Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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, K.F. (2004) Pathophysiologic role of the renin-angiotensin-aldosterone and sympathetic nervous systems in heart failure. Am J Health-Syst Pharm 61: pp. S4-13
- Nolan, P.E. (2004) Integrating traditional and emerging treatment options in heart failure. Am J Health-Syst Pharm 61: pp. S14-22
- Burnier, M. (2001) Angiotensin II type 1 receptor blockers. Circulation 103: pp. 904-12 CrossRef
- Franzosi, M.G. (1998) 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 97: pp. 2202-12 CrossRef
- Flather, M.D., Yusuf, S., Køber, L. (2000) 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 355: pp. 1575-81 CrossRef
- Spencer, F.A., Meyer, T.E., Gore, J.M. (2002) Heterogeneity in the management and outcomes of patients with acute myocardial infarction complicated by heart failure. Circulation 105: pp. 2605-10 CrossRef
- Vaur, L., Danchin, N., Genès, N. (1999) Epidemiology of myocardial infarction in France: therapeutic and prognostic implications of heart failure during the acute phase. Am Heart J 137: pp. 49-58 CrossRef
- Hasdai, D., Topol, E.J., Kilaru, R. (2003) 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 145: pp. 73-9 CrossRef
- Pitt, B., Remme, W., Zannad, F. (2003) 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 348: pp. 1309-21 CrossRef
- Pfeffer, M.A., McMurray, J., Leizorovicz, A. (2000) Valsartan in acute myocardial infarction trial (VALIANT): rationale and design. Am Heart J 140: pp. 727-34 CrossRef
- Patterson, J.H. (2003) Angiotensin II receptor blockers in heart failure. Pharmacotherapy 23: pp. 173-82 CrossRef
- Cohn, J.N., Tognoni, G. (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure: the Valsartan Heart Failure Trial Investigators. N Engl J Med 345: pp. 1667-75 CrossRef
- Pfeffer, M.A., McMurray, J.J., Velazquez, E.J. (2003) 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 349: pp. 1893-906 CrossRef
- Markham, A., Goa, K.L. (1997) Valsartan: a review of its pharmacology and therapeutic use in essential hypertension. Drugs 54: pp. 299-311 CrossRef
- Wellington, K., Goa, K.L. (2002) Valsartan: in chronic heart failure. Am J Cardiovasc Drugs 2: pp. 267-74 CrossRef
- Criscione, L., Gasparo, M., Buhlmayer, P. (1993) Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II ATI-receptor subtype. Br J Pharmacol 110: pp. 761-71 CrossRef
- Gasparo, M., Whitebread, S. (1995) Binding of valsartan to mammalian angiotensin AT1 receptors. Regul Pept 59: pp. 303-11 CrossRef
- Criscione, L., Bradley, W.A., Bühlmayer, P. (1995) Valsartan: preclinical and clinical profile of an antihypertensive angiotensin-II antagonist. Cardiovasc Drug Rev 13: pp. 230-50 CrossRef
- Mazayev, V.P., Fomina, I.G., Kazakov, E.N. (1998) Valsartan in heart failure patients previously untreated with an ACE inhibitor. Int J Cardiol 65: pp. 239-46 CrossRef
- Baruch, L., Anand, I., Cohen, I.S. (1999) 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 99: pp. 2658-64 CrossRef
- Wong, M., Staszewsky, L., Latini, R. (2002) Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol 40: pp. 970-5 CrossRef
- Makino, T., Hattori, Y., Matsuda, N. (2003) 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 304: pp. 370-9 CrossRef
- Gurevich, A.K., Falk, S.A., Nemenoff, R.A. (2002) Effects of angiotensin receptor blockade on haemodynamics and gene expression after myocardial infarction. Drugs R D 3: pp. 239-49 CrossRef
- Jugdutt, B.I., Menon, V. (2004) Valsartan-induced cardioprotection involves angiotensin II type 2 receptor upregulation in dog and rat models of in vivo reperfused myocardial infarction. J Card Fail 10: pp. 74-82 CrossRef
- Randsbaek, F., Lund, S., Kimose, H.H. (2003) Angiotensin II inhibition increases cellular glucose transport during reperfusion but not ischemia in pig hearts. Scand Cardiovasc J 37: pp. 205-10 CrossRef
- Kasama, S., Toyama, T., Kumakura, H. (2003) 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 44: pp. 884-90
- Latini, R., Masson, S., Anand, I. (2002) 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 106: pp. 2454-8 CrossRef
- Cohn, J.N., Anand, I.S., Latini, R. (2003) 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 108: pp. 1306-9 CrossRef
- Klingbeil, A.U., John, S., Schneider, M.P. (2002) ATI-receptor blockade improves augmentation index: a double-blind, randomized, controlled study. J Hypertens 20: pp. 2423-8 CrossRef
- Shargorodsky, M., Leibovitz, E., Lubimov, L. (2002) Prolonged treatment with the ATI receptor blocker, valsartan, increases small and large artery compliance in uncomplicated essential hypertension. Am J Hypertens 15: pp. 1087-91 CrossRef
- Klingbeil, A.U., John, S., Schneider, M.P. (2003) Effect of AT1 receptor blockade on endothelial function in essential hypertension. Am J Hypertens 16: pp. 123-8 CrossRef
- Serebruany, V.L., Malinin, A.I., Lowry, D.R. (2004) Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: a possible additional mechanism for clinical benefits. J Cardiovasc Pharmacol 43: pp. 677-84 CrossRef
- Prasad, P.P., Yeh, C.M., Gurrieri, P. (2002) Pharmacokinetics of multiple doses of valsartan in patients with heart failure. J Cardiovasc Pharmacol 40: pp. 801-7 CrossRef
- Muller, P., Flesch, G., Gasparo, M. (1997) Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects. Eur J Clin Pharmacol 52: pp. 441-9 CrossRef
- Flesch, G., Müller, P., Lloyd, P. (1997) Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol 52: pp. 115-20 CrossRef
- Colussi, D.M., Parisot, C., Rossolino, M.L. (1997) Protein binding in plasma of valsartan, a new angiotensin II receptor antagonist. J Clin Pharmacol 37: pp. 214-21
- Waldmeier, F., Flesch, G., Muller, P. (1997) Pharmacokinetics, disposition and bio-transformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose. Xenobiotica 27: pp. 59-71 CrossRef
- Prasad, P., Mangat, S., Choi, L. (1997) Effect of renal function on the pharmacokinetics of valsartan. Clinical Drug Invest 13: pp. 207-14 CrossRef
- Brookman, L.J., Rolan, P.E., Benjamin, I.S. (1997) Pharmacokinetics of valsartan in patients with liver disease. Clin Pharmacol Ther 62: pp. 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, E.J., Pfeffer, M.A., McMurray, J.V. (2003) VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context. Eur J Heart Fail 5: pp. 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]
- Werf, F., Ardissino, D., Betriu, A. (2003) 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 24: pp. 28-66 CrossRef
- Ryan, T.J., Antman, E.M., Brooks, N.H. (1999) 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 100: pp. 1016-30 CrossRef
- Jacoby, D.S., Rader, D.J. (2003) Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch Intern Med 163: pp. 1155-64 CrossRef
- Pfeffer, M.A., Braunwald, E., Moye, L.A. (1992) 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 327: pp. 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, J.E. (1995) A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 333: pp. 1670-6 CrossRef
- Hunt, S.A., Baker, D.W., Chin, M.H. (2001) 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 104: pp. 2996-3007 CrossRef
- Remme, W.J., Swedberg, K. (2001) 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 22: pp. 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. (2002) 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 360: pp. 752-60 CrossRef
- Dargie, H.J. (2001) Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. The CAPRICORN Investigators. Lancet 357: pp. 1385-90 CrossRef
- Wolny, A., Clozel, J.-P., Rein, J. (1997) Functional and biochemical analysis of angiotensin II-forming pathways in the human heart. Circ Res 80: pp. 219-27 CrossRef
- Jorde, U.P., Ennezat, P.V., Lisker, J. (2000) Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure. Circulation 101: pp. 844-6 CrossRef
- Dickstein, K. (2003) What did we learn from the OPTIMAAL trial? What can we expect from VALIANT. Am Heart J 145: pp. 754-7 CrossRef
- McMurray, J.J.V., Östergren, J., Swedberg, K. (2003) 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 362: pp. 767-71 CrossRef
- Bart, B.A., Ertl, G., Held, P. (1999) 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 20: pp. 1182-90 CrossRef
- Granger, C.B., Ertl, G., Kuch, J. (2000) 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 139: pp. 609-17 CrossRef
- Granger, C.B., McMurray, J.J.V., Yusuf, S. (2003) 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 362: pp. 772-6 CrossRef
- Mann, D.L., Deswal, A. (2003) Angiotensin-receptor blockade in acute myocardial infarction: a matter of dose. N Engl J Med 349: pp. 1963-5 CrossRef
American Journal of Cardiovascular Drugs
Volume 4, Issue 6 , pp 395-404
- Cover Date
- Print ISSN
- Online ISSN
- Springer International Publishing
- Additional Links
- Industry Sectors