Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Pharmacological Management of Hypertension in

the Elderly and Frail Populations

Ashish Correa, Yogita Rochlani, Mohammed Hassan Khan & Wilbert S.

Aronow

To cite this article: Ashish Correa, Yogita Rochlani, Mohammed Hassan Khan & Wilbert S.
Aronow (2018): Pharmacological Management of Hypertension in the Elderly and Frail Populations,
Expert Review of Clinical Pharmacology

To link to this article: https://doi.org/10.1080/17512433.2018.1500896

Accepted author version posted online: 13

Jul 2018.

Submit your article to this journal

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ierj20
Pharmacological Management of Hypertension in the Elderly and Frail Populations

Ashish Correaa; Yogita Rochlanib; Mohammed Hassan Khanb; Wilber S. Aronowb

Author affiliations:
a
Department of Medicine, Mount Sinai St. Luke’s – West Hospital/Icahn School of Medicine at

Mount Sinai, New York, NY

t
ip
b
Cardiology Division, Department of Medicine, Westchester Medical Center/New York Medical

College, Valhalla, NY

cr
us
Address for correspondence:

Wilbert S. Aronow
an
Professor of Medicine

Cardiology Division, Westchester Medical Center and New York Medical College
M

Macy Pavilion, Room 141

Valhalla, NY 10595
ed

Telephone number: (914) 493-5311

Fax number: (914) 235-6274

pt

E-mail: wsaronow@aol.com
ce
Ac

Abstract:

1
Introduction: Cardiovascular disease is a leading cause of mortality in the elderly. Hypertension

is an important modifiable risk factor that contributes to cardiovascular morbidity and mortality.

The prevalence of hypertension is known to increase with age, and hypertension has been

associated with an increase in risk for cardiovascular disease in the elderly. There is a wealth of

evidence that supports aggressive control of blood pressure to lower cardiovascular risk in the

t
ip
general population. However, there are limited data to guide management of hypertension in the

elderly and frail patient subgroups. These subgroups are inadequately treated due to lack of

cr
clarity regarding blood pressure thresholds, treatment targets, comorbidities, frailty, drug

us
interactions from polypharmacy, and high cost of care.

Areas covered: We review the current evidence behind the definition, goals and treatments for
an
hypertension in the elderly and frail, and outline a strategy that can be used to guide

antihypertensive pharmacotherapy in this population.

M

Expert Commentary: Lower blood pressure to <130/80 mm Hg in elderly patients if tolerated

and promote use of combination therapy if the blood pressure is >20/10 mm Hg over goal blood
ed

pressure. Antihypertensive treatment regimens must be tailored to each individual based on their

comorbidities, risk for adverse effects and potential drug interactions.

pt
ce

Key words: hypertension; elderly; frail; blood pressure; antihypertensive drug therapy
Ac

1. Introduction

2
As of 2015, there were around 422.7 million cases of cardiovascular disease (CVD) globally and

with a mortality of rate of 17.92 million per year. CVD accounted for a third of all deaths across

the world.1 Hypertension is a major risk factor for CVD, and is associated with increased

incidence of myocardial infarctions (MI), strokes, heart failure (HF) and peripheral artery disease

(PAD).2 In the United States (US), the prevalence of hypertension was 29.0% as of 2015-16 3

t
ip
and 63.1% of those 60 years or older had hypertension.3 The US population is aging fast, and it

is expected that by 2030, almost 20% of the population will be ≥ 65 years of age. As such,

cr
hypertension is a major healthcare challenge,4 and effectively treating hypertension has become a

us
priority.

Given the linear correlation between age and hypertension, the elderly population is
an
particularly susceptible to development of hypertension and its related comorbidities. However,

the need for treatment of hypertension in the elderly and the very elderly has long been debated.
M

Additionally, the definition of hypertension and goals for treatment in this population have been

a moving target for the last several decades. Further, frailty is often regarded as challenging issue
ed

in managing elderly patients due to concerns that the risks of treatment in such frail patients may
pt

outweigh the benefits, resulting in frailty precluding some patients from treatment.

The positive implications of hypertension control in lowering cardiovascular mortality

ce

and morbidity in the general population have been clearly established. Newer evidence now

definitively establishes the importance of the treatment of hypertension in the elderly (including
Ac

the frail) in reducing CVD burden.5–9 Further, the emergence of more recent evidence is now

leading to changes in the treatment thresholds and goals of treatment for hypertension in the

elderly. In this paper, we will review the evidence supporting the need for treatment of

3
hypertension in the elderly and frail patients, the treatment thresholds and on-treatment targets of

therapy, and the various drugs used for anti-hypertensive therapy in the elderly.

2. Need for the Treatment of Hypertension in the Elderly

The approach to the treatment of hypertension and the management of hypertension in the

t
ip
elderly has undergone dramatic changes over the last few decades. Until the 1930s, high blood

pressure was considered to be an inevitable consequence of aging and some believed it to play an

cr
important role as a compensatory mechanism for maintaining the perfusion of organs through

us
stiffened aged vessels.10 However, by the second half of the twentieth century, the attitudes of

the medical community began to change due to mounting evidence that showed an association
an
between hypertension and various comorbidities such as CVD, strokes, renal disease and PAD,

as well as evidence supporting the treatment of hypertension.

M

In the late 1960s, the Veterans Administration Cooperative Study Group conducted a

landmark trial – the first randomized double-blind, placebo-control, multi-center trial in

ed

cardiovascular medicine – which evaluated the effects of the initiation of anti-hypertensive

treatment in patients with non-malignant hypertension. The results of this study clearly
pt

established the beneficial effects of initiating treatment in hypertension.11–13 These findings were
ce

reaffirmed by the Hypertension Detection and Follow-up Program (HDFP) Cooperative Study

Group of the National Heart Lung and Blood Institute (NHLBI) which conducted a large
Ac

multicenter randomized trial that confirmed the beneficial effects of treating even mild diastolic

hypertension, even in those aged 60- 69 years.14,15

Over the subsequent years, other trials confirmed the beneficial impact of anti-

hypertensives in the elderly. The European Working Party on High Blood Pressure in the Elderly

showed significant reduction in cardiovascular mortality in elderly patients (mean age=72±8

4
years) treated with anti-hypertensives.16 The Swedish Trial in Old Patients with Hypertension

(STOP-Hypertension) showed that the beneficial effects of anti-hypertensives persisted among

even older patients.5 This study randomized 1627 Swedish men and women with hypertension

(systolic blood pressure [SBP] of 180 mm Hg or higher with diastolic blood pressure [DBP] at

least 90 mm Hg or DBP above 105 mm Hg irrespective of systolic pressure) aged 70 to 84 years

t
ip
to active treatment (n=812, mean age=75.6±3.7 years) with anti-hypertensive therapy or placebo

(n=815, mean age=75.7±3.7 years). The results showed that compared with placebo, anti-

cr
hypertensives significantly reduced fatal and non-fatal stroke, MI and cardiovascular death. 5

us
However, in STOP-Hypertension, isolated systolic hypertension (ISH) (for the trial, SBP

greater than 180 mm Hg and diastolic pressure less than 90 mm Hg) was an exclusion criterion
an
and the utility of targeting ISH was debated at that time.
M

3. Evidence for Treating Isolated Systolic Hypertension

Isolated systolic hypertension is commonly seen in the elderly population due to

ed

pathophysiologic changes in the arterial walls associated with aging. Systolic hypertension has

been shown to be an independent risk factor for increased cardiovascular mortality, strokes and
pt

all-cause mortality.17
ce

The Systolic Hypertension in the Elderly Program (SHEP) trial was a large multicenter,

randomized, double-blind, placebo-controlled trial that randomized 4736 patients with ISH (SBP
Ac

160 mm Hg or greater with DBP less than 90 mm Hg) from 1985 to 1988 to active treatment

(n=2365, mean age=71.6±6.7 years) with chlorthalidone (and atenolol and reserpine if needed)

or placebo (n=2371, mean age=71.5±6.7 years).6 In spite of the fact that 33% of patients in the

control arm received some sort of anti-hypertensive medication, patients in the active treatment

arm demonstrated a 36% reduction in fatal and non-fatal strokes (risk ratio [RR]: 0.64, 95%
5
confidence intervals [CI]: 0.50-0.82). Additionally, active treatment resulted in marked

significant reductions in transient ischemic attacks (TIA), HF, and the combined end-points of

non-fatal MI or coronary heart disease death, coronary heart disease and CVD. The Systolic

Hypertension in Europe (Syst-Eur) trial was a similar study; it randomized 4695 patients at 198

centers in 23 European countries across 8 years starting in 1989.7 Patients were randomly

t
ip
assigned to active treatment (n=2398, mean age=70.3±6.7 years) with nitrendipine (and enalapril

and hydrochlorthiazide if needed) or placebo (n=2297, mean age=70.2±6.7 years). Patients in the

cr
treatment group benefited from a 42% reduction in all strokes (p=0.003), a 44% reduction in

us
non-fatal strokes (p=0.007), a 26% reduction in all fatal and non-fatal cardiac end-points

(p=0.003), a 33% reduction in non-fatal cardiac end-points and a 31% reduction in all fatal and
an
non-fatal cardiovascular end-points (p<0.001). Another study in China – the Systolic

Hypertension in China (Syst-China) trial8 – showed similar findings, as did a large subsequent
M

meta-analysis.18
ed

4. Evidence for Treatment in the Very Elderly

Most of the large landmark trials on the use of anti-hypertensives in the elderly conducted in the
pt

1980s and ‘90s did not have sufficient numbers of patients over 80 years of age to comment on
ce

any putative favorable outcomes derived from the treatment of hypertension in the very elderly

population.5–7,16 Additionally, it had long been thought that any beneficial effects derived from
Ac

anti-hypertensive therapy in the elderly fell off as patients achieved very advanced age (>80

years).19,20 A sub-group meta-analysis of all patients 80 years of age and older from randomized

control trials on anti-hypertensive therapy in the elderly showed that treatment of hypertension in

these very elderly patients had a beneficial effect on preventing non-fatal cardiovascular events,

but it’s impact on mortality was inconclusive – anti-hypertensive therapy reduced significantly
6
reduced strokes by 34%, major cardiovascular events by 22% and HF by 39%, but had no

significant reduction in cardiovascular death and a relative but non-significant increase in all-

cause mortality. 21

These findings led to concerns that any benefit derived from anti-hypertensive therapy in

the very elderly patients (>80 years) in the community – in particular, those who are frail –

t
ip
would be off-set by the negative impact on mortality, and the utility of anti-hypertensive therapy

in patients over 80 years of age remained an open question for some time.

cr
The Hypertension in the Very Elderly Trial (HYVET), put to rest some of doubts about

us
the utility of treating hypertension in the very elderly.9 In HYVET, 3845 patients from Europe,

China, Australasia, and Tunisia who were 80 years of age or older and had an SBP of 160 mm
an
Hg or higher were randomly assigned to receive either active treatment with the diuretic

indapamide (with the angiotensin-converting enzyme inhibitor [ACE-I] perindopril, if needed) or

M

matching placebos. The goal was to achieve blood pressure of 150/80 mm Hg. At 2 years, the

mean blood pressure in the treatment group was 15/6.1 mm Hg lower than that in the placebo
ed

group and this was associated with a 30% reduction in fatal or nonfatal strokes (95% CI: −1 to
pt

51, p=0.06), a 39% reduction stroke mortality (95% CI: 1 to 62, p=0.05), a 21% reduction in all-

cause mortality (95% CI: 4 to 35, p=0.02), a 23% reduction in cardiovascular mortality (95% CI:
ce

−1 to 40, p=0.06), and a 64% reduction in HF (95% CI: 42 to 78, p<0.001). Active treatment was

also associated with fewer treatment-related adverse events (p=0.001). Unlike previous studies,
Ac

HYVET showed a significant reduction in all-cause mortality with anti-hypertensive therapy

among very elderly patients. Even after HYVET, there was no clear consensus – while many

experts aligned with the findings of HYVET,22–24 others expressed reservations.25–27 One meta-

analysis of hypertensive patients aged 80 years and older from randomized control trials found

7
that while anti-hypertensive therapy reduced strokes and heart failure events, it had no effect on

total mortality.25 The authors that study suggested that the disparity between the results of

HYVET and previous studies stem from the fact that the HYVET was stopped early due to

perceived beneficial effects, thus making it liable to random fluctuations being accepted as true

treatment effects. In an editorial commentary, Reboldi and his colleagues state that since patients

t
ip
in HYVET had a low prevalence of previous cardiovascular disease and specifically excluded

those with certain comorbidities like advanced heart failure and dementia, it results may not be

cr
completely applicable to frail elderly patients with comorbidities.26

us
5. Frailty and Hypertension in Elderly
an
Frailty represents a state of increased vulnerability to impairment of homeostasis leading to an

irreversible decline due to any stressors such as an illness, new medication, or surgical
M

procedure. Frailty results from a gradual decline in physiologic reserve and is known to be a

predictor of adverse outcomes in the elderly population.28

ed

Hypertension and CVD are prevalent in the frail elderly population. However the

approach to management of these conditions in this population is challenging. Observational

pt

studies of hypertension treatment in this population have suggested that aggressive blood
ce

pressure lowering may be harmful.21,29,30

HYVET and the Systolic Blood Pressure Intervention Trial (SPRINT) were two large
Ac

randomized studies for treatment of hypertension which included elderly and frail patients (age ≥

80 and 75 years respectively) with a frailty distribution similar to that in the ambulatory

community living population, showed that pharmacologic therapy for aggressive blood pressure

lowering in this population led to significant risk reduction for cardiovascular events and

mortality.9,31
8
 6. Clinical Evidence for Treatment Thresholds and On-Treatment Targets

The risk of CVD rises with increasing blood pressure; this was shown by a large observational

study including more than a million people which found that death from ischemic heart disease

and stroke rose progressively and in a linear fashion above SBP of 115 mm Hg and DBP of 75

t
ip
mm Hg for those between 40 and 89 years of age.32 For every 20 mm Hg of SBP and every 10

mm Hg of DBP, there was a doubling of mortality. As such, it is prudent to select some threshold

cr
of BP beyond which treatment would be appropriate as well as a target level for BP

us
management, after weighing the benefits of well controlled BP against the risk of hypotension.

The Hypertension Optimal Treatment (HOT) Study included 18,790 patients, 50–80
an
years (mean age of 61·5 years) with hypertension and DBP between 100 mm Hg and 115 mm

Hg (mean 105 mm Hg).33 The participants were randomly assigned to one of 3 target DBP
M

groups: ≤90 mm Hg, ≤85 mm Hg and ≤ 80 mm Hg. The study found that the lowest incidence of

major cardiovascular events occurred at a DBP of 82·6 mm Hg. Additionally, further reduction
ed

in DBP were found to be safe and, in patients with diabetes mellitus, there was a 51% reduction

in major cardiovascular events in the ≤ 80 mm Hg group compared with the ≤90 mm Hg group
pt

(p=0·005).
ce

The Valsartan in Elderly Isolated Systolic Hypertension Study (VALISH) was a

randomized, open-label, blinded end-point study that assessed the impact of intensive BP control
Ac

in versus moderate BP control in elderly Japanese with ISH.34 The study randomized 3260

Japanese patients aged 70 to 84 years (mean age: 76.1 years) with ISH (SBP 160 to 199 mm Hg)

into 2 groups: strict BP control (SBP < 140 mm Hg) and moderate BP control (SBP ≥ 140 mm

Hg to < 150 mm Hg). At 3 years, the study found that goal SBP in the strict BP control group

was safely achievable but it did not have any beneficial impact. However, a subsequent non-
9
randomized analysis of the data from VALISH categorized patients into 3 groups based on their

achieved BP at the end of the 3 year period of the study: < 130 mm Hg, 130 - < 145 mm Hg and

≥ 145 mm Hg,35 and this analysis was able to show that in older adults, SBP between 130 and

144 mm Hg was associated with minimal adverse outcomes and a reduction in CVD and all-

cause mortality.

t
ip
However, in the absence of clear randomized control study data regarding an appropriate

treatment threshold and on-treatment target level, the matter of a BP goal remained an open

cr
question. The 2010 Action to Control Cardiovascular Risk in Diabetes-Blood Pressure

us
(ACCORD BP) Study attempted to answer this question for high-risk diabetic hypertensive

patients.36 The study randomized 4733 hypertensive patients with high-risk for CVD and type 2
an
diabetes mellitus to two groups: the intensive treatment group (target SBP < 120 mm Hg) and the

standard treatment group (target SBP < 140 mm Hg). The study found that at the end of 4.7
M

years, there was no difference in the primary composite end-point of non-fatal MI, non-fatal

stroke, or death from cardiovascular causes between the two groups.

ed

In the case of patients with cerebrovascular disease, the Perindopril Protection Against
pt

Recurrent Stroke Study (PROGRESS) showed that in patients with and without hypertension

with a history of stroke or transient ischemic attack (TIA), BP-reduction (with perindopril and
ce

indapamide combination therapy) resulted in reduced risk of stroke 37. The determination of an

appropriate on-treatment target BP level for patients with a history of strokes was attempted by
Ac

the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.38 This study randomly

assigned 3020 patients with a history of recent small subcortical strokes or TIA to 2 treatment

groups – a standard treatment arm with a target BP of 130-149 mm Hg and an intensive

treatment arm with a target BP < 130 mm Hg. At the end of 3.7 years of follow-up, there was no

10
significant difference in the incidence of strokes between the 2 groups, though the lower BP

levels were well tolerated and there was a non-significant trend towards improved outcomes with

the intensive treatment group.

SPRINT attempted to evaluate appropriate BP targets for hypertensives at risk for CVD

without diabetes or a history of strokes.31 This study randomized 9361 hypertensive patients

t
ip
(SBP ≥ 130 mm Hg) ≥ 50 years of age without diabetes or prior strokes but with increased CVD

risk to a standard treatment group (target SBP < 140 mm Hg) or an intensive treatment group

cr
(target SBP < 120 mm Hg). The study was designed to have a follow-up period of 5 years, but at

us
an interim-analysis at 3 years the intensive-therapy group demonstrated sufficient superiority for

the trial to be stopped early. Intensive treatment resulted a significant decline in the primary
an
composite end-point of MI, acute coronary syndrome without MI, strokes, acute decompensated

HF and death from CVD causes (HR: 0.75, 95% CI: 0.64 to 0.89, p<0.001) as well as a
M

significant decrease in all-cause mortality (HR: 0.73, 95% CI: 0.60 to 0.90, p=0.003). There was

a non-significant increase in adverse events with the intensive treatment group. A randomized
ed

trial of BP control in the elderly (over age 75 years) consisting of patients from SPRINT by

Williamson et al. showed similar results.39 The study included 2636 persons aged 75 years and
pt

older (mean age 79.9 years), of which 33.4% were randomized to intensive BP control and
ce

28.4% of those randomized standard BP control. At 3.14-year median follow-up, the intensive

blood pressure control group had significant reduction in the primary composite endpoint of MI,
Ac

other acute coronary syndromes, stroke, HF, or cardiovascular death by 34% (p=0.001), all-cause

mortality by 33% (p=0.009), HF by 38% (p = 0.003), and the primary composite outcome or

death by 32% (p< 0.001). The absolute cardiovascular event rates were lower for the intensive

BP treatment group within each frailty stratum. The incidence of serious adverse events was

11
noted to be similar in the standard and intensive treatment arms in this elderly population. The

compelling results of the SPRINT trial as led to a widespread re-evaluation of hypertension

guidelines, prompting many international societies and agencies to now recommend lower BP

targets of therapy.

The Heart Outcome Prevention Evaluation (HOPE-3) study, however, showed somewhat

t
ip
different findings.40 The trial randomized 12,705 persons (mean age 65.7 years) without CVD

and at intermediate CVD risk to combination therapy with candesartan and hydrochlorothiazide

cr
or placebo. At 5.6-year years, there was no significant difference in the composite endpoint of

us
CVD death, non-fatal MI, or non-fatal stroke between the treatment and placebo arms. The

difference between the results of SPRINT and HOPE-3 may due to fact that patients in the
an
SPRINT trial achieved a much greater reduction in SBP than those in HOPE-3 (14.8 mm Hg vs 6

mm Hg). Further, SPRINT was a trial on hypertensive patients, while just 40% of the patients in
M

HOPE-3 had hypertension and it was a trial of primary prevention.

Recently, cardiovascular risk assessment has shown to be useful in decision making

ed

regarding the threshold for initiation of antihypertensive therapy and treatment goals,41 and CVD

risk assessment is now being included in the hypertension guidelines.42

pt
ce

7. Evolving Guidelines
Ac

Various governmental agencies and national and international societies have released guidelines,

expert opinions and consensus statements to guide the management of hypertension over the

years. In 2003, the National High Blood Pressure Education Program Coordinating Committee, a

coalition of 39 major professional, public, and voluntary organizations and 7 federal agencies,

administered by NHLBI, released national guidelines, known as the Seventh Report of the Joint
12
National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood

Pressure (JNC 7).43 In JNC 7, the importance of targeting SBP in patients over 50 years of age

was highlighted. The report classified SBP of 120 to 139 mm Hg or a DBP of 80 to 89 mm Hg as

“prehypertension”, SBP of 140 to 159 mm Hg or a DBP of 90 to 99 mm Hg as “Stage 1

Hypertension”, and SBP of ≥ 160 mm Hg or a DBP of ≥ 100 mm Hg as “Stage 2 Hypertension”.

t
ip
The goals of treatment for hypertension were set at <140/90 mm Hg or <130/80 mm Hg for those

with diabetes or chronic kidney disease. The report concluded that treatment should not be

cr
withheld in the elderly and should not be withheld on the basis of age, though it cautioned

us
against lowering DBP to less than 60 mm Hg.

In 2007, a joint task force of the European Society of Hypertension (ESH) and the
an
European Society of Cardiology (ESC) released guideline recommendation for the management

of arterial hypertension.44 These recommendations advocated for a classification of hypertension

M

as follows – high normal BP: SBP 130-139 mm Hg, DBP 85-89 mm Hg; grade 1 hypertension:

SBP 140-159 mm Hg, DBP 90-99 mm Hg; grade 2 hypertension: SBP 160-179 mm Hg, DBP
ed

100-109 mm Hg; and grade 3 hypertension: SBP >180 mm Hg, DBP >110 mm Hg. The
pt

guidelines recommended a target blood pressure of <140/90 mm Hg and a lower target of

<130/80 mm Hg in hypertensive patients with diabetes or other high risk comorbidities (like
ce

stroke, myocardial infarction, renal dysfunction, proteinuria) based on the available

evidence.33,44–51 For elderly patients, the task force recommended that the target be the same as
Ac

that for younger patients, if tolerated, and that successful and well-tolerated anti-hypertensive

therapy in those patients aged 80 years or older should not be interrupted.44

The American College of Cardiology Foundation (ACCF)/American Heart Association

(AHA) 2011 Expert Consensus Document on Hypertension in the Elderly recommended that

13
antihypertensive therapy should be initiated in elderly hypertensives aged 65–79 years with a

SBP ≥140 mm Hg or a DBP ≥ 90 mm Hg.52 Further, based on evidence provided by HYVET,

the document recommended initiating therapy in persons aged 80 years and older with a SBP ≥

150 mm Hg.9,52 While noting the lack of conclusive evidence for setting a specific on-treatment

BP target, the document recommended a therapeutic target of 140/90 mm Hg in persons aged

t
ip
65–79 years and a SBP of 140–145 mm Hg if tolerated in persons aged 80 years and older.52

The European Society of Hypertension (ESH) and the European Society of Cardiology

cr
(ESC) released their next set of guideline recommendations in 2013.53 These guidelines were

us
somewhat of a departure from the previous recommendations of the joint task force; as per the

guideline writers, while there was incontrovertible evidence for treating grade 2 (SBP 160-179
an
mm Hg, DBP 100-109 mm Hg) and grade 3 hypertension (SBP >180 mm Hg, DBP >110 mm

Hg), the evidence for treating low to moderate risk patients with grade 1 hypertension (SBP 140-
M

159 mm Hg, DBP 90-99 mm Hg), including elderly patients, was scarce. As such, the guidelines

recommended pharmacologic treatment in patients with grade 2 and 3 hypertension and only
ed

high-risk patients with grade 1 hypertension to a goal of SBP < 140 mm Hg. For low to moderate
pt

risk patients with grade 1 hypertension, pharmacologic treatment to a SBP goal of <140 mm Hg

was recommended only after lifestyle modifications failed to reduce BP. For elderly patients, it
ce

recommended treatment of grade 2 and 3 hypertension and grade 1 hypertension in those

younger than 80 years, only if they tolerated it. For patients less than 80 years, the on-treatment
Ac

goal was SBP between 140 and 150 mm Hg, though if the patient was “fit”, an SBP < 140 mm

Hg could be targeted. For frail patients, individualized goals were recommended. For very

elderly patients, ie, over 80 years, the on-treatment goal was SBP of 140 to 150 mm Hg if they

14
were in good physical and mental health. In all cases, a DBP target of < 90 mm Hg was

recommended, except in patients with diabetes, in whom a target of < 85 mm Hg was set.53

The 2013 Canadian Hypertension Education Program (CHEP) Recommendations

advocated for treating elderly patients over 80 years of age with a goal of < 150/90 mm Hg.54 For

those younger than 80 years, the goal for non-diabetic patients was < 140/90 mm Hg and for

t
ip
diabetics, it was < 130/80 mm Hg. In January 2014, the American Society of Hypertension

(ASH) and the International Society of Hypertension (ISH) released a statement with clinical

cr
practice guidelines.55 They recommended treating all patients (up to 80 years of age) to a goal of

us
< 140/90 mm Hg. For those over 80 years, the goal was set at 150/90 mm Hg (though if risk

factors were present, the goal was still 140/90 mm Hg).

an
The NHLBI, which had administered the previous Joint National Committees (JNC) and

had released their guideline recommendations – including the 2003 JNC 7 Report – decided in
M

June 2013 to discontinue releasing further guideline recommendation (including ones in

progress) and to partner with the ACCF and AHA to develop further hypertension guidelines.56,57
ed

However, the many experts of the committee originally empaneled by the NHLBI in 2008 to
pt

develop the eighth report of the JNC decided to continue their review. They published their

recommendations in the Journal of the American Medical Association (JAMA) in 2014.58 While
ce

the report was widely adopted, it was not endorsed by the NHLBI, ACCF, AHA or any US

federal agency and there was some concern about the integrity process without the original
Ac

mandate and support of the NHLBI.59 Additionally, there were some controversy around the

recommendation regarding the treatment threshold for patients greater than 60 years of age. For

patients less than 60 years, the report recommended initiating treatment for BP if >/= 140/90 mm

Hg and treating to goal of < 140/90 mm Hg.58 However, the committee felt there was insufficient

15
evidence to support the same threshold and goal for elderly patients (over 60 years) and given

recent evidence, they raised the treatment threshold and the on-treatment BP target to 150/90 mm

Hg.34,58,60 The publication of this report was followed a number of minority reports that raised

dissenting voices against this new target for elderly patients.61,62 In particular, the Association of

Black Cardiologists (ABC) and a working group on women’s cardiovascular health

t
ip
recommended a target blood pressure < 140/90 mm Hg in adults between 60 to 79 years of age

and below 150/90 mmHg in those aged 80 years and older.62

cr
A scientific statement from the AHA, ACCF, and ASH released in 2015 tackled the issue

us
of management of hypertension in patients with coronary artery disease (CAD) and, in particular,

took on the issue of the “J-curve” phenomenon – whereby the relationship between blood
an
pressure and cardiovascular events is J-shaped rather than linear, ie, at very low BP levels, there

is an increase in cardiovascular events, rather than an decrease.63 The writers concluded that the
M

evidence for the J-curve phenomenon was inconsistent, with studies showing contradictory

results.64,65 Ultimately, based on the results of various studies36,64,65 and expert opinion, the
ed

statement recommended a BP target of < 140/90 mm Hg in patients with hypertension and CAD.
pt

Additionally, it stated that it may be appropriate to target a BP of <130/80 mm Hg in patients

with CAD and previous MI, stroke or transient ischemic attack, or CAD risk equivalents (carotid
ce

artery disease, PAD, abdominal aortic aneurysm) and to have goal of < 150/90 mm Hg in

patients over 80 years.63

Ac

With the publication of the SPRINT Trial in 2015,31 numerous societies began to modify

their guidelines to incorporate the new evidence surrounding the beneficial impact of more

intensive blood pressure treatment.

16
 The 2016 Canadian Hypertension Education Program (CHEP) Recommendations, in

addition to reaffirming their previous guidelines, stated that in selected high-risk patients,

intensive BP reduction to a target SBP < 120 mm Hg should be considered to decrease the risk of

CVD events.66 Further, that same year, the Australian National Blood Pressure and Vascular

Disease Advisory Committee, an expert committee of the National Heart Foundation of Australia

t
ip
updated their 2008 guidelines – stating that in selected high cardiovascular risk populations,

aiming for a target SBP of < 120 mm Hg can improve cardiovascular outcomes.67

cr
However, not all societies adapted their guidelines as a result of SPRINT. The American

us
College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) noted

that while SPRINT showed substantial reduction in cardiovascular events and mortality with
an
more intensive BP control (SBP target of <120 mm Hg vs <140 mm Hg), the ACCORD trial

which tested the same targets did not demonstrate significant benefit.31,36,68 As such, the
M

ACP/AAFP clinical practice guidelines recommend initiating treatment in adults aged 60 years

or older only with SBP >/= 150 mm Hg to achieve a target SBP < 150 mm Hg to reduce the risk
ed

for mortality, stroke, and cardiac events. Further, in adults 60 years or older with history of
pt

stroke or transient ischemic attack or at high cardiovascular risk, they recommended initiating

treatment only with SBP ≥140 mm Hg to achieve a target SBP < 140 mm Hg.68
ce

In November 2017, the AHA and the ACCF released clinical practice guidelines that

served as a follow-up to the NHLBI’s 2003 JNC 7 Report.42,43 These clinical practice guidelines
Ac

drew from recent evidence – in particular, the SPRINT trial31 – and reclassified hypertension, in

addition to setting new treatment thresholds and on-treatment targets for hypertension. The

guidelines made the following classification – Normal BP: SBP <120 mm Hg and DBP < 80 mm

Hg, Elevated BP: SBP 120-129 mm Hg and DBP < 80 mm Hg, Stage 1 hypertension: SBP 130-

17
139 mm Hg or DBP 80-89 mm Hg, Stage 2 hypertension: SBP ≥140 mm Hg or DBP ≥ 90 mm

Hg. For decision making regarding treatment threshold and targets, the guidelines advocated the

use of their atherosclerotic cardiovascular disease risk assessment tool – namely, the ASCVD

tool.69,70 The guidelines recommend that for confirmed hypertensives with known clinical CVD

or estimated 10-year ASCVD risk of >10%, BP-lowering medications should be used if SBP

t
ip
≥130 mm Hg or average DBP ≥80 mm Hg. For those with average SBP ≥ 140 mm Hg or average

DBP ≥ 90 mm Hg, ASCVD 10-year is <10%, anti-hypertensives may be initiated. In terms of

cr
on-treatment goals, for those with clinical cardiovascular disease or ASCD risk >10%, the

us
guidelines strongly recommend that a BP < 130/80 mm Hg should be targeted.42 Based on these

guidelines, elderly persons over 75 years of age, must be recognized as hypertensive if SBP is
an
130 mm Hg or higher and DBP is 80 mm Hg or higher. The treatment goal for elderly persons is

<130/80 mm Hg if tolerated.
M

8.
ed

Choice of Drugs

This section briefly discusses pharmacologic management of hypertension in the elderly.

pt

a) Thiazides
ce

Thiazides are diuretics with a long-duration of action and a moderate anti-hypertensive effect.

The commonly used thiazides are hydrochlorothiazide (HCTZ) and chlorthalidone.

Ac

Chlorthalidone is more potent and has a longer duration of action, with once-a-day dosing, which

makes it the preferred agent – including in the elderly. But for this very reason it can be more

problematic as older patients are susceptible to volume depletion and orthostatic hypotension.

18
 These drugs have been the mainstay of anti-hypertensive therapy, particularly in the

elderly, ever since the publication of the Antihypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack Trial (ALLHAT).71 ALLHAT was a randomized, double-blind, active-

controlled clinical trial that compared calcium channel-blockers (CCB) and ACE-I with thiazides

in preventing coronary heart disease (CHD) and CVD. Between 1994 and 2002, the trial

t
ip
randomized 33,357 hypertensives over 55 years (mean age ~67 years) with one other CHD risk

factor to receive chlorthalidone (n=15255), amlodipine (n=9048) or lisinopril (n=9054). After a

cr
mean follow up of 4 to 8 years, no significant difference was seen in the primary end-point of

us
combined CHD death and non-fatal MI or in all-cause mortality. However, compared with

chlorthalidone, amlodipine showed a higher 6-year rate of HF (10.2% vs 7.7%; RR, 1.38; 95%
an
CI, 1.25-1.52) and Lisinopril showed higher 6-year rates of combined CVD (33.3% vs 30.9%;

RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF
M

(8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31). Thus, the trial showed that thiazides were more

effective in long-term hypertension treatment for preventing CVD and being cheaper, were the
ed

best first-choice agents. A large network meta-analysis of studies on anti-hypertensive agents

concluded that thiazides were the most effective agents in reducing cardiovascular morbidity and
pt

mortality.72 Thiazides are widely accepted as first-line anti-hypertensives in the elderly that can
ce

be effectively used for initiating therapy.52

However, the Second Australian National Blood Pressure Study (ANBP2) showed results
Ac

at conflict with those of ALLHAT.73 ANBP2 randomized 6083 hypertensive patients aged 65 to

84 years to treatment with either the ACE-I enalapril or the diuretic hydrochlorthiazide. With BP

reduction being similar in both groups, the risk of the primary outcome of all cardiovascular

events or death from any cause was 11% lower in the ACE-I group than the diuretic group and

19
the benefit was predominantly in men. Later, the conclusions of ALLHAT were further

challenged by the Avoiding Cardiovascular Events through Combination Therapy in Patients

Living with Systolic Hypertension (ACCOMPLISH) trial.74 This trial randomized 11,506

hypertensive patients with increased cardiovascular risk to a combination of benazepril and

amlodipine or to a combination of benazepril and HCTZ, with a mean follow-up of 2.5 years and

t
ip
primary end-point of a composite of death from cardiovascular causes, nonfatal myocardial

infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest,

cr
and coronary revascularization. The benazepril-amlodipine combination showed a relative risk

us
reduction of 19.6% (HR: 0.80, 95% CI: 0.72 to 0.90, p<0.001), demonstrating that a ACE-I and

CCB combination is better than an ACE-I and diuretic combination in preventing cardiovascular
an
disease outcomes. The major criticism of this trial was the fact that the thiazide HCTZ was used

rather than chlorthalidone with has much better 24-hour anti-hypertensives effects, and HCTZ’s
M

short duration of action may have been responsible for the poorer outcomes in those randomized

to the benazepril-HCTZ combination.74 This was also the case with the ANBP2 trial. A recent
ed

large systematic review and meta-analysis75 conducted for the 2017 ACC/AHA hypertension
pt

guidelines showed that thiazides were indeed associated with a lower risk of adverse

cardiovascular outcomes compared with other anti-hypertensives, and multiple recent guidelines
ce

continue to support such low-dose diuretics as first-line anti-hypertensive agents.42,52

The main adverse effects with thiazides include orthostatic hypotension from volume
Ac

depletion and electrolyte abnormalities hyponatremia, hypokalemia, hyperuricemia and

hypercalcemia. When these agents are used in older patients, certain precautions should be taken,

particularly in frail patients: clinicians should be cognizant of the patient’s volume status and

20
should always evaluate for hypovolemia, electrolytes should be closely monitored and patients

with gout should be on effective doses of anti-gout therapy.

b) Other Diuretics

While thiazide diuretics are more effective anti-hypertensives when compared with loop

t
ip
diuretics (furosemide, bumetanide, torsemide) in patients with normal renal function, presumably

due to the former’s longer duration of action, loop diuretics are better for blood pressure control

cr
in patients with CKD. When the glomerular filtration rate (GFR) is less than 30 mL/min, thiazide

us
diuretics are unable to compete with accumulating organic acids for transportation in to the

lumen of the nephron, and thus are unable achieve sufficient concentrations to act in the distal
an
tubule.76 However, loop diuretic molecules are able to achieve sufficient concentration in the

loop of Henle to exert a diuretic effect. Additionally, BP in CKD patients is highly dependent on
M

volume status, and thus the rapid diuretic effect of loop diuretics is effective in lowering BP.

Loop diuretics are also useful in hypertensive patients with HF. Among elderly patients,
ed

particularly among frail patients with poor dietary intake and who are prone to dehydration, close
pt

monitoring of volume status is warranted. Additionally, vigilance for electrolyte disturbances

should be maintained.
ce

Potassium-sparing diuretics include sodium transport channel antagonists (triamterene

and amiloride) and mineralocorticoid antagonists (spironolactone and eplerenone).

Ac

Mineralocorticoid antagonists have a potent antihypertensive effect. They are useful in managing

hypertension secondary to primary hyperaldosteronism. Additionally, they are effective in the

setting of HF. Recent evidence from the Prevention And Treatment of Hypertension With

Algorithm-based therapy 2 (PATHWAY-2) Trial supports their utility in managing resistant

21
hypertension.77 As with all patients, care should be taken to monitor for electrolyte disturbances

in elderly patients on such medications. Gynecomastia is another side effect that can occur in

male patients. Triamterene and amiloride are weak antihypertensives are only effective when

used concomitantly with other diuretics.

Inpadamide is non-thiazide, thiazide-like, sulfonamide diuretic. Early trials, such as the

t
ip
HYVET trial have shown its effectiveness in reducing BP among elderly patients.9 Guidelines

support its use for monotherapy in mild to moderate hypertension, including in the elderly.42,52

cr
us
c) Angiotensin-converting Enzyme Inhibitors

ACE-I exert their anti-hypertensive effects both through reducing the angiotensin II mediated-
an
release of aldosterone from the adrenals (thus reducing all the down-stream effects of the latter),

through reduced degradation of bradykinin and through decrease in peripheral vascular tone.
M

Additionally, ACE-I have renal-protective effects and reduce adverse remodeling of the heart

both in the presence or absence of heart failure, as has been evidenced by multiple studies. The
ed

Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial and the Studies
pt

of Left Ventricular Dysfunction (SOLVD) trial demonstrated the beneficial impact of ACE-I in

congestive heart failure and severe congestive heart failure.78,79 But, it was the Heart Outcomes
ce

Prevention Evaluation (HOPE) trial, that demonstrated the beneficial impact of ACE-I on

cardiovascular outcomes even in the absence of heart failure.80 In this trial, the population
Ac

consisted of patients with high risk for cardiovascular disease and mean age was > 65 years.

HOPE showed that ramipril caused a significant reduction in death, strokes and MI in patients

with multiple cardiovascular comorbidities, but without heart failure. This beneficial impact was

attributed, in a large part, to BP reduction. The MICROHOPE substudy showed that ACE-I

22
cause a significant reduction in overt nephropathy, and this was greater than that could be

accounted for by BP reduction.81

Given the available evidence, ACE-I are considered to first-line anti-hypertensive

monotherapy in the elderly non-black population, and are especially useful in the presence of

concomitant HF and/or diabetes.42,52,58 Multiple studies have demonstrated that ACE-I have

t
ip
poorer outcomes in elderly black patients when compared other agents.82,83 As such, Thiazides

and CCB are the recommended first-line agents for elderly black patients irrespective of their

cr
diabetic status, though ACE-I may be combined with thiazides and CCBs for combination

us
therapy. ACE-I remain first line agents for elderly patients in the presence of CKD with

proteinuria irrespective of race or diabetic status.42,52,62

an
The main adverse effects of ACE-I are hypotension, cough, angioedema, hyperkalemia

and renal impairment. Hypotension and renal impairment are particularly problematic in the
M

elderly and frail populations and thus close monitoring of electrolytes and sometimes switching

to a different class of drugs is warranted. Elderly patients on ACE-I therapy must be educated
ed

regarding these potential adverse effects such as orthostatic hypotension, hyperkalemia.

pt

Medication timing (such as take the medication at bedtime) can be tailored to prevent falls

associated with orthostatic hypotension and avoidance of potassium rich foods and supplements
ce

to prevent hyperkalemia is recommended.

Ac

d) Angiotensin-receptor blockers

Angiotensin-receptor blockers – like ACE-I – act on the renin angiotensin aldosterone system

(RAAS), by blocking the angiotensin II receptors. Thus, their mechanism of action is similar to

that of ACE-I, with the exception of reducing the degradation of bradykinin.

23
 Multiple studies over the years have exhibited the beneficial effects of ARBs. The

Losartan Intervention For Endpoint reduction (LIFE) demonstrated the beneficial effects of

ARBs in the reduction of cardiovascular morbidity and mortality beyond that which could be

accounted for by reduction in BP.84 This trial randomized 9193 hypertensive patients (aged 55 to

80 years) with left-ventricular hypertrophy to once-daily losartan or atenolol. The losartan group

t
ip
demonstrated a significant reduction the primary composite end-point of cardiovascular death,

MI and stroke, driven primarily by a significant reduction in fatal and non-fatal strokes (relative

cr
risk reduction of 25%). Both the Study on Cognition and Prognosis in the Elderly (SCOPE) and

us
the Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary

Prevention (MOSES) Study demonstrated stroke reduction in elderly patients with ARBs.85,86
an
The 2008 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial

(ONTARGET) showed that ARBs are non-inferior to ACE-I in preventing death, MI, and stroke,
M

and the combination of ARBs and ACE-I had no increase in benefit but was associated with

more adverse effects.87

ed

While many of the adverse effects of ACE-I are driven by decreased degradation of
pt

bradykinins (eg., the ACE-I-induced dry cough), ARBs do not cause these side effects. The

Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-

ce

Alternative study and the CHARM-Preserved study demonstrated that ARB are well-tolerated in

patients intolerant to ACE-I and are effective in reducing cardiovascular mortality and HF
Ac

hospitalizations.88,89 These studies highlighted the utility of ARBs, just like ACE-I, as effective

BP-reducing medication in patients with concomitant HF. Telmisartan Randomised Assessment

Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) showed that

ARBs were well tolerated in patients unable to tolerate ACE inhibitors.90

24
 Guideline recommendations for ARBs are similar those of ACE-I. ARBs are considered

first-line anti-hypertensives in elderly patients with diabetes. In elderly patients with HTN and

HF, they are considered alternatives to ACE-I when the side-effects of ACE-I cannot be

tolerated.42,52,58 Similar precaution should be taken in elderly patients on ARBs, as would be

taken in those on ACE-I. Finally, ACE-I and ARBs should never be used in combination due to

t
ip
adverse effects from their concomitant use.87

cr
e) Beta-blockers

us
Beta-blockers inhibit the Beta-adrenergic receptors in the heart and blood vessels. In the heart,

they have negative chronotropic, dromotropic and inotropic effects. They reduce the work of the
an
cardiac myocytes and have an anti-anginal effect, and long-term, they exhibit mortality benefit in

coronary artery disease.

M

While beta-blockers had long been used as anti-hypertensives, the British Medical

Research Council (MRC) trial from over 25 years ago showed that beta-blocker were not as
ed

effective as diuretics in reducing cardiovascular events.91 A large systematic review in 1998

pt

showed similar findings, as did the systematic review and meta-analysis conducted for the 2017

ACC/AHA hypertension guidelines.75,91 Following the LIFE trial which showed the superiority
ce

of losartan compared to atenolol in reducing cardiovascular morbidity and mortality in

hypertensive patients including elderly patients, beta-blockers dropped from the list of first line
Ac

agents for the treatment of hypertension in clinical guidelines.42,58,84 However, more recent data

suggests that this effect may be limited to Atenolol and that other beta blockers have similar

efficacy in treating hypertension and mortality benefit compared to ACE-I, ARB, CCB and

diuretics.92 Beta-blockers can be used for blood pressure management in elderly patients with

25
other comorbidities, where the beta-blockers are also useful in managing the other conditions.52

For example, in elderly hypertensives with CAD, HF or arrhythmias, beta-blockers can provide

an anti-hypertensive effect in addition to managing the associated comorbidity.

Beta-blockers should be used cautiously in elderly patients. The inherent negative

inotropic effects of beta-blockers can exacerbate bradycardia and bradyarrhythmias, and elderly

t
ip
patients tend to be particularly sensitive to these effects. Non-selective beta-blockers can hamper

the effects of bronchodilators in patients with bronchospastic disease. While reported in the past,

cr
beta-blockers do not cause significant depression, fatigue or sexual dysfunction.93

f) Calcium channel blockers

us
an
Calcium channel blockers (CCB) include a wide variety of agents, including dihydropyridines

and non-dihydropyridines (verapamil and diltiazem). All CCB reduce calcium influx into muscle
M

cells, and act on the heart to reduce contractility and chronotropy and on peripheral vessels to

reduce resistance. In addition to their utility anti-arrhythmics and anti-anginals, CCB are widely
ed

used for BP lowering.

pt

Many studies from the 1980s and 90s, like Syst-Eur, Syst-China and the Shanghai trial of

nifedipine in the elderly (STONE), established the beneficial effects of CCB in BP lowering
ce

particularly in the elderly, though ALLHAT showed that thiazides were superior.7,8,71,94 Still,

CCB have wide applications in the treatment of hypertension in older patients. The International
Ac

Verapamil-Trandolapril Study (INVEST) study showed that in the treatment of patient with

hypertension and coronary artery disease, strategies with CCB were as effective as those with

beta-blockers.95 CCB are also regarded as first-line agents for the treatment of HTN in the

26
general non-black elderly population and, along with thiazides, are first agents for black

patients.42,58

The main adverse effects of CCB are related to edema, postural hypertension and

headaches. Clinicians should counsel patients about the increased fall-risk associated with CCB-

related postural hypotension. Verapamil can exacerbate constipation in the elderly, and patients

t
ip
may need laxatives.

cr
g) Alpha-blockers

us
Alpha-adrenergic blocking agents act by producing causing peripheral vasodilation and reducing

vascular tone. In the ALLHAT, the doxazosin arm had to be terminated prematurely and the data
an
from arm was not included in the final analysis after it was shown to be associated with a

significantly increased risk of HF compared with chlorthalidone at an interim analysis.71

M

Doxazosin should never be used to initiate monotherapy in the elderly due to this reason. It may

be used in patients for managing benign prostatic hypertrophy, in which case its BP lowering
ed

effects may be useful if the patient has concomitant hypertension. However, clinicians should be
pt

cognizant about the increased risk of postural hypertension in the elderly associated with it.
ce

h) Nitrates

Nitrates like nitroglycerin and nitroprusside cause nitric oxide-mediated vasodilation of arteries
Ac

and veins. They are useful in treating hypertensive emergencies. Additionally, they have

antianginal effects and are useful in HF exacerbation. However, they have no role in long-term

BP management in the elderly.

27
i)Other Agents

Hydralazine and minoxidil are vasodilators that can be used as antihypertensives. They are not

first-line agents and should be used with caution in the elderly due to their side-effect profiles.

Clonidine is a centrally acting agent that can be used for BP management. It has several

side-effects including bradycardia and sedation, both of which are problematic in the elderly and

t
ip
frail. Additionally, cessation of this agent can cause tachycardia and reflex hypertension. As

such, it is considered a fourth-line agent in all adults.

cr
Aliskiren is a direct renin inhibitor that is at least as effective as ACE-I and ARBs in

us
lowering BP, and it has been shown to be well tolerated in elderly patients > 75 years of age with

no dose adjustment necessary.96 It should not be combined with ACE-I and ARB.
an
While all the major classes of drugs including thiazide diuretics, ACE-I, ARB, CCB and even
M

beta blockers have been shown to be equally effective,92 each drug class has the potential to offer

additional benefit in the setting of comorbidities, such as beta blockers in coronary disease or
ed

ACE-I/ARB in diabetes or chronic kidney disease. The current guidelines recommend that
pt

elderly patients could be treated with diuretics, ACE-I, angiotensin receptor blockers, CCB, and

beta blockers, and the decision should be based on relative efficacy, tolerability, presence of
ce

specific comorbidities and cost. Given a high prevalence of comorbidities and polypharmacy in

the elderly population, it is important to consider drug interactions with other medications prior
Ac

to choosing an antihypertensive regimen. Combination antihypertensive therapy is also a useful

strategy and its use is recommended if the blood pressure is >20/10 mm Hg over goal blood

pressure.42 Combination therapy usually involves lower doses of the individual drugs, thus

reducing the risk of the adverse effects of higher doses. Additionally, beyond the summative

28
effects multiple BP-lowering therapies, the pharmacodynamics of the individual agents might

complement and enhance each other, resulting in a greater antihypertensive effect. Numerous

trials have demonstrated the beneficial effects of combination therapy.5,9,74 However, multiple

drugs may be cumbersome for elderly patients and thus combination pills offer the best strategy.

t
ip
9. Management of Hypertension with Comorbidities

Coronary Artery Disease

cr
In elderly patients with CAD, the initial drug of choice should be a beta-blocker, as part of

us
guideline-directed medical therapy for CAD.52,63 In the setting of persistent angina, a CCB may

be added. In the presence of HF with low EF, an ACE-I or ARB should be added. Spironolactone
an
may also be added.52 A combination of beta-blockers and ACE-Is are useful in preventing

coronary events in high-risk elderly patients. Guidelines now suggest that a BP of < 130/80 mm
M

Hg should be targeted in patients with HTN and CAD.42

ed

Cerebrovascular Disease

As per the American Heart Association/American Stroke Association 2014 Guidelines, it is

pt

reasonable to target a BP < 140/90 mm Hg in patients with prior ischemic strokes or TIA,97
ce

though based on the results of the SPS3-BP Trial it might be reasonable to target SBP < 130 mm

Hg.38
Ac

Peripheral Artery Disease

Recent guidelines suggest that patients with PAD should be treated to the same targets as those

without it, ie, < 130/80 mm Hg, and this applies to elderly patients as well.42

29
Diabetes mellitus

Results from the ACCORD-BP trial found 1no benefit with intensive BP treatment to SBP < 120

mm Hg compared with SBP target < 140 mm Hg.36 Still, recent guidelines recommend treating

adults, including the elderly, to a target < 130/80 mm Hg.42 In the setting of albuminuria, ACE-

I/ARB are beneficial. Thiazides should be used with caution as they can cause hyperglycemia.

t
ip
Heart Failure

cr
Patients with systolic HF should be treated with ACE-I/ARBs and beta-blockers, along with

us
diuretics for symptomatic management of edema and spironolactone if needed.52For elderly

black patients, a combination of hydralazine and isosorbide dinitrate may be used.98

an
Hypertension in the elderly is frequently associated with diastolic HF and adequate BP control is

an important component of management of such HF.

M

Chronic Kidney Disease

ed

In patients with CKD, while benefit is derived largely from effective BP control, the presence or
pt

absence of proteinuria plays an important role in determining the choice of drug. For CKD Stage

3 or greater or even Stage 1 or 2 with albuminuria, guidelines suggest that treatment may be
ce

initiated with ACE-I/ARB. In CKD, volume status largely determines BP and thus diuretics,

particularly loop diuretics, play a major role in BP control.

Ac

10. Conclusions

Based on the evidence presented in this paper it is clear that hypertension predicts worse

outcomes even in elderly and frail populations. Treatment of hypertension lowers cardiovascular

and cerebrovascular morbidity and mortality in this population. Comorbidites and frailty make
30
management of hypertension challenging in these patients and the approach to pharmacotherapy

cannot be simplified into an algorithm like in the general population. Recent guidelines now

support that elderly frail patients should not be precluded from anti-hypertensive therapy, but

physicians should individually tailor therapy after weighing the benefits of cardiovascular risk

reduction against putative harmful effects of such therapy. Treatment of hypertension in this

t
ip
patient population should not be guided by chronological age alone and must be individualized

based on comorbidities, and other clinical and social factors.

cr
us
11. Expert Commentary

The randomized clinical trial data from HYVET and SPRINT unequivocally have demonstrated
an
that frail elderly hypertensive persons with hypertension should be treated with antihypertensive

drug therapy to reduce cardiovascular events and mortality. However, these clinical trials were
M

performed in noninstitutionalized persons. Randomized clinical trials need to be performed in

frail elderly persons with hypertension residing in nursing homes to determine the benefits and
ed

adverse effects of antihypertensive drug therapy in this vulnerable population. In addition to

using antihypertensive drug therapy, the use of lifestyle measures for treating hypertension as
pt

strongly recommended by the 2017 ACC/AHA hypertension guidelines needs to be investigated

ce

in clinical trials in noninstitutionalized persons and in nursing home residents who are frail

elderly persons with hypertension.42,99

Ac

SPRINT is currently investigating in their elderly population aged 75 years and older

who are frail and who are not frail the effect of reducing the SBP to less than 120 mm Hg versus

reducing the SBP to less than 140 mm Hg on cognitive function. The effect of reducing the SBP

to less than 120 mm Hg versus reducing the SBP to less than 140 mm Hg also needs

investigation in frail elderly persons with hypertension who have dementia, who have multiple
31
comorbidities, who have diabetes mellitus, who have heart failure with a reduced left ventricular

ejection fraction, and who have heart failure with a preserved left ventricular ejection fraction.

Long-term follow-up data from SPRINT from the persons who developed acute kidney injury

also needs to be obtained.

Physicians and other health care professionals need to be instructed to accurately measure

t
ip
BP by automated BP measurement as recommended by the 2017 ACC/AHA hypertension

guidelines. BP must also be measured by standing to detect if orthostatic hypotension is present.

cr
Postprandial hypotension must also be avoided.100 ASCVD risk assessment must be obtained in

us
all elderly persons with hypertension.

Initiation of antihypertensive drug therapy must be undertaken cautiously in elderly frail

an
persons, and these persons need to be monitored very carefully for the development of

orthostatic hypotension, falls, and syncope. Elderly frail persons with prevalent and frequent
M

falls, marked cognitive impairment, and multiple comorbidities may be at risk of developing

adverse clinical outcomes with intensive BP lowering, especially if they require multiple
ed

antihypertensive drugs for BP control. These persons have not been included in randomized
pt

clinical trials. In addition, data on intensive BP lowering in persons older than 85 years are

sparse. This population needs clinical trial data to help management of hypertension in this
ce

population. The effect of different antihypertensive drugs on clinical outcomes including adverse

events needs to be investigated in elderly frail persons with hypertension and different
Ac

comorbidities. Finally, antihypertensive drug therapy plus lifestyle measures must be

individualized for the treatment of hypertension in frail elderly persons with different

comorbidities.

12. 5-Year View

32
 Randomized clinical trials need to be performed in frail elderly persons with hypertension

residing in nursing homes to determine the benefits and adverse effects of antihypertensive drug

therapy in this vulnerable population. In addition to using antihypertensive drug therapy, the use

of lifestyle measures for treating hypertension as strongly recommended by the 2017 ACC/AHA

hypertension guidelines needs to be investigated in clinical trials in noninstitutionalized persons

t
ip
and in nursing home residents who are frail elderly persons with hypertension. SPRINT is

currently investigating in their elderly population aged 75 years and older who are frail and who

cr
are not frail the effect of reducing the SBP to less than 120 mm Hg versus reducing the SBP to

us
less than 140 mm Hg on cognitive function, and we are awaiting these results. The effect of

reducing the SBP to less than 120 mm Hg versus reducing the SBP to less than 140 mm Hg also
an
needs investigation in frail elderly persons with hypertension who have dementia, who have

multiple comorbidities, who have diabetes mellitus, who have heart failure with a reduced left
M

ventricular ejection fraction, and who have heart failure with a preserved left ventricular ejection

fraction.
ed

Elderly frail persons with prevalent and frequent falls, marked cognitive impairment, and
pt

multiple comorbidities may be at risk of developing adverse clinical outcomes with intensive BP

lowering, especially if they require multiple antihypertensive drugs for BP control. These
ce

persons need to be included in randomized clinical trials. In addition, data on intensive BP

lowering in persons older than 85 years are sparse. This population needs clinical trial data to
Ac

help management of hypertension in this population. The effect of different antihypertensive

drugs on clinical outcomes including adverse events needs to be investigated in elderly frail

persons with hypertension and different comorbidities.

33
 13. Key Issues

• Cardiovascular disease is a leading cause of mortality in the elderly. Hypertension is an

important modifiable risk factor for cardiovascular disease in this population, and is

associated with an increased risk for myocardial infarction, stroke, peripheral arterial

disease and heart failure.

t
ip
• The definition of hypertension and treatment goals for blood pressure in the elderly

population have been in flux due to concerns about frailty and the possible adverse

cr
effects of hypotension and antihypertensive medications.

us
• There is unequivocal evidence to establish that use of pharmacotherapy for blood

pressure lowering in hypertensive elderly persons causes a significant reduction in

an
cardiovascular morbidity and mortality.

• Based on current guidelines, elderly persons should be considered hypertensive if the

M

systolic blood pressure is 130 mm Hg or higher or the diastolic blood pressure is 80 mm

Hg or higher, and should be treated to a blood pressure target of <130/80 mm Hg if

ed

tolerated.
pt

• Pharmacotherapy for hypertension should be individualized and selected based on

comorbidities. Combination therapy should be used if the pre-treatment blood pressure is

ce

greater than 140/90 mm Hg in persons with a 10-year risk of atherosclerotic

cardiovascular disease of 10% and higher.

Ac

Funding

This manuscript was not funded.

Declaration of Interest

34
The authors have no relevant affiliations or financial involvement with any organization or entity

with a financial interest in or financial conflict with the subject matter or materials discussed in

the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

t
ip
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

cr
us
an
M

References
ed

Papers of special note have been highlighted as:

* of interest
pt

** of considerable interest
ce

1. Roth GA, Johnson C, Abajobir A, et al. Global, Regional, and National Burden of

Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1-

Ac

25. doi:10.1016/j.jacc.2017.04.052.

2. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve

cardiovascular diseases: Lifetime risks, healthy life-years lost, and age-specific

associations in 1·25 million people. Lancet. 2014;383(9932):1899-1911.

doi:10.1016/S0140-6736(14)60685-1.

35
3. Fryar CD, Ostchega Y, Hales CM, Zhang G, Kruszon-Moran D. Hypertension Prevalence

and Control among Adults: United States, 2015–2016. NCHS Data Brief, No 289.

Hyattsville, MD: National Center for Health Statistics.; 2017.

https://www.cdc.gov/nchs/data/databriefs/db289.pdf.

4. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics--2009

t
ip
update: a report from the American Heart Association Statistics Committee and Stroke

Statistics Subcommittee. Circulation. 2009;119(3).

cr
doi:10.1161/CIRCULATIONAHA.108.191261.

us
5. Dahlöf B, Hansson L, Lindholm LH, Scherstén B, Ekbom T, Wester PO. Morbidity and

mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension).

an
Lancet. 1991;338(8778):1281-1285. doi:10.1016/0140-6736(91)92589-T.

6. SHEP Cooperative Study Group. Prevention of Stroke by Antihypertensive Drug

M

Treatment in Older Persons With Isolated Systolic Hypertension Final Results of the

Systolic Hypertension in the Elderly Program ( SHEP ). J Am Med Assoc.

ed

1991;265(24):3255-3264.

7. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo

pt

and active treatment for older patients with isolated systolic hypertension. The Systolic
ce

Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350(9080):757-764.

8. Liu L, Wang JG, Gong L, Liu G, Staessen J a. Comparison of active treatment and
Ac

placebo in older Chinese patients with isolated systolic hypertension. J Hypertens.

1998;16(12, Pte. 1):1823-1829.

9. Beckett N, Peters R, Fletcher A, et al. Treatment of Hypertension in Patients 80 Years of

Age or Older. N Engl J Med. 2008;358(18):1887-1898.

36
10. Mancia G. Blood Pressure Reduction and Cardiovascular Outcomes: Past, Present, and

Future. Am J Cardiol. 2007;100(3 SUPPL.). doi:10.1016/j.amjcard.2007.05.008.

11. Veterans Administration Cooperative Study Group. Effects of treatment on morbidity in

hypertension. Results in patients with diastolic blood pressures averaging 115 through 129

mm Hg. JAMA. 1967;202(11):1028-1034.

t
ip
12. Veterans Administration Cooperative Study Group. Effects of treatment on morbidity in

hypertension II. Results in patients with diastolic blood pressure averaging 90 through 114

cr
mm Hg. JAMA. 1970;213(7):1143-1152.

us
13. Veterans Administration Cooperative Study Group. Effects of treatment on morbidity in

hypertension III. Influence of age, diastolic pressure, and prior cardiovascular disease;
an
further analysis of side effects. Circulation. 1972;45(5):991-1004.

14. Hypertension Detection and Follow-up Program Cooperative Group. Five-Year Findings
M

of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of

persons with high blood pressure, including mild hypertension. JAMA.

ed

1979;242(23):2562. doi:10.1001/jama.1979.03300230018021.

15. Hypertension Detection and Follow-up Program Cooperative Group. Five-Year Findings
pt

of the Hypertension Detection and Follow-up Program. II. Mortality by race-sex and age.
ce

JAMA. 1979;242(23):2562. doi:10.1001/jama.1979.03300230018021.

16. Amery A, Birkenhager W, Brixko P, et al. Mortality and morbidity results from the
Ac

European Working Party on High Blood Pressure in the Elderly trial. Lancet.

1985;1(8442):1349-1354.

17. Antikainen R, Jousilahti P, Tuomilehto J. Systolic blood pressure, isolated systolic

hypertension and risk of coronary heart disease, strokes, cardiovascular disease and all-

37
 cause mortality in the middle-aged population. J Hypertens. 1998;16(5):577-583.

18. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic

hypertension in elderly: meta- analysis of outcome trials. Lancet. 2000;355:865-872.

19. Langer RD, Criqui MH, Barrett-Connor EL, Klauber MR, Ganiats TG. Blood pressure

change and survival after age 75. Hypertension. 1993;22:551-559.

t
ip
doi:10.1161/01.HYP.22.4.551.

20. Satish S, Freeman DH, Ray L, Goodwin JS. The relationship between blood pressure and

cr
mortality in the oldest old. J Am Geriatr Soc. 2001;49(4):367-374. doi:10.1046/j.1532-

us
5415.2001.49078.x.

21. Gueyffier F, Bulpitt C, Boissel J-P, et al. Antihypertensive drugs in very old people: a
an
subgroup meta-analysis of randomised controlled trials. Lancet. 1999;353(9155):793-796.

doi:10.1016/S0140-6736(98)08127-6.
M

22. Aronow WS. Older age should not be a barrier to the treatment of hypertension. Nat Clin

Pract Cardiovasc Med. 2008;5(9):514-515. doi:10.1038/ncpcardio1291.

ed

23. Aronow WS. Why and how we should treat elderly patients with hypertension? Curr Vasc

Pharmacol. 2010;8(6):780-787.
pt

24. Aronow WS. Treatment of hypertension in the elderly. J Am Med Dir Assoc.
ce

2013;14(11):847. doi:10.1016/j.jamda.2013.07.005.

25. Bejan-Angoulvant T, Saadatian-Elahi M, Wright JM, et al. Treatment of hypertension in

Ac

patients 80 years and older: The lower the better? A meta-analysis of randomized

controlled trials. J Hypertens. 2010;28(7):1366-1372.

doi:10.1097/HJH.0b013e328339f9c5.

26. Reboldi G, Gentile G, Angeli F, Verdecchia P. Blood pressure lowering in the oldest old.

38
 J Hypertens. 2010;28(7):1373-1376. doi:10.1097/HJH.0b013e32833b47c0.

27. Schall P, Wehling M. Treatment of arterial hypertension in the very elderly: a meta-

analysis of clinical trials. Arzneimittelforschung. 2011;61(04):221-228. doi:10.1055/s-

0031-1296191.

28. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet

t
ip
(London, England). 2013;381(9868):752-762. doi:10.1016/S0140-6736(12)62167-9.

29. Odden MC, Peralta CA, Haan MN, Covinsky KE. Rethinking the association of high

cr
blood pressure with mortality in elderly adults: the impact of frailty. Arch Intern Med.

us
2012;172(15):1162-1168. doi:10.1001/archinternmed.2012.2555.

30. Wu C, Smit E, Peralta CA, Sarathy H, Odden MC. Functional Status Modifies the
an
Association of Blood Pressure with Death in Elders: Health and Retirement Study. J Am

Geriatr Soc. 2017;65(7):1482-1489. doi:10.1111/jgs.14816.

M

31. ** The SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-

Pressure Control. N Engl J Med. 2015;373(22):2103-2116. doi:10.1056/NEJMoa1511939.

ed

Among patients at high risk for cardiovascular events but without diabetes, targeting a

systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg,
pt

resulted in lower rates of fatal and nonfatal major cardiovascular events and death from
ce

any cause, although significantly higher rates of some adverse events were observed in the

intensive-treatment group.
Ac

32. Collaboration PS. 1-s2.0-S0140673602119118-main. 2002;360:1903-1913.

doi:10.1016/S0140-6736(02)11911-8.

33. 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

39
 Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118):1755-1762.

doi:10.1016/S0140-6736(98)04311-6.

34. 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. 2010;56(2):196-202.

t
ip
doi:10.1161/HYPERTENSIONAHA.109.146035.

35. Yano Y, Rakugi H, Bakris GL, et al. On-Treatment Blood Pressure and Cardiovascular

cr
Outcomes in Older Adults with Isolated Systolic Hypertension. Hypertension.

us
2017;69(2):220-227. doi:10.1161/HYPERTENSIONAHA.116.08600.

36. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control
an
in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.

doi:10.1056/NEJMoa1001286.
M

37. MacMahon S, Neal B, Tzourio C, et al. Randomised trial of a perindopril-based blood-

pressure-lowering regimen among 6105 individuals with previous stroke or transient

ed

ischaemic attack. Lancet. 2001;358(9287):1033-1041. doi:10.1016/S0140-

6736(01)06178-5.
pt

38. The SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: The
ce

SPS3 randomised trial. Lancet. 2013;382(9891):507-515. doi:10.1016/S0140-

6736(13)60852-1.
Ac

39.** Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs Standard Blood Pressure

Control and Cardiovascular Disease Outcomes in Adults Aged >/=75 Years: A

Randomized Clinical Trial. JAMA. 2016;315(24):2673-2682.

doi:10.1001/jama.2016.7050.

40
 Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120

mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly

lower rates of fatal and nonfatal major cardiovascular events and death from any cause.

40. Yusuf S, Lonn E, Pais P, et al. Blood-Pressure and Cholesterol Lowering in Persons

t
ip
without Cardiovascular Disease. N Engl J Med. 2016;374(21):2032-2043.

doi:10.1056/NEJMoa1600177.

cr
41**. Muntner P, Whelton PK. Using Predicted Cardiovascular Disease Risk in Conjunction

us
With Blood Pressure to Guide Antihypertensive Medication Treatment. J Am Coll

Cardiol. 2017;69(19):2446-2456. doi:10.1016/j.jacc.2017.02.066.

an
This paper provides recommendations for using cardiovascular disease risk in combination

with blood pressure to guide antihypertensive treatment.

M

42**. Whelton PK, Carey RM, Aronow WS, et al. 2017

ed

ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the

Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A

pt

Report of the American College of Cardiology/American Heart Association Task Force on

ce

Clinical Pr. Hypertension. November 2017. doi:10.1161/HYP.0000000000000065.

The 2017 American College of Cardiology/American Heart Association hypertension

Ac

guidelines recommend treatment goals and use of antihypertensive drug therapy plus

lifestyle measures for treating hypertension in persons aged 50 years and older.

43. Chobanian A V., Bakris GL, Black HR, et al. Seventh report of the Joint National

41
 Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Hypertension. 2003;42(6):1206-1252. doi:10.1161/01.HYP.0000107251.49515.c2.

44. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of

Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of

the European Society of Hypertension (ESH) and of the European Society of Cardiology

t
ip
(ESC). J Hypertens. 2007;25(6):1105-1187. doi:10.1097/HJH.0b013e3281fc975a.

45. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. The Felodipine Event Reduction

cr
(FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive

us
patients. J Hypertens. 2005;23(12):2157-2172. doi:10.1097/01.hjh.0000194120.42722.ac.

46. Weber MA, Kjeldsen SE, Brunner HR, et al. Blood pressure dependent and independent
an
effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet.

2004;363:2045-2051. http://image.thelancet.com/extras/04let5020web.pdf.
M

47. Pepine CJ, Kowey PR, Kupfer S, et al. Predictors of adverse outcome among patients with

hypertension and coronary artery disease. J Am Coll Cardiol. 2006;47(3):547-551.

ed

doi:10.1016/j.jacc.2005.09.031.

48. Turner R, Matthews D, Neil A, Mcelroy H. Tight blood pressure control and risk of
pt

macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J.

ce

1998;317:703-713. doi:10.1136/bmj.317.7160.703.

49. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control
Ac

in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney

Int. 2002;61(3):1086-1097. doi:10.1046/j.1523-1755.2002.00213.x.

50. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on

diabetic microvascular complications in patients with hypertension and type 2 diabetes.

42
 Diabetes Care. 2000;23 Suppl 2:B54-64.

51. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and

effective for the prevention of recurrent stroke: The PROGRESS trial. J Hypertens.

2006;24(6):1201-1208. doi:10.1097/01.hjh.0000226212.34055.86.

52**. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on

t
ip
hypertension in the elderly: A report of the American college of cardiology foundation

task force on clinical expert consensus documents. J Am Coll Cardiol. 2011;57(20):2037-

cr
2114. doi:10.1016/j.jacc.2011.01.008.

us
The 2011 American College of Cardiology/American Heart Association hypertension

guidelines discuss treatment goals and use of antihypertensive drug therapy plus lifestyle
an
measures in the treatment of elderly patients with hypertension.

53. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management
M

of arterial hypertension: The Task Force for the management of arterial hypertension of

the European Society of Hypertension (ESH) and of the European Society of Cardiology
ed

(ESC). Eur Heart J. 2013;34(28):2159-2219. doi:10.1093/eurheartj/eht151.

54. Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian hypertension education
pt

program recommendations for blood pressure measurement, diagnosis, assessment of risk,

ce

prevention, and treatment of hypertension. Can J Cardiol. 2013;29(5):528-542.

doi:10.1016/j.cjca.2013.01.005.
Ac

55. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the

management of hypertension in the community a statement by the american society of

hypertension and the international society of hypertension. J Hypertens. 2014;32(1):3-15.

doi:10.1097/HJH.0000000000000065.

43
56. Gibbons GH, Shurin SB, Mensah GA, Lauer MS. Refocusing the agenda on

cardiovascular guidelines: An announcement from the national heart, lung, and blood

institute. J Am Coll Cardiol. 2013;62(15):1396-1398. doi:10.1016/j.jacc.2013.08.003.

57. Gibbons GH, Harold JG, Jessup M, Robertson RM, Oetgen WJ. The next steps in

developing clinical practice guidelines for prevention. J Am Coll Cardiol.

t
ip
2013;62(15):1399-1400. doi:10.1016/j.jacc.2013.08.004.

58. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the

cr
Management of High Blood Pressure in Adults. JAMA. 2014;311(5):507.

us
doi:10.1001/jama.2013.284427.

59. O’Brien E. End of the joint national committee heritage? Hypertension. 2014;63(5):904-
an
906. doi:10.1161/HYPERTENSIONAHA.113.03097.

60. JATOS study group. Principal results of the Japanese trial to assess optimal systolic blood
M

pressure in elderly hypertensive patients (JATOS). Hypertens Res. 2008;31(12):2115-

2127. doi:10.1291/hypres.31.2115.
ed

61. Wright J, Fine LJ, Lackland DT, Ogedegbe G. Evidence Supporting a Systolic Blood

Pressure Goal of Less Than 150 mmHg in Patients Aged 60 Years or Older : The Minority
pt

View. Ann Intern Med. 2014;(14):499-504. doi:10.7326/M13-2981.

ce

62. Krakoff LR, Gillespie RL, Ferdinand KC, et al. 2014 Hypertension recommendations

from the eighth joint national committee panel members raise concerns for elderly black
Ac

and female populations. J Am Coll Cardiol. 2014;64(4):394-402.

doi:10.1016/j.jacc.2014.06.014.

63. Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with

coronary artery disease: A scientific statement from the American Heart Association,

44
 American College of Cardiology, and American Society of Hypertension. J Am Coll

Cardiol. 2015;65(18):1998-2038. doi:10.1016/j.jacc.2015.02.038.

64. Denardo SJ, Gong Y, Nichols WW, et al. Blood pressure and outcomes in very old

hypertensive coronary artery disease patients: An INVEST substudy. Am J Med.

2010;123(8):719-726. doi:10.1016/j.amjmed.2010.02.014.

t
ip
65. Nissen SE, Tuzcu EM, Libby P, et al. Effect of Antihypertensive Agents on

Cardiovascular Events in Patients With Coronary Disease and Normal Blood Pressure.

cr
JAMA. 2004;292(18):2217. doi:10.1001/jama.292.18.2217.

us
66. Leung AA, Nerenberg K, Daskalopoulou SS, et al. Hypertension Canada’s 2016 Canadian

Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis,

an
Assessment of Risk, Prevention, and Treatment of Hypertension. Can J Cardiol.

2016;32(5):569-588. doi:10.1016/j.cjca.2016.02.066.
M

67. Gabb GM, Mangoni AA, Anderson CS, et al. Guideline for the diagnosis and management

of hypertension in adults — 2016. Med J Aust. 2016;205(2):85-89.

ed

doi:10.5694/mja16.00526.

68. Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA. Pharmacologic
pt

treatment of hypertension in adults aged 60 years or older to higher versus lower blood
ce

pressure targets: A clinical practice guideline from the American College of Physicians

and the American Academy of Family Physicians. Ann Intern Med. 2017;166(6):430-437.
Ac

doi:10.7326/M16-1785.

69. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment

of cardiovascular risk: A report of the American college of cardiology/American heart

association task force on practice guidelines. Circulation. 2014;129(25 SUPPL. 1).

45
 doi:10.1161/01.cir.0000437741.48606.98.

70. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the

treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A

report of the American college of cardiology/American heart association task force on

practice guidelines. J Am Coll Cardiol. 2014;63(25 PART B):2889-2934.

t
ip
doi:10.1016/j.jacc.2013.11.002.

71. The ALLHAT Officers. Major Outcomes in High-Risk Hypertensive Patients Randomized

cr
to or Calcium Channel Blocker vs Diuretic. J Am Med Assoc. 2002;288(23):2981-2997.

us
doi:10.1001/jama.288.23.2981.

72. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with
an
antihypertensive therapies used as first-lines agents. J Am Med Assoc. 1997;277(19):739-

745. doi:10.1016/S1062-1458(03)00272-1.
M

73. Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-

converting--enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med.
ed

2003;348(7):583-592. doi:10.1056/NEJMoa021716.

74. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or
pt

hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med.

ce

2008;359(23):2417-2428. doi:10.1056/NEJMoa0806182.

75. Reboussin DM, Allen NB, Griswold ME, et al. Systematic Review for the 2017
Ac

ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the

Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J

Am Coll Cardiol. 2017. doi:10.1016/j.jacc.2017.11.004.

76. REUBI FC, COTTIER PT. Effects of reduced glomerular filtration rate on responsiveness

46
 to chlorothiazide and mercurial diuretics. Circulation. 1961;23:200-210.

77. Williams B, Macdonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol,

and doxazosin to determine the optimal treatment for drug-resistant hypertension

(PATHWAY-2): A randomised, double-blind, crossover trial. Lancet.

2015;386(10008):2059-2068. doi:10.1016/S0140-6736(15)00257-3.

t
ip
78. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe

congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival

cr
Study (CONSENSUS). N Engl J Med. 1987;316(23):1429-1435.

us
doi:10.1056/NEJM198706043162301.

79. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left
an
ventricular ejection fractions and congestive heart failure. N Engl J Med.

1991;325(5):293-302. doi:10.1056/NEJM199108013250501.
M

80. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an

angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk

ed

patients. N Engl J Med. 2000;342(3):145-153. doi:10.1056/NEJM200001203420301.

81. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril
pt

on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of

ce

the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation

Study Investigators. Lancet (London, England). 2000;355(9200):253-259.

Ac

82. Ogedegbe G, Shah NR, Phillips C, et al. Comparative effectiveness of angiotensin-

converting enzyme inhibitor-based treatment on cardiovascular outcomes in hypertensive

blacks versus whites. J Am Coll Cardiol. 2015;66(11):1224-1233.

doi:10.1016/j.jacc.2015.07.021.

47
83. Leenen FHH, Nwachuku CE, Black HR, et al. Clinical events in high-risk hypertensive

patients randomly assigned to calcium channel blocker versus angiotensin-converting

enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart

attack trial. Hypertension. 2006;48(3):374-384.

doi:10.1161/01.HYP.0000231662.77359.de.

t
ip
84. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the

Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised

cr
trial against atenolol. Lancet (London, England). 2002;359(9311):995-1003.

us
doi:10.1016/S0140-6736(02)08089-3.

85. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly
an
(SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens.

2003;21(5):875-886. doi:10.1097/01.hjh.0000059028.82022.89.
M

86. Schrader J, Luders S, Kulschewski A, et al. Morbidity and Mortality After Stroke,

Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a

ed

prospective randomized controlled study (MOSES). Stroke. 2005;36(6):1218-1226.

doi:10.1161/01.STR.0000166048.35740.a9.
pt

87. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for
ce

vascular events. N Engl J Med. 2008;358(15):1547-1559. doi:10.1056/NEJMoa0801317.

88. Granger CB, Mcmurray JJ V, Yusuf S, Held P. Effects of candesartan in patients with
Ac

chronic heart failure and reduced lef ... Lancet. 2003;362(March 2001):772-776.

89. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic

heart failure and preserved left-ventricular ejection fraction: The CHARM-preserved trial.

Lancet. 2003;362(9386):777-781. doi:10.1016/S0140-6736(03)14285-7.

48
90. Yusuf S, Teo K, Anderson C, 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. Lancet (London, England).

2008;372(9644):1174-1183. doi:10.1016/S0140-6736(08)61242-8.

91. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy

t
ip
for hypertension in the elderly? A systematic review. J Am Med Assoc. 1998;279(0098-

7484 (Print)):1903-1907.

cr
92. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure-lowering on outcome

us
incidence in hypertension: 5. Head-to-head comparisons of various classes of

antihypertensive drugs - overview and meta-analyses. J Hypertens. 2015;33(7):1321-

an
1341. doi:10.1097/HJH.0000000000000614.

93. Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker
M

therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA.

2002;288(3):351-357.
ed

94. Gong L, Zhang W, Zhu Y, et al. Shanghai trial of nifedipine in the elderly (STONE). J

Hypertens. 1996;14(10):1237-1245.
pt

95. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-
ce

calcium antagonist hypertension treatment strategy for patients with coronary artery

disease. The International Verapamil-Trandolapril Study (INVEST): a randomized

Ac

controlled trial. JAMA. 2003;290(21):2805-2816. doi:10.1001/jama.290.21.2805.

96. Verdecchia P, Calvo C, Mockel V, Keeling L, Satlin A. Safety and efficacy of the oral

direct renin inhibitor aliskiren in elderly patients with hypertension. Blood Press.

2007;16(6):381-391. doi:10.1080/08037050701717014.

49
97. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in

patients with stroke and transient ischemic attack: a guideline for healthcare professionals

from the American Heart Association/American Stroke Association. Stroke.

2014;45(7):2160-2236. doi:10.1161/STR.0000000000000024.

98. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine

t
ip
in blacks with heart failure. N Engl J Med. 2004;351(20):2049-2057.

doi:10.1056/NEJMoa042934.

cr
99. Aronow WS. Lifestyle measures for treating hypertension. Arch Med Sci.

us
2017;13(5):1241-1243. doi:10.5114/aoms.2017.68650.

100. Aronow WS, Ahn C. Association of postprandial hypotension with incidence of falls,
an
syncope, coronary events, stroke, and total mortality at 29-month follow-up in 499 older

nursing home residents. J Am Geriatr Soc. 1997;45(9):1051-1053.

M
ed
pt
ce
Ac

50
Figure 1: Challenges in the management of hypertension in elderly and frail populations

t
ip
Comorbidites Polypharmacy

cr
Challenges in

us
management of
hypertension in
elderly and frail
an
populations

Adverse effects Compliance

M
ed
pt
ce
Ac

51