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Amlodipine in hypertension: A first-line agent with efficacy for improving

blood pressure and patient outcomes

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DOI: 10.1136/openhrt-2016-000473

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Cardiac risk factors and prevention

Amlodipine in hypertension: a first-line

agent with efficacy for improving blood
pressure and patient outcomes
Hassan Fares,1 James J DiNicolantonio,2 James H O’Keefe,2 Carl J Lavie1

To cite: Fares H, ABSTRACT

DiNicolantonio JJ, KEY QUESTIONS
Objectives: Hypertension is well established as a
O’Keefe JH, et al. Amlodipine
major risk factor for cardiovascular disease. Although What is already known about this subject?
in hypertension: a first-line
agent with efficacy for
there is undeniable evidence to support the beneficial ▸ It is well known that many antihypertensive
improving blood pressure effects of antihypertensive therapy on morbidity and medications reduce the risk of stroke and heart
and patient outcomes. Open mortality, adequate blood pressure management still attack. This is generally believed to be a class
Heart 2016;3:e000473. remains suboptimal. Research into the treatment of effect however.
doi:10.1136/openhrt-2016- hypertension has produced a multitude of drug classes
000473 with different efficacy profiles. These agents include What does this study add?
β-blockers, diuretics, ACE inhibitors, angiotensin ▸ This review paper focusing on amlodipine
receptor blockers and calcium channel blockers. One showing how its unique properties may provide
Received 2 June 2016 of the oldest groups of antihypertensives, the calcium enhanced cardiovascular protections compared
Revised 10 August 2016 channel blockers are a heterogeneous group of with other antihypertensive agents.
Accepted 15 August 2016 medications.
How might this impact on clinical practice?
Methods: This review paper will focus on amlodipine, ▸ This paper sheds light on the evidence in
a dihydropyridine calcium channel blockers, which has support of amlodipine as a first-line antihyper-
been widely used for 2 decades. tensive agent for the prevention of strokes in
Results: Amlodipine has good efficacy and safety, in particular.
addition to strong evidence from large randomised
controlled trials for cardiovascular event reduction.
Conclusions: Amlodipine should be considered a calcium influx into vascular smooth muscle
first-line antihypertensive agent. cells and myocardial cells, which results in
decreased peripheral vascular resistance
(PVR). Amlodipine is indicated for the treat-
INTRODUCTION ment of high blood pressure (BP)/HTN and
Calcium channel blockers (CCBs) were first angina. In addition, a number of randomised
introduced over 35 years ago initially for cor- trials have ascertained its utility in angina
onary heart disease (CHD), but they soon pectoris.2 Amlodipine is usually dosed on a
gained wide recognition for their efficacy in once daily basis because of its long half-life,
hypertension (HTN). The initial indication, which is favourable for patient compliance. A
besides HTN, also included angina, periph- starting dose of 5 mg is usually recom-
eral vascular disease and some arrhythmic mended with a maximum daily dose of
conditions.1 Amlodipine has many unique 10 mg. In the elderly population and those
qualities that set it apart from other agents in with hepatic failure, a starting dose of 2.5 mg
1
Department of this class. The aim of this review is to is recommended. Amlodipine has a gradual
Cardiovascular Diseases, compare amlodipine with other antihyper- onset of action and hence no significant
John Ochsner Heart and tensive agents with particular focus on the reflex neuroendocrine activation. Activating
Vascular Institute, Ochsner reflex mechanisms, such as increased PVR
Clinical School-The University
ability to improve cardiovascular (CV) health
and reduce adverse CV outcomes. and elevated heart rate, can cause negative
of Queensland School of
Medicine, New Orleans,
effects on lipid and carbohydrate metabol-
Louisiana, USA ism. These notable adverse effects are com-
2
Saint Luke’s Mid America CLINICAL INDICATIONS, monly seen with other agents including the
Heart Institute, Kansas City, PHARMACODYNAMICS AND first generation β-blockers (BBs; such as aten-
Missouri, USA PHARMACOKINETICS olol and metoprolol) and earlier generation
Correspondence to
Amlodipine is a long-acting, lipophilic, third of DHPs. Amlodipine has a high bioavailabil-
Dr James J DiNicolantonio; generation dihydropyridine (DHP) CCBs ity, ranging from 60% to 80%; it undergoes
jjdinicol@gmail.com that exerts its action through inhibition of hepatic metabolism and shows some

Fares H, DiNicolantonio JJ, O’Keefe JH, et al. Open Heart 2016;3:e000473. doi:10.1136/openhrt-2016-000473 1
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Open Heart

impaired elimination in the setting of liver cirrhosis but Previous trials have established the beneficial role of
no accumulation with renal failure. Amlodipine also has ACEIs on cardiac remodelling but other studies with
a slow rate of elimination over 40–60 hours. If amlodi- ARBs versus amlodipine showed a greater benefit in
pine is discontinued, BP generally returns to baseline the CCB class. Thus, the effect of losartan and amlodi-
over 1 week without any dangerous rebound elevations pine on LV diastolic function and atherosclerosis in
in BP (unlike clonidine).3 Japanese patients with mild-to-moderate HTN ( J-ELAN)
trial was undertaken to compare the effects of an ARB
(losartan) versus a CCB (amlodipine) on LV diastolic
SIDE EFFECT PROFILE
dysfunction. J-ELAN enrolled 57 patients with LVH and
The most commonly reported adverse effect hindering
mild-to-moderate HTN and randomised them to either
compliance with amlodipine is peripheral oedema.
losartan or amlodipine.6 The doses of these drugs were
However, this adverse effect can be minimised if the
uptitrated over an 18-month period and then other
agent is given at bedtime, and lower doses (2.5 or
anti-HTN agents were added, to achieve goal BP control,
5 mg/day) are used. Indeed, the bedtime administration
except those agents that affect LVH such as ACEIs,
of nifedipine gastrointestinal therapeutic system was
ARBs, other CCBs or BBs. Both groups showed similar
associated with a 93% reduction in oedema compared
reduction in BP but the losartan group had a greater
with morning dosing (1% vs 13%, p<0.001, respect-
effect on carotid intimal–medial thickness.7 In addition,
ively).4 Other reported side effects include dizziness,
there was no significant difference in terms of LV mass
fatigue, headache, palpitations and nausea, although
in the two groups. These findings suggest that amlodi-
these are generally not bothersome enough to cause dis-
pine is non-inferior to ARBs with respect to its effects on
continuation of the drug. Amlodipine is contraindicated
LV remodelling.6 7
in breastfeeding women, cardiogenic shock and unstable
The ALLHAT (Antihypertensive Lipid-Lowering
angina. Also, its vasodilatory effect can lead to decreased
Treatment to Prevent Heart Attack Trial) was one of
cardiac output in the setting of aortic stenosis.
the largest BP trials performed to date, which enrolled
over 33 000 patients with HTN and one CHD risk factor.
ROLE AS MONOTHERAPY IN HTN The objective of this landmark trial was to determine
Several HTN trials have investigated the efficacy of whether the incidence of CHD or other CV diseases
amlodipine monotherapy versus other agents, including would be lower in those patients treated with a CCB, an
diuretics, ACE inhibitors (ACEIs) and angiotensin recep- ACEI, or a diuretic. Patients were randomised to
tor blockers (ARBs). The outcomes of these trials suggest chlorthalidone, amlodipine, or lisinopril with a mean
that amlodipine has a neutral effect on several pre- follow-up of about 4.9 years.8 Primary outcomes
existing comorbid states, which will be discussed below. included fatal CHD or non-fatal MI and secondary out-
The Comparison of Amlodipine versus Enalapril to comes included all-cause mortality. There was no signifi-
Limit Occurrence of Thrombosis (CAMELOT) trial, cant difference among the groups for the reduction in
enrolled 1991 patients with angiographically documen- the primary or secondary outcome of all-cause mortality.
ted coronary artery disease (CAD) and randomised It was determined that thiazide diuretics are superior in
them to amlodipine 10 mg, enalapril 20 mg, or placebo preventing one or more forms of CV disease and also
and followed them over 24 months. Atherosclerotic pro- since they are less expensive should be a first-line agent
gression was also assessed in a substudy of 274 patients in the treatment of HTN. However, other commentaries
as well using intravascular ultrasound. Although the suggested that this finding may be attributed to the fact
baseline BP was low to begin with, 129/78, both groups that thiazides are better at treating volume-dependent
showed similar BP lowering, 4.8/2.5 and 4.9/2.4 for HTN, such as the elderly and African-Americans who
amlodipine and enalapril, respectively. Amlodipine sig- comprised a large portion of the patient demographics
nificantly reduced non-fatal myocardial infarction (MI) for this study.8–10 Although this may be the case, this
by 26% and stroke or transient ischaemic attack by 50% very large study showed that amlodipine was neither
(number needed to treat=16), whereas enalapril had no superior nor inferior to thiazide diuretics or ACEIs in
significant benefit compared with placebo.5 Moreover, managing HTN in patients with other comorbid
there was a statistically significant reduction in hospital- conditions.10
isation rate for angina ( p=0.003) with amlodipine versus Studies have shown that nitric oxide (NO) production
enalapril. This study suggests that normotensive patients is diminished in patients with HTN.11 12 A small study
treated with amlodipine show reduced rates of CV events carried out by Masayoshi and colleagues measured
and hospitalisations compared with enalapril and evi- exhaled NO in seven previously untreated participants
dence of slowing of atherosclerotic progression.5 to assess whether amlodipine has an effect on NO.13
A Japanese study, although small, investigated the Their study found that NO production in the pulmonary
effect of losartan and amlodipine on left ventricular circulation was increased as evidenced by increased NO
(LV) diastolic function in patients with mild-to-moderate measurements in exhaled air after 2 months of amlodi-
HTN. LV diastolic dysfunction has a direct correlation pine therapy. Another small study by Zhang and collea-
with LV hypertrophy (LVH) and myocardial fibrosis. gues evaluated NO production in explanted hearts,

2 Fares H, DiNicolantonio JJ, O’Keefe JH, et al. Open Heart 2016;3:e000473. doi:10.1136/openhrt-2016-000473
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Cardiac risk factors and prevention

which were harvested during transplant. Previous studies fosinopril may have a greater benefit for the reduction
suggest that NO release from endothelial cells is a kinin- of stroke/MI. However, this trial enrolled a small
mediated mechanism. Kinins are usually degraded by number of patients and the thus the CIs were wide and
ACE. ACEIs facilitate the accumulation of these com- the CV event reduction with fosinopril was not signifi-
pounds, which was the rational for enlisting ramiprilat cant compared with amlodipine. A larger trial is needed
for comparison.14 While amlodipine was found to to clarify these results.18
increase NO production in these failing hearts, it was Another study by Mugellini and colleagues looked at
similar to the NO production noted with ramiprilat. The 391 patients with metabolic syndrome who had at least
authors postulated that this may be one of the mechan- two episodes of atrial fibrillation (AF) in 6 months.19
isms of amlodipine’s beneficial effects in heart failure These patients were randomised to telmisartan, ramipril
(HF), which is not a feature shared by other members or amlodipine for 12 months and results showed that all
of the CCB class. Thus, the enhancement of NO pro- three groups similarly reduced both systolic and diastolic
duction may account for the beneficial effects of this BP. In terms of the AF however, telmisartan showed the
drug on the CV system.14 Additionally, amlodipine has greatest effect on reducing recurrence.19
anti-inflammatory and antioxidative effects giving it vaso-
protective effects beyond its BP-lowering benefits.15
Interestingly, these benefits were noted by the authors to ATHEROSCLEROSIS AND CAD
be caused by an increase in endothelial NO synthase Calcium regulation has been implicated in the patho-
expression and inhibition of ACE. Thus, amlodipine genesis of atherosclerotic plaque formation, which has
may even be beneficial for patients with high renin generated interest in the potential role for this CCB in
HTN.15 the prevention of atherosclerosis.20 Several mechanisms
The VALUE (Valsartan Antihypertensive Long-term have been proposed to account for amlodipine’s poten-
Use Evaluation) trial was another large trial enrolling tial benefit in atherosclerosis. In vivo and in vitro studies
over 15 000 patients with HTN who were previously suggest that amlodipine inhibits oxidative damage to the
treated with anti-HTN therapy.16 This study looked at lipid bilayer of the cell membrane and this has been
the efficacy of amlodipine versus valsartan in attaining a attributed to its lipophilicity and chemical structure,
BP goal of <140/90. The doses were uptitrated to 10 mg which prevents the formation of free radicals. This
of amlodipine or 160 mg of valsartan. Two additional process is prevented by the donation of protons by this
steps were done that included adding hydrochlorothia- drug to lipid peroxide molecules. In atherogenesis,
zide (HCTZ) then another agent (excluding ACEIs, the packing of phospholipid molecules becomes disar-
ARBs or other CCBs). The outcomes showed that both rayed and this causes swelling of the lipid bilayer, which
monotherapy groups had similar improvements in BP is an impetus for smooth muscle proliferation and ather-
with average BPs in the 130s/80s for both groups. oma development. Enhancement of NO production has
However, valsartan caused a significant increase (19%, been proposed as a potential reason for amlodipine’s
p=0.02) in total MI (fatal and nonfatal) in comparison antiatherosclerotic effect. Zhang and Hintze21 noted
with amlodipine. Although some have criticised these increased NO production in canine coronary microvas-
results due to the faster BP lowering of amlodipine early culature, which was an unexpected feature of this CCB
on, the Kaplan-Meier MI curves indicated that as BP and is not a quality that is shared by other members of
became similar between the two groups (as the trial pro- its class. Additionally, amlodipine has been shown to
gressed), the curves continued to diverge; suggesting a upregulate the expression of interleukins, which may
BP-independent beneficial effect on MI with amlodipine also have antiproliferative effects, and to have favourable
versus valsartan. New-onset diabetes was reported in 580 effects on extracellular matrix remodelling.22 23
(11.5%) patients on valsartan and in 718 (14.5%) One of the pivotal trials assessing amlodipine’s role in
patients on amlodipine.16 17 atherosclerosis was the Prospective Randomized
The Fosinopril versus Amlodipine Cardiovascular Evaluation of the Vascular Effects of Norvasc
Events Randomized Trial (FACET) showed different (PREVENT) trial. PREVENT assessed the development
results on fasting glucose levels. The goal of the FACET and progression of atherosclerosis in patients with
was to compare the effects of these two agents on lipid known CAD. This was a multicentre, randomised,
and diabetes control in patients with HTN.18 Three placebo-controlled, double-blinded study, which looked
hundred and eighty patients were randomised to 20 mg at 825 patients with angiographically documented
of fosinopril or 10 mg of amlodipine daily with a CAD.20 Patients were followed over a 3-year period and
follow-up period of 3.5 years. Results showed no differ- the primary end point was change in mean diameter
ence on the lipid profiles or fasting glucose levels. over 36 months in segments with a baseline of 30% sten-
However, fosinopril was associated with a 38.5% relative osis. It has been suggested that acute coronary syndrome
risk reduction (RRR) in the combined end point (fatal does not usually result from more stable plaques but
or non-fatal stroke and fatal or non-fatal MI; RR=0.6151, rather rupture of minimal lesions. PREVENT also
95% CI 0.3266 to 1.1587). These findings suggest that assessed the rate of progression of carotid atherosclerosis
while amlodipine may have similar effects on BP control, which was assessed by CIMT. The data showed that there

Fares H, DiNicolantonio JJ, O’Keefe JH, et al. Open Heart 2016;3:e000473. doi:10.1136/openhrt-2016-000473 3
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Open Heart

was no effect on the risk of all-cause mortality or major effects due to reflex stimulation of the sympathetic
CV events, and amlodipine did not alter the develop- nervous system and negative inotropic effects, features
ment of or slow the progression of CAD lesions. not seen with amlodipine.28–30 Thus, amlodipine may be
However, there was a statistically significant effect on the safe in patients with HF.31 The Prospective Randomized
progression of carotid artery atherosclerosis ( p=0.007).24 Amlodipine Survival Evaluation (PRAISE) trial estab-
Yet, the study had low statistical power for the detection lished the safety of amlodipine for angina and HTN in
of a treatment difference in mortality and major morbid- patients with advanced LV dysfunction (amlodipine).32
ity rates because of the relatively low event rates (ie, The PRAISE trial studied over 1100 patients with severe
<2%/year for MI). When major and other documented ischaemic and non-ischaemic New York Heart
vascular events/procedures were combined (increasing Association class III and IV HF with an LV ejection frac-
the power to determine an effect), there were fewer tion (LVEF) of <30% despite being on digoxin, diuretics
events in the amlodipine group. Additionally, amlodi- or an ACEI. They were also allowed to be on a nitrate
pine did show reduced rates of unstable angina and cor- but no other vasodilating therapy. They were rando-
onary revascularisation, which is comparable to data mised to either amlodipine or placebo and followed for
seen with treatment with BB, nitrates and lipid-lowering 33 months. There was no significant difference in the
agents. Angiographic trials with nifedipine or nicardi- primary end point (combined risk of all-cause mortality
pine did not show these effects. The authors of and CV disease morbidity) with amlodipine treatment;
PREVENT did report that when the event rates for although amlodipine did show a 9% risk reduction of a
unstable angina and coronary revascularisation were primary fatal or non-fatal event. There was a difference
assessed closely, these curves diverged very early (in the however, in the non-ischaemic HF group, where amlodi-
first year). Thus, while amlodipine may not have shown pine showed a 46% reduction in mortality.32
a significant role in prevention of progression of early The PRAISE trial showed that amlodipine did not
coronary atherosclerotic lesions, it does have a beneficial affect the natural history of HF or increase the risk of
effect in reducing hospitalisation rates for angina and death as other trials with CCBs have suggested.31 The
coronary revascularisation.24 In the randomised trial investigators pointed out that it was interesting that
Coronary Angioplasty Amlodipine Restenosis Study amlodipine seemed to greatly benefit the non-ischaemic
(CAPARES), patients had a reduced incidence of repeat group. The PRAISE II trial was then carried out to
percutaneous transluminal coronary angioplasty when further investigate the potential for amlodipine to reduce
treated with amlodipine.25 mortality in the non-ischaemic group. This trial looked at
The beneficial effects of amlodipine go beyond 1652 patients with normal arteriograms but with the sys-
calcium channel blockade for HTN management. tolic HF and average LVEF was 21%. There was no signifi-
Although many of these trials show that amlodipine is cant difference found between the amlodipine versus
not superior to other agents in preventing CAD, it can placebo group in terms of all-cause or CV disease mortal-
be safely used in patients with CAD for the management ity or CV disease events. Taken together, PRAISE I and II
of HTN. suggest that amlodipine can be safely used to treat angina
or HTN in patients with coexisting HF.33 34
ROLE IN RENOPROTECTION
In the ACCOMPLISH trial, HCTZ was inferior to amlo-
ROLE IN COMBINATION THERAPY FOR HTN
dipine for the prevention of end-stage renal disease.
While thus far amlodipine has shown to be non-inferior
Furthermore, in patients who were >65 years old at base-
to many other anti-HTN therapies, the focus on HTN
line, there was a 70% RRR in patients progressing to dia-
treatment seems to be shifting more towards combin-
lysis in the amlodipine group versus the HCTZ group
ation therapy. Less than 50% of patients with stage I or
( p=0.053, for the difference).26 In the intention-to-treat
II HTN are adequately controlled with monotherapy,
population, the amlodipine group had a 48% RRR for
and thus initial treatment for HTN in the majority of
chronic kidney disease (CKD) progression, defined as
patients will require two agents. The classical approach
doubling of serum creatinine, estimated glomerular fil-
to treating HTN where one first-line agent is maximised
tration rate (eGFR) <15 mL/min, or dialysis compared
before another is added may be flawed since this is a
with the HCTZ group. Furthermore, patients with CKD,
multifactorial disease often occurring with a number of
defined as an eGFR of 45.1 mL/min at baseline, showed
comorbidities. Many studies show that individuals with
a significantly greater decline in renal function with
more CV risk factors generally need more anti-HTN
HCTZ versus amlodipine (−2.3 vs −1.6 mL/min;
agents to successfully manage their BP. Combination
p=0.001).26 27
therapy using different mechanisms can lead to more
effective BP lowering. In addition, combination therap-
ROLE IN HF ies block counter-regulatory mechanisms that often limit
Traditionally CCBs were discontinued for the treatment the efficacy of monotherapy. Furthermore, using
of angina or HTN in patients with HF. Previous studies multiple agents to lower doses may reduce side effects,
with CCBs such as nifedipine, have shown unfavourable and thus improve patient compliance.

4 Fares H, DiNicolantonio JJ, O’Keefe JH, et al. Open Heart 2016;3:e000473. doi:10.1136/openhrt-2016-000473
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Cardiac risk factors and prevention

The issue arises as to which fixed combinations amlodipine monotherapy group, 18.7% vs 7.6%,
provide the most benefits. Thiazides in combination p=0.011, respectively. In addition, the reported inci-
with ACEIs or ARBs have synergistic BP-lowering activity, dence of peripheral oedema was lower in the combin-
whereas thiazides and BBs have deleterious effects on ation group.38
the metabolic profile. CCBs are powerful vasodilators The Candesartan and Diuretic versus Amlodipine in
but can result in renin–angiotensin–aldosterone system hypertensive patients (CANDIA) trial evaluated cande-
(RAAS) activation, thus an ACEI or ARB counteracts this sartan+HCTZ combination versus amlodipine monother-
mechanism and leads to enhanced antihypertensive apy.39 This multicentre, double-blinded, randomised
effect. Growing evidence from trial data also shows that trial assessed patients with mild-to-moderate HTN not
CCBs with ACEIs or ARBs may provide the best long- adequately controlled with monotherapy. After 8 weeks
term outcomes. of therapy, there was no significant difference between
The ACCOMPLISH trial was a randomised, controlled the two groups. Systolic BP decreased by about
trial in which 11 506 patients with HTN with high risk 15 mm Hg; however, there was a higher discontinuation
for adverse CV events were assigned amlodipine+benaze- rate with amlodipine versus the combination drug due
pril versus HCTZ+benazepril.35 The primary end point to peripheral oedema, 18% vs 6%, respectively. These
was the composite of CV death or major adverse CV findings suggest that while both agents are effective in
events. The amlodipine+benazepril combination was lowering BP, the candesartan+HCTZ combination was
superior to the HCTZ+benazepril for lowering CV death better tolerated and hence may lead to better patient
and adverse events (figure 1).35 compliance.39
The Anglo-Scandinavian Cardiac Outcomes Trial The Combination of Olmesartan Medoxomil and
(ASCOT) included a total of 19 257 patients with HTN Amlodipine Besylate in Controlling High blood Pressure
(baseline BP, 164/95 mm Hg) and at least three other (COACH) study was a study evaluating an ARB+amlodi-
cardiac risk factors.36 This trial, which was stopped pine combination versus placebo.40 The 1940 patients in
for benefit after 5.5 years, showed that the amlodipine this 8-week treatment study showed achievement of BP
+perindopril versus atenolol+thiazide diuretic signifi- goals (<140/90) with the combination therapy and
cantly reduced all-cause mortality (RRR, 11%; p=0.0247; again, a lower incidence of peripheral oedema.40 These
figure 2). Additionally, amlodipine+perindopril reduced findings were echoed in the Telmisartan plus
CV mortality by 24% ( p=0.001), coronary events by 13% Amlodipine Study in amlodipine 5 mg (TEAMSTA-5),
( p=0.007) and strokes by 23% ( p=0.0003).37 At the which tested another ARB+amlodipine combination.
point where rates of CV death diverged (red arrow) The study showed that the combination of telmisartan
most of the patients (78%) were treated with the com- 40/80 mg plus amlodipine 5 mg was superior to amlodi-
bination of perindopril+amlodipine rather than amlodi- pine 10 mg monotherapy.41
pine monotherapy.36 CCBs are potent vasodilators and hence reduce BP
The Assessment of combination Therapy of effectively but can result in RAAS activation. Therefore,
Amlodipine/Ramipril (ATAR) study was an 18-week ran- the rational for a CCB/RAAS inhibitor combination
domised prospective double-blinded Brazilian study drug would theoretically provide vasodilation while buf-
which compared the combination of amlodipine and fering RAAS activation. Another combination with RAAS
ramipril versus amlodipine monotherapy. The mean blocker and HCTZ has been shown to be effective.
changes in ambulatory BP measurements were statistic- Triple therapy with valsartan+amlodipine+HCTZ was
ally significant between the combination versus the compared with dual combination with valsartan+HCTZ,

Figure 1 ACCOMPLISH: the

amlodipine+benazepril
combination lowered the primary
end point by a relative risk
reduction was 20% (HR 0.80;
95% CI 0.72 to 0.90; p<0.001).35

Fares H, DiNicolantonio JJ, O’Keefe JH, et al. Open Heart 2016;3:e000473. doi:10.1136/openhrt-2016-000473 5
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Open Heart

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data are available.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
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Fares H, DiNicolantonio JJ, O’Keefe JH, et al. Open Heart 2016;3:e000473. doi:10.1136/openhrt-2016-000473 7
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Amlodipine in hypertension: a first-line agent

with efficacy for improving blood pressure
and patient outcomes
Hassan Fares, James J DiNicolantonio, James H O'Keefe and Carl J
Lavie

Open Heart 2016 3:

doi: 10.1136/openhrt-2016-000473

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