Amlodipine/Valsartan Fixed Dose Combination: Its Role in the Treatment of Hypertension

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1 Amlodipine/Valsartan Fixed Dose Combination: Its Role in the Treatment of Hypertension Tehreem F Butt, MBChB (UK), MRCP (UK); Bernard MY Cheung, MB BChir, PhD, FRCP A substantial number of patients with hypertension are undertreated, and over two-thirds of hypertensive patients will require more than one antihypertensive agent to achieve adequate blood pressure control. British, European and American hypertension society guidelines encourage the use of effective drug combinations. This article reviews the role of amlodipine/valsartan fixed dose combination in the treatment of hypertension. Introduction Hypertension increases an individual s risk of developing cardiovascular disease, as confirmed by numerous population-based and cohort studies. 1,2 The risk of developing ischaemic heart disease, heart failure, stroke and hypertensive renal disease escalates with increasing blood pressure. The importance of treating hypertension is evident from multiple long-term cohort studies, and meta-analyses of randomized controlled trials, which show a significant reduction in the risk of cardiovascular events with antihypertensive treatment. 3 National surveys in the UK have shown that a substantial number of patients with hypertension are undertreated, and this is thought to be due to the predominant use of monotherapy alone to control blood pressure. 4,5 The American ALLHAT study (The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) showed that 60% of patients who had achieved a good blood pressure control of <140/90 mm Hg had received two or more antihypertensive agents, and only 30% of patients overall had achieved blood pressure control with a single drug. 6 As many patients require more than one drug to control blood pressure, and clinical trials have shown that following treatment algorithms achieves better blood pressure control, the British Hypertension Society (BHS) recommends a treatment algorithm based on the AB/CD rule, encouraging the effective use of drug combinations. 4 (Figure 1) Drug combinations recommended both by the BHS, and by the European Society of Hypertension (ESH), 7 include the combination of an angiotensin receptor blocker (ARB) and calcium channel blocker (CCB). In addition, the BHS recommends that when fixed dose combination therapy replicates the desired treatment plan for a patient, and when there is no cost disadvantage to their use, they provide a sensible means of reducing the number of tablets required, and may thus aid compliance. The American Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure also recommends the use of a combination of two or more antihypertensives, selected from different drug classes, to achieve blood pressure control. 8 There are now an increasing number of combination therapies on the market, and amlodipine/valsartan fixed dose combination therapy (Exforge ) is a recent addition. Amlodipine/Valsartan Fixed Dose Combination Therapy Indications Amlodipine/valsartan fixed dose combination therapy (Exforge ) is a new ARB and CCB combination, which has been licensed for use in the treatment of 238 Medical Progress May 2008

2 Figure. British Hypertension Society guidelines for combining blood pressure lowering drugs. A = ACE inhibitor or angiotensin receptor blocker (ARB); B = β-blocker; C = calcium-channel blocker; D = diuretic (thiazide) *Combination therapy with B and D may induce more new onset diabetes compared with other combination therapies. essential hypertension, and is indicated in patients whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy. 9 The manufacturers recommend individual dose titration with the component drugs prior to changing to the fixed dose combination, and where clinically appropriate, direct change from monotherapy to the fixed dose combination may be considered. It is currently available in 5 mg/80 mg, 5 mg/160 mg and 10 mg/160 mg combination tablets, and the recommended dose is one tablet a day. Pharmacodynamic and Pharmacokinetic Profile CCBs are amongst the most commonly prescribed antihypertensive medications. 10 Amlodipine, a dihydropyridine CCB, is well known to lower blood pressure effectively. 11,12 Amlodipine inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of its antihypertensive action involves a direct relaxation of vascular smooth muscle and vasodilation, causing reductions in peripheral vascular resistance and blood pressure. After oral administration, peak plasma concentrations of amlodipine are reached in around 6 to 12 hours, and absolute bioavailability is thought to be between 64% and 80%. In vitro studies have shown that over 97% of the drug is bound to plasma proteins, and it is extensively metabolised by the liver. Ten percent of amlodipine and 60% of amlodipine metabolites are renally excreted. Valsartan is a highly selective, nonpeptide antagonist of the angiotensin II receptor, with proven efficacy in blood pressure control. 13 It acts selectively on the receptor subtype AT1, which is responsible for the main vascular actions of angiotensin II. 14 Unlike angiotensin-converting enzyme (ACE) inhibitors, valsartan does not inhibit the breakdown of bradykinins, and hence, is not associated with dry cough. Following oral administration, peak plasma concentrations are achieved within 2 to 4 hours, and mean absolute bioavailability is 23%. Valsartan is also highly bound to plasma proteins, but unlike amlodipine, does not undergo extensive metabolism, and is primarily excreted unchanged in the faeces. Contraindications Absolute contraindications include hypersensitivity to any of the component drugs or dihydropyridine derivatives, and severe hepatic or renal impairment. As excessive hypotension was seen in 0.4% of hypertensive patients in placebo-controlled studies, sodium or volume depleted patients should avoid taking the drug. Also, as with all other vasodilators, particular caution should be taken in patients with aortic or mitral valve stenosis, and hypertrophic obstructive cardiomyopathy. Amlodipine/valsartan combination therapy is contraindicated in pregnancy, particularly in the second and third trimesters, as drugs that interfere with the renin-angiotensin system may cause a number of complications in the fetus, including renal impairment, oligohydramnios, and intrauterine growth retardation. Drug Interactions No drug interaction studies have been performed with amlodipine/valsartan as combination therapy. Diltiazem inhibits the metabolism of amlodipine, probably through the inhibition of cytochrome P3A4 (CYP3A4), increasing the plasma concentration and effect Medical Progress May

3 of amlodipine. Concomitant use of CYP3A4 inducers, including phenytoin and rifampacin, may lead to reduced plasma concentrations of amlodipine. Increases in serum lithium concentrations and toxicity have been reported with ACE inhibitors, and although there is little experience of concomitant use of lithium with valsartan, this combination is not recommended. Adverse Effects A number of controlled clinical trials have evaluated adverse drug reactions associated with both monotherapy and combination therapy. Peripheral oedema, a common adverse effect of amlodipine monotherapy, has been observed at a lower incidence in patients receiving combined amlodipine/valsartan therapy. This could be related to the effect of valsartan of counteracting sodium retention. Other common additional adverse effects associated with amlodipine monotherapy include vomiting, flushing, headache and dizziness. Valsartan monotherapy can cause hyperkalaemia and an acute rise in creatinine. Evidence Base for use in the Treatment of Hypertension Monotherapy with valsartan has been compared to amlodipine in the headto-head Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. 15 The VALUE trial was designed to test the hypothesis that for the same level of blood pressure control, the ARB valsartan would achieve a greater reduction in cardiac morbidity and mortality when compared to amlodipine, in hypertensive patients at high cardiovascular risk. Although blood pressure was reduced in both treatment arms, amlodipine was in fact significantly more effective in reducing blood pressure when compared with valsartan (target blood pressure achieved in 62% of the amlodipine group compared with 56% of the valsartan group). The main outcome of cardiac disease did not differ significantly between the treatment groups. It was noted, however, that peripheral oedema occurred in almost 33% of the amlodipine treated group; over twice that reported in the valsartan treated group. The Val-Syst study, a 24-week, randomized, double blind, active controlled trial, compared the risk/ benefit profiles of valsartan and amlodipine in elderly patients with isolated systolic hypertension, and was conducted at 35 outpatient centres in Italy. 16 Four hundred and twenty-one patients were randomized to either treatment with valsartan 80 mg once a day (208 patients) or amlodipine 5 mg once a day (213 patients). After 8 weeks of treatment, patients with poorly controlled systolic blood pressure underwent dose titration of valsartan to 160 mg, and amlodipine to 10 mg. At week 16, in patients whose SBP was still not adequately controlled, a low-dose thiazide diuretic was added for an additional 8 weeks. The study found that the efficacy of valsartan-based treatment in reducing SBP was similar to that of amlodipine-based treatment, but as in the VALUE study, the frequency of adverse events such as peripheral oedema was significantly higher with amlodipine than with valsartan. Several studies have compared valsartan/hydrochlorothiazide combination therapy to amlodipine monotherapy, showing that combination therapy is as effective as amlodipine, but better tolerated Randomized controlled trials have similarly since evaluated the efficacy and tolerability of amlodipine and valsartan both in combination and as monotherapy in hypertension, to determine whether combination therapy provides enhanced efficacy when compared to its individual components. Philipp et al conducted two 8-week multinational, multicentre, randomized, double-blind and placebo-controlled trials. 21 In study 1, a total of 1,911 patients were randomized to receive either amlodipine monotherapy, (2.5 mg or 5 mg once daily); valsartan monotherapy (40 to 320 mg, once daily); amlodipine and valsartan combination therapy (2.5 or 5 mg combined with 40 to 320 mg respectively); or placebo. Study 2 randomized 1,250 patients into similar groups to those in study 1, but used higher doses of amlodipine (10 mg) and valsartan (160 mg to 320 mg) both as monotherapy and combined therapy. Primary efficacy was assessed by measuring the reduction from baseline of mean sitting diastolic and systolic blood pressures (MSDBP and MSSBP, respectively), and safety was assessed in terms of adverse events. The combination regimens in both studies were associated with significantly greater reductions in MSDBP and MSSBP when compared with their individual components and placebo, and a positive dose response was associated with all combinations. The incidence of peripheral oedema with combination therapy was also lower when compared with amlodipine monotherapy. Another randomized, double-blind, parallel group study by Poldermans et al evaluated the overall safety profile and efficacy of amlodipine/valsartan combination therapy in comparison to lisinopril/hydrochlorothiazide combination therapy, over a 6-week period, in patients with stage 2 hypertension (SBP >160 or DBP >100 mm Hg). 22 Of the 130 patients who were randomized to treatment, 128 completed the study (63 in the amlodipine/valsartan group, and 65 in the lisinopril/ hydrochlorothiazide group). Both regimens were generally well tolerated; although adverse events were reported in 40.6% of patients receiving amlodipine/ valsartan and 31.8% patients receiving 240 Medical Progress May 2008

4 Practice Points Good blood pressure control reduces cardiovascular events and improves outcome. Most patients with hypertension require more than one drug to control blood pressure. An amlodipine/valsartan combination reduces blood pressure effectively and is well tolerated. The simple dosage regimen may aid compliance with therapy. lisinopril/hydrochlorothiazide, most were mild to moderate in severity. The commonest adverse events in the amlodipine/valsartan group included headache (10.9%) and peripheral oedema (7.8%), whereas diarrhoea (6.1%) and pharyngitis (6.1%) were the commonest in the lisinopril/ hydrochlorothiazide group. Peripheral oedema occurred more frequently in the amlodipine/valsaratan group than the lisinopril/hydrochlorothiazide group (7.8% vs 1.5%, respectively), whereas the incidence of cough was lower in the amlodipine/valsartan group than in the lisinopril/hydrochlorothiazide group (1.6% vs 3.0%). At 6 weeks, both groups had achieved significant reductions in blood pressure from baseline, and the response rates (proportion of patients with an MSDBP <90 mm Hg or a >10 mm Hg reduction from baseline) at the end of the study were similar in both patient groups, with 100% of patients receiving amlodipine/valsartan, and 95.5% of patients receiving lisinopril/ hydrochlorothiazide responding to treatment. Overall blood pressure control of <140/90 mm Hg was achieved in 67.2% and 56.1%, respectively. The long-term outcomes of treatment with amlodipine or valsartan have been investigated in large scale randomized clinical trials. 23,24 An amlodipine-based regimen has been shown to be superior in terms of blood pressure control and event reduction. 23 Although valsartan may appear less efficacious than amlodipine in the immediate control of blood pressure, 15 it reduces the risk of development of diabetes. Candesartan, another drug in the same class, has been shown to delay the development of hypertension. 25 The combination of amlodipine and valsartan may therefore provide the combined benefits of good blood pressure control and protection against end-organ damage and diabetes. Place in Therapy In Asia, diabetes and dysglycaemia are common, especially in people with hypertension. 26 In hypertensive patients with these conditions, diuretics and β-blockers might be less desirable as first-line drugs. Conversely, amlodipine does not worsen the metabolic profile while valsartan might actually help to prevent progression to diabetes. Both are very well tolerated in Asians, 27 whereas ACE inhibitors are less well tolerated in Chinese because of dry cough. 28 Over two-thirds of hypertensive patients will require more than one antihypertensive agent to achieve adequate blood pressure control. Amlodipine/valsartan fixed dose combination therapy is relatively well tolerated, and has been associated with greater significant reductions in blood pressure, when compared to its individual components. Other major advantages of combination therapy include a lower incidence of peripheral oedema, and although trial evidence is lacking, the possibility of improved compliance with treatment. References 1. Padwal R, Straus SE, McAlister FA. Cardiovascular risk factors and their effects on the decision to treat hypertension: Evidence-based review. BMJ 2001;322: Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: A meta-analysis. Lancet 2001;358: Turnbull F; Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressurelowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials. Lancet 2003;362: Williams B, Poulter, Brown MJ, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS IV): Summary. BMJ 2004;328: Primesta P, Brookes M, Poulter NR. Improved hypertension management and control: Results from the health survey for England Hypertension 2001;38: Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American Settings: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens 2000;2: Mancia G, De Backer G, Dominiczak A, et al. Guidelines for the management of arterial hypertension: The Task Force for the management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertension 2007;25: Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure. Hypertension 2003;42: Amlodipine/Valsartan SPC (Exforge 5mg/80 mg, 5mg/160 mg, 10 mg/160 mg film coated tablets). Available at: Accessed 11 Mar Cheung BMY, Wong YL, Lau CP. Queen Mary Utilisation of Antihypertensive Drugs Study: Use of antihypertensive drug classes in the hypertension clinic Brit J Clin Pharmacol 2005;30: Lau CP, Cheung BMY. Relative efficacy and tolerability of lacidipine and amlodipine in patients with mild-tomoderate hypertension: A randomised double-blind study. J Cardiovasc Pharmacol 1996;28: Cheung BMY, Lau CP, Wu BZ. Efficacy and tolerability of three new dihydropyridine calcium channel blockers: Amlodipine, felodipine and isradipine. Clin Ther 1998;2: Criscione L, De Gasparo M, Buhlmayer P, et al. Pharmacological profile of valsartan: A potent, orally active, nonpeptide antagonist of the angiotensin II AT1 receptor. Br J Pharmacol 1993;110: Cheung BMY. The therapeutic potential of angiotensin receptor blockers for hypertension. Expert Opin Investig Drugs 2006;15: Julius S, Kjeldsen SE, Weber M, et al. Outcomes in Medical Progress May

hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet 2004;363:2022-2031. 16.

A randomized, double blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: The Val-Syst study.

5 hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet 2004;363: Malacco E, Vari N, Capuano V, et al. A randomized, double blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: The Val-Syst study. Clin Ther 2003;25: Franco RJ, Goldflus S, McQuitty M, Oigman W. Efficacy and tolerability of the combination valsaratan/ hydrochlorothiazide compared with amlodipine in a mild-tomoderately hypertensive Brazilian population. Blood Press Suppl 2003;2: Ruilope LM, Malacco E, Khyder Y, Kandra A, Bonner G, Heintz D. Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: The VAST study. Clin Ther 2005;27: Palatini P, Malacco E, Fogari R, Carretta R. A multicenter, randomized double-blind study of valsartan/hydrochlorothiazide combination versus amlodipine in patients with mild to moderate hypertension. J Hypertens 2001;19: Weir MR, Ferdinand KC, Flack JM, Jamerson KA, Daley W, Zelenkofske S. A noninferiority comparison of valsartan/ hydrochlorothiazide combination versus amlodipine in black hypertensives. Hypertension 2005;46: Philipp T, Smith TR, Glazer R et al. Two multicenter, 8-week randomised, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. Clinical Therapeutics 2007;29: Poldermans D, Glazes R, Kargiannis S, et al. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension. Clin Ther 2007;29: Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre randomised controlled trial. Lancet 2005;366: Cheung BMY, Cheung GTY, Lauder IJ, Lau CP, Kumana CR. Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension. J Hum Hypertens 2006; 20: Julius S, Nesbitt SD, Egan BM, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354: Cheung BMY, Wat NMW, Man YB, et al. Relationship between metabolic syndrome and the development of hypertension in the Hong Kong Cardiovascular Risk Factor Prevalence Study 2. Am J Hypertens 2008;21: Cheung BMY, Wong YL, Lau CP. Queen Mary Utilisation of Antihypertensive Drugs Study: Side-effects of antihypertensive drugs. J Clin Pharm Ther 2005;30: Woo KS, Nicholls MG. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. Br J Clin Pharmacol 1995;40: About the Authors Dr Butt is a Lecturer and Specialist Registrar and Professor Cheung is Professor at the Department of Clinical Pharmacology and Therapeutics, University of Birmingham, and University Hospitals Birmingham NHS Trust, United Kingdom. b.cheung@bham.ac.uk CALL FOR PAPERS Medical Progress welcomes papers of the following categories: Review Articles Comprehensive reviews providing the latest clinical information on all aspects of management of medical conditions. Case Studies Interesting cases seen in general practice and their management. Pictorial Medicine Vignettes of cases illustrated with clinical photographs. For more information, please refer to the Instructions for Authors on our Website or contact: The Editor Medical Progress Unit , 9th Floor, AXA Centre 151 Gloucester Road Wan Chai, Hong Kong Tel: (852) Fax: (852) enquiry@medicalprogress.com 242 Medical Progress May 2008

In the Literature 1001 BP of 1.1 mm Hg). The trial was stopped early based on prespecified stopping rules because of a significant difference in cardi

In the Literature 1001 BP of 1.1 mm Hg). The trial was stopped early based on prespecified stopping rules because of a significant difference in cardi Is Choice of Antihypertensive Agent Important in Improving Cardiovascular Outcomes in High-Risk Hypertensive Patients? Commentary on Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators.