Efficacy of Fixed-Dose Combination Therapy in the...

Efficacy of Fixed-Dose CombinationTherapy in the Treatment of Patientswith HypertensionFocus on Amlodipine/Valsartan

Pedro Marques da Silva

Nucleo de Investigacao Arterial, Medicina IV-Hospital de Sta Marta, CHLC, EPE, Lisbon, Portugal

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6251. Combination Antihypertensive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6262. Rationale for the Use of a Combination of a Renin-Angiotensin-Aldosterone System Inhibitor

and a Calcium Channel Blocker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6273. Amlodipine/Valsartan in Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

3.1 Rationale for the Use of Amlodipine and Valsartan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6313.2 Amlodipine/Valsartan Fixed-Dose Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638

Abstract Early initiation of rational and effective combination therapy consisting ofantihypertensive drugs with two different and complementary mechanisms ofactions is increasingly becoming accepted in clinical practice and by guidelinesas a first-line approach to control blood pressure (BP) and prevent cardio-vascular outcomes in patients with hypertension. Once-daily combinationtherapy provides more rapid control of BP, which is important for preventingcardiovascular events, with similar or improved tolerability compared withthe component monotherapies, and improved adherence because of regimensimplification. Combination therapywith a calcium channel antagonist (calciumchannel blocker [CCB]) and an inhibitor of the renin-angiotensin-aldosteronesystem (RAAS) is a rational approach to achieve BP goals and provide protectionagainst renal and cardiovascular morbidity and mortality. A number ofCCB/RAAS inhibitor combinations, including CCB/angiotensin-convertingenzyme (ACE) inhibitor and CCB/ angiotensin II type 1 receptor antagonist(angiotensin receptor blocker [ARB]) combinations are available as fixed-doseformulations. There is substantial evidence for the BP-lowering efficacy ofCCB/RAAS inhibitor combinations in diverse patient populations, and theiruse in combination is associated with favourable tolerability and fewer adversemetabolic effects than some other combination therapies. Recent evidencefrom large outcome trials supports the use of CCB/RAAS inhibitor combi-nations for reducing the risk of cardiovascular and renal events, particularlyin high-risk patients, together with evidence that the benefits of CCB/RAAS

REVIEW ARTICLEClin Drug Investig 2010; 30 (9): 625-641

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inhibitor combinations may extend beyond their efficacy in lowering BP interms of protecting against fatal and nonfatal stroke, myocardial infarctionand cardiovascular-related deaths. The efficacy of the CCB amlodipine andthe ARB valsartan in lowering BP and protecting against cardiovascularevents and stroke across a range of hypertensive patient populations has beenestablished over many years. Fixed-dose amlodipine/valsartan combinationsare available in many countries and have shown greater BP reductions andbetter BP control than the respective monotherapies in diverse patient popu-lations, together with a favourable tolerability profile. Once-daily amlodipine/valsartan is a rational and convenient treatment option for the effectivemanagement of patients with hypertension, improving adherence to anti-hypertensive medication and protecting against cardiovascular and renalmorbidity and mortality.

Current practice guidelines for the manage-ment of hypertension, such as the Seventh Reportof the US Joint National Committee on Preven-tion, Detection, Evaluation, and Treatment ofHigh Blood Pressure (JNC 7)[1] and the EuropeanSociety for Hypertension-European Society ofCardiology (ESH-ESC),[2] define hypertension assystolic blood pressure (SBP) ‡140mmHg and/ordiastolic BP (DBP) ‡90mmHg. Isolated systolichypertension is defined as SBP ‡140mmHg andDBP <90mmHg. The guidelines recommend aBP goal of <140/90mmHg; more stringent goals(<130/80mmHg) are recommended for patients athigh cardiovascular risk.[1,2] There is strong evidencedemonstrating that antihypertensive agents fromseveral classes, including angiotensin-convertingenzyme (ACE) inhibitors, angiotensin II type 1(AT1) receptor antagonists (angiotensin receptorblockers [ARBs]), calcium channel antagonists(calcium channel blockers [CCBs]), b-blockersand thiazide diuretics, are effective in loweringBP.[3-9]

ESH-ESC, WHO, the British Society of Hyper-tension and the JNC 7 all acknowledge thatmost hypertensive patients will require two ormore antihypertensive agents to reach BP goalsassociated with reduced risk of cardiovascularevents.[1,2,10,11] Furthermore, in the light of recentimportant hypertension studies published sincethe 2007 ESH-ESC guidelines, the 2009 reappraisalof the European Guidelines on hypertensionmanagement recommends a more individuallytailored approach for the management of hyper-

tension, particularly in high-risk patients.[12]

Early initiation of BP-lowering treatment with atwo-drug antihypertensive combination is re-commended in patients with stage 2 hypertension(i.e. BP >20/10mmHg above BP goal),[1,2] and inpatients with high cardiovascular risk because ofthe presence of multiple risk factors such as dia-betes mellitus or renal or cardiovascular disease,in order to minimize the development or pro-gression of target organ damage or to preventcardiovascular events.[2,12] The additive BP-low-ering effect of two drugs with complementarymechanisms of action facilitates more rapid BPlowering than with monotherapy while minimiz-ing the individual adverse effects of the compo-nent agents, as lower doses of the individualcomponents can be used to achieve a similar orhigher level of antihypertensive efficacy.[1,2] Two-drug combination therapies currently availableinclude ACE inhibitor/thiazide diuretic, ARB/thiazide diuretic, CCB/thiazide diuretic, ACEinhibitor/CCB, ARB/CCB and b-blocker/CCB.

1. Combination AntihypertensiveTherapy

Fixed-dose combinations have a number ofadvantages over free combinations, includingbetter adherence (because of regimen simplifica-tion) and cost savings.[13,14] Meta-analysis of 68studies of fixed-dose combinations involving atotal of 11925 patients found a 26% decrease inthe risk of non-adherence compared with free-drug

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ª 2010 Adis Data Information BV. All rights reserved. Clin Drug Investig 2010; 30 (9)

combination strategies, with a 24% reduction instudies specific to antihypertensive medication.[14]

Consequently, as better adherence can translateinto improved clinical outcomes,[15] fixed-dosecombinations should be considered in patientswith hypertension. The possible disadvantage ofless flexibility in terms of dosage has been ad-dressed by the current availability of severalfixed-dose combinations, marketed in multiplefixed doses, which minimize the inconvenience ifthe dose of one drug but not the other needs to beincreased.[1,12,16] Usually agents from two differ-ent classes with complementary mechanisms ofaction are combined, and the 2009 reappraisalof the European Guidelines, outlining the ad-vantages of combination antihypertensives overmonotherapy and discussing preferred drugs,quoted a recent meta-analysis of 42 factorialtrials involving a total of 10 968 patients thatshowed that combining two agents from any twoclasses of antihypertensives is approximately fivetimes more effective than doubling the dose of asingle agent, supporting the use of combinationtherapy as the preferred first-line strategy inthe treatment of hypertension.[17] The EuropeanGuidelines reappraisal recommends initiation oftreatment with a combination of two antihyperten-sives in patients with a high initial BP or who areat high or very high cardiovascular risk, beforetarget organ damage develops or becomes irre-versible, or before cardiovascular events occur.[12]

The reappraisal also supports an SBP goal of<140mmHg in elderly and very elderly patients,and lowering SBP as much as possible below140mmHg in patients with diabetes, while ac-knowledging the difficulty of reaching a BP goalof 130/80mmHg.[12] In patients with diabetes, theguidelines specify that an inhibitor of the renin-angiotensin-aldosterone system (RAAS) shouldalways be included in combination treatmentbecause of its superior protection against initia-tion or progression of nephropathy.[1,2,12] CCBsare also favoured because of their efficacy in re-ducing cardiovascular events.[1]

Combination treatment should use agents fromclasses with different and complementary phar-macological profiles.[2] Combining antihyperten-sive agents with complementary modes of action,

e.g. CCBs and RAAS inhibitors, is a rationaltherapeutic approach that provides more effec-tive control of hypertensive symptoms thanequivalent monotherapies.[16,18-22]

2. Rationale for the Use of a Combinationof a Renin-Angiotensin-AldosteroneSystem Inhibitor and a Calcium ChannelBlocker

Dihydropyridine CCBs such as amlodipinepreferentially inhibit calcium influx via the L-typechannels of vascular smooth muscle, lowering BPthrough the resulting reduction in peripheralvascular resistance while promoting cardiac con-tractility and increasing AV conduction.[18,23,24]

The efficacy of dihydropyridine CCBs in lower-ing BP and preventing cardiovascular outcomes,including stroke and coronary events, is well est-ablished, as reviewed in Nathan et al.[23] andRam.[24] Compelling indications for their use in-clude high-risk coronary disease and diabetes.[1,2]

The main adverse events associated with dihydro-pyridine CCBs include oedema, headache andflushing.[24]

The RAAS has a central role in the regulationof cardiovascular, renal and adrenal functions,and is essential to the maintenance of haemo-dynamic stability.[25,26] Hypertension, diabeticand nondiabetic nephropathy, coronary arterydisease and other clinical disease states are wellestablished pathological consequences of over-activity of the RAAS.[25] There is well establishedevidence for the antihypertensive efficacy ofcombining RAAS blockade using ACE inhibitorsor ARBs with CCBs (reviewed in Chrysant[27]).

ACE inhibitors inhibit ACE activity, leadingto decreased formation of angiotensin II, with asimilar downstream effect to that of ARBs.[24]

Unlike ARBs, ACE inhibitors prevent the break-down of bradykinin, which mediates in part theirbeneficial vascular and endothelial effects, and isalso assumed to be the cause of ACE inhibitor-induced cough.[24,28] ACE inhibitor/CCB combi-nations have been shown to be significantly moreeffective at lowering BP than monotherapy witheither agent alone.[29-34] Compelling indicationsfor the use of ACE inhibitors include heart failure,

Amlodipine/Valsartan in Hypertension 627


left ventricular dysfunction, post-myocardial in-farction, high coronary disease risk, diabetes,chronic kidney disease and recurrent strokeprevention.[1,2]

ARBs such as valsartan block the vasocon-stricting and aldosterone-secreting activity ofangiotensin II via selective inhibition of thebinding of angiotensin II to AT1 receptors in theheart, blood vessels and adrenal cortex.[35,36]

They have similar BP-lowering efficacy and sharesimilar activity in reversing or inhibiting vaso-constriction, myocardial hypertrophy, vascularhypertrophy and aldosterone secretion to thatof ACE inhibitors, and have well establishedefficacy in preventing or reducing cardiovascu-lar outcomes, including stroke and coronaryevents.[16,18,23,24] As a class, ARBs are noted forplacebo-like tolerability, with transient mildheadache, nasopharyngitis and fatigue being themost common ARB-associated adverse eve-nts.[24,37] Compelling indications for the use ofARBs include heart failure, diabetes and chronickidney disease.[1,2] The principal overlapping and

complementary indications of ARBs and CCBsin patients with hypertension are summarized infigure 1.

Inhibition of the RAAS with ACE inhibitorsor ARBs has gained support as a rational choicefor use in combination therapy for the initialtreatment of hypertension.[38] RAAS inhibitorsare commonly available in combination with di-uretics and CCBs, and an RAAS inhibitor incombination with a CCB (ACE inhibitor/CCB orARB/CCB) is among the preferred two-drugcombinations recommended by guidelines and issupported by a depth of evidence demonstratingeffective BP lowering and reduction of cardio-vascular events.[12] As previously mentioned,fixed-dose combinations are favoured by theguidelines because of the contribution that sim-plification of the treatment regimen makes to fa-cilitating compliance.[1,2,12]

Combining a dihydropyridine CCB and anARB, such as amlodipine and valsartan or am-lodipine and olmesartan medoxomil, may notonly enhance BP-lowering efficacy compared

Calcium channelblockers

(dihydropyridines)

Angiotensin receptorblockers

Isolated systolic hypertension (elderly)

Angina pectoris

Hypertension in blacks

Left ventricular hypertrophy

Post-myocardial infarction

Heart failure

Atrial fibrillation

Metabolic syndrome

Carotid/coronary atherosclerosis

Proteinuria/microalbuminuria

Diabetic nephropathy

Proteinuria/microalbuminuria

Pregnancy

Fig. 1. Principal indications favouring the use of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers) and dihydropyridinecalcium channel antagonists (calcium channel blockers) according to the European Society of Hypertension-European Society of Cardiology(ESH-ESC) guidelines for the management of hypertension.[2] Reproduced with permission from Waeber and Ruilope.[16]

628 Da Silva


with component monotherapies, but may alsooffset the counter-regulatory response of thesympathetic nervous system to CCB-inducedvasodilation via the sympathetic nervous systemmoderated by concomitant blockade of theRAAS (as reviewed in Waeber and Ruilope).[22]

Consequently, the antihypertensive effect is ad-ditive or more than additive. The CCB-mediatedrenin release and reflex sympathetic nervous sys-tem activation is counterbalanced by ARB-mediated RAAS antagonism and modulation ofsympathetic activity, together with a natriureticeffect that may also contribute to angiotensinII-dependent maintenance of BP.[22] Use of anRAAS-inhibitor in conjunction with a CCB alsocounteracts pedal oedema, the most commonadverse event associated with CCBs.[39] This wasclearly demonstrated for valsartan in two recenttrials in patients with moderate-to-severe hy-pertension, in which peripheral oedema was re-ported in 5.4% of amlodipine/valsartan recipientscompared with 8.7% of those receiving amlodi-pine monotherapy (p < 0.05).[21] Thus, combina-tion therapy helps alleviate adverse events. Fur-thermore, neither CCBs nor ARBs are associatedwith increased risk of new-onset diabetes in hy-pertensive patients, unlike diuretics and b-block-ers.[7,40-42] While CCBs are metabolically neutral,ARBs in fact delay or reduce the risk of dia-betes.[43,44] That RAAS inhibitors play an im-portant role in preventing type 2 diabetes wasconfirmed by a meta-analysis of 12 randomizedcontrolled clinical trials of ARBs or ACE in-hibitors that showed an overall highly significant25% reduction in the incidence of new-onset dia-betes (23% for ARBs and 27% for ACE in-hibitors) compared with other antihypertensiveagents or placebo.[44] This finding, based on datafrom a total of 72 333 non-diabetic patients,supports the choice of an ARB or ACE inhibitoras a logical component of first-line antihyperten-sive therapy, particularly in patients at increasedrisk of diabetes. Although the mechanisms arenot fully established, the protective effect ofARBs and ACE inhibitors may involve improvedinsulin sensitivity as a result of the effect on ske-letal muscle blood flow of peripheral vasodila-tion and/or the promotion of the differentiation

of pre-adipocytes to mature adipocytes as aresult of increased adiponectin levels.[43] A directprotective effect on pancreatic b-cell function isalso possible.[43]

There is robust evidence supporting the effi-cacy in lowering BP and in preventing or reducingcardiovascular morbidity of RAAS blockadeusing ACE inhibitors or ARBs, and of CCBs inreducing BP and the complications of hyperten-sion in diverse patient populations, includingpatients with diabetes, the elderly and patientsat high risk of cardiovascular events (reviewedin Ram[24]). For these reasons, RAAS inhibitor-based combination therapies have been gain-ing increasing support as initial treatment ofhypertension.[38,45] The efficacy of an RAASinhibitor-based strategy alone or in combinationwith a diuretic in lowering BP and preventinghypertension-associated complications such ascardiovascular events and stroke was shown inpart by intervention studies such as LIFE[7] (seetable I for trial names) and SCOPE,[46] whichused strategies based on an ARB (losartan andcandesartan cilexetil, respectively) with the addi-tion of hydrochlorothiazide, and in PROGRESS,where the combination of an ACE inhibitor anddiuretic (perindopril plus indapamide) reducedthe risk of stroke in hypertensive patients.[8,47]

Table I. Trial names

ACCOMPLISH Avoiding Cardiovascular Events through

Combination Therapy in Patients Living with

Systolic Hypertension

ASCOT Anglo-Scandinavian Cardiac Outcomes Trial

ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial-

Blood Pressure Lowering Arm

LIFE Losartan Intervention For Endpoint reduction in

hypertension study

ONTARGET Ongoing Telmisartan Alone and in Combination

with Ramipril Global Endpoint Trial

PROGRESS Perindopril Protection Against Recurrent Stroke

Study

SCOPE Study on Cognition and Prognosis in the Elderly

Val-HeFT Valsartan Heart Failure Trial

VALIANT Valsartan in Acute Myocardial Infarction Trial

VALUE Valsartan Antihypertensive Long-term Use

Evaluation



Other landmark trials have demonstrated theefficacy of combination therapy for BP loweringand subsequent improvements in cardiovascularmorbidity and mortality. For example, the recentACCOMPLISH[48] study results strongly suggestthat CCB-based treatment in combination withan ACE inhibitor is preferable to a diuretic/ACEinhibitor combination in high-risk hypertensivepatients. In total, 11 506 patients aged ‡55 yearswith SBP >160mmHg or currently receivingantihypertensive medication and who had evi-dence of cardiovascular or renal disease or target-organ damage were enrolled in this study; 60%had diabetes and many had coronary disease.ACCOMPLISH was stopped early after a meanfollow-up of 36 months because the benaze-pril/amlodipine strategy was more effective thantreatment with benazepril/hydrochlorothiazide.Overall, 73% of patients achieved a target BP of<140/90mmHg within 6 months of startingcombination therapy.[49] However, despite simi-lar BP lowering with the two strategies, theRAAS inhibitor/CCB combination reduced therelative risk of cardiovascular morbidity andmortality by 19.6% compared with the RAASinhibitor/diuretic combination,[48] challengingcurrent treatment guidelines for hypertension,some of which indicated a preference for the in-clusion of a thiazide diuretic in combinationregimens.[1] The findings of studies such as AC-COMPLISH support the early use of combina-tion therapy as the initial antihypertensive strat-egy in patients with hypertension, particularlythose at high risk of cardiovascular events, andsuggest that an RAAS inhibitor/CCB combina-tion may provide superior cardiovascular out-comes. However, the choice of initial drugsshould also consider compelling indications orcontraindications, co-morbid conditions, thetolerability profile of the component agents andthe clinician’s experience.

Regarding choice of antihypertensive agents,the suggestion that ARBs may be inferior to ACEinhibitors in protecting against myocardial in-farction has been largely undermined by the re-sults of ONTARGET,[50] together with those ofmeta-analyses of ACE inhibitors and ARBs thatincluded more recent as well as older trials, which

concluded that ACE inhibitors and ARBs offerthe same protection against myocardial infarc-tion.[51,52] ONTARGET randomized a total of25 620 patients with vascular disease or high-riskdiabetes to treatment based on the ARB telmi-sartan (8542 patients), the ACE inhibitor rami-pril (8576) or a combination of the two drugs(8502). ARB monotherapy and combinationtherapy were more effective at lowering BP thanthe ACE inhibitor strategy (p < 0.001 for combi-nation therapy vs ramipril), and telmisartan wasnot inferior to ramipril for preventing the pri-mary outcome of death from cardiovascularcauses, myocardial infarction, stroke or hospita-lization for heart failure. Similarly, the ARB andACE inhibitor strategies provided similar levelsof protection against death from cardiovascularcauses, myocardial infarction or stroke, andagainst the component outcomes: myocardialinfarction, stroke, death from cardiovascularcauses and all-cause death.[50] However, thecombined ARB/ACE inhibitor strategy did notreduce cardiovascular or renal endpoints com-pared with monotherapy and was associated withmore renal adverse events, and use of such acombination is not generally supported.[12]

An amlodipine-based regimen with the addi-tion of an ACE inhibitor (perindopril) wascompared with a b-blocker (atenolol)-based re-gimen with the addition of a diuretic (bendro-flumethiazide) in the ASCOT-BPLA study of19 257 hypertensive patients at risk of developingcardiovascular events (‡3 cardiovascular riskfactors at baseline).[53] Amlodipine-based ther-apy was more effective than atenolol-based ther-apy in lowering BP throughout the study, moreeffectively reduced total cardiovascular events,and induced fewer cases of new-onset diabetesthan atenolol-based therapy. After a median of5.5 years of follow-up, the difference betweenstrategies in all-cause mortality was 11% in fa-vour of the amlodipine-based regimen (hazardratio [HR] 0.89, 95% CI 0.81, 0.99; p= 0.0247),contributed to by a 24% reduction in cardio-vascular mortality (HR 0.76, 95% CI 0.65, 0.90;p = 0.001). Other secondary endpoints also fa-voured the amlodipine-based regimen, with a23% reduction in fatal and nonfatal stroke

630 Da Silva


(p = 0.0003), a 13% reduction in total coronaryevents (p = 0.007), a 16% reduction in totalcardiovascular events and procedures (p < 0.001),a 13% reduction in nonfatal myocardial infarc-tion (excluding silent events) and fatal coronaryheart disease (p = 0.0458), and a 30% reduction innew-onset diabetes (p < 0.0001). The primaryendpoint (all nonfatal myocardial infarction plusfatal coronary heart disease) was reduced by 10%with the amlodipine-based regimen, although thedifference had not reached statistical significancewhen the study was terminated early because ofthe superiority of the amlodipine/ACE inhibitorregimen.[53]

In ASCOT, the use of amlodipine with orwithout perindopril was associated with a 34%reduction in the risk for new-onset diabetes com-pared with use of atenolol with or without thia-zide, regardless of the baseline risk category.[54]

While fasting plasma glucose was the most robustrisk factor for new-onset diabetes, amlodipine-based therapy was the strongest protective factor,suggesting amlodipine as a rational considerationwhen choosing antihypertensive agents in routineclinical practice.[54]

As noted above, the benefits of first-line therapywith RAAS inhibitors and CCBs in reducingcardiovascular risk have been firmly established.RAAS inhibitor/CCB combination therapy hasalso been shown to effectively prevent cardiovas-cular events in several large-scale cardiovascularoutcomes trials using ACE inhibitor/CCB regi-mens.[48,55] Furthermore, a recent trial showed thatamlodipine/valsartan (with potential addition ofdiuretics or b-blockers) improved measures ofdiastolic dysfunction in patients with hypertensionand diastolic dysfunction.[56] The trial randomizedpatients with stage II hypertension and echo-cardiographic evidence of diastolic dysfunction,and was designed to examine whether intensive BPlowering with an amlodipine/valsartan-based regi-men improved parameters of hypertensive end-organ damage. Diabetes and heart failure wereexclusion criteria. Therapy was initiated with am-lodipine/valsartan 5mg/160mg and uptitratedwith additional antihypertensive medicationsbeing added if required to reach intensive versusstandard BP control (SBP <130mmHg vs SBP

<140mmHg). BP was reduced significantly inboth the intensive and the standard control arms,and there were significant improvements in mea-sures of diastolic function and vascular func-tion in both arms. Mean – SD mitral annularrelaxation velocity (the primary efficacy endpoint)increased from 7.6– 1.1 to 9.2– 1.7 cm/s in the inten-sive control arm and from 7.5 – 1.3 to 9.0 – 1.9cm/s in the standard control arm (p < 0.0001 forboth groups), a change of 1.54 – 1.4 cm/sec and1.48 – 1.6 cm/sec in the intensive versus standardcontrol arms, respectively, from baseline to week24 (p = 0.58 between groups). Although no dif-ferences in the achieved improvement in myo-cardial relaxation velocity or measures of arterialstiffness were observed between strategies, thedegree of improvement was associated with theextent of SBP reduction.[56] The study furthersupports the role of fixed-dose CCB/RAAS in-hibitor combinations for cardiovascular risk re-duction in hypertensive patients.

3. Amlodipine/Valsartan in Hypertension

3.1 Rationale for the Use of Amlodipine andValsartan

The efficacy of amlodipine and valsartan asmonotherapies in the treatment of hypertensionhas been well established over many years ofclinical studies and clinical practice. A recent ar-ticle by Black et al.[37] reviewed the experience ofmore than a decade of valsartan use in the man-agement of hypertension. In brief, valsartan hasbeen studied in more than 100 000 patients andhas been shown in a number of large-scale hyper-tension studies to demonstrate dose-dependentefficacy in lowering SBP and DBP over a once-daily dosage range of 80–320mg across a range ofadult hypertensive patient populations.[37] Theseinclude the elderly, obese patients, patients athigh risk of cardiovascular events, patients withdiabetes and patients with chronic kidney disease,regardless of race, age, sex or hypertension se-verity. The BP-lowering efficacy of valsartan issimilar to that of other antihypertensive agents,including ACE inhibitors, b-blockers, diuretics,CCBs and other ARBs. Large outcome trials



have demonstrated the efficacy of valsartan inprotecting against cardiovascular events andstroke in various patient populations, with a simi-lar efficacy and a more favourable tolerabilityprofile to that of ACE inhibitors. Valsartan hasalso been shown to improve markers of chronickidney disease, such as albuminuria and proteinexcretion, in diabetic and non-diabetic patients.The drug has also been shown to be efficacious inpatients with isolated systolic hypertension. Theability of valsartan to provide adequate andconsistent BP control over the full dosing intervalhas been demonstrated in a number of studiesusing ambulatory BP monitoring, with similar orgreater 24-hour BP reductions to those producedby clinically comparable doses of losartan, ol-mesartan medoxomil, telmisartan, aliskiren andamlodipine.[37] As previously noted, valsartanshares a placebo-like tolerability profile withother ARBs, independent of dose up to a testedlevel of 320mg/day (the optimal starting dose ofvalsartan has been established as 160mg/day inessential hypertension) and consistent across dif-ferent patient populations.[37] However, limiteddata are available on the paediatric use of val-sartan. Valsartan monotherapy is associated withsignificantly lower rates of peripheral oedemathan amlodipine monotherapy.[21]

Short- and long-term studies reviewed byHaria and Wagstaff[57] indicate that once-dailyamlodipine monotherapy in doses of 2.5–10mg/dayis an effective antihypertensive treatment, low-ering mild-to-moderate BP with similar efficacyto other established agents, such as ACE inhibi-tors,b-blockers, diuretics, ARBs and otherCCBs.[57]

Amlodipine significantly reduces SBP and DBPin a dose-dependent manner in patients with es-sential hypertension, including young and elderlypopulations, and patients with renal dysfunction,diabetes or hyperlipidaemia, regardless of race.[18,57]

Amlodipine also reduces mean ambulatory BPthroughout a 24-hour dose interval, withoutaccompanying reflex tachycardia or posturalhypotension, and with a tolerability profile gen-erally comparable to that of other conventionalantihypertensive agents.[57] The main adverseevents associated with amlodipine monotherapyare dose-dependent vasodilatory effects including

oedema, headache, flushing and dizziness. How-ever, the main amlodipine-related adverse event,peripheral oedema, is usually mild or moderate inseverity and generally tolerated without treat-ment withdrawal.[57]

The benefits of valsartan in reducing cardio-vascular endpoints have been shown in large-scale trials such as Val-HeFT (in patients withheart failure),[58-62] VALIANT (in patients with pre-vious myocardial infarction)[63] and VALUE.[64,65]

Specifically, in the VALUE trial of 15 245 pa-tients aged ‡50 years with hypertension and athigh risk of cardiac events (one or more pre-specified risk factors or diseases), both valsartanand amlodipine reduced cardiac morbidity andmortality with no significant differences betweenthe two drugs in terms of the composite endpointof cardiac mortality and morbidity (HR 1.04,95% CI 0.94, 1.15; p = 0.49) after a mean follow-up of 4.2 years. However, although achievementof the BP target of <140/90mmHg was similarin the two groups at the end of the study (56%in the valsartan group and 62% in the amlodipinegroup), there were differences in BP lowering fa-vouring the amlodipine-based regimen, partic-ularly in the first year. As the majority of strokesobserved occurred in the first 6 months of thestudy, rising to 76% by the end of the firstyear, these findings emphasize the importanceof rapid control of BP to achieve improvementsin cardiovascular outcome in patients at highcardiovascular risk.[64] In VALUE, treatmentcommenced with valsartan 80mg/day or amlo-dipine 5mg/day; doses could be uptitrated andfurther antihypertensive drugs could be added ifnecessary to achieve BP control. However, itshould be noted that valsartan could be titratedto only 160mg, while amlodipine could be titratedto 10mg, indicating possible underdosing of val-sartan in the light of its use at doses up to 320mgin subsequent trials.

The differences in between-group BP levelslimited the ability of VALUE to compare the ef-fects of valsartan and amlodipine on cardiacendpoints. However, post hoc analysis of tightly-paired cohorts of patients who achieved similarBP control at 6 months showed that combinedcardiac events, myocardial infarction, stroke and

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mortality were almost identical for both regi-mens.[66] The only exception was hospitalizationfor heart failure, which was significantly lower inthe valsartan group. This, along with a sig-nificantly lower rate of new-onset diabetes inpatients receiving valsartan,[67] suggests that val-sartan may offer benefits beyond BP lowering.For example, during a median follow-up of 3.1years in the Jikei Heart Study, similar reductionsin BP and similar rates of BP control wereachieved by the addition of valsartan to standardcardiovascular treatment (including CCBs in67% of patients) or by increasing the dose ornumber of standard drugs in Japanese patientswith cardiovascular disease.[68] However, theprimary endpoint of a composite of cardio-vascular morbidity and mortality was reachedby significantly fewer patients treated with thevalsartan-based strategy than in those givenadditional non-ARB treatment (6.0% vs 9.7%,p= 0.0002; HR 0.61). This 39% relative risk re-duction was driven by reductions in stroke (40%reduction), angina pectoris (65% reduction), dis-secting aortic aneurysm (81% reduction) andheart failure (47% reduction). These benefits wereobserved across various subgroups.

In the recent KYOTO HEART study, theaddition of valsartan to standard treatment inhigh-risk Japanese patients with uncontrolledhypertension was significantly more effective inpreventing the primary endpoint (a composite offatal and nonfatal cardiovascular events) andindividual cardiovascular endpoints (angina,stroke) than non-ARB conventional antihyper-tensive treatment.[69] Of interest, 63% of pa-tients in the valsartan group were using CCBs at12 months to assist in reaching BP targets of<140/90mmHg (<130/80mmHg in patients withdiabetes or renal disease). For a similar degree ofBP lowering in each group, the valsartan-basedstrategy was associated with a 45% risk reduc-tion in the primary endpoint (5.5% vs 10.2%;p= 0.00001), a 45% risk reduction in stroke (1.6%vs 3.0%; p= 0.1488) and a 49% risk reduction inangina (1.5% vs 2.9%; p= 0.01058) comparedwith the non-ARB strategy. There was a non-significant 35% reduction in the risk of acutemyocardial infarction with the valsartan-based

strategy. The study was terminated early after amedian follow-up of 3.27 years because of theunequivocal benefit in the valsartan group.[69]

These findings suggest that a valsartan-basedstrategy in which the majority of patients alsoreceived a CCB provided a cardiovascular pro-tective effect in a high-risk Japanese hypertensivepopulation. Asians may be particularly receptiveto the protective effects of ARBs, and whetherthe benefits will fully translate to Western popu-lations is unclear.

3.2 Amlodipine/Valsartan Fixed-DoseCombination Therapy

Fixed-dose oral combinations of amlodipine/valsartan and amlodipine/olmesartan medoxomilare available in several European countries forthe treatment of hypertension in patients in-adequately controlled with amlodipine and val-sartan monotherapy, and in the US for patientswhose BP is inadequately controlled with amlodi-pine (or another CCB) and valsartan (or anotherARB) monotherapy. Furthermore, two otherCCB/ARB single-pill formulations are available inother regions (amlodipine/losartan)[70] or under-going development (amlodipine/telmisartan).[71]

The introduction of an amlodipine/valsartan/hydrochlorothiazide combination can also benoted, supporting the recommendations of the2009 reappraisal of the European Guidelines thatan RAAS inhibitor, a CCB and a diuretic at effec-tive doses is the most rational combination whentwo drugs are insufficient to achieve BP control.[12]

Two similarly designed pivotal studies involv-ing a total of 3161 adult patients with mild-to-moderate hypertension demonstrated the efficacyand safety of fixed-dose amlodipine/valsartancompared with their component monotherapiesand placebo.[21] The studies evaluated a range ofcombinations of amlodipine/valsartan, includingthe widely used dose of 5mg/160mg once daily.Each dosage of combination therapy producedsignificantly greater BP reductions than eithercomponent or placebo. Table II and figure 2(study 1) and table III and figure 3 (study 2)summarize the mean BP reductions at study end(after 8 weeks of double-blind treatment) for the



combinations and component monotherapies.For each dosage of active treatment, the meanreduction in BP was significantly greater thanthat with placebo. The BP-lowering efficacy ofcombination therapy increased with increasingdose over the range of fixed doses studied. Exceptfor amlodipine/valsartan 2.5mg/40mg in study 1,co-administration of amlodipine with valsartanwas significantly more effective than equivalent

doses of monotherapy. In study 1, amlodipine/valsartan 5mg/160mg, probably the most widelyused dose in clinical practice internationally,was very effective at lowering BP, reducing meanseated SBP by 19.5mmHg from baseline andmean seated DBP by 14.2mmHg. Amlodipine/valsartan 5mg/40mg and 5mg/80mgwere similarlyeffective in reducing BP, with a small additionalreduction in BP when the combination was given

Table II. Mean reductions in sitting systolic/diastolic blood pressure (SBP/DBP, mmHg) after 8 weeks of treatment with different doses of

amlodipine and valsartan given alone or in combination in 1911 patients with mild-to-moderate essential hypertension (mean DBP

95–109 mmHg) [data from study 1, Philipp et al.[21]]

Amlodipine dose (mg) Valsartan dose (mg)

0 40 80 160 320

0a 7.3/7.1 11.8/10.1 12.9/9.7 15.1/11.0 15.7/13.4

2.5 12.4/9.3 15.5*-/10.8 17.0*-/13.4*- 16.7-/13.3*- 18.3-/14.2*-

5 15.1/11.5 19.6*-/14.6*- 20.8*-/14.5*- 19.5*-/14.2*- 22.7*-/15.9*-

a Patients received placebo.

* p < 0.05 vs the same dose of valsartan monotherapy; - p < 0.05 vs the same dose of amlodipine monotherapy.

−7.3

−12.

4

−15.

1

−11.

8

−12.

9

−15.

1

−15.

7

−15.

5

−17.

0

−16.

7

−18.

3

−19.

6

−20.

8

−19.

5

−22.

7

−7.1

−9.3

−11.

5

−10.

1

−9.7

−11.

0

−13.

4 −10.

8

−13.

4

−13.

3

−14.

2

−14.

6

−14.

5

−14.

2

−15.

9

−35

−30

−25

−20

−15

−10

−5

0

Valsartan

80 160

AmlodipinePlacebo

Drug and dose (mg/day)

2.5

5 40

Amlodipine/valsartan

320

2.5/

80

2.5/

160

2.5/

40

2.5/

320

5/80

5/16

05/

405/

320

*†

*†

*†

*†

*†

*†*†

*†

*†*†

*†

*†

*†*†

*†

SBPDBP

Mean baseline SBP: 152.8 mmHgMean baseline DBP: 99.3 mmHg

Cha

nge

in s

ittin

g B

P (

mm

Hg)

Fig. 2. Mean change from baseline in sitting blood pressure (BP) after 8 weeks of treatment with different doses of amlodipine or valsartan,alone or in combination (study 1 of the Philipp et al.[21] trial). DBP = diastolic blood pressure; SBP = systolic blood pressure. * p < 0.05 vs thesame dose of valsartan monotherapy; - p < 0.05 vs the same dose of amlodipine monotherapy. All active treatments p < 0.05 vs placebo.

634 Da Silva


at the highest dose evaluated, 5mg/320mg. Instudy 2, the two combinations evaluated, amlo-dipine/valsartan 10mg/160mg and 10mg/320mg,were both very effective in lowering BP.[21] BPcontrol (defined as mean seated DBP <90mmHg)was highest with combination therapy and a posi-tive dose response was observed, reaching 82.5%in study 1 and 84.1% in study 2. The lowest ratesof BP control were with placebo (33.9% and42.6% in study 1 and study 2, respectively).[21] Sub-

group analysis showed that amlodipine/valsartanwas also associated with greater BP-lowering effectsthan the component monotherapies or placeboacross all subgroups evaluated, specifically in pa-tients with stage 2 hypertension, the elderly (age‡65 years), younger patients (age <65 years),Black patients and White patients.[72]

Analysis of the combined safety population of3155 patients showed that combination treat-ment was generally well tolerated, regardless ofage, race or sex.[21] There was no significant dif-ference in overall adverse event rates betweenrecipients of amlodipine/valsartan, amlodipinemonotherapy or placebo. However, there was asignificant difference in overall adverse eventsbetween amlodipine/valsartan and valsartanmonotherapy (p < 0.05). Figure 4 summarizes thetolerability data for the combined safety popu-lation.[21] The incidence of peripheral oedemawas significantly lower with combination therapycompared with amlodipine monotherapy (5.4%vs 8.7%, p = 0.014), significantly higher than withvalsartan monotherapy (2.1%), and statistically

Table III. Mean reductions in sitting systolic/diastolic blood pres-

sure (SBP/DBP, mmHg) after 8 weeks of treatment with different

doses of amlodipine and valsartan given alone or in combination in

1250 patients with mild-to-moderate essential hypertension (mean

DBP 95–109 mmHg) [data from study 2, Philipp et al.[21]]

Amlodipine dose (mg) Valsartan dose (mg)

0a 160 320

0a 12.9/8.8 20.2/13.3 19.8/13.3

10 24.1/15.6 27.8*-/17.6*- 28.4*-/18.6*-

a Patients received placebo.

* p < 0.05 vs the same dose of valsartan monotherapy; - p < 0.05 vs

same dose of amlodipine monotherapy.

−12.9

−24.1

−20.2 −19.8

−27.8 −28.4

−8.8

−15.6

−13.3 −13.3

−17.6−18.6

Valsartan

160

Amlodipine

10

Amlodipine/valsartan

320 10/160 10/320

*†

*†*†

*†

Drug and dose (mg/day)

−30

−25

−20

−15

−10

−5

0

Cha

nge

in s

ittin

g B

P (

mm

Hg)

Placebo

SBPDBP

Mean baseline SBP: 156.7 mmHgMean baseline DBP: 99.1 mmHg

Fig. 3. Mean change from baseline in sitting blood pressure (BP) after 8 weeks of treatment with different doses of amlodipine or valsartan,alone or in combination (study 2 of the Philipp et al.[21] trial). DBP = diastolic blood pressure; SBP = systolic blood pressure. * p < 0.05 vs thesame dose of valsartan monotherapy; - p < 0.05 vs the same dose of amlodipine monotherapy. All active treatments p < 0.05 vs placebo.



similar to that with placebo (3.0%). The lowerincidence of peripheral oedema associated withcombination therapy was likely to be related to adecrease in both arteriolar and venous resistance,in contrast to a reduction only in arteriolarresistance that would be anticipated with amlo-dipine. Headache was significantly lower inamlodipine/valsartan recipients compared withthose receiving amlodipine monotherapy (4.3% vs7.6%, p < 0.01), and similar to that with valsartanmonotherapy (4.8%) and placebo (5.9%). Over-all, reported adverse events were similar withamlodipine/valsartan and amlodipine mono-therapy (44.1% and 45.7%, respectively), butsignificantly higher than with valsartan mono-therapy (39.8%, p< 0.05). Only 1.8% of combi-

nation therapy recipients discontinued treatment,which was similar to the rate of discontinuationsin the placebo group (2.1%). Peripheral oedema(0.4%), vertigo (0.2%) and headache (0.1%) werethe most common adverse events leading to studydiscontinuation in combination therapy recipi-ents. The favourable effect on peripheral oedemaof the dual mechanism of action of amlodipineand valsartan acting on arteries and veins wasalso supported by a study designed to evaluatethe effect of valsartan in combination with am-lodipine on objective measures of ankle oedema.[74]

In this study, amlodipine/valsartan 10mg/160mgonce daily for 6 weeks produced a significantlylower increase than amlodipine 10mgmonotherapyin both measures, i.e. ankle foot volume (6.8% vs23.0%, p < 0.01) and pretibial subcutaneous tissuepressure (23.2% vs 75.5%, p < 0.001).

Studies have further shown that amlodipine/valsartan provides additional BP control inhypertensive patients not controlled by an ACEinhibitor/CCB combination,[75] and compared withvalsartan monotherapy,[76] amlodipine mono-therapy[77] or felodipine monotherapy.[77] In amulticentre study of 133 patients with moderatehypertension who had not responded to 5 weeks’treatment with the ACE inhibitor/CCB combi-nation of ramipril 5mg and felodipine 5mg, anadditional 5 weeks of treatment with amlodipine/valsartan 10mg/160mg resulted in clinicallyand statistically significant additional mean BPreductions of 15.4/7.0mmHg (p < 0.0001).[75]

Only 13% of patients achieved the target SBP of<140mmHg with the ACE inhibitor/CCB treat-ment, compared with 69.5% of patients treatedwith amlodipine/valsartan. Treatment with am-lodipine/valsartan was well tolerated, and noperipheral oedema was observed.

Amlodipine/valsartan combination therapywas significantly more effective at lowering BPthan valsartan monotherapy in a double-blindstudy of patients with mild-to-moderate essentialhypertension.[76] A total of 947 patients wererandomized to once-daily amlodipine/valsartan5mg/160mg, amlodipine/valsartan 10mg/160mgor valsartan 160mg monotherapy for 8 weeks.Mean SBP/DBP reductions from baseline were12.2/9.6mmHg and 14.3/11.5mmHg for the

0.9

2.1

1.8

5.9

3.0

2.4

1.4

4.0

4.8

2.1

1.5

2.4

3.5

7.6

8.7

2.1

2.9

4.3 *

4.3

5.4

0 1 2 3 4 5Percentage of patients

6 7 8 9 10

Dizziness

URTI

Nasopharyngitis

Headache

Peripheraloedema

†‡

‡

Amlodipine/valsartan (n = 1437)Amlodipine (n = 460)Valsartan (n = 921)Placebo (n = 337)

†

Fig. 4. Pooled tolerability data (%) from 3155 patients with mild-to-moderate hypertension treated in two randomized, double-blind,8-week factorial trials of different doses of amlodipine and valsartan,alone or in combination.[21] Adverse events are those reported in‡2% of patients treated with amlodipine/valsartan. Reproduced withpermission from Plosker and Robinson.[73] URTI = upper respira-tory tract infection. * p < 0.05 vs placebo; - p < 0.05 vs valsartan;‡ p < 0.05 vs amlodipine.

636 Da Silva


two amlodipine/valsartan combinations (bothp< 0.0001), and 8.3/6.7mmHg for valsartanmonotherapy. There was a higher rate of succes-sful responders (defined as a DBP <90mmHg or‡10mmHg decrease from baseline at study end)with combination therapy; 81% and 68% foramlodipine/valsartan10mg/160mgand5mg/160mg,respectively, compared with 57% for valsartan160mg monotherapy. In addition, a greater pro-portion of combination therapy versus mono-therapy recipients had achieved DBP control (meanDBP<90mmHg) at study endpoint.[76] Amlodipine/valsartan 5mg/160mg and valsartan 160mgmonotherapy were similarly well tolerated, withadverse events being reported in 24.2% and 25.3%of patients treated with these regimens, respect-ively. Most events were mild or moderate in se-verity, and discontinuations due to adverse eventswere infrequent, occurring in 0.9% of pa-tients in the amlodipine/valsartan 5mg/160mggroup and 0.6% in the valsartan 160mg group.Peripheral oedema was the most frequent adverseevent leading to discontinuation and was dosedependent, occurring in 9.1% of amlodipine/valsartan 10mg/160mg recipients, compared with0.9% and 1.3% of patients in the 5mg/160mgcombination and valsartan 160mg groups, re-spectively, and overall leading to discontinuationin only 1.0% of patients,[76] reflecting the low ratesof treatment discontinuation due to adverse eventsobserved in clinical trials of amlodipine/valsartan.

Amlodipine/valsartan 5mg/160mg has alsobeen shown to produce clinically and statisticallyadditional BP lowering in patients not adequatelycontrolled by amlodipine 5mg or felodipine 5mgmonotherapy.[77] In this study of 214 patients withmoderate essential hypertension (defined as SBP160–179mmHg), 85% had not achieved an SBPof <140mmHg after 4 weeks and were treatedwith amlodipine/valsartan 5mg/160mg for a fur-ther 4 weeks. An additional mean BP reduction of13.1/5.3mmHg was achieved with combinationtreatment (p < 0.0001 vs either monotherapy),and 51% of patients reached the target BP goal.Adverse events, mostly mild or moderate in se-verity, were low with both monotherapy andamlodipine/valsartan combination therapy, andwere considered to be drug related in only 5.6% of

patients in the monotherapy phase and 0.6% inthe combination phase. The most common adverseevents during combination treatment, regardless ofrelationship to study drug, were peripheral oedema(0.6%), headache (0.6%) and urinary tract infection(1.1%). There were no clinically significant changesin laboratory values during the study.

In another study, both amlodipine/valsartan5mg/160mg (titrated to 10mg/160mg if needed)and lisinopril/hydrochlorothiazide 10mg/12.5mg(titrated to 20mg/12.5mg if needed) significantlyreduced BP and controlled BP at a similar rate inadult patients with stage 2 hypertension.[78] After6 weeks of treatment, mean reductions in seatedBPwere -35.8/-28.6mmHg and -31.8/-27.6mmHgwith amlodipine/valsartan and lisinopril/hydro-chlorothiazide, respectively (both p< 0.001 vs base-line). Both treatment regimens were generally welltolerated and resulted in similar rates of treat-ment response and DBP control.

In another recent study, a total of 894 patientsnot previously controlled on antihypertensivemonotherapy were switched to fixed-dose amlo-dipine/valsartan (with or without the additionof hydrochlorothiazide). The primary outcomeof BP control was attained in over 70% ofpatients at study end, with no significant differ-ence between amlodipine/valsartan 5mg/160mgand 10mg/160mg groups (72.7% and 74.8%, re-spectively).[79] Incremental reductions in BP wereachieved throughout the study, irrespective ofprior antihypertensive therapy, hypertension se-verity, diabetic status, age or body mass index.Fixed-dose amlodipine/valsartan was well toler-ated; the most frequent adverse events were mildto moderate in severity and, as expected with aCCB/ARB combination, consisted of peripheraloedema, headache, back pain, dizziness andmuscle spasms. However, peripheral oedemaconsidered to be related to treatment occurred inonly 6.8% of amlodipine/valsartan 5mg/160mgrecipients, and led to discontinuation in 2.3%.There was no treatment-related headache ordizziness at this dosage.

Amlodipine/valsartan 5mg/160mg (increasedto 10mg/160mg if needed) produced similar BPreductions to irbesartan/hydrochlorothiazide300mg/12.5mg (increased to 300mg/25mg if



needed) in a 24-week study in very elderly (aged75–89 years) patients with hypertension.[80] How-ever, amlodipine/valsartan had advantages interms of less pronounced orthostatic BP changesand absence of metabolic adverse events. Al-though there was no difference between the twocombinations in terms of reducing sitting andlying BP, mean BP changes after moving from thelying to the standing position were significantlygreater in the irbesartan/hydrochlorothiazidegroup (-17.2/-9.1mmHg) than in the amlodipine/valsartan group (-10.1/-1.9mmHg, p < 0.05 forSBP and p < 0.01 for DBP vs irbesartan/hydrochlorothiazide). Both regimens provided apersistent and smooth antihypertensive effectthroughout the dosing period, as indicated by24-hour ambulatory BP monitoring. Further-more, clinic and ambulatory heart rate were notsignificantly affected by either combination. Inaddition, levels of serum potassium significantlydecreased and uric acid significantly increasedin irbesartan/hydrochlorothiazide recipients, re-presenting adverse metabolic changes that weremost probably associated with the diuretic. Therewere no significant changes in metabolic para-meters with amlodipine/valsartan, supportinga lack of metabolic adverse effects with thiscombination.[80]

4. Conclusions

The use of combination antihypertensivetherapy is widely acknowledged to be necessaryto achieve BP targets associated with cardio-vascular risk reduction in the majority of hyper-tensive patients.[1,2,12] Accordingly, the benefitsof initiating antihypertensive therapy with a two-drug combination chosen from therapeutic class-es with complementary mechanisms of actionis increasingly becoming regarded as a preferredfirst-line option for the effective management ofhypertension. In this regard, the 2009 reapprais-al of the European Guidelines on hypertensionmanagement recommends a more individuallytailored approach for the initiation of antihyper-tensive therapy, especially in high-risk patients.[12]

Simplification of fixed-dose combinations con-tributes to better adherence, which is likely to be

reflected in improved outcomes, and the combi-nation of an inhibitor of the RAAS, such as anARB or ACE inhibitor, with a long-acting CCBis a rational approach to the management ofhypertension, providing effective BP control withgood tolerability. Furthermore, the final resultsof the landmark ACCOMPLISH trial have est-ablished the benefit of initiating treatment withan RAAS inhibitor/CCB combination over anRAAS inhibitor/diuretic in preventing cardio-vascular mortality and morbidity, including fataland nonfatal stroke, myocardial infarction andcardiovascular-related deaths, despite similar re-ductions in BP.[48] Not only is such a combinationwell tolerated and highly effective in helpingpatients to achieve target BP, ACCOMPLISHdemonstrated a 20% relative risk reduction incardiovascular events for the RAAS inhibitor/CCB combination in this high-risk population.Amlodipine/valsartan has demonstrated BP-lowering efficacy in diverse patient populationswith hypertension and is associated with greaterBP reductions and better BP control than therespective monotherapies, in conjunction witha favourable tolerability profile. Amlodipine/valsartan is a rational and convenient treatmentoption for the effective management of patientswith hypertension.

Acknowledgements

The author has received honoraria from Merck Sharp &Dohme, Pfizer, Servier, Bayer and Novartis. Medical writingservices for this manuscript were provided by Ray Hill,inScience Communications, a Wolters Kluwer business.Funding for this service was provided by Bial Farmaceutica,Portugal.

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Correspondence: Dr Pedro Marques da Silva, Nucleo deInvestigacao Arterial, Medicina IV-Hospital de Sta Marta,CHLC, EPE. Rua de Santa Marta, n� 50 1169-024 Lisboa,Portugal.E-mail: [email protected]



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