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Contents lists available at ScienceDirect

Archives of Gerontology and Geriatrics

journal homepage: www.elsevier.com/locate/archger

Review

A systematic review of hypertension outcomes and treatment strategies in 0$5.

older adults
Julienne K. Kirka,⁎, Julie Allsbrookb, Maggie Hansella, Emily M. Manna
a
Wake Forest School of Medicine, Department of Family and Community Medicine, Winston-Salem, NC 27157, United States
b
Campbell University, College of Pharmacy and Health Sciences, Buies Creek, NC 27506, United States

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

Keywords: Objective: To evaluate the literature regarding blood pressure control and management in older adult patient
Hypertension population over 70 years of age.
Older adults Methods: A literature search was conducted using PubMed and capturing the data from 2006 to 2016. Terms
Treatment used included MeSH headings for hypertension/therapy and antihypertension agents. A systematic review of
published studies was performed. Articles including older patients (average age 70 years or older) being treated
for hypertension were included. We analyzed the blood pressure goals and treatment regimens along with
cardiovascular outcomes.
Results: Six trials were evaluated that met criteria for inclusion. A range of countries were represented including
Europe, China, Australia, Tunisia, US, and Japan. The population size in the trials ranged from 142 to 4736. All
studies included had adequate power to assess treatment effects. Blood pressure goals were variable and ranged
from a systolic of <120 to <160 with a diastolic goal of <80 mmHg. Some studies reported outcomes including
all-cause mortality, composite cardiovascular events, cardiovascular mortality, fatal and non-fatal stroke or
myocardial infarction, and fatal or nonfatal heart failure. Many trials were stopped early because of the sig-
nificant findings in mortality and cardiovascular outcomes.
Conclusions: The studies discussed had a range of blood pressure goals. The optimal management of hyperten-
sion in older adults is still being debated. Data from the clinical trials show that treating blood pressure to tight
goals of at least <140/80, or lower if tolerated, confers benefit in cardiovascular outcomes.

1. Introduction Excellence guideline for hypertension does not specifically address

Hypertension in the elderly is a modifiable risk factor for cardio-
vascular disease, stroke and all-cause mortality. The treatment strate-
gies and goals for elderly patients are evolving as data accumulates.
There is variability between current guidelines and more recent evi-
dence regarding target blood pressures, treatment regimens and con-
sideration for comorbidities.
Currently, European Society of Hypertension and the European
Society of Cardiology target a systolic blood pressure of <140–150 mm
Hg with lower goals in fit and healthy patients. The diastolic blood
pressure goal is <85 mm Hg in those with diabetes and <90 mmHg
otherwise (Mancia, Fagard, Narkiewicz, Redon, & Zanchetti, 2013). The
European guideline only recommends initiation of treatment for per-
sons aged 80 years or older if systolic blood pressure is >180 mm Hg.
Hypertension guidelines from France advocate a systolic goal of
<150 mm Hg in those over 80 years of age (Blacher, Halimi,
Hanon, & Mourad, 2014). The National Institute for Health and Care
older individuals’ blood pressure goals (NICE, 2016).
The US guideline from the Eighth Joint National Committee
(JNC8) recommends a blood pressure goal of <150/90 mm Hg in
patients over 60 years of age or <140/90 with concomitant
chronic kidney disease or diabetes (James, Oparil, Carter,
Cushman, & Dennison-Himmelfarb, 2014). While the majority of the
JNC8 Committee supported the higher systolic blood pressure goal,
there was a minority of members that argued to continue the pre-
viously recommended systolic blood pressure goal of <140 mm Hg.
The American Diabetes Association 2017 Standards recommends a
general goal of <140/90 mm Hg with a lower target of <130/80 in
patients with a high risk of cardiovascular disease if achievable
without undue burden. The American College of Cardiology Founda-
tion and the American Heart Association permit discrimination about
treatment of hypertension in patients over 80 years of age who are
more frail or medically compromised (Aronow, Fleg, Pepine,
Aetinian, & Bakris, 2011). Recently, guidelines from the American

⁎
Corresponding author at: Family and Community Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084, United States.
E-mail address: jkirk@wakehealth.edu (J.K. Kirk).

http://dx.doi.org/10.1016/j.archger.2017.07.018
Received 30 January 2017; Received in revised form 12 May 2017; Accepted 21 July 2017
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‹(OVHYLHU%9$OOULJKWVUHVHUYHG

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J.K. Kirk et al.
College of Physicians and the American Academy of Family Physicians
recommend initiating treatment in 60 years or older with systolic
blood pressure above 150 mm Hg and for those at high cardiovascular
risk a goal blood pressure of <140 mm Hg to reduce the risk of stroke
and cardiac events (Quaseem, Wilt, Rich, Humphrey, & Frost, 2017).
Overall, guidelines vary and are not currently reflective of more
recent clinical trials. With lag time between clinical trials and guideline
implementation, a review of the most recent randomized controlled
trials assessing approaches and outcomes for hypertension treatment in
the older population is needed. We reviewed clinical trials to help de-
lineate the most appropriate target goals for patients greater than 70
years of age, specific treatment strategies and how to incorporate frailty
and other comorbidities in the decision making process.
2. Methods
2.1. Criteria for study inclusion/exclusion
According to titles and abstracts, the articles were first evaluated for
inclusion using the following criteria:
2.1.1. Study design and article type
Only intervention studies (randomized-controlled trials) published
in peer-reviewed journals were considered. The search was limited to
full articles available in the English language.
2.1.2. Population
All studies where all participants were aged 65 years or older (be-
cause of search strategies to capture age) were assessed. We only in-
cluded studies with an average age of 70 years without exclusion for
comorbid conditions.
2.2. Search strategy
A literature search was conducted in PubMed in September 2016.
The terms hypertension/therapy [Majr:NoExp] or antihypertensive
agents/therapeutic use [Majr] were combined with OR, yielding 48,822
citations. We limited this result to clinical trials, human, English, and

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$UFKLYHVRI*HURQWRORJ\DQG*HULDWULFV²
aged 65+, resulting in 6987 studies. Of these, 1878 were published in
the past 10 years. Duplicates were eliminated. The title and abstract of
all identified references in the literature search were examined by two
independent reviewers. Subsequently, selection criteria were applied to
all the articles retrieved in full text. We read the full text and biblio-
graphies citations. From this, we excluded studies involving individuals
with an average age less than 70 years. We only included studies that
were at least one year in length. Where there was a difference of opi-
nion about inclusion of the study, a third reviewer was consulted.
2.3. Quality assessment
This systematic review was conducted in accordance with the
PRISMA statement (http://www.prisma-statement.org). Once studies
were collected, a more detailed assessment of the study eligibility was
conducted as depicted by Fig. 1. Afterwards, the quality of trials was
systematically assessed according to the Cochrane Collaboration risk of
bias assessment (http://methods.cochrane.org/bias/assessing-risk-bias-
included-studies).
3. Results
3.1. Literature search
Of the articles published in the past 10 years, we reviewed the titles
and abstracts of 1878 citations. We read the full text and bibliographies
of 88 articles. From this, we excluded 82 studies involving individuals
with an average age less than 70 years. The reference list of included
articles yielded no additional citations for clinical trials meeting our
criteria. A total of six studies met the search criteria, which included
reporting of the treatment strategies for hypertension.
3.2. Study characteristics
All of the studies were randomized-controlled trials undertaken in
older patients with hypertension, representing a multitude of countries
and published within the last 10 years. Table 1 includes study design,
number of patients, inclusion criteria, blood pressure target,
Fig. 1. Flowchart of Study Inclusion.
 J.K. Kirk et al.
Table 1
Elderly hypertension trial characteristics.
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Study Location Design N Inclusion Blood Pressure Blood Pressure Follow-up

Criteria (BP) target, (BP) Period
mm Hg Medications

Beckett et al. Europe, China, double-blind, 1933 active Age 80+ years BP < 150/80 Step 1: 1 year
(2008) Australia, placebo (mean age 83.6 indapamide SR extension
Tunisia controlled RCT years) 1.5 mg/day from 2 year
Extension with open label 1912 placebo SBP 160–199 Step 2: original
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

Trial extension indapamide

(2012) sustained
release
1.5 mg/day
± other agents
HYVET 1712 extension
Study

Williamson US RCT open-label 2636 Age ≥ 75 yea- SBP < 120 or Initiate 3 years
et al. rs SBP < 140 treatment with
(2016) 1–2 drugs,
SPRINT SBP 130–180 then titrate
Study number/
Community dosage of
dwelling drugs based on
formulary


Kostis et al. US double-blind, 4736 Average age SBP < 160 or chlorthalidone 22 years
(2014) placebo- 71.6 years decrease by 20 12.5–25 mg/
controlled RCT if initial SBP day vs. placebo
160–179
SHEP Study SBP ≥ 160,
DBP < 90

Ogihara Japan prospective, 3260 Average age SBP < 140 Step 1: 3 years
et al. open-label, 76.1 + 4.1 ye- valsartan
(2010) blinded ars with ISH, 40–80 mg/day
endpoint RCT SBP > 160
DBP < 90
VALISH SBP < 150 Step 2:

$UFKLYHVRI*HURQWRORJ\DQG*HULDWULFV²

Study valsar-
tan ≤ 160 mg/
day, ± other
agents

Ogawa et al. Japan prospective, 1164 Average age BP < 140/90 Step 1: 3 years
(2012) open-label, 73.6 years olmesartan
blinded end- 20 mg/day
point RCT
OSCAR SBP ≥ 140 m- Step 2:
Study m Hg or olmesartan
40 mg/day
+ CCB
DBP ≥ 90 mm

(continued on next page)

 J.K. Kirk et al.
Table 1 (continued)

Study Location Design N Inclusion Blood Pressure Blood Pressure Follow-up

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Criteria (BP) target, (BP) Period

mm Hg Medications

Hg

Sato et al. Japan prospective, 142 Average age 74 BP < 140/90 Step 1: fixed- 1 year
(2013) randomized, years dose
open-label, combination
RCT losartan
(50 mg) & HC-
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TZ (12.5 mg)
or ARB
+ amlodipine
5 mg/day. Step
2: add losartan
or other ARB
± other agents
CAMUI Prior tx with BP < 130/80
Study ARB for diabetes or
renal disease
SBP > 140
and/or
DBP > 90
DM/renal
disease
SBP > 130
and/or


DBP > 80

ARB = angiotensin receptor blocker, BP = blood pressure, CCB = calcium channel blocker, CKD = chronic kidney disease, DBP = diastolic blood pressure, HCTZ = hydrochlorathiazide, ISH = isolated systolic hypertension, RCT = randomized
controlled trial, SBP = systolic blood pressure.

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J.K. Kirk et al. $UFKLYHVRI*HURQWRORJ\DQG*HULDWULFV²

antihypertensive medications and follow-up. Five of these studies re- or left ventricular ejection fraction <35% (Williamson, Suplano,
ported some type of cardiovascular outcome outlined in Table 2. We Applegate, Berlowitz, & Campbell, 2016).
pulled the original trials from two large studies to include baseline data The Systolic Hypertension in the Elderly Program (SHEP) study was
information for Table 1 as the outcomes were later published from conducted from 1980 to 1983. The full trial was first published in 1991
extension trials (Beckett, Peters, Fletcher, Staessen, & Liu, 2008; SHEP with patients not previously on antihypertensive treatments rando-
Cooperative Research Group, 1991). All studies met the criteria for mized to placebo (n = 2371) or active treatment (n = 2365) (SHEP
selection bias including random sequence generation, allocation con- Cooperative Research Group, 1991). Initial systolic blood pressure
cealment, performance, detection, attrition and reporting bias as ap- ranged from 160 to 219 mm Hg with diastolic blood pressure <90 mm
propriate. A brief overview of study design for each of the trials meeting Hg. There were 57% women and 14% black patients studied. The
the search criteria is discussed. follow-up of SHEP is outlined in Table 2 (Kostis, Cabrera, Messerli,
Cheng, & Sedjro, 2014). Treatment goal was to reduce systolic blood
pressure at least 20 mm Hg from baseline and below 160 mm Hg with
3.3. Study designs
minimal amounts of study medication. Exclusion criteria included al-
cohol or liver disease, renal dysfunction, a competing risk for study
Please reference study characteristics in Table 1.
endpoint or presence of medical management problems.
The Hypertension in the Very Elderly Trial (HYVET) was designed
Valsartan in Elderly Isolated Hypertension (VALISH) study com-
to assess the risks and benefits of reducing blood pressure in the very
pared the incidence of cardiovascular events in patients 70–85 years of
elderly patient as well as to clarify the impact of hypertension control
age with isolated systolic hypertension between two target blood
on stroke prevention and non-stroke death. Entry criteria are included
pressures, 140 mmHg versus 150 mmHg, using valsartan. Primary
in Table 1. Patients with isolated systolic hypertension were recruited
endpoints are outlined in Table 2. Patients with malignant hyperten-
from 11 countries (with many from China and Eastern Europe). En-
sion, systolic blood pressure >200 mmHg and/or diastolic
rolled patients with preexisting cardiovascular disease comprised only
>90 mmHg, cardiovascular disease, myocardial infarction, coronary
about 12% of the study population. Exclusions included heart failure
arterioplasty in the past six months, severe heart failure, atrial fi-
requiring more than digoxin, secondary hypertension, gout, residence
brillation, aortic stenosis, valvular disease, serum creatinine over 2 mg/
in a nursing home, and inability to stand or walk, to name a few
dl and serious liver dysfunction were excluded (Ogihara, Saruta,
(Beckett et al., 2008).
Rakugi, Matsuoka, & Shimamoto, 2010).
The Systolic Blood Pressure Intervention Trial (SPRINT) randomly
The Olmesartan and Calcium Antagonists Randomized (OSCAR)
assigned patients with a systolic blood pressure of 130–180 mm Hg or
study investigated whether high-dose angiotensin receptor blocker
higher and an increased cardiovascular risk to a systolic blood pres-
monotherapy (n = 578) or combination therapy using an angiotensin
sure target of <120 mm Hg (intensive treatment) or a target of
receptor blocker and calcium channel blockers (n = 586) was more
<140 mm Hg (standard treatment). The primary composite outcomes
effective in reducing the incidence of cardiovascular events and
are outlined in Table 2. Increased cardiovascular risk was defined as
noncardiovascular death in high-risk hypertensive patients not ade-
the presence of one or more of the following: clinical or subclinical
quately controlled by standard dose angiotensin receptor blocker
cardiovascular disease, chronic kidney disease (estimated glomerular
alone. Exclusion criteria included secondary hypertension or malig-
filtration rate of 20–59 mg/min), a Framingham Risk Score for 10-year
nant hypertension, heart failure (New York Heart Association func-
CVD risk >15%, and/or age >75 years. Exclusion criteria included
tional classification III or IV), required treatment for malignant
diabetes, history of stroke, systolic blood pressure <110 mm Hg after
tumor, serious liver or renal dysfunction (serum creatinine >2.5 mg/
1 min of standing, symptomatic heart failure within the past 6 months

Table 2
Outcomes of hypertension trials in the elderly.

Study All-cause mortality CV events composite CV mortality Fatal/non-fatal stroke Fatal/non-fatal MI Death from Stroke Fatal/Non-fatal HF

Williamson et al. (2016) intensive vs. standard treatment (SPRINT)

Hazard Ratio 0.67 0.60 0.72 0.69 0.63
95% CI (0.49–0.91) (0.33–1.09) (0.43–1.21) (0.45–1.05) (0.40–0.96)
P Value 0.009 0.09 0.22 0.09 0.03
Beckett et al. (2008) treatment vs. placebo (HYVET)
Hazard Ratio 0.79 0.66 0.77 0.70 0.72 0.61 0.36
95% Confidence Interval (0.65–0.95) (0.53–0.82) (0.6–1.01) (0.49–1.01) (0.30–1.70) (0.38–0.99) (0.22–0.58)
P Value 0.02 <0.001 0.06 0.06 0.45 0.046 <0.001
Beckett et al. (2012) 1 year extension
Hazard Ratio 0.48 0.78 0.19 1.92 0.28
95% Confidence Interval (0.26–0.87) (0.36–1.72) (0.04–0.87) (0.59–6.22) (0.03–2.73)
P Value 0.02 0.55 0.03 0.28 0.28
Kostis et al. (2014) treatment vs. placebo (SHEP 22 year follow-up)
Hazard Ratio 0.88
95% Confidence Interval (0.78–0.98)
P Value 0.021
Ogihara et al. (2010) strict vs. moderate BP control, VALISH Study
Hazard Ratio 0.78 0.89 0.97 0.68 1.23
95% Confidence Interval (0.46–1.33) (0.60–1.34) (0.42–2.25) 0.36–1.29) (0.33–4.56)
P Value 0.362 0.38 0.950 0.237 0.761
Ogawa et al. (2012) comparison of 2 treatments, OSCAR Study
Hazard Ratio 1.63a 1.56
95% Confidence Interval (1.06–2.52) (0.64–3.83)
P Value 0.03 0.33

HF = Heart Failure, HYVET = Hypertension in the Very Elderly Trial, MI = Myocardial Infarction, SHEP = Systolic Hypertension in the Elderly Program.
a
Patients with Cardiovascular (CV) disease.



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J.K. Kirk et al.
dL or with dialysis treatment) (Ogawa, Kim-Mitsuyama, Matsui,
Jinnouchi, & Jinnouchi, 2012).
The CAMUI trial included patients who had not achieved target
blood pressure with standard angiotensin receptor blocker dosages by
randomly assigning patients to receive either a fixed-dose combination
of angiotensin receptor blocker plus a diuretic or calcium channel
blocker (Sato, Saijo, Sasagawa, Morimoto, & Tekachi, 2013). Changes in
blood pressure, laboratory values and cognitive function were eval-
uated. Those with secondary hypertension, heart failure, history of se-
vere hepatic or renal disease, hypersensitivity to losartan or hydro-
chlorothiazide (or like drugs) were excluded.
3.4. Hypertension treatment regimens
The hypertension treatment regimens for the six clinical trials re-
viewed are outlined in Table 1. Regarding hypertension drug choice,
there is also a plethora of pharmacotherapy choices. Some studies
employed a broad formulary, while other used upward titration versus
a stepped approach to achieve blood pressure targets. The majority of
the studies did not provide detail on treatment tolerability or side
effect profile.
HYVET utilized an active treatment regimen of indapamide 1.5 mg
sustained release or placebo with the addition of perindopril
2 mg–4 mg or placebo if needed to reach a target blood pressure of
<150/80 mmHg (Beckett et al., 2008). There was no detail provided
regarding adverse effects and overall a significantly lower occurrence
of serious reactions was reported in the treatment arm compared to
the placebo arm.
SPRINT utilized a formulary which included a variety of anti-
hypertensive agents including angiotensin converting enzyme in-
hibitors, angiotensin receptor blockers, direct vasodilators, thiazide-
type diuretics, loop diuretics, potassium-sparing diuretics, beta-
blockers, sustained-release calcium channel blockers, alpha1-receptor
blockers, and sympatholytics (Williamson et al., 2016). The use of
diuretics, angiotensin-converting enzyme inhibitors, and angiotensin
receptor blockers was noted to have more of a potential intrarenal
hemodynamic effect in the intensive treatment group. There was no
statistically significant difference in any specific adverse events be-
tween the intensive and standard treatment groups.
The SHEP trial antihypertensive drug therapy was a chlorthalidone-
based stepped-care regimen (SHEP Cooperative Research Group, 1991).
For the active treatment group, therapy included chlorthalidone 12.5 or
25 mg per day with the addition of atenolol 25 or 50 mg per day or
reserpine 0.05 or 0.10 mg per day as needed. The reported number of
clinical complaints was greater in the active treatment group compared
to placebo. Laboratory abnormalities including serum potassium, uric
acid, glucose, cholesterol and sodium occurred more commonly in the
active treatment group.
The VALISH study used an angiotensin receptor blocker, valsartan,
at a dose of 40–80 mg daily as the initial therapy (Ogihara et al., 2010).
The most common adverse events included gastrointestinal and re-
spiratory symptoms that were similar in both treatment groups. The
rate of discontinuation attributed to valsartan was 1.9% in the strict
control group versus 1.2% in the moderate control group.
The remaining two studies from Japan compared treatment regi-
mens. The OSCAR trial compared a high dose angiotensin receptor
blocker to standard dose angiotensin receptor blocker plus a calcium
channel blocker (Ogawa et al., 2012). Higher dose olmesartan, 40 mg
daily monotherapy, was compared to olmesartan 20 mg daily plus
amlodipine or azelnidipine. There were no significant differences in
adverse effects between groups with a reported rate around 8% for
both.
The CAMUI trial compared an angiotensin receptor blocker plus a
diuretic to an angiotensin receptor blocker plus a calcium channel
blocker. Specifically, losartan 50 mg and hydrochlorothiazide 12.5 mg
(n = 72) was compared to amlodipine 5 mg and the typical dosage of

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an angiotensin receptor blocker (n = 68) (Sato et al., 2013). The au-
thors noted that the diuretic combination caused a decrease in esti-
mated glomerular filtration rate compared to the calcium channel
blocker combination but the diuretic combination seemed to be asso-
ciated with improvement in proteinuria.
3.5. Trial outcomes
The HYVET trial was stopped early after two years because of
significant reduction in stroke deaths and mortality, with a median
follow-up of 1.8 years, and only half of the treatment group achieving
their target blood pressure goals. At two years in the primary HYVET,
48% of patients in the active treatment group reached goal blood
pressure versus only 19.9% in placebo (p < 0.001) and there were
several significant cardiovascular outcomes as outlined in Table 1
(Beckett et al., 2008). The hazard ratios and associated p-values in-
dicate a significant reduction in the rate of death from stroke, all-cause
mortality and heart failure associated with active treatment of hy-
pertension. The HYVET one year extension trial consisting of 1712
patients found a significant reduction in cardiovascular events, total
mortality and mortality from stroke (Beckett, Peters, Tuomilehto,
Swift, & Potter, 2012).
In SPRINT, among those over 75 years, the primary composite
outcome (nonfatal myocardial infarction, acute coronary syndrome,
nonfatal stroke, nonfatal acute decompensated heart failure, and death
from cardiovascular causes) occurred in 102 patients in the intensive
treatment group versus 148 in the standard treatment group with ha-
zard ratio 0.66 [95% CI, 0.51–0.85] (Williamson et al., 2016). Intensive
therapy was also associated with decreased all-cause mortality, with 73
deaths in the intensive treatment group versus 107 in the standard
treatment group (hazard ratio, 0.67 [95% CI, 0.49–0.91]).
The primary endpoint in the SHEP trial was the incidence of fatal
and non-fatal stroke (SHEP Cooperative Research Group, 1991). Sec-
ondary endpoints were cardiovascular and coronary morbidity and
mortality, and all-cause mortality. The incidence of stroke was sig-
nificantly reduced by 36%, along with a reduction in major cardio-
vascular events equating to a 5-year absolute benefit of 55 events per
1000. The 22 year follow-up data showed a gain in life expectancy free
from cardiovascular death in the active treatment group was 158 days
(Kostis et al., 2014). The hazard ratio for cardiovascular mortality was
0.88 (95% CI, 0.78–0.98, p = 0.021) with blood pressure lowering via
antihypertensive therapy two decades after the original trial.
The expected median follow up of three years in the VALISH study
focused on a composite of events including sudden death, fatal or
nonfatal stroke, fatal or nonfatal myocardial infarction, death because
of heart failure, and other cardiovascular death (Ogihara et al., 2010).
A two-sided α level of 0.05 and 80% power was used to detect the
difference in incidence of cardiovascular events between the target le-
vels based on estimation of the cardiovascular ratio as 21.5/1000 pa-
tient-years and 29.1/1000 patient-years.
The OSCAR study found that more patients in the angiotensin re-
ceptor blocker plus calcium channel blocker group achieved target
blood pressure of <140/90 compared to the high dose angiotensin
receptor blocker group (70.5% versus 62.1%, respectively; p = 0.003)
(Ogawa et al., 2012). Between the two treatment regimens, the only
significant difference in coronary events (sudden death, myocardial
infarction, angina pectoris, asymptomatic myocardial ischemia) at 36
months was in the subgroup with pre-existing cardiovascular disease.
Of this subgroup, those treated with high dose angiotension receptor
blockers alone had more cardiovascular events than those treated with
the combination of angiotensin receptor blocker and calcium channel
blocker with a hazard ratio of 1.63 (p = 0.03).
The CAMUI trial only evaluated blood pressure at 6 months (Sato
et al., 2012). At one year, the urine albumin/creatinine ratio was sig-
nificantly decreased from the geometric mean of 17.1–9.6 mg/g in the
angiotensin receptor blockers plus diuretic group, whereas it was
J.K. Kirk et al.
increased from 19.8 to 23.7 mg/g in the angiotensin receptor blockers
plus calcium channel blocker group. The estimated glomerular filtration
rate decreased in the angiotensin receptor blocker plus diuretic group.
4. Discussion
4.1. Treatment of hypertension and blood pressure targets
The present review systematically examined the six most relevant
intervention trials pertaining to optimal blood pressure goals and
treatment regimens in patients >70 years of age over the last ten years.
Given the wide variability in study designs, inclusion and exclusion
criteria, blood pressure targets and treatment regimens, limited con-
clusions can be drawn. Across all the studies, treating high blood
pressure in older patients is beneficial and there is compelling evidence
to consider blood pressure control for all older patients. The optimal
blood pressure goal remains to be determined and consideration to
specific patient environment (i.e. community dwelling versus nursing
home) and frailty must be considered. JNC-8 recommended relaxing
blood pressure control for the elderly in 2014 (James et al., 2014).
European guidelines do not recommended initiation of treatment in
patient’s >80 years of age for systolic blood pressure <180 mm Hg
(Mancia et al., 2013). Our review reveals that treatment of systolic
hypertension with antihypertensive pharmacotherapy and lower blood
pressure targets are associated with improved cardiovascular outcomes
and mortality in the elderly population. Generalizability of this data is
still unclear.
HYVET and SHEP, the two studies that assess treatment for hy-
pertension versus placebo, demonstrate a significant reduction in death
from stroke, incidence of heart failure, mortality (HYVET) and cardio-
vascular mortality (SHEP) with treatment of systolic hypertension in
elderly patients (Beckett et al., 2012; Kostis et al., 2014). Both studies
targeted blood pressures <180 (<150 and <160, respectively), which
brings the continued appropriateness of the European guideline that
only advises treatment for pressure >180 into question. HYVET spe-
cifically examined patients >80 years, while SHEP had an average age
of 71.6 years, but cardiovascular mortality reduction remained sig-
nificant many years out. HYVET and SHEP generally support the widely
accepted principle that hypertension is a modifiable risk factor for
cardiovascular disease and mortality that warrants pharmacologic
treatment. However, they do not address the optimal blood pressure
target or answer the question about whether stricter control is better
than moderate control in the elderly. SPRINT and VALISH specifically
address these issues by comparing strict and moderate blood pressure
targets, albeit with different definitions of strict and moderate.
The SPRINT Program for patients over 75 years of age targeted an
aggressive systolic blood pressure goal of <120 mm Hg compared to
<140 mm Hg (Williamson et al., 2016). Given the statistically sig-
nificant decrease in all-cause mortality, heart failure, and cardiovas-
cular composite outcomes, our review suggests that SPRINT targets
should be considered in the appropriate patient. We suspect that
guidelines will ultimately reflect his recommendation. VALISH did not
demonstrate a statistical difference in cardiovascular or mortality out-
comes for moderate versus tight blood pressure control defined as
<150 mm Hg versus <140 mm Hg, respectively (Ogihara et al., 2010).
Lack of significance could be due to lack of power, but it is also possible
that the clinical difference between 150 and 140 mm Hg is not as im-
pactful on vascular health as the difference between 140 and 120 mm
Hg. Regardless, there did not appear to be harm associated with stricter
blood pressure control in the VALISH trial, which would lend toward
following the implications of SPRINT. Overall, these four trials would
suggest that hypertension treatment with tight blood pressure control in
the non-diabetic, non-heart failure and non-frail patient is optimal with
a systolic target of 120 mm Hg; however, generalizability of these trials
is challenging.

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4.2. Generalizability of hypertension studies
Population generalizability requires us to review the inclusions and
exclusions from these trials. Although SPRINT suggested that high
cardiovascular risk was an inclusion criteria age ≥75 years alone ca-
tegorized participants at high cardiovascular risk (Williamson et al.,
2016). Thus, SPRINT included healthy adults ≥75 years of age without
exclusion for adults with clinical or subclinical cardiovascular disease,
chronic kidney disease (estimated glomerular filtration rate of
20–59 mg/min) or a Framingham Risk Score for 10-year cardiovascular
disease risk >15%. SPRINT had an overall decrease in blood pressure
of 14.8 mm/Hg and required, on average, one new blood pressure
medication to reach goal with significant composite outcomes. SPRINT
excluded patient with certain blood pressure cutoffs based on number
of medications already employed to achieve their blood pressure. It is
unclear if benefits would persist if multiple medications were required
to achieve stricter control as polypharmacy could be associated with
additional serious adverse events.
The populations of older adults in the HYVET and SPRINT trials may
represent a “healthier” population of elderly patients. This could be due
in part to the lower amount of cardiovascular disease in the primary
HYVET study and the exclusion of diabetes patients in the SPRINT
study. These issues deserve consideration when assessing aggressive
blood pressure goals. The SHEP reported impressive 22 year follow-up
data (Kostis et al., 2014). The longevity of the SHEP original partici-
pants also raises questions about the robustness of participants. The
inclusion of “healthier” participants with an overall longer life ex-
pectancy should be considered when generalizing the result of these
studies.
Heart failure patients were generally excluded from the treatment
versus placebo and strict versus moderate control trials due to specific,
evidence based guidelines already in place for treatment of heart
failure, which include several classes of antihypertensives and compli-
cate the treatment protocols. Recommendations for these patients
generally derive from the cardiology literature and will not be reviewed
in this study. On the other hand, patients with severe renal dysfunction
were excluded from OSCAR and VALISH, the two trials assessing regi-
mens including angiotensin receptor blockers.
4.3. Relationship between frailty and study outcomes
Two of the studies in this review evaluated frailty. The HYVET study
constructed a frailty index score to categorize patients to assess differ-
ences in cardiovascular events (Warwick, Falashcetti, Rockwood,
Mitnitski, & Thijs, 2015). Categories based on the index included: frail,
prefrail, and robust. Other tests of frailty, including walking speed and
grip strength were not included. HYVET found a consistent benefit of
antihypertensive treatment on stroke, cardiovascular events and total
mortality irrespective of baseline frailty status. The frailty level in
HYVET may represent a robust study group.
SPRINT also assessed frailty. A 36-item frailty index classified pa-
tients as fit, less fit, or frail (Pajewski, Williamson, Applegate,
Berlowitz, & Bolin, 2016). Approximately one fourth of the population
(27.6%) was classified as frail. A multivariable analyses showed that a
1% increase in the frailty index was correlated with significantly in-
creased risk for self-reported falls (HR = 1.03), injurious falls (hazard
ratio = 1.035), and all cause hospitalizations (hazard ratio = 1.038). A
more significant improvement in cardiovascular outcome events was
found in the frail and less fit patient categories than in the fit. Fur-
thermore, the fastest category of gait speed had significant outcomes.
The PARTAGE study did not make our criteria for table inclusion
but is important to briefly mention. This longitudinal analysis was
undertaken in 1126 older nursing home residents (average age 87.6
years) in France and Italy treated with multiple blood pressure medi-
cations (Benetos, Labat, Rossignol, Fay, & Rolland, 2015). A significant
interaction was found between low systolic blood pressure (<130 mm
J.K. Kirk et al.
Hg) and two or more antihypertensive agents that resulted in about a
two-fold higher mortality risk (unadjusted hazard ratio 1.8, 95% con-
fidence interval, 1.36–2.37). A 10 mm Hg increase in systolic, diastolic
or mean blood pressure resulted in a significant decrease in mortality.
The patients more commonly received loop diuretics, potassium-
sparing diuretics, and less frequently received calcium channel
blockers, thiazide diuretics, or angiotensin receptor blockers.
A pivotal issue that warrants discussion is how frailty factors into
lowering blood pressure. Should frailty, defined as a biological state of
deterioration of multiple body systems physiologically that can lead to
clinical manifestations including loss of muscle mass, low activity level
and poor endurance (Zhang, Cheng, & Wang, 2016), be considered an-
other comorbidity? Some advocate walking speed as an optimal method
to identify elderly adults at higher risk for adverse outcomes related to
elevated blood pressure (Odden, Peralta, Haan, & Covisky, 2012). The
majority of the trials excluded frail adults. HYVET and SPRINT excluded
nursing home patients and HYVET excluded patents with limited mobi-
lity. Both of these trials had methods for stratifying frailty, but both
populations were fairly robust compared to the general population.
4.4. Antihypertensive medication choices
Current guidelines have variable recommendations regarding initial
antihypertensive therapy, but thiazide diuretics and calcium channel
blockers are generally widely accepted as first line therapies. JNC-8 re-
commends initial therapy with thiazide-type diuretics, angiotensin con-
verting enzyme inhibitors, angiotensin receptor blockers or calcium
channel blockers in non-black patients and thiazide-type diuretics or
calcium channel blockers in black patients. European guidelines specify a
preference for diuretics or calcium channel blockers in isolated systolic
hypertension, but otherwise do not specify (NICE, 2011) and to offer
people over 80 the same antihypertensive drug treatment as those 55–80
years of age. Two of the trials reviewed compared treatment regimens
head to head, though neither investigated first line therapy. The re-
maining four trials had variable treatment choices as outlined below.
Reductions in mortality were demonstrated with different treatment
regimens in HYVET and SHEP. HYVET’s treatment arm used a diuretic
+/− an angiotension converting enzyme inhibitor, while SHEP’s treat-
ment arm used a diuretic +/− a beta blocker or reserpine (a central-
monoamine depleting agent). The diuretic was the common denominator,
while beta blockers and reserpine are rarely considered first or even
second line therapies anymore, but still managed to result in a significant
reduction in cardiovascular events, which may suggest that treatment
choice is not as important as blood pressure reduction. SPRINT demon-
strated mortality benefit through tighter blood pressure control with a
wide variety of medications from a broad formulary. VALISH did not
demonstrate a statistical difference in moderate <150 versus tighter
<140 control of blood pressure with an angiotensin receptor blocker.
The three Japanese trials specifically examined dosages and com-
binations of angiotensin receptor blocking agents. OSCAR and CAMUI
were the only trials that compared two different regimens head to head.
OSCAR did not show any significant differences in outcomes between
high dose angiotensin receptor blocker and combination angiotensin
receptor blocker and calcium channel blocker except in patients with
underlying cardiovascular disease, who had significant reduction in
cardiovascular events associated with the combination. CAMUI did not
measure cardiovascular outcomes because a previous trial had de-
monstrated that angiotensin converting enzyme inhibitor and calcium
channel blocker was superior in reduction of cardiovascular events
compared with angiotensin converting enzyme inhibitor with diuretic,
though outside the scope of this review (Sato et al., 2013). The CAMUI
trial did find a reduction in estimated glomerular filtration rate asso-
ciated with an angiotensin receptor blocker with diuretic combination
compared with an angiotensin receptor blocker with calcium channel
blocker combination. However, the diuretic combination was asso-
ciated with improvement in albuminuria.

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4.5. Limitations
Some trials may have been missed if published after September
2016. Of the trials included, all six trials varied in design and evaluated
for different blood pressure goals, included slightly different popula-
tions with variable co-morbidities and degrees of risk and frailty and
generalizability between such studies is limited. Treatment regimens
differed without clear head to head data except as outlined in the
OSCAR and CAMUI trials. The studies had varying lengths of subject
participation and follow-up including extension trials, so distinction in
the mortality benefits and adverse effects of treatments can only be
assessed within the trial periods for each individual trial. Side effects
were not consistently defined or measured across studies.
4.6. Further research needed
As a whole, people are living longer in industrialized countries.
With increasing longevity comes increasing focus on modifiable risk
factors for cardiovascular events and mortality associated with aging,
specifically, hypertension. Guidance is needed to determine how to best
care for these patients in regards to optimal target goals for hyperten-
sion and treatment regimens to prevent cardiovascular disease. An
appropriately powered randomized controlled trial comparing several
different blood pressure targets with well powered subgroup analyses
for some of the co-morbidities discussed above, including frailty, heart
failure and diabetes would be optimal. Head to head trials for specific
medication regimens with consideration of co-morbidities would also
aid clinicians in decision making. These would require substantial
funding and enrollment. The overwhelming number of variables makes
a perfectly delineated, data-supported algorithm unlikely in the coming
years, so medical judgement and consideration of risks and benefits
alongside patients continue to be valuable tools in treating hyperten-
sion in the geriatric patient. Ultimately, the studies reviewed in this
systematic review indicate that aggressive blood pressure control must
be individualized if implemented and is variably associated with re-
duction in cardiovascular outcomes in older adults and the optimal
medication regimen is yet to be determined.
Financial support
None.
Conflicts of interest
The authors have no conflicts of interest.
Acknowledgments
We would like to thank Rochelle Kramer, MLS, AHIP, Reference
Librarian for her expertise in completing searches for this manuscript.
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