1. Valsartan is as effective as captopril in reducing morbidity and mortality in post-MI patients with HF or LVD.
2. In this population, combined therapy [an ARB + an ACE-I] increased adverse effects but did not decrease morbidity or mortality over either agent alone in this patient population.
3. In patients with chronic symptomatic systolic HF, other studies (Val- HeFT, CHARM) suggest that combination therapy decreases hospitalizations for CHF.

Source of Funding

Novartis Pharmaceuticals

Study Design

Randomized, double-blind trial at 931 centers in 24 countries

Participants

14703 mostly white subjects (mean age 65, 30% female) who were post-MI (median 4.9 days; range 0.5-10 days) complicated by predominantly Killip class I and II HF or had evidence of left ventricular systolic dysfunction (EF <35%). The majority of MIs were anterior with Q waves. Many patients received either thrombolytic therapy or percutaneous interventions, and at baseline 39% were on ACE-Is, 70% on B-blockers, 91% on ASA, 25% on other antiplatelet drugs, 50% on a diuretic and 34% on statins.

Exclusions

Systolic blood pressure<100 mmHg, serum Cr > 2.5 mg/dL, previous intolerance or contraindication to an ACE-I or ARB, clinically significant valvular disease, or presence of another disease known to limitlife expectancy.

Intervention/Exposure

Patients were randomized to either valsartan 20mg daily, valsartan 20mg plus captopril 6.25mg, or 6.25mg captopril and subsequently titrated up to a maximum of valsartan 160mg BID, valsartan 80mg BID plus captopril 50mg TID or captopril 50mg TID by 3 months.

Primary Outcome

Death from any cause

Secondary Outcomes

Death from cardiovascular causes, recurrent MI, or hospitalization for HF

Follow-up

24.7 months; 0.9% lost to follow-up

Analysis

Intention to treat

Results

	Valsartan N=4909	Combination*  N=4885	Captopril N=4909	Valsartan vs Captopril	Combination vs. Captopril
				HR (97.5% CI)	HR (97.5% CI)
All-Cause Mortality	19.9%	19.3%	19.5%	1.00 (0.90-1.11) p=0.98	0.98 (0.89-1.09) p=0.73
CV Death, MI, or HF	31.1%	31.1%	31.9%	0.95 (0.88-1.03)  p=0.20	0.97(0.89-1.05)  P=0.37
CV Death or HF	27%	27.2%	27%	0.97 (0.90-1.05) p=0.51	1.0 (0.92-1.09) p=0.94

*Combination= Valsartan plus Captopril
HF= heart failure hospitalizations

• Valsartan was equally efficacious in reducing primary and secondary endpoints compared to captopril.
• Combination therapy did not offer any additional benefit over either agent alone.
• Adverse effects resulting in dose reduction were greater with combination therapy: valsartan 29.4%, captopril 28.4%, and combination 34.8% (**p<0.05, compared to captopril)

Comments

1. There have been three recent large, well-designed studies in patients with LVD + HF comparing the mortality and morbidity of treatment with an ACE-I to that of combination therapy with an ARB and an ACE-I. This study revealed that combination therapy provided no additional benefit in patients with a very recent MI complicated by HF or low EF. The other two studies (CHARM¹-candesartan, Val-HeFT²-valsartan) were conducted in patients with chronic systolic HF who were more symptomatic from HF at baseline. In these studies, the primary outcome was combined mortality plus hospitalization for worsening heart failure. Both studies found that the combination significantly improved the primary outcome, mainly due to a significant decrease in heart failure hospitalizations.
2. ACE-I should still be used as first line therapy for patients post-MI complicated by heart failure or LVD due to reduced costs, however, valsartan would be an equally effective alternative if a patient cannot tolerate an ACE-I.

Journal Club created by: Sharon See, Pharm. D, St. John's University College of Pharmacy and Allied Health Professions