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Core Evidence 2009:4 1–11
Core Evidence
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Exforge® (amlodipine/valsartan combination)
in hypertension: the evidence of its therapeutic
impact
Jean-Marie Krzesinski1
Eric P Cohen2
1Division of Nephrology/Transplantation,
University of Liège – Sart Tilman,
Belgium; 2Nephrology Division, Medical
College of Wisconsin, Milwaukee,
Wisconsin, USA
Correspondence: Jean-Marie Krzesinski
Division of Nephrology/Transplantation,
University of Liège-Sart Tilman,
PO Box 4000 Liège, B35 Belgium
Email jm.krzesinski@chu.ulg.ac.be
Introduction: Hypertension is an important risk factor for cardiovascular disease and its
management requires improvement. New treatment strategies are needed.
Aims: This review analyses one of these strategies, which is the development of effective
and safe combination therapy. Indeed, at least two antihypertensive agents are often needed to
achieve blood pressure control. Exforge® (Novartis) is a new drug combination of the calcium
channel blocker, amlodipine, and the angiotensin II receptor blocker, valsartan.
Evidence review: The amlodipine/valsartan combination is an association of two well-known
antihypertensive products with specific targets in cardiovascular protection, namely calcium
channel blockade and antagonism of the renin-angiotensin-aldosterone system. This kind of
association, with neutral metabolic properties and significant antihypertensive efficacy, could
be a useful new antihypertensive product. Currently available data have shown that this new
combination is well-tolerated and effective even in severe hypertension.
Clinical value: Clinical trials are ongoing for further assessment of the efficacy, compliance,
and safety of this combination and its congeners. No data exist to prove that the amlodipine/
valsartan combination is better than other antihypertensive strategies for cardiovascular or renal
protection, but some trials with other combination therapies show such potential advantage.
Keywords: arterial hypertension, treatment, combination therapy, calcium channel blocker,
amlodipine, angiotensin II receptor blocker, valsartan
Core evidence clinical impact summary for Exforge® (amlodipine/valsartan) in
hypertension
Outcome measure Evidence Implications
Patient-oriented evidence
Improvement in cardiovascular
morbidity and mortality
Clear (for each
agent alone)
Trials on both drugs as monotherapy have
shown either direct protection against
cardiovascular events or surrogate benet
by reducing blood pressure
Reduced atrial brillation Moderate Reduced recurrent atrial brillation
Patient acceptability Limited Low rate of adverse events
Improvement in quality of life Moderate Less edema, better tolerability
Disease-oriented evidence
Effective control of blood
pressure
Clear
Combination more effective than
monotherapy
Economic evidence
Cost effectiveness as
antihypertensive therapy
Limited
No studies to show the long term
efcacy for lowering blood pressure and
decreasing morbidity or mortality in spite
of higher cost of the xed combination
Number of times this article has been viewed
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Scope, aims, and objectives
This article discusses the place of combination therapy in
arterial hypertension (HTN) and concentrates on the potential
advantage of Exforge® (Novartis), the first commercially
available combination of a dihydropyridine calcium channel
blocker (CCB) (amlodipine) and an angiotensin II receptor
blocker (ARB) (valsartan). These are two of the most commonly
prescribed antihypertensive drugs in their classes. Their
combination aims to secure better control of blood pressure
(BP) along with simultaneous cardiovascular and renal risk
reduction and few side effects. The scope of this article is in the
area of human hypertension and its treatment, with particular
focus on amlodipine, valsartan, and their combination.
Methods
An extensive literature search on amlodipine/valsartan was
conducted as follows.
Peer reviewed articles and abstracts (English-language
only) were identified from Medline, EMBASE, BIOSIS,
the National Institute for Health and Clinical Excellence
(NICE), and the York University Centre for Reviews and
Dissemination Database (http://www.crd.york.ac.uk/
crdweb/) using the terms “antihypertensive combination,
amlodipine, valsartan, CCB, and ARB.”
PubMed was used for the terms “amlodipine and
valsartan” with the search limits “clinical trial, meta-analysis,
practice guideline, randomized controlled trial, hypertension
treatment”, and English language only. Forty-nine records
were found, of which 11 were reviews on the topic. Only
15 of the records appeared relevant to the combination of
both drugs. The search also produced records of trials that
compared amlodipine and valsartan; they were included in
this review to substantiate the evidence of the efficacy and
tolerability of each individual drug.
A search on the site of the European Medicines Agency
(EMEA), (www.emea.europa.eu), was also done with
Exforge as the topic searched. EMBASE and BIOSIS
were also consulted with the same search keywords, but
the records that were identified were already found in the
PubMed results. For NICE, no records were found. From
the York University Centre for Reviews and Dissemination
Databases, four records were identified, but for the purpose
of the present article, none were judged relevant. The results
of the literature search are shown in Table 1.
The main aims of all the studies selected were the efficacy
of antihypertensive effect and tolerability.
Most of these articles were the results of prospective,
randomized, either double-blind or open-label multicenter
studies, placebo-or active-treatment controlled, with samples
including men and women of a mean age around 60 years.
Additional references were obtained from the authors’ files.
Disease overview
Hypertension is a well-known risk factor for cardiovascular
disease, affecting more than 1 billion people worldwide.
Recently, Lawes et al1 summarized the worldwide burden
of disease attributable to high BP and found that 7.6 million
premature deaths and 92 million disability-adjusted life years
were attributed to high BP. Half of strokes and ischemic heart
disease worldwide were attributable to high BP. About half
this burden was in people with HTN, the remainder was in
those with lesser degrees of high BP. The prevalence of HTN
varies according to the country, with a range between 5% in
rural India to 70% in Poland.2
The economic impact of HTN is enormous, representing
US$24 billion in the US in 1995, and more than one-third
of that cost is due to drug treatment.3 Further, Goetzel et al4
suggest that HTN carries a high per-employee cost, even
higher than that of heart disease, depression, or arthritis.
Despite the effort to increase the awareness and treatment
of HTN, recent data for the US show that only 39% of patients
have their BP adequately controlled.5 In Europe, BP control
was achieved in only 12% of Polish hypertensives and up
to 36% of Spanish hypertensives.6 These statistics show the
need to change the landscape of BP management.
Current therapy options
The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of HTN7
Table 1 Evidence base included in the review
Category Number of records
Full papers Abstracts
Initial search 49 12
Records excluded 34
Records included 15 1
Additional studies identied 46 1
Total records included 61
Level 1 clinical evidence 10
(systematic review, meta
analysis)
Level 2 clinical evidence (RCT) 37
Level 3 clinical evidence 11 2
trials other than RCT
Economic evidence 3
Notes: For denitions of levels of evidence, see Core Evidence website (http://www.
dovepress.com/core-evidence-journal).
Abbreviation: RCT, randomized controlled trial.
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recommends a BP treatment goal of 140/90 mmHg for most
patients and 130/80 mmHg for those with diabetes mellitus
or chronic kidney disease. These targets conform to the more
recent European guidelines.8 These target BP goals should
reduce the long-term risk of cardiovascular disease and death.
In most hypertensive subjects, optimal control of the BP will
depend on effective and trouble-free medication.
Choosing the appropriate medications for individual
patients and adherence to these regimens are the key
factors for successful treatment of HTN. Diuretics remain
an important drug class with a large amount of evidence
for their efficacy. They are also inexpensive, but they have
potential adverse metabolic side effects. When used alone,
they are often stopped during the first year of their use, with
a one-year persistence rate of only 34%.9
Medications that act on the renin-angiotensin-aldosterone
system (RAAS) are now frequently prescribed because they
block important renal mechanisms that play a crucial role
in salt and volume homeostasis, and because of additional
extrarenal actions. They also reduce major cardiovascular
events in high-risk patients.10,11
For their part, calcium antagonists have regained popularity
in spite of worries about short-acting calcium antagonists.12
They have been used in many recent hypertension treatment
trials (eg, ALLHAT, VALUE, ASCOT) and may have utility
because of their neutral metabolic effects and also potential
antiatherosclerotic properties.
The current market share in the US for angiotensin-
converting enzyme (ACE) inhibitors and angiotensin-
receptor blockers (ARBs) is near 50%, while that of calcium
blockers is 20%.13 These are thus major drug classes for the
treatment of hypertension.
Unmet needs
Of the unmet medical needs in the management of HTN, there
is strong evidence to support simpler treatment regimens that
effectively control BP and that are still used by patients in
the long term because they are well tolerated.
Major trials, such as LIFE, ASCOT, and VALUE, have
shown that up to 80% of hypertensive patients need more
than one antihypertensive agent to get to and maintain their
BP goal. In the Hypertension Optimal Treatment study
(HOT), an average of 3.3 drugs were required to attain a
diastolic BP goal of 80 mmHg.14 Furthermore, the JNC7
recommendations state that “when BP is more than 20 mmHg
above systolic goal or above 10 mmHg diastolic goal,
consideration should be given to initiate with 2 drugs, either
as separate prescriptions or in fixed-dose combinations”.7
For those with reduced kidney function, the number of
medications needed to control BP rises as the glomerular
filtration rate (GFR) falls15 (Figure 1). Combination therapy
thus appears to be an attractive option for the 10% of
hypertensives who have stage II hypertension or more and
for those with chronic kidney disease and HTN.
Combination therapy could improve adherence to therapy
(“compliance”), due to reduction of the daily pill intake.16
Better adherence to HTN therapy could enhance individual
and population-level BP control. Some authors consider
that improvement of treatment compliance could yield the
greatest gain both in cost effectiveness and efficiency.17
In addition, BP has multiple regulatory pathways, including
the sympathetic nervous system, RAAS, and total body sodium.
Combination therapy relies on efficient and complementary
blockade of more than one of these, by separate and different
agents, and without resorting to a high dose of either. This was
shown by Andreadis et al18 who noted that low-dose ARBs and
CCBs had comparable effects in patients with grade I and II
HTN. In patients who were not controlled by low-dose mono-
therapy, low-dose combination therapy using agents blocking
different BP control pathways was more effective than was
high-dose monotherapy. Such a complementary advantage
was also reported by Stergiou et al19 who showed that adding
amlodipine or chlorthalidone to valsartan was more effective
than add-on therapy with benazepril.
Additional reasons for inadequate BP control could derive
from a suboptimal approach by physicians.20 Yet the role
of BP reduction in cardiovascular risk prevention is quite
clear, and a greater reduction in BP yields greater reduction
GFR (mL/min)
SBP-138-144
*
SBP-128-136
SBP-136-142
SBP-138-141
SBP-140-142
Number of BP medications
90–99 80–89 60–69 50–59 40–49
4.5
3.5
2.5
1.5
0.5
Figure 1 Relationship between level of baseline GFR and number of antihypertensive
medications needed to achieve BP goal. SBP reects BP ranges in the studies reviewed.
Copyright © 2005. Adapted from studies reviewed in 2004 Disease Outcomes Quality
Initiative-Blood Pressure (DOQI – BP) guidelines. Black squares are diabetic studies;
black diamonds are nondiabetic studies. This gure is reprinted by permission of the
American Society of Nephrology and by Dr George Bakris, from NephSAP 4:101,
2005, the Nephrology Self-Assessment Program published by the American Society
of Nephrology.
Abbreviations: BP, blood pressure; GFR glomerular ltration rate; SBP, systolic BP.
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in risk.21,22 Getting to goal BP may require more than one
antihypertensive drug.
Over the years, several combinations with fixed-dose
drugs have been developed and shown to be effective. Some
have had specific indications based on hemodynamic and
metabolic criteria.23 These have included:
1. Thiazide diuretics and either beta blocker, ACE inhibitor,
or ARB, for uncomplicated HTN, for heart failure, or left
ventricular hypertrophy, respectively.
2. CCB and betablocker for HTN and coronary artery dis-
ease, or CCB and ACE inhibitor for HTN with kidney
disease or with high cardiovascular risk.
The side effects of diuretics, beta blockers, and ACE
inhibitors may limit the benefit of combinations using these
drugs and also decrease patient adherence to treatment.
The combination of amlodipine/valsartan has been
developed to try to improve efficacy and tolerability and thus
deliver the promise of better treatment. Both amlodipine and
valsartan have a favorable side effect profile, so their combi-
nation is attractive. Both drugs act on different mechanisms
of hypertension and thus could be complementary in the
benefit that they offer.
Pharmacodynamic prole
The CCB is effective in low-renin HTN and the ARB in
high-renin HTN, thus combining both classes could improve
the success of treatment. Both drugs have generally neutral
effects on metabolic parameters such as blood lipid levels
and insulin sensitivity, although plasma norepinephrine
levels are increased with amlodipine therapy. This effect is
not attenuated when combined therapy is used.24
Amlodipine
Amlodipine is a third generation CCB that acts on specific
high-affinity binding sites in the L-type calcium channel
complex of vascular smooth muscle cells. This causes vaso-
dilatation of arteries and arterioles by reducing the influx of
calcium into vascular smooth muscle. Calcium channels play
important roles in cardiac contractility and electrophysiology
but much higher concentrations of amlodipine are needed
in vitro to influence those functions.25 Its protein binding
and elimination kinetics help to explain its long duration
of action. Amlodipine produces a gradual onset of action
and a prolonged effect that enables once-daily dosing. This
explains the high trough-to-peak ratio of the antihypertensive
effect and reduced variability of BP with once-daily admin-
istration. The vasodilatation can induce flushing, headache,
and ankle edema.
Experimental data indicate that amlodipine has the
potential to produce an antiatherosclerotic effect in humans,
in part due to antioxidant effect or its endothelin antago-
nistic properties. Amlodipine can improve endothelium
dysfunction, thanks to reduction of calcium influx, and, by
its R-enantiomer, facilitate the action of nitric oxide or its
production. In kidney transplant patients, amlodipine can also
increase the glomerular filtration rate and renal blood flow,
and decrease plasma uric acid concentration.7
Valsartan
Valsartan is a specific blocker of the binding of angiotensin II
to the AT1 receptor, blocking the vasoconstrictor effect and
the adrenal aldosterone secretion induced by this peptide.
Valsartan does not significantly increase bradykinin
concentrations, in contrast to ACE inhibitors. It reduces BP
without increasing the heart rate. It has a 24-hour effect on
BP control due to blockade of the AT1 receptor, but there may
be an increase in angiotensin II concentration acting on AT2
receptors, with consequent vasodilatation. In the kidneys,
especially at the renal tubular level, the stimulation of AT2
could mediate natriuresis which could also contribute to the
antihypertensive effect.26,27 Stopping valsartan intake is not
associated with rebound of the BP level.
Pharmacokinetic prole
Limited data are available on the pharmacokinetic proper-
ties of fixed-dose combinations of amlodipine/valsartan. No
drug interaction studies have been conducted with fixed-dose
combinations and other drugs.
Amlodipine
When orally absorbed, peak plasma concentrations of
amlodipine are reached in 6–8 hours and its bioavailability
is 64–80%. It has an inherently long half-life of between 30
and 50 hours with gradual onset of action and a prolonged
effect, which is useful for once-daily dosing, and no rebound
of HTN when the drug is abruptly stopped. It has 98% plasma
protein binding and is extensively metabolized in the liver
to inactive metabolites.28,29
Amlodipine can interfere with the metabolism of
some drugs through the enzyme CYP3A, because this
enzyme constitutes the pathway of its catabolism. Any
substance that induces or inhibits CYP3A could affect
amlodipine concentration, and amlodipine could also modify
the concentration of the coadministered drug.30 An increase
in cyclosporin concentrations may occur but is of limited
clinical significance.
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Valsartan
Peak plasma concentrations of valsartan are reached 3 hours
after oral administration. Its bioavailability is 23% and this
is not influenced by food. Its half-life is 6 hours and its
plasma protein binding is over 95%. Like amlodipine, it is
metabolized by the liver. Valsartan is eliminated mainly as
unchanged drug in the faeces (83% of the dose) and urine
(13% of a dose). It is not metabolized by the CYP system
and thus has little interference with other drugs. In hepatic
failure its concentration is increased. In renal impairment,
its dosage does not need modification and it is not removed
by dialysis. Its main contraindication is pregnancy, because
antagonists of the RAAS may be teratogens. Valsartan can
worsen kidney function in patients with bilateral renal artery
stenosis, and in this condition of use requires surveillance of
serum potassium and creatinine.28,29
Clinical evidence with amlodipine
The long-acting third-generation dihydropyridine calcium
antagonist amlodipine is one of the most commonly used
antihypertensive agents, and is approved for the treatment
of HTN and angina at doses from 2.5 to 10 mg/day. It has
no effects on lipids or insulin sensitivity, but it can increase
plasma norepinephrine levels. It has been shown to activate
the sympathetic system during the day and to decrease the
parasympathetic activity during the night.31
Amlodipine has been studied in patients with coronary
artery disease and shows benefit compared with placebo
or enalapril in terms of cardiovascular events, with a trend
towards an antiatherosclerotic effect even in normotensive
patients who have coronary heart disease.32 It may exert a
preferential effect in lowering central aortic pressures.33
Amlodipine is not recommended as first-line treatment in
hypertensives with proteinuric renal disease because it may
aggravate proteinuria.34,35 It is possible that this is related to
an increase in glomerular capillary pressure that may occur in
patients taking amlodipine.36 Compared with RAAS blockers,
amlodipine use in proteinuric kidney disease was not as
useful in preventing renal disease progression.37,38
Clinical evidence with valsartan
Valsartan is an ARB that has been marketed for HTN since
1996. It is available in the US at 80–320 mg/day and in
Europe at 80–160 mg/day. Valsartan is approved for the
treatment of HTN, for congestive heart failure, and also for
postmyocardial infarction patients in some countries.
Valsartan has also been described as having antiinflammatory
properties reducing the high sensitivity C-reactive protein
level, as shown in the Val-MARC trial. However, this
antiinflammatory effect has not been confirmed in the VIVALDI
study comparing valsartan with telmisartan.39,40
Comparisons of amlodipine
and valsartan
Although not the focus of this review, some comparisons
of amlodipine and valsartan are relevant to the discussion of
the combination of both drugs.
Wogen et al41 compared patient adherence with amlodipine,
lisinopril, or valsartan therapy in people treated for HTN. In
a usual-care setting, patients receiving valsartan rather than
lisinopril or amlodipine appear to be more compliant with
treatment, due to less subjective side effects. Moreover,
Elliott et al42 reported that, probably for the same reasons,
the risk of discontinuation of four antihypertensive drugs
(hydrochlorothiazide, amlodipine, lisinopril, and valsartan)
was different. The lowest risk of discontinuation was seen with
the ARB, followed by the ACE inhibitor, then the CCB, with
the highest discontinuation rate being noted with the thiazide.
This could be explained by a superior tolerance profile of ARB
compared with the other antihypertensive classes.
For cardiovascular protection, an action on oxidative stress
may be beneficial. Dihydropyridine CCBs have antioxidant
and antiinflammatory effects that may be independent of their
BP-lowering action and that yield synergistic vasoprotective
activity with RAAS blockers.43 The reduction of oxidative
stress and plasma methyl arginine, an endogenous inhibitor
of nitric oxide synthase, has also been noted in patients
with chronic renal failure treated with either amlodipine or
valsartan.44 However, valsartan seems to be more effective
than amlodipine in restoring endothelial function and
decreasing oxidative stress in essential HTN.45
Clinical evidence with amlodipine/
valsartan combination
Exforge® is a fixed-dose combination of amlodipine, as the
besilate salt, and valsartan, in the form of film-coated tablets.
Fixed-dose combinations of amlodipine (5 or 10 mg) and
valsartan (160 or 320 mg) have been available in the US
and several countries in Europe since September 2007 for
once-daily oral administration in patients with HTN who
have not had an adequate response to amlodipine (or another
dihydropyridine CCB) or valsartan (or another ARB alone)
as monotherapy. Exforge® was recently approved by the
FDA as initial or first-line therapy in patients likely to need
multiple drugs to achieve their BP goals.
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There have been only a few studies testing this
combination of the two drugs. The addition of valsartan
80 mg/day to amlodipine 5 mg/day in patients not controlled
with amlodipine 5 mg alone has been shown to improve
exercise performance assessed by measurements of cardiac
output and total peripheral resistance at rest and at peak
exercise.46 As noted above, in hypertensives not controlled
with valsartan as monotherapy, a combination of amlodipine
and valsartan has been shown to be well-tolerated, safe, and
effective.19 Combination amlodipine/valsartan was very
effective in lowering BP in patients in whom monotherapy
with various other antihypertensives was incompletely
effective.47 In this study, a variety of drugs were used at base-
line as monotherapy before the use of amlodipine/valsartan.
Poldermans et al48 showed that amlodipine/valsartan com-
bination therapy was as effective in patients with stage II
hypertension as lisinopril/hydrochlorothiazide combination
therapy.
While several trials have been designed to test the
antihypertensive efficacy of this combination, very few
studies have been devoted to analyze its potential benefit in
terms of cardiovascular or renal protection. The particular
case of atrial fibrillation was tested by Fogari et al49 who
showed that amlodipine/valsartan combination therapy was
better than atenolol/amlodipine in preventing recurrent atrial
fibrillation in hypertensive diabetics, although comparisons
with an ACE inhibitor and a CCB or a diuretic would be more
appropriate comparators in this patient population.
Currently, no information on albuminuria is available for
the amlodipine/valsartan combination. Nonetheless, Fogari
et al50 showed that the amlodipine/telmisartan combination
has been very useful in decreasing urinary albumin excretion
in hypertensive diabetic patients with microalbuminuria. The
clinical development program for amlodipine/valsartan fixed
combination products has included bioequivalence studies
and phase III clinical efficacy/safety studies, including
placebo- and active-controlled studies to justify proposed
dosages. All of these studies showed efficacy in all grades of
HTN, as well as efficacy in nonresponders to monotherapy
or to previous combination therapy (Table 2).
To date, some clinical trials with combinations of both
drugs have been published, with a focus on BP control but
Table 2 Randomized trials with amlodipine/valsartan combination in hypertension
Trial Design Treatment Patients
Efcacy51,52 EMEA study
2201 + 2307
Multicenter, double-blind,
randomized, placebo-controlled,
parallel group
8 weeks of amlodipine 2.5, 5 mg;
valsartan 40, 80, 160, and
320 mg, all possible combina-
tions and placebo
1911 patients with mild-to-moderate
diastolic HTN
Efcacy51,52 EMEA study
2201 + 2307
Multicenter, double-blind,
randomized, active-controlled,
parallel group
8 weeks of amlodipine/valsartan
(5/160 mg and 10/160 mg)
compared with valsartan 160 mg
1250 patients with mild-to-moderate
diastolic HTN
Efcacy and safety in
severe HTN48 EMEA
study 2308
Multicenter, double-blind,
randomized, active-controlled,
parallel group
8 weeks of amlodipine/valsartan
(5/160 mg and 10/160 mg)
compared with valsartan 160 mg
947 adults with mild-to-moderate
HTN uncontrolled by valsartan
160 mg
Efcacy and safety
EX-FAST47 EMEA study
2401 mild-to-moderate
HTN
Multicenter, double-blind,
randomized, active-controlled,
parallel group
16 weeks of amlodipine 5 or
10 mg/ valsartan 160 mg compared
with previous monotherapy
894 patients receiving the
combination (443 with amlodipine
5 mg and 451 with amlodipine
10 mg) with mild-to-moderate HTN
uncontrolled by monotherapy
Efcacy and safety
EX-EFFeCTS study53
EMEA study 2403
Multicenter, double-blind,
randomized, active-controlled,
parallel group
8 weeks amlodipine/valsartan
vs amlodipine monotherapy in
systolic stage II HTN
646 patients with stage II and III HTN
receiving either the amlodipine 5 or
10 mg/valsartan 160 mg combination
(n = 322) or amlodipine monotherapy
5 or 10 mg (n = 324)
Nonresponder study
ExPress-C trial54
Open-label, simple arm 5 weeks amlodipine/valsartan
10/160 mg compared with
ramipril 5 mg/felodipine 5 mg
105 patients with stage II HTN
uncontrolled by ramipril/felodipine
after 5 weeks
Nonresponder study55
EXPRESS-M trial
Open-label, simple arm 8 weeks amlodipine/valsartan
compared with amlodipine or
felodipine monotherapy
181 patients stage II HTN
uncontrolled by CCB monotherapy
Abbreviations: CCB, calcium channel blocker; EMEA, European Medicines Agency; HTN, hypertension.
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without using home or ABPM, and only one study has been
published on systolic HTN.53 Several studies have shown
the efficacy of each component drug in reducing BP and
cardiovascular events, as reviewed above.
Published randomized studies
1. Combination therapy with amlodipine/valsartan has been
compared with that of amlodipine or valsartan monotherapy
in two large randomized double-blind, placebo-controlled
studies and their subgroup analyses.51,52 These studies
included 3161 patients with mild-to-moderate HTN. The
primary efficacy endpoint was the change from baseline
in mean sitting diastolic (D) BP at the end of the 8-week
study period. Secondary endpoints were the percentage of
patients achieving a DBP 90 mmHg or a 10 reduction
from baseline, and change of mean systolic (S) BP.
The efficacy of the combination was better than either mono-
therapy at the same dose. More than 80% of patients treated
with amlodipine/valsartan 5/80 mg, 5/160 mg, or 5/320 mg
met the criteria for response. This was also the case when
the amlodipine dose in the combination was 10 mg.
The same group51 showed that ∼50% of the patients
treated with the combination of amlodipine 10 mg and
valsartan 320 mg achieved the BP goal of 140/90 mmHg
at 2 weeks. The combination therapy was associated
with greater reductions in BP than each separate
monotherapy or placebo across all patient subgroups,
including those aged 65 years, black patients, and those
with stage II HTN.52
2. A large, randomized, double-blind, phase IIIb-IV trial
in almost 900 patients evaluated a direct switch to
amlodipine/valsartan 5/160 mg or 10/160 mg once daily in
patients whose BP was previously uncontrolled by mono-
therapy with various antihypertensive agents.47 Patients
whose BP was uncontrolled with the combination after 8–
12 weeks could receive diuretics. BP control was achieved
in 76% and 71 % of patients after 8 weeks of combination
with amlodipine/valsartan 10/160 mg or 5/160 mg, respec-
tively. For both dosage regimens, the magnitude of SBP
reductions was similar regardless of the class of antihy-
pertensive drug used prior to randomization.
3. Brachmann et al55 recently showed that the addition of
an ARB to CCB-based antihypertensive therapy may be
associated with enhanced efficacy and reduced risk of
adverse events. In this 8-week, open-label, single-arm trial,
the efficacy and tolerability of the combination of amlodipine
and valsartan was evaluated in patients not responding
adequately to treatment with amlodipine or felodipine
alone. Patients aged 18 years with moderate essential
hypertension (defined as mean sitting SBP 160 and
180 mmHg) were treated for 4 weeks with amlodipine
5 mg or felodipine 5 mg once daily. At week 4, patients
not adequately responding were treated for an additional
4 weeks with a fixed dose combination of once-daily
amlodipine/valsartan 5/160 mg. Of 214 patients treated
for 4 weeks with amlodipine 5 mg or felodipine 5 mg,
181 failed to achieve mean sitting SBP 140 mmHg.
These 181 nonresponders were treated for an additional
4 weeks with amlodipine/valsartan 5/160 mg: over half of
them achieved target BP level ( 140/90 mmHg).
4. Poldermans et al48 showed that better BP control was
achieved with the combination of amlodipine/valsartan
5/160 mg or 10/160 mg than with the combination of
lisinopril 10 or 20 mg and hydrochlorothiazide 12.5
or 25 mg in adult patients with stage II HTN. Mean sitting
SBP/DBP was reduced by 36/29 mmHg and 32/28 mmHg,
respectively, but this was not statistically significant.
Subgroup analyses showed that both combination
regimens reduced BP from baseline in two important
patient groups; those aged 65 years at baseline and those
with SBP 180 mmHg at baseline (ie, stage III HTN).
5. Trenkwalder et al54 tested the efficacy of treatment with
the combination of ramipril 5 mg and felodipine 5 mg.
In patients who were resistant to this combination, they
evaluated the efficacy of switching to amlodipine/valsartan
10/160 mg. The amlodipine/valsartan combination led to
a significant additional BP reduction, of 15 mmHg for
SBP and 7 mmHg for DBP (P 0.001). Moreover, there
was a better safety and tolerability profile for amlodipine/
valsartan compared with ramipril/felodipine.
6. Destro et al53 assessed the efficacy and safety of
amlodipine/valsartan versus amlodipine monotherapy
in patients with systolic stages II and III HTN (sitting
SBP between 160 and 200 mmHg) in a randomized,
double-blind, 8-week trial. A total of 646 patients were
enrolled, of whom 322 were treated with amlodipine/
valsartan 5/160 mg (group 1) and 324 were treated with
amlodipine 5 mg for 2 weeks (group 2). For the remainder
of the study, there was a dose increase to 10/160 mg in
group 1 and 10 mg in group 2. At week 4, if patients
were not controlled (SBP 130 mmHg), open label
hydrochlorothiazide 12.5 mg could be added.
At week 4, the change from baseline SBP was
significantly greater with amlodipine/valsartan compared
with amlodipine monotherapy (decrease in SBP of 30 mmHg
versus 24 mmHg; P 0.0001). By the end of the study,
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SBP was reduced from a baseline of 171 to 137 mmHg in
the amlodipine/valsartan arm compared with 145 mmHg in
the amlodipine treatment arm (P 0.0001). The difference
in response was similar whatever the subgroup analysis
(ie, the elderly, those with severe HTN, obese patients, or
those with diabetes mellitus).
Tolerability and safety
The most frequently reported adverse events with amlodipine/
valsartan were ankle edema, headache, nasopharyngitis,
upper respiratory tract infection, and dizziness. The aggregate
frequency of adverse events was not different for amlodipine
monotherapy (46%) as compared with amlodipine/valsartan
combination (44%) but was higher than that reported for
valsartan alone (40%).51 The frequency of ankle edema
was greatest with amlodipine alone (9%), followed by the
combination (5%), and was least common with valsartan
monotherapy (2%). For the placebo group, the frequency of
edema was 3%.51
Ankle edema was studied in detail by Fogari et al56
Objective ankle foot volume and pretibial subcutaneous
tissue pressure were masked endpoints after 6 weeks
of amlodipine monotherapy or amlodipine/valsartan
combination therapy. Ankle edema was most common in
those on amlodipine monotherapy, least common in those
on valsartan monotherapy, and of intermediate frequency
in those on combination therapy. The ankle edema with
CCB may be due to high capillary hydrostatic pressure from
precapillary vasodilatation. Several drug classes have relevant
venodilating potential, including ACE inhibitors, ARBs, and
nitrates. The use of valsartan, which has a mixed vasodilating
effect on arteriolar and venular sites, may decrease the post-
capillary pressure thereby normalizing transcapillary pressure
and reducing edema. Another mechanism explaining a less
frequent development of edema with the combination of
amlodipine and valsartan could be the natriuretic effect of
angiotensin blockade.
In the study published by Poldermans et al48 most of the
adverse events were not considered to be related to the study
drugs. Mild-to-moderate adverse events were reported in 41%
of patients treated with amlodipine/valsartan and 32% in
the group treated with lisinopril/hydrochlorothiazide. Headache
(11%) and peripheral edema (8%) were reported mainly in
the amlodipine/valsartan group whereas diarrhea and phar-
yngitis occurred mainly in the lisinopril/hydrochlorothiazide
group (6% for both). Cough occurred in 3% of those on
lisinopril, but in fewer than 2% of those in the amlodipine/
valsartan combination.
Economic evidence
In HTN without any other associated cardiovascular risk
factor, the treatment cost increases as the target for HTN
is lowered but this effect is attenuated when the population
tested is older or has higher cardiovascular risk. Cost effec-
tiveness may be better for older compared to younger people
and for higher starting levels of BP. Cost effectiveness of
treatment for HTN is also improved in secondary prevention
or in the presence of diabetes.57
The large majority of trials in the treatment of HTN have
shown that the benefit from the treatment correlates with
the decrease in BP. Recently some trials have suggested
a benefit in addition to the BP decrease when using CCB
and/or a blocker of the RAAS such as was observed in the
LIFE or ASCOT trials.58,59 However, the combination of
two blockers of the RAAS (ie, ACE inhibitor and ARB) has
not demonstrated such benefit. In the VALIANT study, the
combination of valsartan and captopril increased the rate of
adverse events.60 Similarly, in the Valsartan Heart Failure
Trial (Val-HeFT), the combination of valsartan and ACE
inhibitors or beta blocker was associated with a higher rate of
adverse events.61 In the ONTARGET trial, the combination
of ramipril and telmisartan conferred no additional benefit
compared with monotherapy in high cardiovascular risk
populations.11 Considering absolute cost, paying for
amlodipine and valsartan separately is cheaper, as shown in
Table 3. However, the problem of compliance is inversely
linked to the number of pills to be taken, which may cancel
that small cost advantage.16
Patient group/population
For the amlodipine/valsartan combination, the population
who may benefit from its use are those patients with stage II
or III HTN and those who have not sufficiently responded to
Table 3 Average wholesale price (AWP) for Exforge® and its separate
components
Drug AWP for 30 days ($US)
Amlodipine 5 mg 10.34
Amlodipine 10 mg 14.19
Valsartan 160 mg 58.56
Valsartan 320 mg 74.09
Exforge 5/160 mg 85.86
Exforge 5/320 mg 108.91
Exforge 10/160 mg 97.39
Exforge 10/320 mg 123.63
Notes: The AWP is a prescription drugs term referring to the average price at which
wholesalers sell drugs to physicians, pharmacies, and other customers.
Core Evidence 2009:4 9
Exforge® (amlodipine/valsartan)
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an antihypertensive monotherapy. An additional population
of interest is those with chronic kidney disease, especially
when the estimated GFR is less than 60 mL/min/1.73 m3.
No specific drug interaction studies have been conducted
with this combination, but interaction of the individual single
agents with other drugs exists and should be kept in mind
(see above).
In April 2008, the EMEA published information about the
avoidance of this drug combination throughout pregnancy.
Since the fourth of December 2007, the FDA has appoved
the use of valsartan for treating children with HTN, so
amlodipine/valsartan could now be used in patients under
18 years of age but not in patients allergic to amlodipine or
other medicines in the dihydropyridine class or with allergy
to valsartan.
Regarding safety, it should be kept in mind that this
combination includes a blocker of the action of angiotensin II.
Thus, in all clinical situations such as fever, dehydration, or
diarrhea, in which the renal blood blow must autoregulate
to avoid renal insufficiency, the ARB must be stopped and
amlodipine alone continued if the patient still requires
antihypertensive therapy. Potassium and creatinine should
be monitored in those with moderate renal impairment.
Moreover, in therapeutic conditions that predispose to
hyperkalemia (eg, use of NSAIDs, spironolactone, or ACE
inhibitors, as well as acute or chronic renal insufficiency),
the presence of the ARB valsartan could mean that the
combination may need to be stopped. Caution is advised
when prescribing fixed-dose amlodipine/valsartan to patients
with hepatic impairment, or biliary obstruction, or when
increasing the dosage of the combination in elderly patients.
Bilateral renal artery stenosis is another contraindication for
the use of this combination.
Dosage, administration,
and formulation
In the US, Exforge® is available as film-coated tablets of
amlodipine 5 and 10 mg and valsartan 160 and 320 mg,
to be administered once daily, taken with water, with or
without food. Although a direct switch from monotherapy
to the fixed dose may be appropriate for some patients,
individual dose titration with amlodipine and valsartan is
generally recommended before changing to a fixed-dose
combination.28
Clinical value
As reviewed, this combination is effective in terms of
reduction in BP. HTN is an important risk factor for
cardiovascular complications and its management still needs
improvement. The development of new strategies to improve
the BP control is welcome. The development of efficient and
safe combination therapy is one of these strategies as many
patients with HTN need at least two antihypertensive agents
to achieve BP control. Exforge is a new drug combination
associating two well-tested antihypertensive products: the
CCB amlodipine and the ARB valsartan. The amlodipine/
valsartan combination is an association with potential
advantages in cardiovascular protection.
Clinical trials are ongoing to assess the efficacy and
safety of this combination, and it is likely that others will
follow. Currently available data have shown that this new
formulation is well tolerated and effective even in severe
HTN. Its cost, however, remains high compared with
the individual component drugs and economic studies
quantifying the possible benefit associated with improved
compliance would be welcome.
Ackowledgments
We would like to thank Sandra Rosenberger, RPh,
Froedtert Hospital, Milwaukee, for providing the Average
Wholesale Price (AWP) data on amlodipine and valsartan.
Drs Krzesinski and Cohen declare that they have no conflicts
of interest.
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