JC 2019-00197

C LI NI CA L PR AC TI C E G U ID EL IN E M E TA - AN A LY S IS
Antihypertensive Agents in Older Adults: A Systematic

Review and Meta-Analysis of Randomized Clinical Trials
Mohammad Hassan Murad,1 Laura Larrea-Mantilla,1 Abdullah Haddad,1,2

Gabriela Spencer-Bonilla,1 Valentina Serrano,1,3 Rene Rodriguez-Gutierrez,1,4
Neri Alvarez-Villalobos,1,4 Khaled Benkhadra,1 Michael R. Gionfriddo,5
Larry J. Prokop,1 Juan P. Brito,1,6 and Oscar J. Ponce1,7
Downloaded from https://academic.oup.com/jcem/article/104/5/1575/5413487 by guest on 25 October 2024

1
Evidence-Based Practice Center, Mayo Clinic, Rochester, Minnesota 55905; 2Section of Cardiology, Temple
University-Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140; 3Department of Nutrition,
Diabetes and Metabolism, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331010,
Chile; 4Plataforma INVEST Medicina UANL–KER Unit (KER Unit México), Subdireccion de Investigacion,
Universidad Autónoma de Nuevo León, Monterrey, Nuevo Leon 66455, México; 5Center for Pharmacy
Innovation and Outcomes, Geisinger Health System, Forty Fort, Pennsylvania 18704; 6Division of
Endocrinology, Diabetes, Metabolism, Nutrition, Mayo Clinic, Rochester, Minnesota 55905; and 7Unidad de
Conocimiento y Evidencia (CONEVID), Universidad Peruana Cayetano Heredia, Lima 15102, Peru
ORCiD numbers: 0000-0001-5502-5975 (M. H. Murad).
Background: This systematic review summarizes the benefits of treating blood pressure (BP) in
individuals 65 years and older.
Methods: We included randomized trials that evaluated BP-lowering medications or BP targets in

individuals 65 years and older. Trials were selected and appraised by pairs of independent
reviewers.
Results: We included 19 trials (42,134 patients). In individuals 65 years or older, antihypertensive

therapy was associated with a reduction in all-cause mortality [relative risk: 0.88 (95% CI: 0.81 to
0.94); high certainty evidence; mean follow-up 31 months], cardiovascular mortality, myocardial
infarction, heart failure, stroke, and chronic kidney disease. Individuals 75 years or older had a
significant reduction in the risk of all-cause and cardiovascular mortality, stroke, and heart failure.
Strict systolic BP targets (,120 mm Hg and ,130 mm Hg) were associated with a significant
reduction in the risk of all-cause and cardiovascular mortality and heart failure, whereas more
liberal systolic targets (,150 mm Hg and ,160 mm Hg) were associated with lower risk of heart
failure and stroke. Older adults with type 2 diabetes mellitus (DM) had lower risk of chronic kidney
disease without a significant reduction in other outcomes. However, there was no significant
difference in estimates (i.e., interaction) between those with and without DM.
Conclusions: Individuals aged 65 years and older or 75 years and older who receive antihypertensive
therapy have statistically significant reduction in the risk of all-cause and cardiovascular mortality,
heart failure, and stroke. There was no statistically significant difference in estimates between those
with and without DM. (J Clin Endocrinol Metab 104: 1575–1584, 2019)
ypertension is considered the leading risk factor cardiovascular disease events in adults (2–4). The prev-
H for global disease burden in 2010 (1). Elevated
blood pressure (BP) leads to drastically higher risk for
alence of hypertension worldwide and in the United
States has substantially increased over the last 40 years
ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; BP, blood pressure; DM,
Printed in USA diabetes mellitus; RCT, randomized clinical trial; RR, relative risk; RRR, ratio of relative risk;
Copyright © 2019 Endocrine Society SPRINT, Systolic Blood Pressure Intervention Trial; T2DM, type 2 diabetes mellitus.
Received 25 January 2019. Accepted 25 January 2019.
First Published Online 23 March 2019
doi: 10.1210/jc.2019-00197 J Clin Endocrinol Metab, May 2019, 104(5):1575–1584 https://academic.oup.com/jcem 1575
1576 Murad et al Antihypertensive Agents in Older Adults J Clin Endocrinol Metab, May 2019, 104(5):1575–1584
and is greater in the elderly (5, 6). Prevalence may reach mortality, chronic kidney disease, heart failure, myocardial
77% and 75% in men and women aged 65 to 74, reinfarction, and stroke in older adults (65 years old or older).
The interventions of interest included the following:
spectively, and 79% and 85% in men and women aged
older than 75 years, respectively (7). 1. Low vs high BP target (e.g., systolic BP ,120 mm Hg vs
Managing hypertension in older individuals is chal- 130 to 140 mm Hg),
lenging. Patients and clinicians are usually concerned 2. Any BP target vs placebo or no treatment (e.g., systolic
BP ,140 mm Hg vs placebo), and
about the effectiveness of treating hypertension in the 3. Any BP-lowering strategy vs placebo or no treatment
elderly, polypharmacy, tolerability to antihypertensive (e.g., angiotensin II receptor blockers vs placebo).
agents, and, most importantly, unwanted side effects
The trials needed to have a minimum sample size of 100
such as orthostatic hypotension, increasing the risk of
patients and follow-up of 12 months, and they were included
falls and fractures (8). An observational study suggests irrespective of language of publication.

higher mortality in older patients with more aggres-
sive antihypertensive treatment (9). An essential dilemma Data sources and searches
when managing hypertension in the elderly is setting a BP Comprehensive searches were developed, with input from
goal. Both the US and the European guidelines have authors, by a medical reference librarian (L.J.P.). The searches
lowered the BP thresholds for treatment in older adults. were performed in the following databases: Ovid MEDLINE
In the 2017 US guidelines, the target in older patients is In-Process & Other Non-Indexed Citations, Ovid MEDLINE,
Ovid Embase, Ovid Cochrane Database of Systematic Reviews,
systolic BP ,130 mm Hg and ,140/90 mm Hg in the
Cochrane Central, and Scopus. We used an umbrella strategy (15)
European guidelines (10). This is a substantial reduction (i.e., a systematic search for published systematic reviews) for
compared with the 2014 guidelines (in which systolic BP RCTs fulfilling the eligibility criteria from each database inception
goal ,150 mm Hg and diastolic BP goal ,90 mm Hg to 29 June 2016. We updated the search strategy of the most
were recommended in the elderly), which significantly comprehensive systematic review with identical eligibility crite-
rion to ours (16) through 18 August 2016. The detailed search
increases the proportion of individuals recommended for
strategies are available in an online repository (13).
antihypertensive treatment (11). Although randomized
trials have shown BP reduction in the elderly to be
Study selection
beneficial, most of these trials have consistently recruited
We selected systematic reviews of randomized trials com-
patients who were overall healthy and not frail, which paring any BP-lowering medication or BP target to any other
limits the applicability of the evidence that docu- intervention (including placebo or no treatment) in the adult
ments effectiveness of antihypertensive therapy in the population (18 years of age or older, if reported with a sub-
elderly population at large. The Systolic Blood Pressure group aged 65 years or older). Two investigators (O.J.P. and
L.L.-M.) manually retrieved all of the trials from the included
Intervention Trial (SPRINT) is an exception, showing
systematic reviews. The pool of trials was complemented with
similar benefit in frail and nonfrail older individuals (12). ones retrieved from the second search strategy, which was
A task force from the Endocrine Society has com- reviewed by content experts from the Endocrine Society and
missioned the conduct of this systematic review to evaluate assessed for completeness.
the evidence about managing hypertension in the elderly. Abstract and full-text screening was done independently by
The task force is interested in managing hypertension in pairs of reviewers. Studies included by at least one reviewer in the
abstract screening phase were considered for full-text screening.
older adults with diabetes mellitus (DM), but the scope of
Disagreements at this level were resolved by a consensus between
this review was expanded to include older individuals with two of the reviewers (L.L.-M. and O.J.P.). Articles included by
and without diabetes because data on older individuals two reviewers proceeded to data extraction.
with diabetes are limited.
Data collection and management
Methods For each included trial, pairs of independent reviewers used a
website-based data extraction form (DistillerSR) to collect the
Supplemental material to this manuscript is publicly shared following information: (i) inclusion and exclusion criteria, (ii)
(13). This systematic review was performed in accordance with baseline characteristics (age, sex, systolic and diastolic BP, DM
an unpublished prespecified protocol approved by a task force status, and history of coronary artery disease), (iii) intervention
commissioned by the Endocrine Society. This report adheres to characteristics (antihypertensive treatment strategy, dose, unit,
the Preferred Reporting Items for Systematic Reviews and frequency, and duration and BP target), (iv) events and risk
Meta-analysis statement (14). measures of outcomes of interest at the longest follow-up (all-
cause mortality, cardiovascular mortality, chronic kidney dis-
Eligibility criteria ease, heart failure, myocardial infarction, and stroke), (v) if the
We included randomized clinical trials (RCTs) assessing the included trial was exclusively done in older adults or if it
efficacy of any pharmacological intervention aimed to reach reported a subgroup analysis based on age, including only older
low BP targets compared with any other strategy designed to adults in one of the groups, and (vi) risk of bias indicators,
achieve higher BP targets on all-cause mortality, cardiovascular including whether the trial was stopped early.
doi: 10.1210/jc.2019-00197 https://academic.oup.com/jcem 1577
Trials were classified as (i) drug trials [trial compares any BP- Results
lowering medication to no treatment or placebo (e.g., angiotensin
II receptor blockers vs placebo)], and (ii) target trials [trial com- Characteristics of the included trials
pares low to higher BP targets (e.g., systolic BP ,120 mm Hg vs The study selection process is depicted in an online
130 to 140 mm Hg), including trials that compare a BP target to no
repository (13). A total of 19 trials (42,134 older adults;
treatment or placebo (e.g., systolic BP ,140 mm Hg vs placebo)].
For trials reporting fatal and nonfatal events for the same 65 years of age or older) were included in this systematic
outcome, we extracted data on the nonfatal events. If this in- review. Eight trials with 14,115 participants were drug trials
formation was not available, we extracted data on the combined and compared beta-blockers, angiotensin-converting enzyme
events (i.e., nonfatal and fatal). Fatal outcomes were not analyzed inhibitor (ACEi), and ACEi plus diuretic against placebo
unless cardiovascular mortality was not reported. In that case, (22–29). The remaining 11 trials (12, 30–39) were target
cardiovascular mortality was imputed from the combined death
trials (28,019 participants), consisting of five trials com-
events due to myocardial infarction, acute coronary syndrome,

heart failure, stroke, or coronary revascularization. paring low to higher BP targets (12, 30, 35, 37, 39) and six
trials comparing a BP target to placebo (31–34, 36, 38). Ten
Risk of bias trials (27,996 participants) included only adults who were
Risk of bias was assessed using the Cochrane Collaboration tool 65 years or older, and nine reported effect measures of a
for RCTs, a tool that takes into consideration seven domains: (i) subgroup consisting of only older adults. Two trials (24, 30)
random sequence generation, (ii) allocation concealment, (iii) included only patients with DM (8230 participants), and
blinding of participants, (iv) blinding of outcome assessment, (v)
another two (12, 33) excluded patients with DM (7032
incomplete outcome data, (vi) selective reporting, and (vii) other
sources of bias (only reported when present). We summarized each participants). Furthermore, nine (26,402 participants), five
trial risk of bias domains into an overall risk of bias. The overall (4742 participants), and four (4393 participants) trials had
judgment was performed by emphasizing domains corresponding to hypertension, coronary artery disease, and heart failure as
selection bias (random sequence generation and allocation con- inclusion criteria, respectively. Follow-up across trials varied
cealment) and attrition bias (incomplete outcome data). These do-
from 12 to 96 months. Baseline characteristics are sum-
mains have empirically been found to have a greater influence on the
effect estimates, compared with the other domains (17). The criterion marized in an online repository (13).
was the following: (i) “high risk of bias” was attributed to trials with Overall risk of bias was deemed high for five trials (22,
at least one of these domains judged as high risk, (ii) “low risk of 30, 32, 33, 37), low for six trials (12, 23, 24, 31, 35, 39),
bias” was attributed to those having low risk of bias in the three and unclear for eight trials (25–29, 36–38). Only three
domains, and (iii) “unclear risk of bias” was attributed to those not trials were stopped early: two were because of benefit
having any high risk of bias and having at least one unclear risk of
(12, 32) and one because of safety (34). The risk of bias
bias in any of the three domains. Disagreements were resolved by
consensus of the two reviewers (O.J.P. and L.L.-M.). Summary of evaluation is described in an online repository (13).
risk of bias evaluation is available in an online repository (13). Forest plots for all of the analyses, including overall
analysis, subgroup analysis, sensitivity analysis, and target
Summary measures and synthesis of results trials analysis, are available in an online repository (13).
The outcomes of interest were all binary and pooled using the
random-effects model (18) generating relative risk (RR) and 95% Overall analysis
CIs. This model was chosen because of anticipated heterogeneity All 19 trials (drug and target trials) were included in this
of trials’ settings and populations. Heterogeneity was evaluated by analysis. In patients aged 65 years or older, low compared
visually observing CI overlap and by calculating the I2 index,
with higher BP targets significantly reduced the risk of all-
which suggests important heterogeneity across studies if values
are .50% (19). For the overall analysis, trials comparing an active cause mortality (RR: 0.89, 95% CI: 0.83 to 0.95; high cer-
arm or BP target to a no-treatment or placebo arm were considered tainty), cardiovascular mortality (RR: 0.81, 95% CI: 0.72 to
as comparing a low to higher BP targets. Additional analysis was 0.92; high certainty), chronic kidney disease (RR: 0.77, 95%
performed by only including trials in which the BP target was CI: 0.70 to 0.85; high certainty), heart failure (RR: 0.67, 95%
explicit (target trials). Sensitivity analysis was performed for three CI: 0.49 to 0.90; high certainty), myocardial infarction (RR:
arm trials. If no differences were found, we opted to keep the
0.78, 95% CI: 0.62 to 0.99; high certainty), and stroke (RR:
strategy that was most used across trials. Possible causes of het-
erogeneity were explored by subgroup analyses based on age ($75 0.75, 95% CI: 0.66 to 0.86; high certainty) (Fig. 1; Table 1).
years), presence of DM, and presence of hypertension. We tested
the interaction between subgroups following the method suggested Subgroup analysis
by Altman and Bland (20), in which we calculated the ratios of the Analysis including older adults with DM shows that
RRs (RRRs) of the subgroups. All statistical analyses were per- lower vs higher BP targets were associated with signifi-
formed using the STATA software package (Release 15; StataCorp cant reduction in the risk of chronic kidney disease and
LLC, College Station, TX). Certainty in the evidence was de-
heart failure. RRRs were nonsignificant for any outcome
termined using the Grading of Recommendations, Assessment,
Development and Evaluation approach (21). We based impreci- [suggesting no statistically significant differences between
sion judgments on the total number of events, sample size, and the estimates of those with vs without DM (i.e., no
whether CIs included appreciable benefits and harms. statistical interaction based on DM status)].
Subgroup analyses based on age strata showed that in Hg to a target of 130 to 139 mm Hg (12, 30), one trial
the older group (75 years or older), lower vs higher BP compared a systolic BP target ,130 mm Hg to a target
targets were associated with significant reduction in of 130 to 149 mm Hg (37), two trials (7678 partici-
the risk of all-cause and cardiovascular mortality, heart pants) compared a systolic BP target ,140 mm Hg to a
failure, and stroke. Similarly, RRRs were nonsignificant target of 140 to 160 mm Hg (35, 39), three trials [5128
for any outcome (suggesting no statistically significant participants, number of participants not reported in one
differences between the estimates of different age strata). trial (38)] compared a systolic BP target ,150 mm Hg to
The results of subgroup analyses are available in Fig. 1 placebo (31, 32, 38), and three trials (10,960 partici-
and Table 1. pants) compared a systolic BP target ,160 mm Hg to
placebo (33, 34, 36).
Sensitivity analysis
These exploratory analyses by different BP targets

Two trials had three arms. The Hypertension in the
demonstrated that in older adults, all-cause mortality (RR:
Very Elderly Trial pilot (32) included diuretic, ACEi, and
0.67, 95% CI: 0.49 to 0.91) and heart failure (RR: 0.62,
no treatment arms. The Medical Research Council (UK)
95% CI: 0.46 to 0.83) were significantly reduced when a
elderly trial (33) included diuretic, beta-blocker, and
systolic BP target ,120 mm Hg was compared with a target
placebo arms. The BP targets for the active arms were
of 130 to 139 mm Hg. Only cardiovascular mortality (RR:
,150 mm Hg and ,160 mm Hg for the Hypertension in
0.42, 95% CI: 0.18 to 0.98) was significantly reduced
the Very Elderly Trial pilot (32) and Medical Research
with a systolic BP target ,130 mm Hg compared with a
Council (UK) elderly trial (33), respectively. Sensitivity
target of 130 to 149 mm Hg. Risk of heart failure was also
analyses (13) showed that the overall effect estimates did
significantly reduced when a systolic BP target ,150 mm
not significantly change based on choice of trial arm
Hg was compared with placebo (RR: 0.36, 95% CI: 0.22 to
included in analysis.
0.58). Lastly, the risk of stroke was significantly reduced
Target trials analysis when comparing a systolic BP target ,150 mm Hg (RR:
Eleven trials were included in this analysis. Two trials 0.69, 95% CI: 0.50 to 0.95) or ,160 mm Hg (RR: 0.72,
(4253 participants) compared a systolic BP target ,120 mm 95% CI: 0.58 to 0.91) against placebo (Fig. 2; Table 2).
Figure 1. Forest plot of RRs comparing low against higher BP targets by outcomes and group population. *P , 0.05 for heterogeneity (I2).
# indicates number; + indicates no subgroup analysis available, and only exploratory analysis was performed. HT, hypertension.
Table 1. Summary of Findings and Certainty in the Body of Evidence of Higher Compared With Lower BP
Targets by Outcomes and Population
Risk
Baseline Difference Quality of
Population Risk per 1000 per 1000 N of Participants Evidence (Domain
Outcomes Group RR (95% CI) Patients Patients (N of Studies) of Concern)
All-cause Overall 0.89 (0.83, 0.95) 112 6 40,028 (18) High
mortality
DM 0.86 (0.74, 1.00) 112 16 6613 (1) Moderate (imprecision)
No DM 0.86 (0.55, 1.35) 119 17 5951 (2) Low (imprecision,
inconsistency)
HT 0.88 (0.75, 1.04) 81 10 24,895 (8) Low (imprecision,

inconsistency)
$65–75 0.85 (0.66, 1.11) 109 16 9604 (3) Low (imprecision,
inconsistency)
$75 0.81 (0.71, 0.92) 110 21 8840 (5) High
Cardiovascular Overall 0.81 (0.72, 0.92) 53 10 35,715 (13) High
mortality
DM 0.78 (0.6, 1.01) 60 13 6613 (1) Moderate (imprecision)
No DM 0.85 (0.5, 1.47) 59 9 5951 (2) Moderate (imprecision)
HT 0.87 (0.75, 1.02) 41 5 24,895 (9) Moderate (imprecision)
$65–75 0.8 (0.59, 1.08) 70 14 9655 (4) Low (imprecision,
inconsistency)
$75 0.72 (0.59, 0.88) 52 14 8840 (5) High
Chronic kidney Overall 0.77 (0.7, 0.85) 116 27 15,452 (4) High
disease
DM 0.76 (0.69, 0.84) 267 64 6614 (1) High
No DM 2.45 (0.48, 12.64) 1 22 3260 (1) Low (imprecision,
inconsistency)
HT 1.28 (0.64, 2.56) 3 21 8839 (3) Moderate (imprecision)
$65–75 0.76 (0.68, 0.84) 182 44 8154 (2) High
$75 0.88 (0.58, 1.33) 57 7 5513 (3) Moderate (imprecision)
Heart failure Overall 0.67 (0.49, 0.90) 39 13 13,001 (6) High
DM 0.61 (0.41, 0.91) NA NA NA (1) High
No DM 0.63 (0.41, 0.98) 42 15 2636 (1) Moderate (imprecision)
HT 0.57 (0.33, 0.98) 22 9 10,899 (3) High
$75 0.48 (0.28, 0.83) 35 18 6481 (2) High
Myocardial Overall 0.78 (0.62, 0.99) 20 4 21,952 (8) High
infarction
DM 0.69 (0.45, 1.05) 40 12 2636 (1) Low (serious imprecision)
HT 0.9 (0.71, 1.14) 14 1 20,723 (6) Low (serious imprecision)
$75 0.7 (0.49, 1.01) 20 6 6975 (3) Low (serious imprecision)
Stroke Overall 0.75 (0.66, 0.86) 40 10 25,789 (11) High
DM 0.84 (0.38, 1.85) 45 7 599 (1) Low (serious imprecision)
No DM 0.76 (0.62, 0.93) 43 10 10,289 (3) High
HT 0.74 (0.64, 0.85) 35 9 24,939 (9) High
$65–75 0.84 (0.62, 1.14) 61 10 3315 (1) Low (serious imprecision)
$75 0.74 (0.59, 0.92) 35 9 8887 (5) High
Abbreviations: HT, hypertension; NA, not applicable.
Discussion BP targets such as systolic BPs ,120 and ,130 mm Hg

were associated with a significant reduction in all-cause
Main findings and cardiovascular mortality and heart failure, whereas
High-certainty evidence shows that a low, compared more liberal targets such as ,150 or ,160 mm Hg were
with higher, BP target significantly reduces the risk of all- associated with lower risk of heart failure and stroke.
cause and cardiovascular mortality, chronic kidney dis- Cardiovascular disease is a major cause of mortality in
ease, heart failure, myocardial infarction, and stroke. The patients with type 2 DM (T2DM). Due to the high
presence of diabetes and age strata (65 to 75 years vs prevalence of diabetes and hypertension, their coexis-
older than 75 years) does not appear to have a significant tence is common. Therefore, it is critical to evaluate
effect on the efficacy of the intervention. Furthermore, antihypertensive therapy in this population. In this
the results of grouping trials based on different BP tar- analysis, antihypertensive therapy in individuals with
gets do not suggest a particular trend, except that strict T2DM was not associated with a significant reduction in

Figure 2. Forest plot of RRs comparing different BP targets by outcomes. # indicates number. *P , 0.05 for heterogeneity (I2). HT, hypertension.
the risk of all-cause or cardiovascular mortality but was its population), and most trials excluded institutionalized
associated with a statistically significant reduction in the elderly, those with prevalent strokes, or those with
risk for chronic kidney disease. This may be explained by symptomatic heart failure. These findings suggest that
the high prevalence of other concomitant risk factors for more research is needed to appropriately assess the
coronary disease in patients with diabetes. These risk optimal BP targets that provide clinical benefit to the
factors (e.g., atherosclerosis, microalbuminuria, and elderly, especially individuals with frailty and comor-
hyperlipidemia) may be effect modifiers that attenuate bidities. Meanwhile, to guide clinical practice, such ev-
the impact of BP control on cardiovascular risk in in- idence may have to be extrapolated from trials in adults
dividuals with diabetes. Conversely, the lack of a sta- under the age of 65 years. Similarly, evidence in older
tistically significant effect in patients with diabetes could individuals with T2DM is sparse and imprecise, but
be due to imprecision (i.e., smaller number of studies and inferences may be extrapolated from those without DM.
patients leading to wide CIs). Therefore, a true benefit in The strengths of this systematic review relate to the
older individuals with diabetes is plausible and not ruled comprehensive literature search, selecting and appraising
out. Importantly, the lack of significant difference (i.e., evidence by pairs of independent reviewers, the analysis
statistical interaction) between estimates in older in- of different BP targets, and collaboration with content
dividuals vs those without DM suggests that extrapo- experts from the Endocrine Society to inform clinical
lation from the overall older population to those with practice guidelines.
DM may be possible.
Practical implications
Limitations and strengths The Framingham Heart Study suggests that in-
The current evidence supporting effectiveness of an- dividuals aged 65 years old have a 90% residual lifetime
tihypertensive therapy in older adults warrants high risk of developing hypertension and a 60% lifetime
certainty. However, the evidence base is limited when it probability of receiving antihypertensive medications
comes to determining a specific BP target. Results dis- (40). Thus, hypertension in the elderly is an enormous
playing the effect of different BP targets are hampered public health burden, particularly with future anticipated
due to significant imprecision given by the small number increased life expectancy.
of trials and patients. The lack of participating frail older BP goals in the elderly remain controversial (39,
adults is also a prominent feature of the body of evidence. 41). The 2017 American College of Cardiology/American
SPRINT was the only trial to include frail adults (31% of Heart Association guidelines recommend a systolic BP
Table 2. Summary of Findings and Certainty in the Body of Evidence of Higher Compared With Lower BP
Targets by Outcomes and BP Targets
Risk N of
Baseline Difference Participants Quality of Evidence
BP Targets Risk per 1000 per 1000 (N of (Domain of
Outcomes (mm Hg) RR (95% CI) Patients Patients Studies) Concern)
All-cause ,120 vs 130–139 0.67 (0.49, 0.91) 81 27 2636 (1) Moderate (imprecision)
mortality
,130 vs 130–149 0.83 (0.55, 1.26) 163 28 494 (1) Low (serious imprecision)
,150 vs placebo 0.86 (0.64, 1.16) 101 14 4702 (2) Moderate (imprecision)
,160 vs placebo 0.91 (0.71, 1.15) 117 11 9879 (3) Low (imprecision,

inconsistency)
Cardiovascular ,120 vs 130–139 0.6 (0.33, 1.09) 22 9 2636 (1) Low (serious imprecision)
mortality
,130 vs 130–149 0.42 (0.18, 0.98) 69 40 494 (1) Moderate (imprecision)
,150 vs placebo 0.81 (0.65, 1) 52 10 4702 (3) Moderate (imprecision)
,160 vs placebo 0.88 (0.65, 1.2) 66 8 9879 (3) Moderate (imprecision)
Chronic kidney ,120 vs 130–139 2.45 (0.48, 12.57) 1 22 3260 (1) Low (serious imprecision)
disease
Heart failure ,120 vs 130–139 0.62 (0.46, 0.83) 42 16 2636 (2) Moderate (imprecision)
,150 vs placebo 0.36 (0.22, 0.58) 30 19 3845 (1) High
Myocardial ,120 vs 130–139 0.69 (0.45, 1.05) 40 12 2636 (1) Low (serious imprecision)
infarction
,150 vs placebo 0.72 (0.3, 1.71) 6 2 3845 (1) Low (serious imprecision)
,160 vs placebo 1.05 (0.76, 1.46) 22 21 6564 (2) Low (serious imprecision)
Stroke ,120 vs 130–139 0.68 (0.4, 1.15) 25 8 2636 (1) Low (serious imprecision)
,130 vs 130–149 0.89 (0.62, 1.27) NA NA NA (1) Low (serious imprecision)
,150 vs placebo 0.69 (0.5, 0.95) 30 9 4702 (2) High
,160 vs placebo 0.72 (0.58, 0.91) 51 14 9879 (3) High
Abbreviation: NA, not applicable.
goal of ,130 mm Hg for community-dwelling adults at of stroke and heart failure was significantly reduced
age 65 years or older, a class I recommendation (42). when treated to targets ,160 mm Hg and ,150 mm Hg,
SPRINT (12) has demonstrated a reduction in the risk of respectively. Treatment goals for individuals with fre-
all-cause mortality and cardiovascular disease in adults quent falls and advance cognitive impairment who reside
aged 75 years or older when treating to a systolic BP at nursing home or assisted living facilities are unclear as
target of ,120 mm Hg. However, achieving this goal they were underrepresented in randomized controlled
constitutes a major challenge and could carry a higher trials (42).
risk of adverse events. Only ;50% of patients in the One could argue that the control of BP to lower
intensive treatment group were able to reach a goal of a thresholds may result in an increased risk of falls and
systolic BP ,120 mm Hg (12, 41). Other trials have injuries. SPRINT has shown benefit of treating hyper-
concluded that even a small reduction in BP (as small as 4 tension in frail, community-dwelling population, which
and 2 mm Hg in systolic and diastolic BP, respectively) is appeared to offset the potential side effects (12). The rates
associated with substantial reductions in the incidence of of syncope (2.4%) and hypotension (3%) in the intensive
most types of cardiovascular events (43). In our meta- treatment group in SPRINT were generally low and not
analysis, results were diverse. Trials comparing intensive importantly different from the higher BP target group. A
BP targets vs higher, or no targets, showed that the closer look at the subgroup of patients aged 75 years or
risk of all-cause mortality and heart failure events older has demonstrated that the difference in these two
was significantly reduced when treated to a systolic BP adverse outcomes were not statistically significant (12,
target ,120 mm Hg. Similarly, the risk of cardiovascular 41). In the Action to Control Cardiovascular Risk in
mortality was significantly reduced when treated to a Diabetes trial (44), intensive BP control (,120 mm Hg)
systolic BP target of ,130 mm Hg. Conversely, the risk in patients with T2DM was not associated with increased
risk of falls or nonvertebral fractures (albeit the mean Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe
Z, Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A,
age was only 62 years). An observational study of 722
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Acknowledgments Lancet. 2014;383(9932):1899–1911.
4. Yano Y, Reis JP, Colangelo LA, Shimbo D, Viera AJ, Allen NB,
Financial Support: This work was partially funded by the Gidding SS, Bress AP, Greenland P, Muntner P, Lloyd-Jones DM.
Endocrine Society. Association of blood pressure classification in young adults using
Correspondence and Reprint Requests: Mohammad the 2017 American College of Cardiology/American Heart Asso-
Hassan Murad, MD, MPH, Evidence-Based Practice Center, ciation Blood Pressure Guideline with cardiovascular events later in
life. JAMA. 2018;320(17):1774–1782.
Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. 5. Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L,
E-mail: murad.mohammad@mayo.edu. Alexander L, Estep K, Hassen Abate K, Akinyemiju TF, Ali R,
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disclose. A, Bekele T, Bennett DA, Biadgilign S, Catalá-López F, Feigin VL,
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C LI NI CA L PR AC TI C E G U ID EL IN E M E TA - AN A LY S IS

Antihypertensive Agents in Older Adults: A Systematic

Mohammad Hassan Murad,1 Laura Larrea-Mantilla,1 Abdullah Haddad,1,2

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ORCiD numbers: 0000-0001-5502-5975 (M. H. Murad).

Methods: We included randomized trials that evaluated BP-lowering medications or BP targets in

Results: We included 19 trials (42,134 patients). In individuals 65 years or older, antihypertensive

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Abbreviations: HT, hypertension; NA, not applicable.

Discussion BP targets such as systolic BPs ,120 and ,130 mm Hg

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