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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.
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