A, Ilieva A, et al. Effects of verapamil added-on trandolapril therapy

in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B

randomized trial. J Hypertens. Feb 2011;29(2):207-216.

29. Amery A, Brixko P, Clement D, et al. Mortality and morbidity results from the European

Working Party on High Blood Pressure in the Elderly trial. The Lancet.

1985;325(8442):1349-1354.

30. Liu L, Zhang Y, Liu G, et al. The Felodipine Event Reduction (FEVER) Study: a

randomized long-term placebo-controlled trial in Chinese hypertensive patients. J

Hypertens. Dec 2005;23(12):2157-2172.

31. Progress Collaborative Group. Randomised trial of a perindopril-based blood-pressurelowering regimen among 6,105 individuals with previous stroke or transient ischaemic

attack.[Erratum appears in Lancet 2002 Jun 15;359(9323):2120], [Erratum appears in

Lancet 2001 Nov 3;358(9292):1556]. Lancet. Sep 29 2001;358(9287):1033-1041.

32. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and

cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med.

2001;345(12):861-869.

33. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly

(SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens.

May 2003;21(5):875-886.

34. Hara A, Thijs L, Asayama K, Jacobs L, Wang JG, Staessen JA. Randomised double-blind

comparison of placebo and active drugs for effects on risks associated with blood

pressure variability in the systolic hypertension in europe trial. PLoS ONE. 2014;9(8).

35. TRANSCEND Investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor

blocker telmisartan on cardiovascular events in high-risk patients intolerant to

angiotensin-converting enzyme inhibitors: a randomised controlled trial.[Erratum appears

in Lancet. 2008 Oct 18;372(9647):1384]. Lancet. Sep 27 2008;372(9644):1174-1183.

36. Beckett N, Peters R, Leonetti G, et al. Subgroup and per-protocol analyses fromthe

hypertension in the very elderly trial. J Hypertens. 2014;32(7):1478-1487.

37. ACCORD Study Group. Supplement to: The ACCORD Study Group. Effects of

intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med

2010;362:1575-85. DOI: 10.1056/NEJMoa1001286.

38. Kjeldsen SE, Kolloch RE, Leonetti G, et al. Influence of gender and age on preventing

cardiovascular disease by antihypertensive treatment and acetylsalicylic acid. The HOT

study. J Hypertens. 2000;18(5):629-642.

39. White CL, Szychowski JM, Pergola PE, et al. Can blood pressure be lowered safely in

older adults with lacunar stroke? The Secondary Prevention of Small Subcortical Strokes

study experience. J Am Geriatr Soc. Apr 2015;63(4):722-729.

40. Staessen JA, Thijs L, Gasowski J, Cells H, Fagard RH. Treatment of isolated systolic

hypertension in the elderly: further evidence from the systolic hypertension in Europe

(Syst-Eur) trial. Am J Cardiol. Nov 12 1998;82(9B):20R-22R.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

72

41. van Dieren S, Kengne AP, Chalmers J, et al. Effects of blood pressure lowering on 

cardiovascular outcomes in different cardiovascular risk groups among participants with 

type 2 diabetes. Diabetes Res Clin Pract. Oct 2012;98(1):83-90. 

42. Zanchetti A, Hansson L, Clement D, on behalf of the HOTSG, et al. Benefits and risks of 

more intensive blood pressure lowering in hypertensive patients of the HOT study with 

different risk profiles: does a J-shaped curve exist in smokers? J Hypertens. 

2003;21(4):797-804. 

43. Ferrucci L, Furberg CD, Penninx BW, et al. Treatment of isolated systolic hypertension 

is most effective in older patients with high-risk profile. Circulation. Oct 16 

2001;104(16):1923-1926. 

44. Voyaki SM, Staessen JA, Thijs L, et al. Follow-up of renal function in treated and 

untreated older patients with isolated systolic hypertension. Systolic Hypertension in 

Europe (Syst-Eur) Trial Investigators. J Hypertens. Mar 2001;19(3):511-519. 

45. Beckett N, Forette F, Tuomilehto J, et al. Incident dementia and blood pressure lowering 

in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVETCOG): a double-blind, placebo controlled trial. The Lancet.Neurology. 2008;7(8):683-

689. 

46. Forette F, Seux ML, Staessen JA, et al. The prevention of dementia with antihypertensive 

treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) 

study.[Erratum appears in Arch Intern Med. 2003 Jan 27;163(2):241.]. Arch Intern Med. 

Oct 14 2002;162(18):2046-2052. 

47. Williamson JD, Launer LJ, Bryan RN, et al. Cognitive function and brain structure in 

persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid 

levels: a randomized clinical trial. JAMA Intern Med. Mar 2014;174(3):324-333. 

48. Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with 

perindopril and indapamide therapy on dementia and cognitive decline in patients with 

cerebrovascular disease. Arch Intern Med. May 12 2003;163(9):1069-1075. 

49. Skoog I, Lithell H, Hansson L, et al. Effect of baseline cognitive function and 

antihypertensive treatment on cognitive and cardiovascular outcomes: Study on 

COgnition and Prognosis in the Elderly (SCOPE). Am J Hypertens. Aug 

2005;18(8):1052-1059. 

50. McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients 

without prior cerebrovascular disease for prevention of cognitive impairment and 

dementia. Cochrane Database Syst Rev. 2009(4):CD004034. 

51. Bird AS, Blizard RA, Mann AH. Treating hypertension in the older person: an evaluation 

of the association of blood pressure level and its reduction with cognitive performance. J 

Hypertens. Feb 1990;8(2):147-152. 

52. Liu H, Gao S, Hall KS, et al. Optimal blood pressure for cognitive function: findings 

from an elderly African-American cohort study. J Am Geriatr Soc. Jun 2013;61(6):875-

881. 

53. Sacktor N, Gray S, Kawas C, Herbst J, Costa P, Fleg J. Systolic blood pressure within an 

intermediate range may reduce memory loss in an elderly hypertensive cohort. J Geriatr 

Psychiatry Neurol. 1999;12(1):1-6. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

73

54. Peng J, Lu F, Wang Z, et al. Excessive Lowering of Blood Pressure Is Not Beneficial for

Progression of Brain White Matter Hyperintensive and Cognitive Impairment in Elderly

Hypertensive Patients: 4-Year Follow-Up Study. J Am Med Dir Assoc. 2014;15(12):904-

910. 

55. Black HR, Curb JD, Pressel S, Probstfield JL, Stamler J, eds. Systolic Hypertension in

the Elderly Program (SHEP): baseline characteristics of the randomized sample.

Hypertens. 1991;17(Suppl 2):162-167.

56. Applegate WB, Pressel S, Wittes J, et al. Impact of the treatment of isolated systolic

hypertension on behavioral variables. Results from the systolic hypertension in the

elderly program. Arch Intern Med. Oct 10 1994;154(19):2154-2160.

57. Fletcher AE, Bulpitt CJ, Thijs L, et al. Quality of life on randomized treatment for

isolated systolic hypertension: results from the Syst-Eur Trial. J Hypertens. Oct

2002;20(10):2069-2079.

58. Wiklund I, Halling K, Ryden-Bergsten T, Fletcher A. Does lowering the blood pressure

improve the mood? Quality-of-life results from the Hypertension Optimal Treatment

(HOT) study. Blood Press. Nov 1997;6(6):357-364.

59. Degl'Innocenti A, Elmfeldt D, Hofman A, et al. Health-related quality of life during

treatment of elderly patients with hypertension: results from the Study on COgnition and

Prognosis in the Elderly (SCOPE). J Hum Hypertens. Apr 2004;18(4):239-245.

60. Margolis KL, Palermo L, Vittinghoff E, et al. Intensive blood pressure control, falls, and

fractures in patients with type 2 diabetes: the ACCORD trial. J Gen Intern Med.

2014;29(12):1599-1606.

61. Peters R, Beckett N, Burch L, et al. The effect of treatment based on a diuretic

(indapamide) +/- ACE inhibitor (perindopril) on fractures in the Hypertension in the Very

Elderly Trial (HYVET). Age Ageing. Sep 2010;39(5):609-616.

62. Fried TR, Tinetti ME, Iannone L, O'Leary JR, Towle V, Van Ness PH. Health outcome

prioritization as a tool for decision making among older persons with multiple chronic

conditions. Arch Intern Med. Nov 14 2011;171(20):1854-1856.

63. Fried TR, McGraw S, Agostini JV, Tinetti ME. Views of older persons with multiple

morbidities on competing outcomes and clinical decision-making. J Am Geriatr Soc. Oct

2008;56(10):1839-1844.

64. Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and

quality of care for older patients with multiple comorbid diseases: implications for pay

for performance. Jama. Aug 10 2005;294(6):716-724.

65. Boyd CM, Ritchie CS, Tipton EF, Studenski SA, Wieland D. From Bedside to Bench:

summary from the American Geriatrics Society/National Institute on Aging Research

Conference on Comorbidity and Multiple Morbidity in Older Adults. Aging Clin Exp Res.

Jun 2008;20(3):181-188.

66. Sundstrom J, Arima H, Jackson R, et al. Effects of blood pressure reduction in mild

hypertension: a systematic review and meta-analysis. Ann Intern Med. Feb 3

2015;162(3):184-191.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

74

67. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure

lowering in type 2 diabetes: a systematic review and meta-analysis. Jama. Feb 10

2015;313(6):603-615.

68. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on

cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet.

Jan 30 2016;387(10017):435-443.

69. Staessen JA, Fagard R, Thijs L, et al. Subgroup and per-protocol analysis of the

randomized European Trial on Isolated Systolic Hypertension in the Elderly. Arch Intern

Med. Aug 10-24 1998;158(15):1681-1691.
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

75

APPENDIX A. SEARCH STRATEGIES 

Databases Searched: 

Ovid Medline

PubMed [Publisher status segment]

Embase

Cochrane Library (Ovid EBM Reviews): Cochrane Central Register of Controlled Trials;

Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects;

Health Technology Assessment; NHS Economic Evaluation Database

Grey Literature Sources: 

ClinicalTrials.gov

World Health Organization International Clinical Trials Registry Platform (WHO

ICTRP)

International Standard Randomised Controlled Trials Number registry (ISRCTN)

Conference Papers Index

Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) 1946 to January Week 4 2015

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations January 29, 2015

Date of search: January 30, 2015

1 Hypertension/ 193547 

2 hypertension, malignant/ 2172 

3 hypertension, renal/ 12991 

4 hypertension, renovascular/ 6296 

5 (hypertensive or hypertension or ((high or elevated or raised) adj2 blood pressure)).ti,ab. 333658 

6 blood pressure/ 238359 

7 systole/ 16952 

8 diastole/ 14899 

9 (blood pressure* or arterial pressure* or systole* or (systol* and (pressure* or mm Hg or mm Hg)) or 

diastole* or (diastol* and (pressure* or mm Hg or mm Hg)) or BP or DBP or (SBP not spontaneous 

bacterial peritonitis)).ti,ab.

401649 

10 or/1-9 757490 

11 antihypertensive agents/ or acebutolol/ or alprenolol/ or amlodipine/ or atenolol/ or 

bendroflumethiazide/ or bepridil/ or betaxolol/ or bethanidine/ or bisoprolol/ or bupranolol/ or 

captopril/ or carteolol/ or celiprolol/ or chlorisondamine/ or chlorothiazide/ or chlorthalidone/ or 

cilazapril/ or clonidine/ or cyclopenthiazide/ or diazoxide/ or dihydralazine/ or diltiazem/ or 

doxazosin/ or enalapril/ or enalaprilat/ or felodipine/ or fosinopril/ or guanabenz/ or guanfacine/ or 

hydralazine/ or hydrochlorothiazide/ or hydroflumethiazide/ or indapamide/ or indoramin/ or 

isradipine/ or labetalol/ or lisinopril/ or losartan/ or methyldopa/ or metipranolol/ or metolazone/ or 

metoprolol/ or mibefradil/ or minoxidil/ or nadolol/ or nicardipine/ or nimodipine/ or nisoldipine/ or 

nitrendipine/ or oxprenolol/ or pempidine/ or penbutolol/ or perindopril/ or pinacidil/ or pindolol/ or 

polythiazide/ or prazosin/ or propranolol/ or ramipril/ or reserpine/ or timolol/ or todralazine/ or 

trichlormethiazide/ or xipamide/ or (antihypertensive or anti-hypertensive).ti,ab.

191932 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

76

12 adrenergic alpha-antagonists/ or adrenergic alpha-1 receptor antagonists/ or doxazosin/ or indoramin/ 

or labetalol/ or prazosin/ or adrenergic alpha-2 receptor antagonists/ or adrenergic beta-antagonists/ or 

alprenolol/ or bunolol/ or bupranolol/ or carteolol/ or dihydroalprenolol/ or iodocyanopindolol/ or 

levobunolol/ or metipranolol/ or nadolol/ or oxprenolol/ or penbutolol/ or pindolol/ or propranolol/ or 

sotalol/ or timolol/ or adrenergic beta-1 receptor antagonists/ or acebutolol/ or atenolol/ or betaxolol/ 

or bisoprolol/ or celiprolol/ or metoprolol/ or practolol/ or adrenergic beta-2 receptor antagonists/ or 

adrenergic beta-3 receptor antagonists/ or (adrenergic alpha-antagonist* or adrenergic 

alphaantagonist*).ti,ab.

93013 

13 angiotensin-converting enzyme inhibitors/ or captopril/ or cilazapril/ or enalapril/ or enalaprilat/ or 

fosinopril/ or lisinopril/ or perindopril/ or ramipril/ or angiotensin-converting enzyme inhibitor*.ti,ab.

43990 

14 angiotensin receptor antagonists/ or angiotensin ii type 1 receptor blockers/ or losartan/ or saralasin/ or 

angiotensin ii type 2 receptor blockers/ or angiotensin receptor antagonist*.ti,ab.

17586 

15 calcium channel blockers/ or amlodipine/ or amrinone/ or bencyclane/ or bepridil/ or cinnarizine/ or 

diltiazem/ or felodipine/ or fendiline/ or flunarizine/ or gallopamil/ or isradipine/ or lidoflazine/ or 

mibefradil/ or nicardipine/ or nifedipine/ or nimodipine/ or nisoldipine/ or nitrendipine/ or tiapamil 

hydrochloride/ or verapamil/ or calcium channel blocker*.ti,ab.

70143 

16 diuretics/ or acetazolamide/ or amiloride/ or bendroflumethiazide/ or bumetanide/ or chlorothiazide/ or 

chlorthalidone/ or clopamide/ or cyclopenthiazide/ or ethacrynic acid/ or ethoxzolamide/ or 

furosemide/ or hydrochlorothiazide/ or hydroflumethiazide/ or indapamide/ or mefruside/ or 

methazolamide/ or methyclothiazide/ or metolazone/ or muzolimine/ or polythiazide/ or 

spironolactone/ or ticrynafen/ or triamterene/ or trichlormethiazide/ or xipamide/ or diuretics, osmotic/ 

or isosorbide/ or diuretics, potassium sparing/ or epithelial sodium channel blockers/ or 

mineralocorticoid receptor antagonists/ or sodium chloride symporter inhibitors/ or sodium potassium 

chloride symporter inhibitors/ or diuretic*.ti,ab.

77139 

17 vasodilator agents/ or acetylcholine/ or adenosine/ or "adenosine-5'-(n-ethylcarboxamide)"/ or 

alprostadil/ or amiodarone/ or amrinone/ or amyl nitrite/ or bencyclane/ or bepridil/ or betahistine/ or 

bradykinin/ or calcitonin gene-related peptide/ or celiprolol/ or chromonar/ or colforsin/ or 

cromakalim/ or cyclandelate/ or diazoxide/ or dihydroergocristine/ or dihydroergocryptine/ or dilazep/ 

or diltiazem/ or dipyridamole/ or dyphylline/ or enoximone/ or ergoloid mesylates/ or erythritol/ or 

erythrityl tetranitrate/ or flunarizine/ or hexobendine/ or iloprost/ or isosorbide dinitrate/ or 

isoxsuprine/ or isradipine/ or khellin/ or lidoflazine/ or mibefradil/ or milrinone/ or minoxidil/ or 

molsidomine/ or moxisylyte/ or nafronyl/ or niacin/ or nicardipine/ or nicergoline/ or nicorandil/ or 

nicotinyl alcohol/ or nifedipine/ or nimodipine/ or nisoldipine/ or nitrendipine/ or nitroglycerin/ or 

nitroprusside/ or nonachlazine/ or nylidrin/ or oxprenolol/ or oxyfedrine/ or papaverine/ or 

pentaerythritol tetranitrate/ or pentoxifylline/ or perhexiline/ or phenoxybenzamine/ or pinacidil/ or 

pindolol/ or pituitary adenylate cyclase-activating polypeptide/ or polymethyl methacrylate/ or 

prenylamine/ or s-nitroso-n-acetylpenicillamine/ or s-nitrosoglutathione/ or s-nitrosothiols/ or sodium 

azide/ or suloctidil/ or theobromine/ or theophylline/ or thiouracil/ or tolazoline/ or trapidil/ or 

trimetazidine/ or vasoactive intestinal peptide/ or verapamil/ or xanthinol niacinate/ or endotheliumdependent relaxing factors/ or nitric oxide/ or vasodilator*.ti,ab.

350538 

18 Aldosterone/ 21964 

19 Chlorisondamine/ 543 

20 Mineralocorticoids/ or Desoxycorticosterone/ or Desoxycorticosterone Acetate/ 8175 

21 Pempidine/ 163 

22 Renin-Angiotensin System/ 14256 

23 or/11-22 632178 

24 exp Cardiovascular Diseases/ 1901992 

25 exp Heart Failure/ 88568 

26 exp Kidney Diseases/ or exp Kidney Failure, Chronic/ 415035 

27 hypotension/ 17869 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

77

28 stroke/ or brain infarction/ or brain stem infarctions/ or lateral medullary syndrome/ or cerebral 

infarction/ or dementia, multi-infarct/ or infarction, anterior cerebral artery/ or infarction, middle 

cerebral artery/ or infarction, posterior cerebral artery/ or stroke, lacunar/

88131 

29 polypharmacy/ 2517 

30 exp cognition disorders/ 63655 

31 exp dementia/ 121166 

32 accidental falls/ 15941 

33 exp fractures, bone/ 142161 

34 "quality of life"/ 121510 

35 (death* or mortalit* or morbidit* or comorbidit* or co-morbidit* or multimorbidit* or multi-morbidit* 

or coexist* or co-exist* or stroke* or infarct* or multiinfarct* or multi-infarct* or transient ischemic 

attack* or TIA or cerebrovascular or (heart adj (disease* or failure*)) or ((renal or nephro* or kidney) 

adj2 (disease* or failure* or disorder* or injury or injuries)) or AKI or fracture* or falls or cognit* or 

dementia* or hypotension or hypotensive or polypharm* or "quality of life").ti,ab.

2265610 

36 or/24-35 3913057

37 and/10,23,36 120955 

38 limit 37 to "all aged (65 and over)" 30492 

39 (elder* or aged or old or older or oldest or senior* or geriatric* or gerontolog* or sexagenarian* or 

septuagenarian* or octogenarian* or nonagenarian*).ti,ab.

1436775 

40 37 and 39 15236 

41 38 or 40 38096 

42 cohort studies/ or follow-up studies/ or longitudinal studies/ or prospective studies/ or retrospective 

studies/ or ((cohort* or trial*) adj3 extension*).ti,ab.

1387757 

43 and/41-42 7501 

44 limit 43 to (comment or editorial or letter) 77 

45 43 not 44 7424 

46 limit 45 to english language [OBSERVATIONAL STUDY RESULTS] 6655 

47 limit 41 to (meta analysis or systematic reviews) 643 

48 47 not 46 541 

49 limit 48 to english language [META-ANALYSIS AND SYSTEMATIC REVIEW RESULTS] 474 

50 and/10,23 162820 

51 (201212* or 2013* or 2014* or 2015*).ed. or (201212* or 2013* or 2014* or 2015*).dc. 2570599 

52 and/50-51 10390 

53 limit 52 to (clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or pragmatic 

clinical trial or randomized controlled trial)

1037 

54 limit 53 to english language 988 

55 remove duplicates from 54 [RCT/CCT RESULTS] 956 

EMBASE (Elsevier)

http://embase.com

Date of search: January 30, 2015 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

78

Search Strategy Results

44 #41 OR #42 OR #43 2,594

43 #39 AND ([controlled clinical trial]/lim OR [randomized controlled trial]/lim) AND 

[english]/lim NOT [medline]/lim

1,138

42 #39 AND [english]/lim AND ([cochrane review]/lim OR [systematic review]/lim OR [meta 

analysis]/lim) NOT [medline]/lim 

186

41 #40 AND [english]/lim NOT ([editorial]/lim OR [letter]//lim OR [medline]/lim) 1,475

40 #39 AND ('cohort analysis'/de OR 'observational study'/de OR 'prospective study'/de OR 

'retrospective study'/de OR 'longitudinal study'/de OR 'follow-up study':ab,ti OR 'follow-up 

studies':ab,ti OR ((cohort* OR trial*) NEAR/3 extension*):ab,ti) 

6,637

39 #37 OR #38 65,498

38 #7 AND #22 AND #35 AND (elder*:ab,ti OR aged:ab,ti OR old:ab,ti OR older:ab,ti OR 

oldest:ab,ti OR senior*:ab,ti OR geriatric*:ab,ti OR gerontolog*:ab,ti OR sexagenarian*:ab,ti 

OR septuagenarian*:ab,ti OR octogenarian*:ab,ti OR nonagenarian*:ab,ti)

37,068

37 #7 AND #22 AND #35 AND ([aged]/lim OR [very elderly]/lim) 42,220

36 #7 AND #22 AND #35 251,536

35 #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #33 OR #34 5,706,843

34 death*:ab,ti OR mortalit*:ab,ti OR morbidit*:ab,ti OR comorbidit*:ab,ti OR 'comorbidity':ab,ti OR 'co-morbidities':ab,ti OR multimorbidit*:ab,ti OR 'multi-morbidity':ab,ti 

OR 'multi-morbidities':ab,ti OR coexist*:ab,ti OR 'co-existing':ab,ti OR stroke*:ab,ti OR 

infarct*:ab,ti OR multiinfarct*:ab,ti OR 'multi-infarction':ab,ti OR 'multi-infarctions':ab,ti OR 

'transient ischemic attack':ab,ti OR 'transient ischemic attacks':ab,ti OR tia:ab,ti OR 

cerebrovascular:ab,ti OR (heart NEXT/1 (disease* OR failure*)):ab,ti OR ((renal OR nephro* 

OR kidney) NEAR/2 (disease* OR failure* OR disorder* OR injury OR injuries)):ab,ti OR 

aki:ab,ti OR fracture*:ab,ti OR falls:ab,ti OR cognit*:ab,ti OR dementia*:ab,ti OR 

hypotension:ab,ti OR hypotensive:ab,ti OR polypharm*:ab,ti OR 'quality of life':ab,ti 

2,969,107

33 'quality of life'/de 268,408

32 'fracture'/exp 215,542

31 'falling'/de 25,824

30 'dementia'/exp 238,471

29 'disorders of higher cerebral function'/exp 553,733

28 'polypharmacy'/de 7,732

27 'cerebrovascular disease'/exp 480,125

26 'hypotension'/exp 106,487

25 'kidney disease'/exp 707,514

24 'heart failure'/exp 322,750

23 'cardiovascular disease'/exp 3,134,649

22 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 

OR #20 OR #21

1,125,178

21 'renin angiotensin aldosterone system'/de 31,112

20 'pempidine'/de 283

19 'deoxycorticosterone acetate'/de 2,712

18 'deoxycorticosterone'/de 7,177

17 'mineralocorticoid'/exp 71,060

16 'chlorisondamine'/de 1,025

15 'aldosterone'/de 31,797

14 'vasodilator agent'/exp OR vasodilator*:ab,ti 430,197

13 'diuretic agent'/exp OR diuretic*:ab,ti 310,799

12 'calcium channel blocking agent'/exp OR 'calcium channel blocker':ab,ti OR 'calcium channel 

blockers':ab,ti

187,980

11 'angiotensin 2 receptor antagonist'/exp OR 'angiotensin ii receptor antagonist':ab,ti OR 

'angiotensin ii receptor antagonists':ab,ti

8,252

10 'angiotensin receptor antagonist'/exp OR 'angiotensin receptor antagonist':ab,ti OR 'angiotensin 

receptor antagonists':ab,ti

63,456

9 'adrenergic receptor blocking agent'/exp OR 'adrenergic alpha-antagonist':ab,ti OR 'adrenergic 

alpha-antagonists':ab,ti OR 'adrenergic alphaantagonist':ab,ti 

342,302
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

79

8 'antihypertensive agent'/exp OR antihypertensive:ab,ti OR 'anti hypertensive':ab,ti 593,629

7 #1 OR #2 OR #3 OR #4 OR #5 OR #6 1,115,118

6 'blood pressure':ab,ti OR 'arterial pressure':ab,ti OR systole*:ab,ti OR (systol*:ab,ti AND 

(pressure*:ab,ti OR mm Hg:ab,ti OR 'mm hg':ab,ti)) OR diastole*:ab,ti OR (diastol*:ab,ti AND 

(pressure*:ab,ti OR mm Hg:ab,ti OR 'mm hg':ab,ti)) OR bp:ab,ti OR dbp:ab,ti OR (sbp:ab,ti 

NOT 'spontaneous bacterial peritonitis':ab,ti)

505,982

5 'diastole'/de 14,230

4 'systole'/de 13,554

3 'blood pressure'/exp 415,778

2 hypertensive:ab,ti OR hypertension:ab,ti OR (((high OR elevated OR raised) NEAR/2 

blood):ab,ti AND pressure:ab,ti)

458,732

1 'hypertension'/exp 513,148

Cochrane Library (Ovid EBM Reviews)

Cochrane Central Register of Controlled Trials December 2014 

Cochrane Database of Systematic Reviews 2005 to December 2014 

Database of Abstracts of Reviews of Effects 4th Quarter 2014 

Health Technology Assessment 4th Quarter 2014 

NHS Economic Evaluation Database 4th Quarter 2014

Date of search: January 30, 2015 

1 (hypertensive or hypertension or ((high or elevated or raised) adj2 blood pressure)).ti,ab. 29303 

2 (blood pressure* or arterial pressure* or systole* or (systol* and (pressure* or mm Hg or mm Hg)) or 

diastole* or (diastol* and (pressure* or mm Hg or mm Hg)) or BP or DBP or (SBP not spontaneous 

bacterial peritonitis)).ti,ab.

44700 

3 and/1-2 16149 

4 (antihypertensive or anti-hypertensive).ti,ab. 8074 

5 (adrenergic alpha-antagonist* or adrenergic alphaantagonist*).ti,ab. 0 

6 angiotensin-converting enzyme inhibitor*.ti,ab. 2444 

7 angiotensin receptor antagonist*.ti,ab. 74 

8 calcium channel blocker*.ti,ab. 1575 

9 diuretic*.ti,ab. 4287 

10 vasodilator*.ti,ab. 2596 

11 or/4-10 16071 

12 (death* or mortalit* or morbidit* or comorbidit* or co-morbidit* or multimorbidit* or multi-morbidit* 

or coexist* or co-exist* or stroke* or infarct* or multiinfarct* or multi-infarct* or transient ischemic 

attack* or TIA or cerebrovascular or (heart adj (disease* or failure*)) or ((renal or nephro* or kidney) 

adj2 (disease* or failure* or disorder* or injury or injuries)) or AKI or fracture* or falls or cognit* or 

dementia* or hypotension or hypotensive or polypharm* or "quality of life").ti,ab.

155570 

13 (elder* or aged or old or older or oldest or senior* or geriatric* or gerontolog* or sexagenarian* or 

septuagenarian* or octogenarian* or nonagenarian*).ti,ab.

70846 

14 and/3,11-13 536 

15 limit 14 to medline records [Limit not valid in CDSR,DARE,CLHTA,CLEED; records were retained] 407 

16 14 not 15 129 

17 limit 16 to english language [Limit not valid in CDSR,DARE; records were retained] 84 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

80

APPENDIX B. STUDY SELECTION 

Table 9. Inclusion Codes, Code Definitions, and Criteria Corresponding to the Key Questions

Code Definition KQ1.What are the 

health outcome 

effects of differing 

blood pressure 

targets?

KQ2. How does age 

modify the benefits 

of differing blood 

pressure targets?

KQ3a. How does the patient 

burden of comorbidities modify 

the benefits of differing blood 

pressure targets?

KQ3b. In patients who have 

suffered a TIA/stroke, does 

treatment of blood pressure to 

specific targets affect outcomes?

KQ4. Do the harms of 

targeting lower blood 

pressure vary with age?

KQ5. Do the harms of 

targeting lower blood

pressure vary with patient 

burden of comorbidities? 

I – Trial Trials with ≥ 6 months of 

follow-up that address any 

of KQs 1-5.

Population: Adults aged ≥60 with hypertension

Intervention: Pharmacologic treatment of hypertension

Comparator: Usual care, or another specified SBP target.

Primary outcomes:

All-cause mortality

Mortality related to stroke, CHD, CHF, and renal disease

Morbidity including stroke, CHD, CHF, and renal disease

Timing: Published 2012 or later. Incidence of outcomes ≥ 6 months of 

hypertension treatment.

Study design: Controlled trials (randomized or non-randomized) with ≥ 6 

months of follow-up.

PICTS as for KQs 1-3, but with harms outcomes:

Changes in cognition

Falls

Changes to quality of life

Hypotension

Acute kidney injury

Code B: large (n>10k) cohort studies that only report

All-cause mortality

Cardiovascular outcomes

I –

Cohort

Cohort studies are 

included for KQs 4-5 only 

if they report harms. 

Large (N>10,000)

multi-center cohort

studies.

Cohort extensions of

major trials.

Data on the primary outcomes listed above will not be abstracted from cohort 

studies. 

Controlled study designs (RCT and non-randomized

controlled clinical trials used for KQs 1-3)

Cohort extensions of trials that examined specific

blood pressure targets

Cohort studies that examined the effects of lower

blood pressure in the context of antihypertensive

medication

Cohort studies that reported the effects of lower blood

pressure despite that hypertension management was

not the primary objective of the intervention studied.

I – Stroke Trials of any duration that 

address KQ3a. 

Population KQ3b: Aged ≥60 with hypertension and recent cerebrovascular accident (≤ 6 months).

Intervention KQ3b: Pharmacologic treatment of hypertension within the first 6 months post-stroke.

Additional outcomes of interest for KQ3b: Recurrent cerebrovascular accident; Functional status; Disability

I – SR Systematic review or 

meta-analysis on any of 

the KQs
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

81

Table 10. Exclusion Codes, Code Definitions, and Criteria Corresponding to the Key Questions

Code Definition KQ1.What are the 

health outcome effects 

of differing blood 

pressure targets?

KQ2. How does age 

modify the benefits 

of differing blood 

pressure targets?

KQ3a. How does the patient burden of 

comorbidities modify the benefits of 

differing blood pressure targets?

KQ3b. In patients who have suffered a 

TIA or stroke, does treatment of blood 

pressure to specific targets affect 

outcomes?

KQ4. Do the harms of 

targeting lower blood 

pressure vary with 

age?

KQ5. Do the harms of 

targeting lower blood 

pressure vary with patient 

burden of comorbidities? 

X1 Non-English 

publication

Note: most foreign language studies will be filtered out during initial library cleaning.

X2 Article does not pertain 

in any way to 

hypertension -Rx 

treatment in older adults

X3 Study population is not 

in scope for any of the 

KQs

Include: Adults with hypertension aged ≥ 60 or mean age ≥60. For KQ3: existing comorbidity or recent cerebrovascular accident (≤ 6 months). 

Exclude: Studies with mean age < 60.

X4 No primary data, or 

study design not in 

scope

Exclude:

Controlled before/after studies

Case reports/case series

RCTs with less than 6 month follow-up

X5 Intervention modality or 

study objectives are not 

in scope

Exclude:

Trials for which hypertension management was not the primary objective, despite

that secondary effects on hypertension may be reported, eg, TNT for the j-curve

effect.

Non-pharmacologic interventions for blood pressure control

Blood pressure interventions during the acute phase post-stroke (KQ3a).

Note: For KQs 4- 5, cohort studies that report harms 

of lower blood pressure may be included even if 

hypertension management was not the primary 

objective of the intervention studied.

X6 None of the reported 

outcomes are in scope

Primary outcomes of interest:

All-cause mortality

Mortality related to stroke, CHD, CHF, and renal disease

Morbidity including stroke, CHD, CHF, and renal disease

Harms of interest:

Changes in cognition

Falls

Changes to quality of life

Polypharmacy

X7 Other reason, specify

B Background Add ‘B’ any of the above X codes (eg, ‘X6–B’) if the article contains information that may be useful for the introduction, discussion, 

limitations, future research, or other contextual purposes. Add comments or keywords as needed.

B = background; KQ = key question; CHD = congenital heart disease; CHF = congestive heart failure; RCT = randomized controlled trials; TIA = transient ischemic attack; TNT = 

treat to new targets 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

82

APPENDIX C. QUALITY ASSESSMENT

Table 11. Assessment of Randomized Controlled Trials for Potential Risk of Bias

Study

Allocation 

sequence 

adequately 

generated?

Allocation 

adequately 

concealed?

Knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Incomplete 

outcome data 

adequately 

addressed?

Free of suggestion 

of selective 

outcome 

reporting?

Free of other 

problems that could 

put it at a high risk 

of bias?

Summary 

assessment

High/Low/ 

Unclear 

Risk of 

Bias

Funder

ACCORD22 Yes: central, 

computer-based 

randomization

Yes Yes: non-blinded 

study, but they used 

dual, blinded outcome 

adjudicators 

Missing data 

assumed to be 

random, sensitivity 

analysis performed 

and outcome 

measures not 

significantly 

changed

Yes Yes Low National

Heart, Lung, 

Blood 

Institute; 

NIH 

agencies

ADVANCE27 Yes: central, 

computer-based, 

randomization 

Yes Yes: participants, 

providers, outcome 

assessors all blinded

Yes: extremely low 

loss-to follow-up, 15 

patients in a sample 

of >11,000

Yes Yes Low Servier; 

National 

Health and 

Medical 

Research 

Council of 

Australia

BENEDICTB28Yes: central, 

computer-based 

randomization

Yes Yes: participants, 

providers, outcome 

assessors all blinded 

Yes: all censored 

events included in 

analysis, power and 

statistical 

significance were 

adequate

Yes Yes Low Mario Negri 

Institute for 

Pharmacolo

gic 

Research/Ins

titute for 

Rare 

Diseases

Cardio-Sis23 Yes: central, 

computer-based 

randomization

Yes Yes: open-label study, 

but outcome 

adjudicators were 

blinded

Yes: only one 

patient lost to 

follow-up

Yes: Primary 

outcome was left 

ventricular 

hypertrophy, but 

cardiovascular and 

mortality endpoints 

were prespecified 

secondary 

outcomes

Yes Low Heart Care 

Foundation; 

BoehringerIngelheim, 

SanofiAventis;

Pfizer
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

83

Study

Allocation 

sequence 

adequately 

generated?

Allocation 

adequately 

concealed?

Knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Incomplete 

outcome data 

adequately 

addressed?

Free of suggestion 

of selective 

outcome 

reporting?

Free of other 

problems that could 

put it at a high risk 

of bias?

Summary 

assessment

High/Low/ 

Unclear 

Risk of 

Bias

Funder

EWPHE29 Probably: patients 

were randomized 

and allocated by a 

central 

coordinating 

center, but exact 

method of 

randomization 

was not reported

Yes: central 

allocation

Yes: providers, 

patients, and outcome 

assessors all blinded

Yes: similar loss to 

follow-up in both 

groups (14 vs 16%), 

ITT analysis for 

mortality outcome

Yes, though ITT 

analysis was only 

performed for 

mortality outcome

Yes Low Belgian 

National 

Research 

Foundation; 

Merck, 

Sharp and 

Dohme and 

Smith; Kline 

and French

FEVER30 Yes: central, 

computer-based 

randomization

Yes Yes Yes: life-status 

could not be 

obtained at study 

end but number was 

low (0.3%)

Yes Yes Low National 

Science and 

Technology 

Ministry; 

Beijing 

Hypertensio

n League 

Institute and 

Shanxi 

Kangbao 

Pharmaceuti

cal 

Company

HOT17 Yes: central, 

computer-based 

randomization

Yes Yes: open-label but 

outcome adjudicators 

were blinded

Yes: 2.6% of 

patients lost to 

follow-up; total of 

1.8% of all patientyears analyzed 

contained in 

censored group; 

analysis conducted 

up to time of loss 

and BP or prior 

morbidity not found 

to be significantly 

different

Yes Yes Low Astra AB, 

Sweden;

Astra Merck 

Inc, USA; 

TEVA, 

Israel; 

Hoechst, 

Argentina
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

84

Study

Allocation 

sequence 

adequately 

generated?

Allocation 

adequately 

concealed?

Knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Incomplete 

outcome data 

adequately 

addressed?

Free of suggestion 

of selective 

outcome 

reporting?

Free of other 

problems that could 

put it at a high risk 

of bias?

Summary 

assessment

High/Low/ 

Unclear 

Risk of 

Bias

Funder

HYVET6 Yes: central, 

computer-based 

randomization

Yes Yes: providers, 

patients, outcome 

assessors blinded

Yes: very low loss 

to follow-up (0.3% 

overall); ITT 

analysis

Yes Yes: though of note 

inclusion criteria 

changed over time

Low British Heart 

Foundation; 

Institut de 

Recherches 

International

es Servier

JATOS24 Yes: central, 

computer-based 

randomization

Yes Yes: outcome 

assessors blinded; 

providers and patients 

likely not blinded but 

not clearly reported

Yes: censored 

events reported but 

no sensitivity 

analysis performed; 

ITT analysis 

Yes Unclear: there was 

not enough precision 

in protocol 

information 

describing outcome 

definitions

Low Shionogi 

and Co. 

LTD

PROGRESS31Yes: central 

computer-based 

randomization 

Yes Yes: providers, 

patients, and outcome 

assessors blinded

Yes: very low loss 

to follow-up, though 

it is unclear whether 

this refers to vital 

status outcome or 

patients attending 

follow-up visits; ITT 

analysis 

Yes Yes Low Servier; 

Health 

Research 

Council of 

New 

Zealand; 

National 

Health and 

Medical 

Research 

Council of 

Australia

RENAAL32 Yes: central, 

computer-based 

randomization

Yes Yes: providers, 

patients, outcome 

assessors blinded

Yes: very low loss 

to follow-up; ITT 

analysis

Yes Unclear - study was 

stopped early because 

of new data that ACE 

inhibitors were 

beneficial for 

population similar to 

that under study 

(considered unethical 

to continue)

Low Merck
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

85

Study

Allocation 

sequence 

adequately 

generated?

Allocation 

adequately 

concealed?

Knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Incomplete 

outcome data 

adequately 

addressed?

Free of suggestion 

of selective 

outcome 

reporting?

Free of other 

problems that could 

put it at a high risk 

of bias?

Summary 

assessment

High/Low/ 

Unclear 

Risk of 

Bias

Funder

SCOPE33 Yes: central 

randomization by 

fax 

Yes Yes: placebo control Yes: losses to 

follow-up accounted 

for, multiple 

outcomes reported, 

ITT analysis

Yes Yes: dual 

independent 

qualitative 

assessment reviews; 

sufficiently powered; 

prospective

Low AstraZeneca

SHEP8 Yes: central 

randomization and 

allocation

Yes Yes: providers, 

patients, outcome 

assessors blinded 

Yes: only 5 patients 

in each group were 

unavailable for 

follow-up; ITT 

analysis

Yes Yes Low National 

Heart, Lung, 

Blood 

Institute; 

National 

Institute on 

Aging

SPRINT11 Yes: central 

computer-based 

randomization

Yes Yes: open-label, but 

outcomes were 

centrally adjudicated 

by blinded assessors

Yes: losses to 

follow-up accounted 

for, multiple 

outcomes reported, 

ITT analysis

Yes Unclear: trial was 

stopped early by 

DSMB for benefit

Low National 

Institutes

of Health

SPS325 Yes: central, 

computer-based 

randomization 

Yes Yes: open-label, but 

outcome assessors 

blinded

Yes: though details 

on those lost to 

follow-up not 

available, overall 

rate low (3%); ITT 

analysis

Yes Yes Low NIH-NINDS

STONE19 No: patients were 

allocated 

alternately by 

entry order 

number 

No Yes: placebo control, 

but patients in placebo 

whose DBP >110 after 

the run-in period were 

switched by their 

physicians to active 

treatment

Yes: 2% loss to 

follow-up; ITT 

analysis

Yes: outcomes 

appear to be fully 

reported, but with 

methodological 

flaws earlier in 

study protocol

Yes: none others 

detected; 

randomization issues 

are serious

High Ministry of 

Health of 

People's 

Republic of 

China; 

Bayer 

Canada
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

86

Study

Allocation 

sequence 

adequately 

generated?

Allocation 

adequately 

concealed?

Knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Incomplete 

outcome data 

adequately 

addressed?

Free of suggestion 

of selective 

outcome 

reporting?

Free of other 

problems that could 

put it at a high risk 

of bias?

Summary 

assessment

High/Low/ 

Unclear 

Risk of 

Bias

Funder

Syst-China20 No: eligible 

patients at each 

center were 

alternatingly 

assigned to type A 

or type B 

medication

No Yes: placebo control Yes: ITT analysis; 

patients who 

withdrew remained 

in open follow-up; 

patients without any 

report within the 

year before the trial 

ended classified as 

lost to follow-up, 

but included in 

analysis up to the 

most recent 

evaluation of health 

status

Yes Yes: randomization 

and allocation flaws 

have unclear effect on 

effectiveness 

estimates; 

methodological flaws

significant

High State 

Planning 

Commission 

of the 

People’s 

Republic of 

China

Syst-Eur34 Yes: central 

randomization and 

allocation

Yes Yes: patients, 

providers, outcome 

assessors blinded

No: losses to followup and adverse 

events incompletely 

discussed, no 

illustrating figures

Yes Yes Low Bayer; 

National 

Fund for 

Scientific 

Research

TRANSCEND35Yes: central, 

computer-based 

randomization

Yes Yes: patients, 

providers, outcome 

assessors blinded

Yes: 99.7% had vital 

status ascertained; 

primary analysis 

included all patients, 

used time-to-event 

approach, counting 

the first occurrence 

of any component of 

the composite 

outcome 

Yes Yes Low Boehringer 

Ingelheim

VALISH26 Yes: Centralized 

computer 

randomization

Yes No: open label Yes: 181 (5.5%) 

patients lost to 

follow-up; censored 

patients analyzed up 

to censoring event; 

ITT analysis

Yes Yes Low Japan 

Cardiovascu

lar Research 

Foundation
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

87

Study

Allocation 

sequence 

adequately 

generated?

Allocation 

adequately 

concealed?

Knowledge of the 

allocated intervention 

adequately prevented 

during the study?

Incomplete 

outcome data 

adequately 

addressed?

Free of suggestion 

of selective 

outcome 

reporting?

Free of other 

problems that could 

put it at a high risk 

of bias?

Summary 

assessment

High/Low/ 

Unclear 

Risk of 

Bias

Funder

Wei, 201321 Yes: random 

numbers table 

computergenerated

Unclear 

whether 

allocation 

itself was 

concealed

No: open label and not 

enough detail about 

outcome adjudication 

procedure

No: concerning that 

those lost-to-followup are not 

mentioned in 

analysis; ITT 

analysis

Yes No: small sample 

size, generalizability; 

no limitations 

section; inadequate 

description of how 

they obtained 

outcome information 

such as mortality or 

how they assessed 

cardiac events 

High Not 

disclosed
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

88

APPENDIX D. DATA SUPPLEMENT 

Table 12. Detailed Results of Trials that Conducted Age-stratified Analyses

Study

Comparison, T vs C

Age groups

(N patients) Results comparing T vs C, by outcome and age group

Studies that compared BP targets (mm Hg)

ACCORD37

SBP < 120 vs < 140

< 65

≥ 65

(Total N = 4733;

 n per age group 

not reported)

Unadjusted HR for combined nonfatal MI, nonfatal stroke, and cardiovascular death

(95% CIs not reported, but were not statistically significant, interpreted from graph):

 < 65: 0.90

≥ 65: 0.91

Age interaction P-value = .98

HOT38

DBP ≤ 80 vs ≤ 85 vs ≤ 90

< 65 (n = 12803)

≥ 65 (n = 5987)

Events/1000 patient-years by DBP group ≤ 80 vs ≤ 85 vs ≤ 90 mm Hg (P-value for 

trend; HR calculated from event rates, 95% CI not reported): 

Total mortality:

 < 65: 5.7 vs 5.5 vs 4.5 (P = .13)

 HR ≤ 80 vs ≤ 85: 1.04

 HR ≤ 80 vs ≤ 90: 1.27

≥ 65: 15.4 vs 13.9 vs 15.7 (P =.89)

 HR ≤ 80 vs ≤ 85: 1.11

 HR ≤ 80 vs ≤ 90: 0.98

Cardiovascular death:

 < 65: 2.2 vs 2.9 vs 1.9 (P = .52)

 HR ≤ 80 vs ≤ 85: 0.76

 HR ≤ 80 vs ≤ 90: 1.16

≥ 65: 8.0 vs 5.7 vs 7.6 (P = .81)

 HR ≤ 80 vs ≤ 85: 1.40

 HR ≤ 80 vs ≤ 90: 1.05

MI:

 < 65: 2.3 vs 2.9 vs 3.2 (P = .13)

 HR ≤ 80 vs ≤ 85: 0.79

 HR ≤ 80 vs ≤ 90: 0.72

≥ 65: 3.2 vs 2.4 vs 4.4 (P = .22)

 HR ≤ 80 vs ≤ 85: 1.33

 HR ≤ 80 vs ≤ 90: 0.73

Stroke:

 < 65: 2.4 vs 3.8 vs 2.3 (P = .77)

 HR ≤ 80 vs ≤ 85: 0.63

 HR ≤ 80 vs ≤ 90: 1.04

≥ 65: 6.7 vs 6.6 vs 7.8 (P = .41)
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

89

Study

Comparison, T vs C

Age groups

(N patients) Results comparing T vs C, by outcome and age group

HR ≤ 80 vs ≤ 85: 1.02

HR ≤ 80 vs ≤ 90: 0.86

JATOS24

SBP < 140 vs < 160

< 75 (n = 2549)

≥ 75 (n = 1869)

RR (95% CI)

P-value for interaction term in Cox regression with treatment, age, sex, and 

interaction between treatment and age as covariates:

Cerebrovascular disease:

< 75: 0.65 (0.29 to 1.45)

≥ 75: 1.52 (0.77 to 3.00)

P = .03

Cardiovascular disease:

< 75: 0.77 (0.26 to 2.25)

≥ 75: 1.07 (0.43 to 2.67) 

P = .50

Renal failure:

< 75: 0.60 (0.09 to 3.91)

≥ 75: 1.25 (0.22 to 7.00)

P = .75

SPS339

SBP < 130 vs 130-149

< 75 (n = 2526)

≥ 75 (n = 494) 

HR (95% CI)

Total mortality

< 75: 1.13 (0.80 to 1.59)

≥ 75: 0.83 (0.53 to 1.29)

Vascular death

< 75: 1.17 (0.68 to 2.01)

≥ 75: 0.42 (0.18 to 0.98)

MI:

< 75: 0.91 (0.56 to 1.48)

≥ 75: 0.77 (0.23 to 2.52)

Recurrent stroke: 

< 75: 0.77 (0.59 to 1.01)

≥ 75: 1.01 (0.59 to 1.73)

VALISH26

SBP < 140 vs < 150

< 75 (n = 1233)

≥ 75 (n = 1846)

Combined sudden death; stroke; MI; death due to CHF; other cardiovascular death; 

unplanned hospitalization for cardiovascular disease; and renal dysfunction, HR 

(95% CI): 

< 75: 0.74 (0.35 to 1.56) 

≥ 75: 0.95 (0.60 to 1.51)

Studies that compared more vs less intensive treatment for hypertension

ADVANCE27 < 65 (n = 4536) Major macrovascular or microvascular events combined, unadjusted RR (95% CI):
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

90

Study

Comparison, T vs C

Age groups

(N patients) Results comparing T vs C, by outcome and age group

(Perindopril + indapamide) vs

placebo

≥ 65 (n = 6604) < 65: 0.95 (0.82 to 1.09)

≥ 65: 0.90 (0.81 to 1.00)

HYVET36

Indapamide vs placebo

80-84 (n = 2807)

≥ 85 (n = 1038)

HR (95% CI):

Total mortality: 

80-84: 0.76 (0.60 to 0.97)

≥ 85: 0.88 (0.64 to 1.20)

Cardiovascular mortality:

80-84: 0.75 (0.55 to 1.05) 

≥ 85: 0.82 (0.53 to 1.32)

Cardiac events: 

80-84: 0.64 (0.49 to 0.83)

≥ 85: 0.75 (0.50 to 1.12)

Stroke:

80-84: 0.70 (0.46 to 1.06)

≥ 85: 0.59 (0.27 to 1.29) 

SHEP8

Chlorthalidone vs placebo

60-69 (n = 1963)

70-79 (n = 2124)

≥ 80 (n = 649)

Stroke RR (95% CI):

60-69: 0.74 (0.48 to 1.14)

70-79: 0.65 (0.46 to 0.92)

≥ 80: 0.53 (0.32 to 0.88)

Syst-China20

(Nitrendipine ± Captopril ± 

Hydrochlorothiazide) vs placebo

< 65 (n = 1079)

65-69 (n = 699)

≥ 70 (n = 616)

Unadjusted HR (P-values interpreted from graph):

Cardiovascular mortality:

 < 65: 0.34 (P < .05)

65-69: 0.67 (P = ns)

≥ 70: 0.89 (P = ns)

Fatal + nonfatal cardiovascular events:

 < 65: 0.54 (P < .05)

65-69: 0.80 (P = ns)

≥ 70: 0.62 (P = ns)

Syst-Eur40,69

Nitrendipine vs placebo

60-69 (n = 2501)

70-79 (n = 1753)

≥ 80 (n = 441)

Unadjusted HR (95% CIs not reported; P-values interpreted from graph):69

Total mortality:

60-69: 0.59 (P = ns) 

70-79: 0.58 (P < .05)

≥ 80: 1.11 (P = ns)

Cardiovascular death:

60-69: 0.58 (P = ns)

70-79: 0.49 (P < .05)

≥ 80: 0.97 (P = ns)

Cardiac events:
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

91

Study

Comparison, T vs C

Age groups

(N patients) Results comparing T vs C, by outcome and age group

60-69: 0.64 (P = ns)

70-79: 0.69 (P = ns)

≥ 80: 0.79 (P = ns)

Stroke:

60-69: 0.46 (P < .05)

70-79: 0.54 (P < .05)

≥ 80: 0.67 (P = ns)

"In Cox regression with adjustment applied for significant covariates, the treatmentby-age interaction term was significant (P = .009) for total mortality and nearly 

significant (P = .09) for cardiovascular mortality, indicating that the benefit of 

treatment was lost after the age of about 75 years. In contrast, the treatment-by-age 

interaction for the combined fatal and nonfatal events was not statistically 

significant."40

TRANSCEND35

Telmisartan vs placebo

< 65 (n = 2375)

65-74 (n = 2576)

≥ 75 (n = 975)

Composite outcome of cardiovascular death, myocardial infarction, or stroke: No 

significant age interaction (P = .80)

Abbreviations: ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease; C = comparator/control; 

CHF = congestive heart failure; CI = Confidence interval; DBP = Diastolic blood pressure; HOT = Hypertension Optimal Treatment; HR = hazard ratio; HYVET 

= Hypertension in the Very Elderly Trial; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; MI = myocardial 

infarction; N = Number randomized; ns = not statistically significant; RR = relative risk; SBP = systolic blood pressure; SHEP = Systolic Hypertension in the 

Elderly Program; SPS3 = Secondary Prevention of Small Subcortical Strokes; Syst-China = Systolic Hypertension in China; Syst-Eur = Systolic Hypertension in 

Europe; T = treatment; TRANSCEND = Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease; VALISH = 

Valsartan in Elderly Isolated Systolic Hypertension. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

92

Figure 8. Relative risk of mortality in trials of patients with history of stroke

CI = confidence interval; PROGRESS = Perindopril Protection Against Recurrent Stroke Study; SPS3 = Secondary 

Prevention of Small Subcortical Strokes 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

93

Figure 9. Relative risk of major cardiac events in trials of patients with history of stroke

CI = confidence interval; PROGRESS = Perindopril Protection Against Recurrent Stroke Study; SPS3 = Secondary 

Prevention of Small Subcortical Strokes
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

94

APPENDIX E. PEER REVIEWER COMMENTS AND AUTHOR RESPONSES

Question Text Reviewer 

Number Comment Response

Are the objectives, scope, and 

methods for this review clearly 

described?

2-10, 12, 

15, 16

All responded: Yes 

Is there any indication of bias 

in our synthesis of the 

evidence?

2-10, 12, 

15, 16

All responded: No 

Are there any published or 

unpublished studies that we 

may have overlooked?

2, 3, 5, 6, 9, 

10, 12, 15, 

16

No 

4 Yes - I'm sure it wasn't overlooked, it just hasn't been published yet. SPRINT. 

NIH held press conference today. because it has not yet been published it cannot 

be included in the meta-analysis, but it could and probably should be mentioned 

in the narrative as being a study to consider when results are published.

SPRINT has been included

7 Yes - The SHEP study did report a significant increase in falls in the intervention 

vs control group (which you note in your table but not the text). 

We added this information in the text. 

There is a very small observational study (JAMA Int Med, Mosello, 2015) 

finding that the combination of multiple blood pressure medications and lowest 

tertile of BP among patients with dementia was associated with greater loss of 

MMSE points.

This was published after our search. The results are in line with 

several other observational studies that fell within our search dates. 

All of the observational studies of cognition, including this one, 

have some issues with confounding. Given that there were 7 RCTs 

examining cognitive outcomes and that we’ve already included 

several obs studies with similar findings as this one, it is unlikely 

that the addition of the Mosello study would alter results. 

There is a very recent trial of withdrawal of blood pressure medications in 

Leiden (the DANTE trial) Annals Internal Medicine 2015 (last week), by 

Noonen et al, that did not find short term improvements in cognition.

Interesting study – falls out of the scope of our key questions. 

8 Yes - I would not say overlooked, but the SPRINT study is obviously going to 

be influential.

SPRINT has been included

Additional suggestions or 

comments can be provided 

below. If applicable, please 

indicate the page and line 

numbers from the draft report.

2 See comments in the attached file.

A matter not addressed in this review is the important but controversial issue of 

BP management in the subacute period after stroke. In general, there is fear that 

dropping BP in the first hours post-stroke (when collaterals may be perfusing atrisk brain) can extend damage in stroke and worsen outcomes, yet a few studies 

using ACE-I or ARB drugs begun within 24- to 48-hours of stroke decreased 

recurrence or mortality. I would urge caution in applying the results of long-term 

trials to the acute post-stroke period.

We have added some language to the methods and results to clarify 

that we did not examine management of acute stroke. 

While no suggestive signal was seen in this review, the issue remains as to 

whether some anti-hypertensive individual drugs or classes of drugs might have 

superior outcomes independent of BP targets or actual reduction in BP achieved.

This has been suggested for ACE-Is and ARBs for the outcome of initial or 

recurrent stroke.

Noted. We were not able to identify a clear pattern, but one would 

really need to look at comparative effectiveness studies and 

individual level data to answer this question. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

95

Question Text Reviewer 

Number Comment Response

3 P31 line 21: I would add that the SPS 3 trial showed a statistically significant 

reduction in intracerebral hemorrhage, a type of stroke with high mortality.

Noted. We’ve reported the outcome of all strokes. SPS3 reports 5 

different stroke outcomes including a variety of hemorrhagic stroke 

outcomes. The intracerebral hemorrhage outcome was the only one 

with p < 0.05. Moreover, the rate of disabling or fatal strokes with 

similar in both groups. It would be misleading for us to report one 

secondary outcome and not all others. 

P 46, line 52: Discussion: Did any of the studies report sex differences in the 

benefits of BP lowering?

We did not systematically evaluate this question. 

P 46, line 47: Would add that even though the absolute benefit may be small, the 

population and health system benefits may be worthwhile

noted

6 Table on page 5,line 11 comment on mortality says "more moderate targets 

(SBP<140mm Hg). Shouldn't it say (SBP>140)?

Page 6: list of abbreviations under the table (line 33) does not include ROB nor 

is ROB listed in the abbreviations list on pages 8-9.

Page 20, line 15 "monotherapy with benzene"--should that be benazepril instead 

of benzene?

page 32, line 33,"described and increased risk" should be "described an 

increased risk"

Appreciated – all noted and corrected. 

8 I am including these as attachments.

9 The report is well-written. Thank you

Page 2, line 39, did cough and hypotension vary with age? There were no data on this. 

Table 10 provides information about risk of bias, but little text is provided about 

how these assessments were made.

We followed standard methods for assessment (ref included). We 

revised table to include more detail, especially for areas in which we 

noted flaws. 

Page 31, line 9, SPS3 had a "rigorous" definition of stroke as stated, but it was 

also restrictive to one type of ischemic stroke (namely only lacunar infarcts); 

therefore, results may not be generalizable to other stroke types (e.g., 

hemorrhagic stroke or large artery atherosclerotic ischemic stroke). How may 

the results be applicable to Veterans with a history of transient ischemic attack?

We’ve revised the language to be more clear about the inclusion 

criteria in both the SPS3 and PROGRESS trials. The progress trial 

did include a broader definition of stroke and TIA. 

Page 45, line 18 (typographical error, errant 6). noted

General comment: consider hyphenating "treat-to-target" studies throughout 

(there are occasions without use of hyphens.

done

Limitations Section: consider including a statement that the included trials used 

pharmacologic treatment of hypertension and therefore excluded trials that 

focused on non-pharmacologic approaches to hypertension management.

We have added this. 

A statement about domains where additional research is needed would be of 

interest.

We have added a brief future research section. 

10 Although a few studies are of questionable quality, they are adequately handled 

and don't bias the conclusions. Although this was written before SPRINT was 

announced, if not mentioned, you could add that it may address this question, or 

you could comment that it is unpublished at this time, but shows benefots for a 

population average age 68 years.

SPRINT has been included

15 see attachment for comments
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

96

Question Text Reviewer 

Number Comment Response

16 A thorough review of evidence regarding intensity of treatment for hypertension 

that provides guidance but perhaps more notably identifies the need for 

additional investigation. 

1. Would encourage consistency in the use of abbreviations (i.e. once define use 

consistently thereafter - risk of bias/ROB).

2. Would also recommend more consistent use of symbols (i.e. < & >) to define 

blood pressure targets rather than prose ((i.e. 140 mm HG or less).

3. Forest plots are somewhat blurred and would benefit from sharpening.

4. Please include justification for exclusion of comparative effectiveness studies.

Noted and revised accordingly

Additional comments – Reviewer #2 Response

Page 3, Line 6: It would be useful to state whether the difference was significant or not, and by what p value, given the 

rather high NNTs. (also insert comma after NNT ##)

As above, all the #’s have changed. We present CI and NNT 

throughout

Page 11, Line 54: An interesting and controversial topic is whether some anti-hypertensive individual drugs or classes of 

drugs have superior outcomes independent of BP target or actual reduction in BP. This has been suggested for ACE-Is and 

ARBs for the outcome of initial or recurrent stroke. I understand this was outside the scope of your review, but did you find 

enough in the literature to suggest this as a future topic for exploration?

Agree an interesting topic, but outside scope – as we note in 

limitations partly this would be answered by comparative 

effectiveness studies which we did not include. 

Page 11, Line 59: We surmised the (change “the” to “that”) Noted

Page 15, Line 37: I gather from the below that no studies were excluded if they targeted DBP rather than SBP? Correct, we have clarified inclusion/exclusion criteria

Page 15 Line 53: In an effort to better understand treatment effects among different age subgroups, we explored the 

possibility of gathering data to conduct analysis (change to analyses) based on individual patient data from blood pressure 

treatment trials.

Noted

Page 16, Line 6: “We anticipate using data from these six trials to conduct meta-analyses examining blood pressure 

treatment benefits and harms in those age 60-69, 70-79, 80-89, and over age 90.” Will the results be disseminated in a 

subsequent report?

We anticipate writing up a separate manuscript of these results. 

Page 18, Line 11: “Overall, there was little to no consistent evidence of a clinically significant

incremental benefit of treating blood pressures to levels substantially below current guideline

recommend (change to recommended) levels of 150/90 in patients over age 60.”

Noted

Page 18, Line 41: “The remaining studies had primary outcomes related to renal disease or microalbuminuria27,31 or

additional outcomes not specified (delete specified) of interest for this review (LVH regression).20”

Noted

Page 18, Line 43: Among trials which specified a particular medication as first-line therapy, seven used ace (ACE - term 

should be defined at first use) inhibitors or angiotensin-receptor blockers, 5 used calcium channel blockers, and six used 

diuretics (Tables 2 and 3). 

Noted

Page 23, Line 25: You might want to comment on reduced significance (p value) with population subset. However, it's 

confusing that CI does not include 1 yet p > 0.05. Is this a mult. comparisons adjustment?

Again, all #’s have changed. We use CI preferentially throughout. 

Just a note that all of the figures appear blurry (out of focus) in my copy. Noted – we have tried to improve the appearance of the figures. 

Page 51, Line 18: Another issue not addressed is the important but controversial issue of BP management in the subacute 

period after stroke. In general, there is fear that dropping BP in the first hours post-stroke (when collaterals may be 

perfusing at-risk brain) can extend damage in stroke and worsen outcomes, yet a few studies using ACE-I or ARB drugs 

begun within 24- to 48-hoours of stroke decreased recurrence or mortality. Perhaps a subject for a future ESP review?

Agree – interesting topic, but out of scope (and we added statement 

clarifying that we did not include acute stroke). 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

97

Additional comments – Reviewer #4 Response

Overall, this is an excellent review of the evidence. These are comments that may help make the review more useful to 

clinicians:

- It is very helpful that the achieved BPs in the trials has been included. 

- The lack of evidence about effect of comorbidity burden is striking and should be a call to clinical trialists to gather more

information in that area. 

We added this to future research section

- Possibly more could be done with the available information about ADE rates, for example, in one place there is mention 

that 4 of 10 trials found increased withdrawals due to ADEs in older individuals (particularly cough and hypotension, with 

hypotension being potentially serious). Page 7 could use more cautions re the ADE statements.

We have added a statement in discussion about potential seriousness 

of hypotension given the increased rate of syncope in 2 studies. 

- There is mention that HYVET study excluded patients with dementia or nursing home; however, my recollection (should 

be checked with source data) is that the individuals in HYVET were quite healthy for age (not just “not frail” but healthier 

than average). Since this group is a major contributor to information about lack of impact on adverse events in those over 

75, it is important to provide more detail about how health this group was.

We have created a new table focused on exclusion criteria of each 

trial to better examine this issues of applicability

- In general, I think it would be good to make more visible the issue of to whom the findings may be generalized. Clinicians 

are looking for guidance. It is important, for example, not to assume that because HYVET had certain findings that these 

findings would apply to all patients over age 80. 

See above

o It would be helpful to have information in the tables with more detailed descriptions of the study populations at baseline,

to make it clearer what where the characteristics of the study populations, so that clinicians managing older Veterans and 

other older adults can more easily compare the patients in the studies to the patient about whom they are making clinical 

decisions, to understand how similar (or not) their patient may be to the patients in the clinical trials that form the evidence 

base.

See above

o Further along those lines, it would be helpful to describe in the narrative some comparisons of the baseline characteristics

and the events in the study groups with the typical prevalence among Veterans (who receive their care in VA) in 

comparable age groups. For example, there is mention of low stroke or other event rates, but the expected rates in the 

typical Veteran population are not shown so it is hard to make the comparison.

We have included more about study event rates. The rates in 

Veterans will vary markedly depending on their risk factor profile. 

We have added more discussion about risk factor profile and study 

inclusion in the treat to target trial section

o Although there were no studies with evidence about the role of comorbidity, it would be helpful at least to describe to the

extent the data are available in the study reports the baseline extent of comorbidity.

See above

o Where ADEs are at low rates, comparison of the rates in general population , or ideally in VA patient population, over

time would be helpful for comparison

We have noted comparison of ADEs within trials, but do not have 

data on these ADEs in general population

- A large study of BP targets is underway in the SPRINT trial. A press briefing by NIH today (9/11/2015) released results. 

The paper has not yet been peer-reviewed and published, so it cannot be included in the meta-analysis, but some mention of 

this study should be in this report. Some information from the trial that we would hope to see in the published report:

SPRINT has been included

o subgroup analysis for the older patients (by decades within the older age groups), with outcomes, length of time in trial,

achieved BPs, variability in SBPs, pulse pressures, etc, length of time in trial and at target BP and/or on final number of 

drugs (i.e., how much time for ADEs to become apparent), quality of life reports, intolerance rates for drugs

These analyses would require individual patient level data – we are 

working on individual patient data meta-analyses with data from 6 

trials to get at some of these issues (eg - outcomes by age decile)

o baseline data on comorbidities broken down by age group Most studies did not report comorbidities in this way. 

o analyses of interactions of age and comorbidity and ADEs:

- It may be hard for some clinical readers to understand why some studies were included by the criterion of comparing more 

intensive to less intensive therapy, but other studies were not. There are several studies that compare drug therapy to 

placebo, so appear to be studies of impact of treating HTN, or studies of impact of a particular drug, rather than specifically 

more vs less intensive treatment (although drug therapy vs placebo is certainly more intense vs less intense). Without 

pulling all the studies and looking at the underlying study design, it isn’t easily clear to the reader why these studies of drug 

vs placebo are included while other studies of drug vs placebo are not.

We have tried to clarify this in the methods section under study 

selection. We did not exclude any studies of drug vs placebo that met 

other criteria (age and hypertensive population). 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

98

Additional comments – Reviewer #4 Response

- the Limitations section acknowledges that there may be specific medication effects that are not part of the analyses in this 

ESP. this is an important point. There are specific drugs with more effect on outcomes (as in ALLHAT) and there are 

specific drugs that may, at least theoretically, have lower rates of particular ADEs (for example, thiazide diuretics may 

block calcium loss and may theoretically decrease risk of osteopenia). I agree that with the already limited number of 

studies with which to examine the key questions it would seem to be impossible to disentangle the effects of particular 

drugs.

Noted

- In addition to evidence regarding comorbidities, it would be useful to have evidence about the impact of the total number 

of medications that patient has apart from antihypertensives. As another descriptive factor about the study populations, 

information about total number of meds at baseline, as compared with total number of meds for VA patients of same age, 

would help clinicians with knowing how well the study patients resemble the patients they are seeing every day.

Most studies did not report this information. 

- with the NNT of 10,000 given on page 28, seems that any conclusions about stroke should be very cautious. We have re-run analyses as noted elsewhere and these numbers have 

changed. 

Additional comments – Reviewer #8 Response

I appreciate the concise executive summary. I was surprised that there was no discussion of how to handle HOT, which 

used DBP targets and the emphasis on achieved BP rather than target BP. In many cases, the studies were described as not 

having a target BP, but usually there was some information about the approach, though it was not used in this summary, 

presumably because the details were not precisely defined. I also did not find a justification for combining very disparate 

intervention and control interventions. Beyond the general idea that one arm achieved at least a tiny bit lower BP than the 

other in every study, there seems little justification for combining a placebo controlled study where the control arm had only 

a target SBP of less than 219 mm Hg to a study like HOT, where everyone targeted a DBP below 90, and some lower still. 

It does not appear the authors considered generating a more qualitative summary or at least some discussion of the 

implications of combining these very different studies. I did appreciate they looked at a number of more homogeneous 

subgroups, but the criteria were limited to baseline characteristics or achieved control in the intervention group, it seems.

The fact that some of the studies had almost no difference in achieved BP, or had very different BP goals/permitted levels 

for the less intensive group was not addressed. 

Appreciate the insightful comments. We have markedly changed 

much of the results section and the summary of evidence table both 

because we re-ran all analyses with SPRINT and in part to respond 

to these comments. Most of the RR/ARR have changed. We have 

clarified the rationale for synthesizing the data the way we did – 

hopefully it will be clear that we examined the data from different 

directions and that we clarified that the treat to target trials are 

distinct from the others. We revamped the way we analyzed and 

discussed the HOT trial. We also, hopefully, more clearly present the 

rationale and results of the numerous sensitivity analyses which 

should get at some of the issues noted here. For instance, we ran 

analyses excluding trials with minimal achieved differences in BP. 

We also included more detail under the “trial characteristics” section. 

Finally, we agree that the combination of all studies is relatively 

meaningless – we’ve explained this in results and deleted the 

combined analysis.

The table on page 5 has some useful numbers, though I found some confusing. In the first, mortality, row the point 

estimates of RR are actually very significant, even though they are not statistically significant. I think that the large N of the 

studies suggests that they pretty definitively ruled out an important benefit, but actually, the ARR seen in the subset is a 

pretty important change – the idea of preventing one death for every 100 persons treated is huge. It is a little hard to 

interpret since you use % when most people would have events per 100 pt – years. Here I can’t tell if is 1% a year, or 1% 

over 20 years of treatment – pretty different things. 

See above - these numbers have changed with new analyses

The stroke row is a really confusing one. The apparently statistically significant RR of 0.72 seems like it would be clinically 

important – a 28% RR reduction is as good as or better than we see with statins and MI in people with CVD!! But then the 

ARR is 0.01% - that is 1/10000. For me to reconcile these two numbers, I have to have an event rate of 3.6/10,000 

compared to an event rate of 2.6/10,000. This seems like the stroke rate per week in some high risk groups and makes the 

NNT of 10,000 not so unimpressive after all!!! Again, the use of percentages is confusing in an ARR presentation. I think 

that a statistical explanation of these numbers would help me. I recognize that they likely come from different approaches to 

synthesizing data, and therefore can’t be quite as simplistically interpreted as if they came from a single trial, but the 

relationship between ARR and RR needs to be transparent. 

See above – numbers have changed. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

99

Additional comments – Reviewer #8 Response

Overall, it seems very hard to say that the evidence justifies the conclusion “Overall, we found moderate-strength evidence

that using a systolic blood pressure target of 140 mm Hg or less did not appreciably improve outcomes in older patients 

compared to slightly higher targets.” Rather, I would say you “found little evidence that using a target of 140 mm Hg or less 

appreciably improve outcomes, but (you) cannot exclude as much as a 1/3 reduction in most important cardiovascular 

outcomes.” If you disagree, you need to reconcile your point estimates and 95% CI with the conclusions in some way that I 

don’t see in the current version. 

See above – we have revised the conclusions based on newer 

analyses

I think the conclusion on stroke is not very useful because it does nto discuss a target but a range. And the range is wide 

enough that people are going to wonder – “so what do you mean? Do you want them below 130 or do you want them below 

140?” It is going to take an extra drug to get someone from 139 to 129, in most cases. So you need to describe what the data 

say iin a little more detail. Are you saying that <130 was better than < 150 and < 140 was better than < 150, but we can’t 

tell if 130 or 140 are any different? Then it seems to me you are saying you can’t tell if any further reduction below 140 is 

worth it. When you discussed the overall numbers, it seems you would not endorse < 140 as better because there was no 

studies where you took people in the 140-160 range and pushed some lower and left some above 140. So to me, you should 

say you don’t have any studies of people < 140 that showed any additional benefit. So the benefit of <130 is not shown at 

all. 

Agree – we have tried to clarify exactly what each trial showed. 

FULL SYNTHESIS

I won’t complain about the summary or the referring to the ‘rate’ of events without any evidence of a time frame, since I 

already said I found it confusing. I think that given the persistent references to the relative unimportance of a relative risk 

reduction of 25% some discussion of why they have that opinion is appropriate. It is greater than the benefit seen in some 

statin trials for primary and even secondary prevention, and similar to that seen with treatment in younger individuals. I 

can’t account for some of the ARR calculations that suggest a remarkably small ARR in the setting of a significant event 

rate and a reasonably large summary estimate of RRR. But at least a reasonable approach would be to apply the observed 

RRR to a typical event rate in the target population and consider whether that would be considered a little more important 

than they consider the statistically significant drops in mortality and stroke, based solely on the quantitative combined 

analysis. 

As above, we have redone our analyses with SPRINT and with the 

HOT subgroups combined differently so the RR and ARR have 

changed substantially as a result. 

The comment on less heterogeneity in mortality among the 3 trials comparing <140 to higher targets, while I assume is 

mathematically true, is counterintuitive, since they include both the study with highest RR and the study with the lower RR 

among the 6 in Table 2. It really reflects the fact that with these smaller trials the fact that the results are quite disparate is 

not as statistically unlikely. Maybe you could tone that comment down. And the summary OR is really just the impact of 

the Wei study, which has 138 of the 164 deaths. I wonder if you should be making some comment on the Wei study, which 

is quite influential both in this analysis, and in the overall comparison of less intensive to more intensive trgets. The Wei 

study has a mortality in the less intensive arm that is more than 20% over 4 years. In contrast, the VALISH study has lower 

than 2% mortality over 3 years. The ages are roughly comparable, the amount of CAD is comparable, and the baseline BP is 

actually higher in VALISH. There is 10% more DM in the Wei study. But the difference in mortality is ENORMOUS. And 

the control group ends up with mean SBP around 150 in Wei, but 142 in VALISH even though both are trying to keep the 

control below 150 mm Hg (to keep a person reliably below 150, one must have a mean quite a bit below 150). The delta in 

SBP between the groups is 14 compared to less than 5 mm Hg.

We have revised this section substantially and no longer include this 

statement. Also, there were several peer review comments about the 

Wei study – we agreed that it seems an unusual study and and was an 

outlier. We conducted sensitivity analyses with and without this 

study. 

The surprising stroke ARR versus RR numbers are again seen here, again without comment. I can’t figure out the math on 

the ARR. Being a simple person, I see VALISH, a study in Japan, where in 3 years of follow up, in people mean age 76 

years old, all with hypertension, the stroke rate is 1/100. Here, the ARR is 7/1000, about 10 times the estimated summary 

ARR – in the other studies the ARR is even higher, often much higher, except in JATOS, a study of 4000 participants, also 

from Japan, where there is no benefit for stroke. Yet the summary estimate is < 1/10,000? This makes no sense. The funny 

treatment of HOT, where you throw the <85 people in the <90 group makes it a little harder to interpret. As I recalled, when 

I looked up the actual hot numbers, the <85 did the worst of anyone, so it did not obscure a big benefit of BP lowering to 

put them in the <90 group – just the opposite – but it does not make sense, since it is targeting a number less than current 

guidelines, which is what you said you wanted to count as the intensive group. 

As above, we have revamped our analyses of HOT. Agree that it 

made more sense to dichotomize 80/85 vs 90. We also conducted 

additional analyses without the middle group. Because the HOT was 

such a large trial, these changes had a large impact on results. We 

added a paragraph to results focused on HOT and the different 

analyses. 
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

100

Additional comments – Reviewer #8 Response

The table 3 would benefit from some information about the targets in the intervention group versus controls. Thus, in SHEP 

the comparison is a target SBP of 140 versus no target SBP, but both groups were treated for a target DBP of <90 – i.e., no 

matter how high the SBP don’t treat the control group unless DBP > 90 mm Hg. In the Sys-Eur study, the control group was 

treated if they got above 219/99. In other studies in this table, e.g., TRANSCEND, all patients were fairly well controlled 

and the intervention simply added a drug. Thus, I don’t see this analysis as very amenable to combination. 

See above. We have examined the data quantitatively from several 

different angles, and added more description of the differences in 

studies and how these prompted various sensitivity analyses. 

The cardiac event data (Figure 8) is also kind of interesting in that the three Asian studies have zero benefit in reducing an 

already incredibly low cardiac event rate – again, note how old they are and still very few events. In the American/European 

studies, lots of benefit. ACCORD is harder to interpret and also had a really low SBP target. Recall that recently we learned

that high risk Japanese people don’t benefit from aspirin in primary prevention of MI. Although you note the heterogeneity, 

you don’t try to interpret it. I think you have a little freedom, and perhaps obligation to think about why there is 

heterogeneity, even though you are trying to make this part of the review a quantitative synthesis. 

We have added a paragraph to the results and statements to the 

discussion describing the differences in event rates and speculating 

whether or not these may have accounted for some of the 

heterogeneity. 

I am not sure why the DBP< 85 group is included with the DBP < 90 group in the HOT study. I would just drop the <85 

people if you don’t want to consider them separately. 

See above

The ARR being greater with greater age is an artifact of higher event rates, not a bigger effect – note the RR are essentially 

the same. 

See above

In the discussion of the results of the trials comparing more and less intensive therapy rather than competing targets, they 

note that the trials showing the largest ARR are ones with achieved SBP > 140. I would have noted that they are the ones 

with the largest delta SBP and the ones with the highest even rate in the control groups. 

These #’s have changed. We focus now on the baseline BP 

subgroups (which overlap substantially with achieved BP groups) – 

the event rates are actually not higher in the higher baseline BP 

groups (overall). 

The analysis of post stroke intensive versus less intensive is interesting in that it is positive and the ARR is considered 

nontrivial by the authors. I note that the event rate in both trials was over 10% for stroke alone and the delta SBP was 9 mm 

Hg and 11 mm Hg in the PROGRESS and SPS3 respectively

Noted

I found that the discussion of Key Question 2 was much more forthcoming about the difficulty of quantitatively combining 

very different studies and (perhaps consequently) very different results. 

Noted

The discussion of KQ 3 found that ARR is higher when event rates are higher. This seems consistent with what one sees if 

one looks at BP Rx in general. Studies like STOP (Swedish Trial in Old People) and EWPHE (included in this review), 

with high event rates and studies like the MRC I and II trials, with low event rates, have similar RR (and RRR) but STOP 

and EWPHE had much larger ARR. 

Noted

I found the discussions of KQ 4 and 5 similarly well calibrated to the relatively scant evidence. Noted

Additional comments – Reviewer #15 Response

General comments: This is an excellent and helpful report. Very well written. Thank you. 

Executive summary:

Next to last line intro---leave out “proposed” since it is done Done

Last line-----I would be more specific about what older is in this report (eg age> 60) done

Quality assessment---were observational studies reviewed for quality? We noted methodologic deficiencies of the few included 

observational studies in the cognitive study section. 

Key findings---line 2----need “with” between compared and more done

Line7---leave out “more” and state direction (what is the effect?) done

Introduction:

~ line 8---I think it should read “age” rather than “ages” groups done

Table 1---GREAT TABLE Thank you 

Data synthesis:

I would rewrite 2nd sentence----“We do not present CVD mortality data in this report since .....” done
Benefits and Harms of Treating Blood Pressure in Older Adults Evidence-based Synthesis Program

101

Additional comments – Reviewer #15 Response

Study level meta-analysis sxn----last line 2nd p---what currently defines mild htn? Do you want to include a lower 

boundary? I thought mild was 160-180?

Done

Detailed study results:

1st p---I think you should say something like “Among 20 studies, X showed benefit from treating more 

intensely/to target. When data from these studies was combined in meta-analysis, more intensive......”

We revised the results section and have added some more detail to 

overview section re: # studies showing benefit

I don’t understand how you can have a RR of 0.89 with CI 0.83-0.96 and 0 ARR These #’s have changed with re-analysis

3rd paragraph, last sentence----would be helpful to add the range of bp’s (160, range 166-174). Also in 3rd p, how 

much absolute risk difference do these 4 studies acct for?

We’ve revamped the entire results section and have included more 

information about the sensitivity analyses and resultant changes in 

ARR. 

I think adding a figure/forrest plot for CVA and CAD for those younger/older than 70 as you do for total mortality 

would be very helpful (like figure 2)

We have revised KQ2 and included the age meta-analysis results 

here. However, because of concerns for ecologic fallacy we did not 

include the forest plots as we can’t really use them to examine agetreatment effects with any degree of confidence

The Wei study stands out both for its results and control event rate. Note that the number of cardiovascular events 

is similar, the number of strokes 15 less in the I group and 36 total differences in death between the 2 groups. I am 

worried about the randomization. What are they dying of? Review of the quality ratings doesn’t suggest this has 

low risk of bias to me. 

Agree. We have revised accordingly. We also re-ran analyses 

without 2 other high risk of bias studies (we had overlooked this in 

first draft)

Page 28----the ARR of 1% for total mortality seems fairly big. Numbers have all changed with SPRINT and additional analyses

Figure 9----title----add in “comparing x to x” Done

Note the format of KQ 2 differs from KQ1 We’ve added subheaders to make more similar 

3rd p, line 3 - “an” rather than “and” Noted

SHEP description in p 3. I might state this: “conversely, the SHEP trial identified a decreased risk of stroke when the 

treated systolic blood pressures in patients with baseline bp’s above 170 was less than 150 (mean X)” to be really 

clear. 

Done

Renal outcomes-----I am uncertain about this but it might be helpful to provide some numbers for changes in 

creatinine/GFR since this is such a common occurrence in practice.

Specific renal outcomes and numbers are presented in Table 6

Cognitive outcomes-----in general (and this is true throughout) I recommend being more specific about bps rather than 

stating “moderately tight” as in first P of this section. Similarly, in the last paragraph “large proportion”----what % - 

this might matter.

The specific BPs are listed in following sentence. Re: large 

proportion with missing data – these numbers are in table –added 

the numbers into paragraph as well. 

Falls/fractures----thoughts on the non-spine fractures? NSS but interesting. ? thiazides? Unclear – mainly looking at this as potential harm – the trend 

towards benefit was seen in 2 studies but not in a third. Not sure we 

can much of the potential reduction in fracture risk. 

The orthostatic hypotension stuff d/n make sense to me. Thoughts? As we note, a number of trials found increased rates of hypotension. 

Three trials looked at syncope and 2 found a higher rate. We added 

sentence to discussion suggesting that the hypotension has potential 

to be serious given the excess rate of syncope in 2 trials. 

Summary/discussion:

Line 2 “compared with....” Noted

Need to discuss the 1% absolute mortality reduction a little bit more when you note that move aggressive 

treatment didn’t “appreciably” improve outcomes

As above, all numbers have changed

Mid paragraph 1-----can you be more explicit rather than say “modest” effect? We have put in NNT throughout

Paragraph 3. It would be interesting to find out usual stroke rates in the general age specific population given the 

low event rates you note.

Added a paragraph to discussion about event rates. 

Tables 2 and 3----it might be helpful to add publication dates in column 1. I think there is a wide range Agree. Done.