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Valsartan (Diovan®) is an oral angiotensin II-receptor antagonist with specificity for the angiotensin II type 1 receptor subtype. It demonstrates antihypertensive activity and slows the progression of chronic heart failure (CHF). Recently it has been evaluated in comparison with an ACE inhibitor regimen in patients with heart failure or left ventricular systolic dysfunction (LVSD) after an acute myocardial infarction (MI), a population known to be at high risk of subsequent death or other major cardiovascular events.
In the VALIANT (VALsartan In Acute myocardial iNfarcTion) trial, valsartan was as effective as captopril at reducing mortality and cardiovascular morbidity in patients who developed heart failure and/or LVSD after surviving an MI. It was also generally well tolerated in this population. Treatment with a combination of valsartan plus captopril provided no additional therapeutic benefit over treatment with captopril and was less well tolerated. Valsartan has a potential role as a new treatment for high-risk patients in the post-MI setting.
In animal models of MI, valsartan reduced left ventricular remodeling, preserved systolic function, and reversed myocardial β-adrenergic derangements.
After administration of multiple oral doses of valsartan 40–160mg twice daily to patients with CHF, valsartan was rapidly absorbed, reaching mean peak plasma concentrations (Cmax) after 2.5–3 hours. Mean Cmax and area under the plasma concentration-time curve values increased in a linear and nearly proportional fashion with increasing valsartan dosages. Steady-state plasma concentrations were reached in 7 days. Mean apparent clearance was approximately 4.5 L/h and the elimination half-life was 5.2–6.6 hours. Age, severity of heart failure, and body weight did not significantly influence the pharmacokinetics of valsartan. Valsartan is minimally metabolized and is excreted largely as unchanged drug, with clearance occurring predominantly via bile.
The VALIANT trial was a large (n = 14 703), randomized, double-blind, multinational study in patients who developed heart failure and/or LVSD after surviving an acute MI. Patients received either valsartan titrated to a target dosage of 160mg twice daily, captopril titrated to a target dosage of 50mg three times daily, or a combination of valsartan titrated to a target dosage of 80mg twice daily plus captopril titrated to a target dosage of 50mg three times daily. Median follow-up was 24.7 months.
The rate of mortality from any cause (primary endpoint) was similar for all three treatment groups (≈20%). The hazard ratio for death for valsartan compared with captopril was 1.00 (97.5% CI 0.90, 1.11; p = 0.98), and that for valsartan plus captopril compared with captopril 0.98 (97.5% CI 0.89, 1.09; p = 0.73).
Secondary endpoints, including death from cardiovascular causes and a hierarchy of composite endpoints of fatal and nonfatal cardiovascular events, were met by similar proportions of patients in all three groups, with hazard ratios for valsartan or valsartan plus captopril versus captopril ranging from 0.95 to 1.00 for each of the endpoints.
Noninferiority analyses confirmed that valsartan was no less effective than captopril at reducing the risk of all-cause death (primary endpoint) and cardiovascular mortality and morbidity (secondary endpoints). The same relative efficacy was found in all subgroups, including those taking β-adrenoceptor antagonists (β-blockers).
In the VALIANT study, valsartan titrated to 160mg twice daily was generally well tolerated in patients with heart failure and/or LVSD after an MI.
Valsartan was associated with significantly fewer treatment discontinuations related to adverse events than captopril. The incidence of adverse event-related dosage reductions or treatment discontinuations was significantly higher among patients who received the combination of valsartan plus captopril (titrated to 80mg twice daily and 50mg three times daily, respectively) than among recipients of captopril.
The valsartan group had a significantly higher incidence of hypotension leading to dosage reduction or treatment discontinuation and significantly more renal dysfunction leading to dosage reduction, but significantly less cough, rash, and taste disturbance leading to dosage reduction or discontinuation than the captopril group.
Various sections of the manuscript reviewed by:
- Adams KF. Pathophysiologic role of the renin-angiotensin-aldosterone and sympathetic nervous systems in heart failure. Am J Health-Syst Pharm 2004 May 1; 61 Suppl. 2: S4–13
- Nolan PE. Integrating traditional and emerging treatment options in heart failure. Am J Health-Syst Pharm 2004 May 1; 61 Suppl. 2: S14–22
- Burnier M. Angiotensin II type 1 receptor blockers. Circulation 2001; 103: 904–12 CrossRef
- Franzosi MG. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998; 97: 2202–12 CrossRef
- Flather MD, Yusuf S, Køber L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. The ACE Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000 May 6; 355: 1575–81 CrossRef
- Spencer FA, Meyer TE, Gore JM, et al. Heterogeneity in the management and outcomes of patients with acute myocardial infarction complicated by heart failure. Circulation 2002; 105: 2605–10 CrossRef
- Vaur L, Danchin N, Genès N, et al. Epidemiology of myocardial infarction in France: therapeutic and prognostic implications of heart failure during the acute phase. Am Heart J 1999; 137: 49–58 CrossRef
- Hasdai D, Topol EJ, Kilaru R, et al. Frequency, patient characteristics, and outcomes of mild-to-moderate heart failure complicating ST-segment elevation acute myocardial infarction: lessons from 4 international fibrinolytic therapy trials. Am Heart J 2003; 145: 73–9 CrossRef
- Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. N Engl J Med 2003 Apr 3; 348(14): 1309–21 CrossRef
- Pfeffer MA, McMurray J, Leizorovicz A, et al. Valsartan in acute myocardial infarction trial (VALIANT): rationale and design. Am Heart J 2000 Nov; 140(5): 727–34 CrossRef
- Patterson JH. Angiotensin II receptor blockers in heart failure. Pharmacotherapy 2003; 23(2): 173–82 CrossRef
- Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure: the Valsartan Heart Failure Trial Investigators. N Engl J Med 2001; 345(23): 1667–75 CrossRef
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003 Nov 13; 349(20): 1893–906 CrossRef
- Markham A, Goa KL. Valsartan: a review of its pharmacology and therapeutic use in essential hypertension. Drugs 1997 Aug; 54(2): 299–311 CrossRef
- Wellington K, Goa KL. Valsartan: in chronic heart failure. Am J Cardiovasc Drugs 2002; 2(4): 267–74; discussion 275-6 CrossRef
- Criscione L, de Gasparo M, Buhlmayer P, et al. Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II ATI-receptor subtype. Br J Pharmacol 1993; 110(2): 761–71 CrossRef
- de Gasparo M, Whitebread S. Binding of valsartan to mammalian angiotensin AT1 receptors. Regul Pept 1995; 59: 303–11 CrossRef
- Criscione L, Bradley WA, Bühlmayer P, et al. Valsartan: preclinical and clinical profile of an antihypertensive angiotensin-II antagonist. Cardiovasc Drug Rev 1995; 13(3): 230–50 CrossRef
- Mazayev VP, Fomina IG, Kazakov EN, et al. Valsartan in heart failure patients previously untreated with an ACE inhibitor. Int J Cardiol 1998 Aug; 65(3): 239–46 CrossRef
- Baruch L, Anand I, Cohen IS, et al. Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure: Vasodilator Heart Failure Trial (V-HeFT) Study Group. Circulation 1999 May 25; 99(20): 2658–64 CrossRef
- Wong M, Staszewsky L, Latini R, et al. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol 2002 Sep 4; 40(5): 970–5 CrossRef
- Makino T, Hattori Y, Matsuda N, et al. Effects of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on β-adrenoceptor signaling in heart failure produced by myocardial infarction in rabbits: reversal of altered expression of β-adrenoceptor kinase and Giα. J Pharmacol Exp Ther 2003 Jan; 304(1): 370–9 CrossRef
- Gurevich AK, Falk SA, Nemenoff RA, et al. Effects of angiotensin receptor blockade on haemodynamics and gene expression after myocardial infarction. Drugs R D 2002; 3(4): 239–49 CrossRef
- Jugdutt BI, Menon V. Valsartan-induced cardioprotection involves angiotensin II type 2 receptor upregulation in dog and rat models of in vivo reperfused myocardial infarction. J Card Fail 2004 Feb; 10(1): 74–82 CrossRef
- Randsbaek F, Lund S, Kimose HH, et al. Angiotensin II inhibition increases cellular glucose transport during reperfusion but not ischemia in pig hearts. Scand Cardiovasc J 2003 Sep; 37(4): 205–10 CrossRef
- Kasama S, Toyama T, Kumakura H, et al. Addition of valsartan to an angiotensinconverting enzyme inhibitor improves cardiac sympathetic nerve activity and left ventricular function in patients with congestive heart failure. J Nucl Med 2003 Jun; 44(6): 884–90
- Latini R, Masson S, Anand I, et al. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). The Val-HeFT Investigators. Circulation 2002 Nov 5; 106(19): 2454–8 CrossRef
- Cohn JN, Anand IS, Latini R, et al. Sustained reduction of aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial. The Valsartan Heart Failure Trial Investigators. Circulation 2003 Sep 16; 108(11): 1306–9 CrossRef
- Klingbeil AU, John S, Schneider MP, et al. ATI-receptor blockade improves augmentation index: a double-blind, randomized, controlled study. J Hypertens 2002; 20: 2423–8 CrossRef
- Shargorodsky M, Leibovitz E, Lubimov L, et al. Prolonged treatment with the ATI receptor blocker, valsartan, increases small and large artery compliance in uncomplicated essential hypertension. Am J Hypertens 2002; 15: 1087–91 CrossRef
- Klingbeil AU, John S, Schneider MP, et al. Effect of AT1 receptor blockade on endothelial function in essential hypertension. Am J Hypertens 2003; 16: 123–8 CrossRef
- Serebruany VL, Malinin AI, Lowry DR, et al. Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: a possible additional mechanism for clinical benefits. J Cardiovasc Pharmacol 2004 May; 43(5): 677–84 CrossRef
- Prasad PP, Yeh CM, Gurrieri P, et al. Pharmacokinetics of multiple doses of valsartan in patients with heart failure. J Cardiovasc Pharmacol 2002 Nov; 40(5): 801–7 CrossRef
- Muller P, Flesch G, de Gasparo M, et al. Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects. Eur J Clin Pharmacol 1997; 52(6): 441–9 CrossRef
- Flesch G, Müller P, Lloyd P. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol 1997; 52(2): 115–20 CrossRef
- Colussi DM, Parisot C, Rossolino ML, et al. Protein binding in plasma of valsartan, a new angiotensin II receptor antagonist. J Clin Pharmacol 1997; 37(3): 214–21
- Waldmeier F, Flesch G, Muller P, et al. Pharmacokinetics, disposition and bio-transformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose. Xenobiotica 1997 Jan; 27(1): 59–71 CrossRef
- Prasad P, Mangat S, Choi L, et al. Effect of renal function on the pharmacokinetics of valsartan. Clinical Drug Invest 1997; 13(4): 207–14 CrossRef
- Brookman LJ, Rolan PE, Benjamin IS, et al. Pharmacokinetics of valsartan in patients with liver disease. Clin Pharmacol Ther 1997; 62(3): 272–8 CrossRef
- Novartis Pharmaceuticals Corporation. Diovan® (valsartan) tablets prescribing information (US). 2002 Aug [online]. Available from URL: http://www.novartis.com [Accessed 2004 Jun 1]
- Velazquez EJ, Pfeffer MA, McMurray JV, et al. VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context. Eur J Heart Fail 2003 Aug; 5(4): 537–44 CrossRef
- Bristol-Myers Squibb Company. Capoten® (captopril tablets) prescribing information (US). 1996 April [online]. Available from URL: http://www.bms.com [Accessed 2004 Jun 2]
- Data on file, Novartis Pharma AG, 2004 Oct 15
- Novartis Pharma. Diovan® prescribing information (Switzerland) [in French]. 2003 Jan [online]. Available from URL: http://kompendium.ch [Accessed 2004 Jun 1]
- Van de Werf F, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003 Jan; 24(1): 28–66 CrossRef
- Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 1999; 100: 1016–30 CrossRef
- Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch Intern Med 2003 May 26; 163: 1155–64 CrossRef
- Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992 Sep 3; 327(10): 669–77 CrossRef
- Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure: Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993 Oct 2; 342 (8875): 821-8
- Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995 Dec 21; 333: 1670–6 CrossRef
- Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). Circulation 2001; 104: 2996–3007 CrossRef
- Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure: Taskforce for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Eur Heart J 2001; 22: 1527–60 CrossRef
- Velazquez EJ, Weaver D, Armstrong P, et al. Heart failure and/or left ventricular systolic dysfunction complicating myocardial infarction is common and accounts for the majority of in-hospital myocardial infarction mortality: results of the VALIANT registry [abstract plus poster]. 52nd Annual Scientific Session of American College Cardiology; 2003 Mar 30–Apr 2; Chicago [online]. Available from URL: http://www.valianttrial.com [Accessed 2004 Jun 1]
- Dickstein K, Kjekshus J, OPTIMAAL Steering Committee. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. The OPTIMAAL Study Group. Lancet 2002 Sep 7; 360: 752–60 CrossRef
- Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. The CAPRICORN Investigators. Lancet 2001 May 5; 357: 1385–90 CrossRef
- Wolny A, Clozel J-P, Rein J, et al. Functional and biochemical analysis of angiotensin II-forming pathways in the human heart. Circ Res 1997; 80: 219–27 CrossRef
- Jorde UP, Ennezat PV, Lisker J, et al. Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 2000 Feb 29; 101(8): 844–6 CrossRef
- Dickstein K. What did we learn from the OPTIMAAL trial? What can we expect from VALIANT? Am Heart J 2003 May; 145(5): 754–7 CrossRef
- McMurray JJV, Östergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003 Sep 6; 362: 767–71 CrossRef
- Bart BA, Ertl G, Held P, et al. Contemporary management of patients with left ventricular systolic dysfunction: results from the study of patients intolerant of converting enzyme inhibitors (SPICE) registry. Eur Heart J 1999; 20: 1182–90 CrossRef
- Granger CB, Ertl G, Kuch J, et al. Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Am Heart J 2000; 139: 609–17 CrossRef
- Granger CB, McMurray JJV, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003 Sep 6; 362: 772–6 CrossRef
- Mann DL, Deswal A. Angiotensin-receptor blockade in acute myocardial infarction: a matter of dose. N Engl J Med 2003 Nov 13; 349(20): 1963–5 CrossRef
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