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(adapted) material if appropriate CLINICAL FOCUS: HYPERTENSION AND RELATED DISORDERS

Angiotensin Receptor Blocker and Dihydropyridine

Calcium Channel Blocker Combinations:
An Emerging Strategy in Hypertension Therapy
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Suzanne Oparil, MD 1 Abstract: Hypertension is a leading contributor to the burden of cardiovascular disease. The
Michael Weber, MD 2 importance of lowering blood pressure (BP) to reduce the risk of cardiovascular events has been
1
Vascular Biology and Hypertension demonstrated in numerous clinical trials. Most patients require combination antihypertensive
Program, Division of Cardiovascular therapy utilizing agents from complementary drug classes to achieve BP goals. A calcium chan-
Diseases, University of Alabama
at Birmingham School of Medicine, nel blocker (CCB)/angiotensin receptor blocker (ARB) combination is a rational approach for
Birmingham, AL; 2SUNY Downstate such an antihypertensive strategy. Benefits of CCB/ARB combination therapy include additive
Medical Center College of Medicine,
New York, NY
BP-lowering effects and lower incidences of adverse events (AEs). These agents demonstrate
benefits associated with their respective drug classes. The ARBs confer stroke protection, renal
protection, and tolerability similar to placebo, without dose-related symptomatic and metabolic
For personal use only.

AEs, while CCBs are beneficial in reducing stroke and treating angina and cardiac ischemia. The
efficacy of this combination has been recently investigated in clinical trials wherein amlodipine
was combined with olmesartan medoxomil or valsartan. This article discusses the rationale for
using CCB/ARB combinations in patients with hypertension.
Keywords: hypertension; calcium channel blockers; angiotensin receptor blockers; combination
therapy; olmesartan medoxomil; amlodipine

Introduction
The global impact of elevated blood pressure (BP) is considerable1 and is known to
be one of the leading contributors to the growing worldwide burden of cardiovascular
disease (CVD).2 There is a direct relationship between BP and the risk of CVD events
such as myocardial infarction (MI) and stroke.3,4 From an epidemiological perspective,
each increment of 20 mm Hg in systolic BP or 10 mm Hg in diastolic BP doubles
the risk of a cardiovascular event, without evidence of a threshold, down to at least
115/75 mm Hg.5
The importance of lowering BP in reducing the risk of cardiovascular events has
been demonstrated in a range of randomized controlled clinical trials.6–10 Although it
is important to gain control of both diastolic BP (DBP) and systolic BP (SBP), SBP is
the major contributor to the adverse outcomes of hypertension,11 and experts advocate
Correspondence: Suzanne Oparil, MD, focusing on SBP rather than DBP in all patients with hypertension, but particularly
Director, Vascular Biology
and Hypertension Program, those aged ⱖ 50 years.12 Relative to DBP, goal SBP can be difficult to obtain.13,14
Division of Cardiovascular Diseases, However, when SBP is controlled to ⬍ 140 mm Hg, a DBP of ⬍ 90 mm Hg is almost
University of Alabama at Birmingham,
703 19th Street South, ZRB 1034, invariably achieved.13,15
Birmingham, AL 35294-0007. Clinical trials and practical experience have shown that in most hypertensive
Tel: 205-934-2580
Fax: 205-975-5119
patients goal BP is unlikely to be achieved with 1 antihypertensive drug.6,16–19
E-mail: soparil@uab.edu Guidelines acknowledge that combination therapy will be required for most patients to

© Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 25
71508e
 Suzanne Oparil and Michael Weber

attain recommended BP targets, and advise that combination relative risk reduction for the primary composite endpoint of
treatment utilizing agents from complementary drug classes cardiovascular death, stroke, or MI in patients treated with
should be considered as first choice, particularly when a large BP the losartan-based regimen, despite a similar degree of BP
reduction is required or if there is high cardiovascular risk.3,4 lowering in the losartan- and atenolol-based groups (Table 1).
Combining a dihydropyridine calcium channel blocker The difference was mainly from a highly significant 25%
(CCB) with an angiotensin II receptor blocker (ARB) is a reduction in the relative risk of fatal or non-fatal stroke. The
rational approach for such an antihypertensive strategy, and beneficial effects of losartan were consistent across most
the antihypertensive efficacy of this combination has been clinical subgroups, including a 40% reduction in the risk of
recently investigated in several clinical trials.20–22 This article stroke in patients with isolated systolic hypertension (ISH)
discusses the rationale for combining these 2 classes of (P ⬍ 0.05).30,31 However, results from a subanalysis based on
agents in patients with hypertension, including the potential race indicated that the hazard ratio for the primary endpoint
benefits resulting from the unique mechanisms of action of favored atenolol in black patients and losartan in non-blacks,
each drug class. leading to the recommendation that losartan should not be
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considered as first-line therapy for black patients with hyper-

Outcome Studies in Patients tension and LVH.32 A similar BP-lowering effect was seen
with Hypertension in both treatment arms of the LIFE study, when measured
ARB Outcomes Trials by both cuff and 24-hour ambulatory BP monitoring,16,33
There is now considerable evidence that ARBs reduce suggesting that BP-independent actions account for the supe-
cardiovascular, renal, and mortality outcomes in a range riority of losartan over atenolol in preventing cardiovascular
of patients, including those with congestive heart failure,23 morbidity and mortality.
chronic kidney disease, 24,25 post-stroke patients, 26,27 In the Valsartan Antihypertensive Long-Term Use
patients at high cardiovascular risk,28 and patients with Evaluation (VALUE) study, 15 245 hypertensive patients at
For personal use only.

hypertension.7,10,29 One of the key ARB outcomes studies high cardiovascular risk were randomized to 4 to 6 years of
in patients with hypertension was the Losartan Intervention treatment with antihypertensive regimens based on valsartan
for Endpoint Reduction in Hypertension (LIFE) study.16 80 to 160 mg/day or amlodipine 5 to 10 mg/day.34 Over a
In this study, 9193 patients with primary hypertension and mean 4.2 years of follow-up, the VALUE study reported
left ventricular hypertrophy (LVH) were randomized to at a significantly more pronounced reduction in BP with
least 4 years of treatment with losartan- or atenolol-based amlodipine than valsartan (2.1/1.7 mm Hg difference). There
therapy, each at doses of 50 to 100 mg. The target BP was, however, no significant difference between valsartan
goal was ⬍ 140/90 mm Hg. There was a significant 13% and amlodipine for the combined primary endpoint of cardiac

Table 1. Blood Pressure and Clinical Outcome Results for Losartan and Candesartan Versus Atenolol and Placebo in the Losartan
Intervention for Endpoint (LIFE)16 Study and the Study on Cognition and Prognosis in the Elderly (SCOPE)35
LIFE (losartan vs atenolol) SCOPE (candesartan vs placeboa)
BP Reduction SBP DBP SBPb DBPb
30.2 vs 29.1 16.6 vs 16.8 21.7 vs 18.5 10.8 vs 9.2
c
Clinical Outcomes Rate/1000 patient years Relative risk Rate/1000 patient years Relative risk
d
Primary endpoint 23.8 vs 27.9 0.87* 26.7 vs 30.0 0.89
CV mortality 9.2 vs 10.6 0.89 15.6 vs 16.6 0.94
Fatal or non-fatal stroke 10.8 vs 14.5 0.75** 9.7 vs 12.8 0.76
Non-fatal stroke NR NR 7.4 vs 10.3 0.72*
Fatal or non-fatal MI 9.2 vs 8.7 1.07 7.6 vs 6.9 1.10
Non-fatal MI NR NR 5.9 vs 5.2 1.13

Abbreviations: BP, blood pressure; CV, cardiovascular; DBP, diastolic BP; MI, myocardial infarction; NR, not reported; SBP, systolic BP.
a
84% of patients in the placebo control group actually received active antihypertensives, mostly diuretics. bAdjusted for country and baseline value. cAdjusted for degree of left ven-
tricular hypertrophy and the Framingham risk score. dLIFE primary endpoint = cardiovascular mortality, stroke, and myocardial infarction; SCOPE primary endpoint = cardiovascular
mortality, non-fatal stroke, and non-fatal myocardial infarction.
*P ⬍ 0.05; **P ⱕ 0.001.

26 © Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 ARB and CCB Combinations: A New Strategy

mortality and morbidity. Among the secondary endpoints, significantly reduced in the olmesartan medoxomil, but not
MI was significantly more frequent in the valsartan group. the atenolol, study arm.40 This finding demonstrated that
Stroke was less common in the amlodipine group, but the blockade of AT1 receptors resulted in superior reversal
the difference did not reach statistical significance. These of adverse remodeling of resistance arteries in patients with
differences in treatment effects, however, no longer existed essential hypertension that was independent of the magnitude
if the differences in achieved BPs were accounted for. of BP reduction.
In the Study on Cognition and Prognosis in the Elderly The impact of ARBs on vascular morphology may help
(SCOPE), in which 4964 elderly patients with mild-to-moderate to explain the effects of these agents in prehypertension. The
hypertension were randomized to 3 to 5 years of treatment Trial of Preventing Hypertension (TROPHY) evaluated the
with candesartan 8 to 16 mg/day or placebo, a slightly effects of candesartan cilexetil or placebo in individuals with
greater reduction in BP with candesartan (3.2/1.6 mm Hg) high-normal BP.41 Patients were eligible for this study if at the
was accompanied by an 11% reduction in the relative risk first clinic visit BP was ⬍ 160/100 mm Hg, and if the average
of the composite primary endpoint of cardiovascular death, of 3 BP readings at 3 prespecified visits was a SBP of 130 to
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non-fatal MI, and non-fatal stroke (Table 1).35 As in the 139 mm Hg and a DBP ⱕ 89 mm Hg or a SBP ⱕ 139 mm Hg
LIFE study, the effect of the ARB on major cardiovascular and a DBP of 85 to 89 mm Hg. After 2 years, there was a
events was driven mainly by an effect on stroke: there relative risk reduction of 66.3% of developing hypertension
was a significant 28% reduction in non-fatal stroke, and a in the candesartan group (P ⬍ 0.001 vs placebo). Moreover,
nonsignificant 24% reduction in the risk of all stroke with the risk of developing hypertension was still 16% lower in
candesartan. It should be noted that 84% of patients in the the candesartan group 2 years after discontinuing active
control group received active antihypertensive agents to treatment (P = 0.007). These results showed that an ARB was
control BP, so SCOPE was really a comparison between a able to favorably influence the natural history of the disease
candesartan group and a group that received various other and reduce the risk of developing hypertension in patients
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antihypertensives, mostly diuretics. It is currently not known with prehypertension over the course of the study.
whether the slightly greater reduction in BP observed in favor One clinically relevant question is whether ARBs are
of the candesartan group or specific effects of angiotensin II superior to other agents that block the renin-angiotensin-
receptor type 1 (AT1)-receptor blockade were responsible for aldosterone system (RAAS), namely angiotensin-converting
the reduction in non-fatal stroke observed in the candesartan enzyme (ACE) inhibitors, for cardiovascular risk reduction,
treatment group.36,37 As in the LIFE study, substantial since most comparative outcomes studies are in patients
benefit was observed in the subgroup of patients with ISH: with established cardiovascular or renal disease. In the
a relative risk reduction for total stroke of 42% (P = 0.049), recent double-blind Ongoing Telmisartan Alone and in
with a slightly better BP reduction (2/1.2 mm Hg) seen for Combination with Ramipril Global Endpoint Trial (ONTAR-
candesartan versus control.38 It has been suggested that this GET), 25 620 patients with high-risk diabetes or vascular
small BP difference could account for part of the observed disease were randomized into 1 of 3 treatment groups.28
benefit with regard to stroke.38 Patients received an ARB (telmisartan 80 mg/day), an ACE
Therefore, the question of whether blockade of the AT1 inhibitor (ramipril 10 mg/day), or combination therapy
receptor with an ARB may reverse vascular pathology (telmisartan 80 mg/day and ramipril 10 mg/day). The study
independent of BP lowering remained in question, and led evaluated whether telmisartan 80 mg/day was noninferior
to studies investigating the effects of ARBs on vascular to ramipril 10 mg/day and whether the combination was
pathology in hypertension. The Vascular Improvement with superior to ramipril alone in preventing vascular events
Olmesartan Medoxomil Study (VIOS) enrolled patients using a composite outcome of death from MI, stroke, car-
with Stage 1 hypertension and no evidence of target organ diovascular causes, or hospitalization for heart failure. The
damage or CVD, and randomized them to treatment based study was a follow-up to the Heart Outcomes Prevention
on olmesartan (20–40 mg) or atenolol (50–100 mg) with Evaluation (HOPE) trial, in which ramipril was shown to
a target BP of ⬍ 140/90 mm Hg. The primary endpoint reduce these outcomes in a similar population of patients. All
was the effect of treatment on the morphology of the small treatments effectively reduced BP. Reductions were 0.9/0.6
resistance vessel, remodeling of which is a hallmark of early mm Hg greater in the telmisartan treatment group and 2.4/1.4
vascular damage associated with hypertension.39 After 1 year mm Hg greater in the combination groups compared with
of treatment, small resistance vessel wall-to-lumen ratio was patients administered ramipril alone. After a 56-month mean

© Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 27
 Suzanne Oparil and Michael Weber

follow-up, a similar benefit was seen in the primary outcome reduction in sitting BP in the nitrendipine-based treatment
in the combination therapy group compared with ramipril group versus the placebo control group. There were also
alone (relative risk, 0.99; 95% confidence interval [CI], significant declines in composite endpoints: 26% for fatal
0.92–1.07). The data show that telmisartan was as effective or non-fatal cardiac events (P = 0.03) and 31% for fatal and
as ramipril for reducing cardiovascular outcomes in patients non-fatal cardiovascular events (P ⬍ 0.001). The Syst-Eur
with high-risk diabetes or vascular disease and was associ- researchers pointed out that the benefits of active treatment
ated with fewer adverse events (AEs). However, there was were observed soon after randomization, when most patients
no clinical advantage in using the combination of an ARB were still on monotherapy with nitrendipine.
and an ACE inhibitor in this population. Furthermore, the In the Intervention as a Goal in Hypertension Treatment
unexpected observation of an increased incidence of renal (INSIGHT) study, 6575 patients with hypertension
dysfunction in the combination therapy arm has led to the and ⱖ 1 additional cardiovascular risk factor were randomized
suggestion that dual blockade of the RAAS system should to first-line nifedipine GITS 30 mg or co-amilozide
be reconsidered as a treatment option.42 (hydrochlorothiazide/amiloride) 25/12.5 mg for ⱖ 3 years.45
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In the Telmisartan Randomized Assessment Study The primary outcome, a composite of cardiovascular death,
in ACE Intolerant Subjects with Cardiovascular Disease non-fatal stroke, MI, and heart failure, occurred in similar
(TRANSCEND) trial, the efficacy of this ARB in patients proportions of patients in each group (6.3% in the nifedipine
with CVD or diabetes with end-organ damage and intolerant and 5.8% in the co-amilozide group). By the end of a 12-week
to ACE inhibitors was assessed. 43 Patients received titration period, mean BP fell by 33/17 mm Hg and remained
telmisartan 80 mg/day or placebo along with concomitant close to 138/82 mm Hg in the 2 treatment groups for the rest
therapies with a median follow-up of 56 months. The primary of the study. More cases of diabetes were diagnosed in the co-
outcome was a composite of cardiovascular death, MI, stroke, amilozide than in the nifedipine arm (5.6% vs 4.6%; P = 0.02).
or hospitalization for heart failure. Telmisartan produced Significantly more patients on co-amilozide than on nifedipine
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a 4 mm Hg mean SBP reduction compared with placebo. had metabolic AEs, including hypokalemia (1.9% vs 6.2%;
However, the difference between the proportions of patients P ⬍ 0.001) and hyperglycemia (5.6% vs 7.7%; P = 0.001),
experiencing the primary outcome in the telmisartan and highlighting the metabolic neutrality of CCBs versus diuretics
placebo groups was not significant (P = 0.216). However, in the management of hypertension.46
the key secondary endpoint of cardiovascular death, stroke, The Anglo-Scandinavian Cardiac Outcomes Trial − Blood
and MI, which was the same endpoint as used in the original Pressure Lowering Arm (ASCOT − BPLA) compared a
HOPE trial, did indicate a significant 13% reduction in events CCB-based regimen (amlodipine 5–10 mg) with a beta
with telmisartan. In the TRANSCEND study, telmisartan was (β)-blocker-based regimen (atenolol 50–100 mg) for the
well tolerated with fewer discontinuations than placebo, an primary prevention of congestive heart disease (CHD) in
important consideration in these patients who were unable patients with hypertension and ⱖ 3 additional cardiovascular
to tolerate RAAS blockade with ACE inhibitors.43 risk factors.18,47 Randomized patients (n = 19 257) were treated
to a BP goal of ⬍ 140/90 mm Hg (⬍ 130/80 mm Hg for patients
CCB Outcomes Trials with diabetes), and the primary endpoint was non-fatal MI and
Although amlodipine is a component of all currently fatal CHD. The study was stopped prematurely after 5.5 years
approved ARB-based, fixed-dose combination therapies, median follow-up because of fewer deaths in the amlodipine-
there are many outcomes studies using other members of based arm. The ASCOT-BPLA trial demonstrated that using
the CCB drug class. The first large-scale outcome study in a CCB-based therapy to which a RAAS-blocking agent was
hypertensive patients using a CCB as first-line treatment added resulted in improved clinical outcomes versus adding a
was the Systolic Hypertension in Europe (Syst-Eur) diuretic to a β-blocker-based regimen in patients with hyper-
trial, a randomized, placebo-controlled trial that enrolled tension and at moderate cardiovascular risk. Compared with
4695 elderly patients with ISH.44 Active treatment was atenolol-based therapy, amlodipine-based therapy resulted
nitrendipine 10 to 40 mg/day. The primary endpoint was in significantly less major cardiovascular events (fatal and
fatal and non-fatal stroke. The study was terminated after a non-fatal stroke, P ⬍ 0.001; total cardiovascular events and
median 2 years of follow-up because of a significant 42% procedures, P ⬍ 0.001; and all-cause mortality, P ⬍ 0.05) and
reduction in the rate of stroke in the active treatment group induced less new-onset diabetes (P ⬍ 0.0001) compared with
(P = 0.003), at which time there was a 10.1/4.5 mm Hg greater the atenolol-based therapy. A greater reduction in BP with

28 © Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 ARB and CCB Combinations: A New Strategy

amlodipine- versus atenolol-based treatment was observed Results from the Avoiding Cardiovascular Events
with an average difference of 2.7/1.9 mm Hg in favor of through Combination Therapy in Patients Living with
the amlodipine-based regimen; however, it was concluded Systolic Hypertension (ACCOMPLISH) trial have been
that the reductions in mortality and other important clinical recently reported.52 Over 11 400 patients were recruited
endpoints appeared greater than would be expected by the and received amlodipine in combination with benazepril
difference seen in BP lowering between the regimens.48 (an ACE inhibitor) or hydrochlorothiazide in combination
Blood pressure is conventionally measured over the with benazepril. The primary composite endpoint of
brachial artery, but this may not accurately reflect pressures cardiovascular morbidity/mortality was defined as death from
in the central circulation, which is an important factor cardiovascular causes, fatal or non-fatal MI or fatal or non-
determining cardiac workload and cardiac hypertrophy.49 fatal stroke, revascularization, or unstable angina requiring
In a substudy of ASCOT, the Conduit Artery Functional hospitalization. The trial was terminated early because the
Endpoint (CAFE) study (involving 2199 patients), the effects predefined efficacy outcome was achieved. Treatment with
of antihypertensive treatment on central aortic pressures a combination of amlodipine and benazepril significantly
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were evaluated.50 Over 6 years of follow-up, brachial BP reduced cardiovascular morbidity/mortality compared with
had declined from baseline and was similar in both treatment the hydrochlorothiazide/benazepril combination (relative risk,
groups (area under the curve [AUC] difference, 0.7 mm Hg; P 0.80; 95% CI, 0.71–0.9). Similar highly significant advantages
= 0.2). However, throughout the study, central aortic pressure observed with the amlodipine combination, as compared
was substantially lower with the amlodipine- versus the with the thiazide combination, included the secondary
atenolol-based regimen in terms of SBP (AUC difference, endpoint of cardiovascular death, stroke, and MI as well as
4.3 mm Hg; P ⬍ 0.0001), as was central aortic pulse pressure revascularization procedures and MI as a single endpoint.
(AUC difference, 3 mm Hg; P ⬍ 0.0001). Notably, central
pulse pressure was significantly associated with a composite Complementary Antihypertensive
Mechanisms of Action
For personal use only.

clinical endpoint (all cardiovascular events and procedures

plus development of renal impairment) that was defined post in Combination Therapy
hoc. Earlier pressure wave reflection and slower heart rate in In general, effective antihypertensive drugs alter physiologic
the atenolol group may have contributed to the differences systems involved in the regulation of BP. Different classes
in central aortic pressure between the 2 treatment arms. of antihypertensive agents work by distinct mechanisms of
The CAFE study results provide a plausible mechanism action. Combining agents with complementary mechanisms
to explain the better clinical outcome for patients treated into a fixed-dose formulation may have a number of advantages
with amlodipine-based therapy in ASCOT, as well as the (Table 2).21,22,53–59 The following section will discuss the
differential effects of other BP-lowering drugs on clinical mechanisms of action of CCB and ARB monotherapy and the
outcomes in other recent trials, such as valsartan versus rationale for combining these 2 drug classes in the treatment
atenolol in the LIFE study. of hypertension.
Amlodipine was shown to have a protective effect against
cardiovascular events in the Comparison of Amlodipine ARB Monotherapy
Versus Enalapril to Limit Occurrences of Thrombosis Angiotensin II (AngII), which is produced through both
(CAMELOT) study which compared amlodipine, enalapril, ACE-dependent and ACE-independent pathways, is the
and placebo in patients with coronary artery disease major effector peptide of the RAAS, and is central to the
(baseline BP, 129/78 mm Hg for all patients).51 Amlodipine pathophysiology of hypertension and associated morbidity.60
therapy significantly reduced the incidence of cardiovascu- Angiotensin receptor blockers effectively block binding of
lar events compared with placebo (hazard ratio, 0.69; 95% AngII to AT1 receptors and achieve specific blockade of AngII
CI, 0.54–0.88; P = 0.003), but not compared with enalapril. and its deleterious hypertensive effects. Selective blockade of
Also, measurement of atherosclerosis progression (via AT1 receptors suppresses AngII-induced vasoconstriction, and
intravascular ultrasound) demonstrated significantly less ARBs are at least as effective as other antihypertensive drug
progression in the amlodipine group for patients with SBP classes, including ACE inhibitors, with an excellent tolerabil-
greater than the mean (P = 0.02 vs placebo). The correlation ity profile.61 These agents have also been shown to provide
between BP lowering and progression of atherosclerosis was both cardiovascular outcomes benefit and renoprotective
not statistically significant. effects.7,9,10,23,25,62,63 The newer ARBs, including olmesartan

© Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 29
 Suzanne Oparil and Michael Weber

Table 2. Potential Benefits of Combining Antihypertensive Agents with Complementary Mechanisms into a Fixed-Dose Formulation
Benefit Reason(s)
• More effective than monotherapy and at least as effective as • Combination blocks more than one pathophysiologic
free combination of same agents53,55 pathway
• More rapid achievement of goal BP compared with • Greater antihypertensive efficacy
monotherapy59
• Lower rate of adverse events21,22,55,58 • Action of one agent ameliorates adverse effects of
the other
• Less need to modify antihypertensive regimen57 • Target BP reached more quickly
• Lower overall cost56,57 • Lower prescription costs; fewer physician visits
because lower need for regimen modifications
• Improved compliance53,54 • Simpler dosing regimen and reduced pill burden

Abbreviation: BP, blood pressure.

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medoxomil and telmisartan, appear to be more effective in peripheral vasodilation and BP lowering.73,74 Compared
in reducing BP than the older ARBs valsartan and losartan with other antihypertensive drug classes, CCBs have at least
potassium.64 Although the effects may not be consistent across comparable BP-lowering efficacy.75
the class,65–68 some ARBs have also been shown to have Amlodipine is a long-acting third-generation CCB that
antioxidant and anti-inflammatory effects. For example, in the has been very well studied in patients with hypertension.76,77
European Trial on Olmesartan and Pravastatin in Inflammation Calcium channel blockers are highly effective in reducing
and Atherosclerosis (EUTOPIA), 6 weeks of treatment with the risk of stroke in patients with hypertension.29 This may
olmesartan 20 mg/day significantly reduced levels of high- be at least partially explained by their effect on slowing the
For personal use only.

sensitivity C-reactive protein (CRP), tumor necrosis factor-α, progression of carotid intima-media thickening.78 A recent
interleukin-6, and monocyte chemoattractant protein-1 meta-analysis has shown that amlodipine reduces the risk of
(P ⬍ 0.05 vs baseline).65 Angiotensin receptor blockers stroke and MI to a greater extent than other antihypertensive
have consistently shown significantly greater regression of agents.79 Common AEs associated with amlodipine adminis-
carotid atherosclerosis compared with atenolol, for a similar tration are attributable to its arteriolar dilator properties, ie,
reduction in BP. This has been demonstrated with losartan edema, flushing, dizziness, and palpitations.80
in the LIFE study,69 with irbesartan in the Swedish Irbesartan
Left Ventricular Hypertrophy Investigation versus Atenolol Therapeutic Benefits of CCB/ARB
(SILVHIA) study,70 and with olmesartan medoxomil in Combination Therapy
the Multicentre Olmesartan Atherosclerosis Regression Combining a CCB with an ARB has a number of important
Evaluation (MORE) study.71 clinical benefits (Figure 1). Firstly, the administration of a
CCB with an ARB has the general therapeutic advantage
CCB Monotherapy of combining 2 agents with different and complementary
Calcium channel blockers (also known as calcium mechanisms of action as recommended by the Seventh Report
antagonists) decrease cellular calcium entry, ultimately of the Joint National Committee on Prevention, Detection,
resulting in vasodilation. Calcium plays an important role Evaluation, and Treatment of High Blood Pressure (JNC 7)
in cellular regulation, function, and communication, stimu- guidelines. Specific benefits include greater efficacy through
lating secondary messenger systems and cellular responses additive BP-lowering effects across a range of patient sub-
including contraction of cardiac and vascular smooth muscle populations and a lower incidence of AEs. For example,
cells.72 Calcium channel blockers can be divided into 1 of 2 data from a study by Morgan et al showed that a CCB/ARB
categories based on their chemical structure, ie, dihydropyri- combination resulted in an additive BP-lowering effect and
dines and nondihydropyridines, with dihydropyridines being fewer side effects in an elderly population with systolic
the more potent vasodilator. Dihydropyridine CCBs are very hypertension compared with CCB monotherapy.81
effective antihypertensive agents that work by antagonism As mentioned above, the complementary mechanisms of
of vascular L-type calcium channels. Inhibition of the influx action of CCBs and ARBs results in enhanced BP-lowering
of calcium ions into vascular smooth muscle cells results efficacy. Administration of a dihydropyridine CCB produces

30 © Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 ARB and CCB Combinations: A New Strategy

Figure 1. Complementary mechanisms by which CCBs and ARBs lower BP.

Calcium Channel Blocker Angiotensin Receptor Blocker

Mechanism of Action Mechanism of Action

Ca2+ Angiotensin II
CCB
ARB

L-type Ca2+ Channel

AT1 AT2
Increased
Additive actions Vasodilation
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Increased
Arterial vasodilation Decreased
Vasoconstriction
Aldosterone secretion
Catecholamine release

INCREASED
BP-LOWERING
EFFICACY
Decreased BP Decreased BP
For personal use only.

Abbreviations: ARBs, angiotension receptor blockers; AT1, angiotensin II receptor type 1; AT2, angiotensin II receptor type 2; BP, blood pressure; Ca, calcium; CCBs,
calcium channel blockers; MOA, mechanism of action.

vasodilation, activating both the RAAS (increasing renin In contrast to diuretics and β-blockers, neither CCBs nor
activity and AngII and aldosterone levels) and sympathetic ARBs have been shown to increase the risk of developing
nervous system. These actions result in reflex vasoconstriction new-onset diabetes.16,85,86 Calcium channel blockers are
and tachycardia.82 However, addition of a RAAS-blocking metabolically neutral87 and ARBs reduce or delay the risk
agent such as an ARB attenuates the CCB-induced activation of new-onset diabetes.88 Angiotensin receptor blockers may
of the RAAS, resulting in additive antihypertensive efficacy.46 improve insulin sensitivity by interfering with the adverse
Coadministration of these agents also enhances tolerability. metabolic effects of AngII activity and also may affect
Angiotensin receptor blockers can ameliorate the dose-related other pathways such as those mediated by the peroxisome
peripheral edema associated with dihydropyridine CCB proliferator-activated receptor gamma (PPARγ).89 PPARγ
administration. Calcium channel blockers dilate arteries to a target genes are involved in carbohydrate and lipid
greater extent than veins, thus increasing capillary pressure metabolism. Each of these agents also demonstrates benefits
and causing fluid to collect in interstitial spaces.83 Angiotensin associated with its respective drug class, eg, ARBs confer
receptor blockers reduce the lower extremity edema induced stroke protection,7 renal protection,62 and tolerability similar
by CCBs because they decrease fluid volume (via inhibition to placebo,90 without dose-related symptomatic and metabolic
of the RAAS) and dilate both arterial and venous capillary AEs.91 Calcium channel blockers are also beneficial in reducing
beds (Figure 2). 84 This balanced vasodilation reduces stroke79 and in treating angina92 and cardiac ischemia.93
capillary pressure and offsets some of the CCB-induced
edema. A recent study showed greater long-term efficacy Compelling Indications
and maintenance of BP control, as well as a 4-fold decrease Although the primary goal for administering an antihypertensive
in the long-term incidence of leg edema, with a CCB/ARB therapy is to achieve BP control and improve cardiovascular
combination compared with CCB monotherapy.20 and renal outcomes in patients with hypertension, an

© Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 31
 Suzanne Oparil and Michael Weber

Figure 2. Effects of CCB monotherapy and CCB/ARB combination therapy on peripheral edema.83

Capillary bed
Afferent arteriole Efferent arteriole

Normotensive

Hypertensive: constriction of blood vessels

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CCB treatment pressure in

capillaries

Preferential dilation
of afferent arteriole
Edema

normalized
CCB + ARB treatment pressure
gradient

Dilation of Dilation of
afferent arteriole efferent arteriole
For personal use only.

Abbreviations: ARB, angiotensin receptor blocker; CCB, calcium channel blocker.

Reprinted with permission from J Clin Hypertens (Greenwich). Sica DA. Calcium channel blocker-related peripheral edema: can it be resolved? 2003;5(4):291–294, 297.

accumulation of clinical evidence has shown that there in the United States (from 29% in 1999–2000 to 37% in
are also compelling indications for choosing specific 2003–2004).94 In recent years, it has been recognized that
drug classes as initial therapy.3,4 For example, compelling most hypertensive patients will require multiple drugs
indications for the use of an ARB include conditions such to control BP, and it was suggested that a readiness to
as heart failure, chronic kidney disease, or atrial fibrillation, use multiple drugs may explain increasing BP control.94
whereas for CCBs such indications would include LVH, However, BP control is only part of the clinical equation
ISH, or angina. Consequently, particular combinations of for measuring the success of an antihypertensive therapy.
agents can demonstrate additional benefits based on the Numerous outcomes studies have shown the benefits of
compelling indications for each individual drug class in the antihypertensive treatment in decreasing cardiovascular
combination. risk, morbidity, and mortality. The choice of specific agents
A comprehensive discussion of the specific evidence should be made in the context of their long-term effects on
behind recommendations for ARBs and CCBs as first-line cardiovascular events and on extending the length and quality
antihypertensive treatment choices in hypertensive patients of life in the individual patient.
with cardiovascular comorbidities is beyond the scope of In this light, CCB/ARB fixed-dose combinations are
this review. However, current major hypertension guidelines emerging as a rational and convenient treatment option.
list the compelling indications for using these drug classes Recently, the Food and Drug Administration (FDA) approved
(Table 3).3,4 the first 2 CCB/ARB fixed-dose combination therapies:
a combination of amlodipine plus valsartan (Exforge®,
Current Development of CCB/ARB Novartis, East Hanover, NJ) received FDA approval in
Fixed-Dose Combinations June 2007 and a combination of amlodipine plus olmesartan
Data from the National Health and Nutrition Examination medoxomil (Azor®, Daiichi Sankyo, Inc., Parsippany, NJ)
Survey (NHANES) show that BP control rates are improving received FDA approval in September 2007.

32 © Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 ARB and CCB Combinations: A New Strategy

Table 3. Compelling Indications for Using ARBs or CCBs as amlodipine alone (Figures 4A–C, 5A–C).21,22 In addition,
Outlined in US and European Guidelines3,4 the study with amlodipine/olmesartan medoxomil also
US Guidelines3 European Guidelines4 reported the proportion of patients achieving BP goals,
ARBs • Heart failure • Heart failure with between 42.5% and 53.2% of patients achieving JNC
• Diabetes • Post-MI 7 targets with the currently approved dosages.22 In all stud-
• Chronic kidney • Diabetic nephropathy ies, the percentage of patients achieving DBP ⬍ 90 mm Hg
disease • Proteinuria/microalbuminuria was significantly higher with the combinations than with
• LV hypertrophy corresponding monotherapies or placebo.21,22 The anti-
• Atrial fibrillation hypertensive efficacy of both amlodipine/ARB combina-
• Metabolic syndrome tions has also been demonstrated in subgroups of patients
• ACE inhibitor-induced cough whose hypertension is sometimes difficult to treat, such
CCBs • High coronary Dihydropyridines as black patients, elderly patients, and those with Stage 2
disease risk • ISH (elderly) hypertension.22,58,95–97 Amlodipine plus valsartan has proven
Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 04/21/15

• Diabetes • Angina pectoris to be at least as effective as the combination of an ACE

• LV hypertrophy inhibitor plus hydrochlorothiazide.98
• Carotid/coronary atherosclerosis The amlodipine/ARB combinations were well tolerated,
• Pregnancy with no unexpected safety concerns. In general, the incidence
• Hypertension in blacks of peripheral edema was lower with combination therapy
Nondihydropyridines than with amlodipine monotherapy.21,22,99
• Angina pectoris
• Carotid atherosclerosis Conclusion
• Supraventricular tachycardia Faced with an extensive choice of combination therapies for
For personal use only.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor their patients, physicians would like to base their decisions
blocker; CCB, calcium channel blocker; ISH, isolated systolic hypertension; LV, left on available evidence. Published outcomes studies support
ventricular; MI, myocardial infarction.
the use of combinations comprising CCBs and agents that
block the RAAS pathway. Calcium channel blocker and
ACE inhibitor combinations improve outcomes but are also
Three factorial-design studies have been undertaken associated with side effects that may reduce compliance in
in relation to ARBs in combination with a CCB. Two of the long term. In both arms of the ACCOMPLISH study
these studies involved amlodipine and valsartan,21 and the ACE inhibitor-related cough was frequently reported along
other involved amlodipine and olmesartan medoxomil with peripheral edema in the CCB/ACE inhibitor arm.52
(Figures 3A–C).22 In the olmesartan medoxomil study, Combinations of CCBs and ARBs are effective and reduce
1940 patients were randomized to 1 of 12 treatment groups: side effects associated with their individual components
placebo, olmesartan medoxomil 10, 20, or 40 mg/day, but there are no outcomes studies. Thus the choice of
amlodipine 5 or 10 mg/day, or combination therapy with combination therapy has to be tailored to each patient’s
1 of the 6 possible combinations of active drug.22 In the individual needs.
first valsartan study, 1911 patients were randomized to 1 of The studies discussed within this article strongly support
15 groups: placebo, valsartan 40, 80, 160, or 320 mg/day, inclusion of ARBs, such as olmesartan medoxomil or valsar-
amlodipine 2.5 or 5 mg/day, or combination therapy with tan, and dihydropyridine CCBs, such as amlodipine, in anti-
1 of the 8 possible combinations of active drug. There were hypertensive drug regimens. In general, the pathophysiologic
6 treatment groups in the other valsartan study: 1250 patients heterogeneity of the hypertensive population and diverse
were randomized to placebo, valsartan 160 or 320 mg/day, mechanisms of the different antihypertensive drug classes
amlodipine 10 mg/day, or combination therapy with 1 of mean that no single drug or drug class will be ideal for
the 2 possible active drug combinations.21 Collectively, controlling BP and prevention of cardiovascular-related
these studies showed that, in patients with hypertension, morbidity and mortality in all hypertensive patients, so the
amlodipine/olmesartan medoxomil and amlodipine/valsartan choice of drugs should be influenced by the patient’s overall
combinations are associated with significantly greater risk profile. Administered together, dihydropyridine CCBs
reductions in both DBP and SBP than the relevant ARB or and ARBs represent a rational treatment strategy irrespective

© Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 33
 Suzanne Oparil and Michael Weber

Figure 3. Study designs of (A) Philipp et al study 1 (amlodipine/valsartan),21 (B) Philipp et al study 2 (amlodipine/valsartan),21 and (C) Chrysant et al study (amlodipine + olm-
esartan medoxomil).22

Baseline to Week 8

A Randomize to:
Placebo
MSDBP ≥ 90 mm Hg AML 2.5 mg/day
and < 110 mm Hg at AML 5 mg/day
pre-randomization 2-week 2- to 4-week VAL 40 mg/day
and ≥ 95 and washout Single-blind VAL 80 mg/day
< 110 mm Hg at run-in VAL 160 mg/day
randomization visit; VAL 320 mg/day
≤ 10 mm Hg AML/VAL 2.5/40 mg/day
Placebo
difference between AML/VAL 2.5/80 mg/day
pre-randomization AML/VAL 2.5/160 mg/day
and randomization AML/VAL 2.5/320 mg/day
visit AML/VAL 5/40 mg/day
AML/VAL 5/80 mg/day
Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 04/21/15

AML/VAL 5/160 mg/day

AML/VAL 2.5/160 mg/day (1 wk) 5/320 mg/day

Screening Double-blind phase

Baseline to Week 8
B

MSDBP ≥ 90 mm Hg Randomize to:

and < 110 mm Hg at Placebo
For personal use only.

pre-randomization 2-week 2- to 4-week AML 10 mg/day

and ≥ 95 and washout Single-blind VAL 160 mg/day
< 110 mm Hg at run-in VAL 320 mg/day
randomization visit; AML/VAL 10/160 mg/day
≤ 10 mm Hg Placebo AML/VAL 5/160 mg/day (1 wk) → 10/320 mg/day
difference between
pre-randomization
and randomization
visit

Screening Double-blind phase

Baseline to Week 8 Week 8 to 52

C
Randomize to: Starting dose:
Placebo AML 5 + OM 40 mg/day
AML 5 mg/day Titration sequence if BP
AML 10 mg/day not controlled
MSDBP ≥ 95 mm Hg Approximate OM 10 mg/day (< 140/90 mm Hg or
and ≤ 120 mm Hg; 2-week OM 20 mg/day < 130/80 mm Hg for
≤ 10 mm Hg washout OM 40 mg/day patients with diabetes):
difference between AML 5 + OM 10 mg/day
pre-randomization AML 5 + OM 20 mg/day AML 10 + OM 40 mg/day
and randomization AML 5 + OM 40 mg/day
Then: AML 10 + OM 40 +
visit AML 10 + OM 10 mg/day
HCTZ 12.5 mg/day
AML 10 + OM 20 mg/day
AML 10 + OM 40 mg/day Then: AML 10 + OM 40 +
HCTZ 25 mg/day

Back titration available

Screening Double-blind phase Open-label extension

Abbreviations: AML, amlodipine; HCTZ, hydrochlorothiazide; MSDBP, mean seated diastolic blood pressure; OM, olmesartan medoxomil; VAL, valsartan.

34 © Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 ARB and CCB Combinations: A New Strategy

Figure 4. Reductions in systolic blood pressure (SBP) in 3 factorial studies involving angiotensin receptor blockers (ARBs) and amlodipine: (A) Philipp et al study 1 (amlodipine/
valsartan),21 (B) Philipp et al study 2 (amlodipine/valsartan),21 and (C) Chrysant et al study (amlodipine + olmesartan medoxomil).22

A
*†
22.7 *†
*† 20.8
*†
19.5 19.6
25 †
*† 15.1

SBP reduction (mm Hg)

†
18.3
16.7 17.0 *†
20 15.5

12.4
15 15.7 15.1
12.9
11.8
10 5
g)
(m
5
6.7
2.5 ose
d
ine
0
0
lo dip
Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 04/21/15

320 160 80 40 0 Am
Valsartan dose (mg)

B
*† *†
28.4 27.8
24.1
30
SBP reduction (mm Hg)

25

20
For personal use only.

19.8 20.2

15
12.9
10 10 mg)
e(
os
5
n ed
0 ipi
0 od
320 160 0 Aml
Valsartan dose (mg)

C
‡§ ‡§
28.5 28.1 ‡§

24.8
35 ‡§
SBP reduction (mm Hg)

‡§ ‡§
30 25.1 18.9
22.6 22.6
25
20 14.3

15 15.4
12.8 10 )
10 10.9 ( mg
5 se
5 do
ne
2.8 0 ipi
0 lod
40 20 10 0 Am
Olmesartan dose (mg)

Least-squares mean values reported for all 3 studies.

*P ⬍ 0.05 vs the same dose of ARB monotherapy; †P ⬍ 0.05 vs the same dose of amlodipine monotherapy; ‡P ⬍ 0.0005 vs the same dose of ARB monotherapy; §P ⬍ 0.0005
vs the same dose of amlodipine monotherapy.
Figure adapted from Clinical Therapeutics.21 Philipp T, Smith TR, Glazer R, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies
evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. 2007;
29(4):563–580. Copyright 2007, with permission from Excerpta Media, Inc.

© Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 35
 Suzanne Oparil and Michael Weber

Figure 5. Reductions in diastolic blood pressure (DBP) in 3 factorial studies involving angiotensin receptor blockers (ARBs) and amlodipine: (A) Philipp et al study 1 (amlodipine/
valsartan),21 (B) Philipp et al study 2 (amlodipine/valsartan),21 and (C) Chrysant et al study (amlodipine + olmesartan medoxomil).22

A *†
15.9 *† *† *†
14.2 14.5 14.6
†

14.2 *† *† 11.5
16 13.3 13.4
DBP reduction (mm Hg) 14
13.4 10.8
12 9.3
11.0
10 9.7 10.1

8
6.8 5
6 )
( mg
4 2.5 o se
d
2
i p ine
0
0 lod
Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 04/21/15

320 160 80 40 0 Am
Valsartan dose (mg)

B
*†
*†
18.6
17.6
20 15.6
18
DBP reduction (mm Hg)

16
14
For personal use only.

13.3 13.3
12
10
8 8.8
6 10 mg)
e(
4 d os
2 ne
0 ipi
0 od
320 160 0 Aml
Valsartan dose (mg)

C
‡§

19.4 ‡§
‡§
17.7
16.7
‡§
20 16.3 ठठ13.3
DBP reduction (mm Hg)

14.6 14.3

15
10.0

10.9
10 9.9
8.8
10
g)
5 e (m
3.5
5
dos
ip ine
0
0 lod
40 20 10 0 Am
Olmesartan dose (mg)
Least-squares mean values reported for all 3 studies.
*P ⬍ 0.05 vs the same dose of ARB monotherapy; †P ⬍ 0.05 vs the same dose of amlodipine monotherapy; ‡P ⬍ 0.0005 vs the same dose of ARB monotherapy; §P ⬍ 0.0005
vs the same dose of amlodipine monotherapy.
Figure adapted from Clinical Therapeutics.21 Philipp T, Smith TR, Glazer R, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies
evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. 2007;
29(4):563–580. Copyright 2007, with permission from Excerpta Media, Inc.

36 © Postgraduate Medicine, Volume 121, Issue 2, March 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 ARB and CCB Combinations: A New Strategy

of patient age, gender, or ethnicity, and in the presence of 8. Turnbull F, Neal B, Algert C, et al; Blood Pressure Lowering Treatment
Trialists’ Collaboration. Effects of different blood pressure-lowering
most comorbid indications. Fixed-dose combination tablets regimens on major cardiovascular events in individuals with and
comprising the dihydropyridine CCB amlodipine and an without diabetes mellitus: results of prospectively designed overviews
ARB (olmesartan medoxomil or valsartan) bring together 2 of randomized trials. Arch Intern Med. 2005;165(12):1410–1419.
9. Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and
distinct and complementary mechanisms of action, resulting independent effects of agents that inhibit the renin-angiotensin system.
in improved BP control and potential for improved target J Hypertens. 2007;25(5):951–958.
10. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens
organ protection relative to either class of agent alone. to lower blood pressure on major cardiovascular events in older
and younger adults: meta-analysis of randomised trials. BMJ.
Conflict of Interest Statement 2008;336(7653):1121–1123.
11. Ingelsson E, Gona P, Larson MG, et al. Altered blood pressure
Suzanne Oparil, MD discloses conflicts of interest with progression in the community and its relation to clinical events. Arch
Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Intern Med. 2008;168(13):1450–1457.
12. Williams B, Lindholm LH, Sever P. Systolic pressure is all that matters.
Bristol-Myers Squibb, Daiichi Sankyo, Inc., Forest Lancet. 2008;371(9631):2219–2221.
Laboratories, GlaxoSmithKline, Novartis, Merck and Co., 13. Mancia G, Grassi G. Systolic and diastolic blood pressure control in
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Inc., Pfizer, sanofi-aventis, and The Salt Institute. Michael A. antihypertensive drug trials. J Hypertens. 2002;20(8):1461–1464.
14. Nash DT. Systolic hypertension. Geriatrics. 2006;61(12):22–28.
Weber, MD discloses conflicts of interest with Boehringer 15. Waeber B, Mourad JJ. Targeting systolic blood pressure: the key to
Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Inc., controlling combined systolic/diastolic hypertension. Am J Hypertens.
2006;19(9):985–986.
Forest Pharmaceuticals, Gilead, GlaxoSmithKline, Novartis, 16. Dahlof B, Devereux RB, Kjeldsen SE, et al; LIFE Study Group.
sanofi-aventis, and Takeda. Cardiovascular morbidity and mortality in the Losartan Intervention
For Endpoint reduction in hypertension study (LIFE): a randomised
trial against atenolol. Lancet. 2002;359(9311):995–1003.
Acknowledgments 17. Prevention of stroke by antihypertensive drug treatment in older
The preparation of this article was supported by Daiichi persons with isolated systolic hypertension. Final results of the Systolic
Hypertension in the Elderly Program (SHEP). SHEP Cooperative
Sankyo, Inc. We thank Alan J. Klopp, PhD, for providing Research Group. JAMA. 1991;265(24):3255–3264.
For personal use only.

editorial assistance in the preparation of this review. 18. Dahlof B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention
of cardiovascular events with an antihypertensive regimen of amlodipine
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