Highlights from the American Heart Association annual scientific sessions 2003: November 9 to 12, 2003☆

Study: 

Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both

Presenter: 

Dr Marc A. Pfeffer, Brigham and Women's Hospital, Boston, Mass

Background: 

Angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to reduce mortality and morbidity after myocardial infarction (MI), especially for patients with low ejection fraction or clinical heart failure.1, 2 Not all patients are able to tolerate ACE inhibitors, however, and there are also ACE-independent pathways by which angiotensin I is converted to angiotensin II. Because of this, angiotensin-receptor blockers (ARBs) offer an attractive potential alternative.

In the past, captopril was compared directly to losartan in high-risk MI patients and there was a trend in favor of the ACE inhibitor in terms of mortality.3 In the OPTIMAAL study, however, there were concerns that the losartan arm was underdosed relative to the captopril group.

The VALIANT investigators sought to compare the ARB valsartan with the ACE inhibitor captopril as well as with a combination of the 2 drugs in patients with MI complicated by low ejection fraction, heart failure, or both. Patients with acute MI (14,808) with evidence of left ventricular dysfunction or clinical heart failure were randomized in a 1:1:1 fashion to receive captopril, valsartan, or both in a double-blinded trial. Therapy was begun between 12 hours and 10 days after the MI. Initial doses were 6.25 mg of captopril, 20 mg of valsartan, or both. Doses were titrated upward to goals of captopril 50 mg 3 times daily (tid), valsartan 160 mg twice daily (bid), or captopril 50 mg tid plus valsartan 80 mg bid by the third month. Investigators were able to increase or decrease the study drug doses as needed.

Importantly, the trial was designed to evaluate both the superiority of valsartan compared with captopril as well as noninferiority. It was decided a priori to use specific statistical methods for this analysis. The study was sponsored by Novartis Pharmaceuticals.

Results: 

Patients randomized to valsartan had a hazard ratio for mortality of 1.00 (97.5% CIs 0.90–1.11, P = .98) compared with patients receiving captopril. The hazard ratio for mortality for the combination therapy arm was 0.98 (97.5% CIs 0.89–1.09, P = .73) compared with captopril. Secondary end points of death from cardiovascular causes, recurrent myocardial infarction, or hospitalization from heart failure were the same in the 3 groups.

In terms of adverse effects, more patients on valsartan, both alone and in combination with captopril, had dose reduction due to hypotension compared with patients receiving only captopril. There was more dose reduction because of renal insufficiency in both groups receiving valsartan, and there was more cough, taste disturbance, and rash in the groups receiving captopril. Overall, the combination-therapy arm experienced the sum of the adverse effects of the 2 individual-therapy arms.

Interpretation: 

Valsartan is as effective as captopril in treating high-risk MI patients with either left ventricular dysfunction or clinical heart failure, or both. Both drugs had equal rates of primary and secondary end points in this trial. Combination therapy did not confer any additional benefit over either individual drug alone, but it did confer additional adverse effects. While there is no reason to use combination therapy in this patient population, valsartan at 160 mg orally (po) bid and captopril at 50 mg po tid confer equal benefit.

Because of ethical considerations, this trial did not include a placebo arm. Nonetheless, the ARB chosen was compared with a proven ACE inhibitor at a proven dose. Clinicians should feel comfortable in using valsartan as an alternative therapy to captopril in the high-risk, post-MI patient. In the words of the trial investigators, the decision between these 2 therapies “will depend on cumulative clinical experience, tolerability, safety, convenience, and cost.”4