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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.
- 5.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: 1575–81PubMedCrossRefGoogle Scholar
- 9.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): 1309–21PubMedCrossRefGoogle Scholar
- 13.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): 1893–906PubMedCrossRefGoogle Scholar
- 20.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): 2658–64PubMedCrossRefGoogle Scholar
- 22.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): 370–9PubMedCrossRefGoogle Scholar
- 28.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): 1306–9PubMedCrossRefGoogle Scholar
- 40.Novartis Pharmaceuticals Corporation. Diovan® (valsartan) tablets prescribing information (US). 2002 Aug [online]. Available from URL: http://www.novartis.com [Accessed 2004 Jun 1]Google Scholar
- 42.Bristol-Myers Squibb Company. Capoten® (captopril tablets) prescribing information (US). 1996 April [online]. Available from URL: http://www.bms.com [Accessed 2004 Jun 2]Google Scholar
- 43.Data on file, Novartis Pharma AG, 2004 Oct 15Google Scholar
- 44.Novartis Pharma. Diovan® prescribing information (Switzerland) [in French]. 2003 Jan [online]. Available from URL: http://kompendium.ch [Accessed 2004 Jun 1]Google Scholar
- 45.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): 28–66PubMedCrossRefGoogle Scholar
- 46.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: 1016–30PubMedCrossRefGoogle Scholar
- 48.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): 669–77PubMedCrossRefGoogle Scholar
- 49.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): 821-8Google Scholar
- 51.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: 2996–3007PubMedCrossRefGoogle Scholar
- 53.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]Google Scholar