Many patients that survive acute myocardial infarction have heart failure or resulting left ventricular dysfunction. These patients have a high risk for death and non-fatal major cardiovascular events. In clinical trials, angiotensin-converting enzyme (ACE) inhibitors reduce this risk by approximately 20%. The ACE inhibitors work by inhibiting the renin-angiotensin system.

Angiotensin II receptor blockers (ARBs) also work by blocking the renin-angiotensin system. The ARBs are newer, more specific and may offer more complete inhibition of angiotensin II than ACE inhibitors.

Because of this, investigators undertook a large, randomized, multicenter international trial to find out if the ARB valsartan provides an advantage over the ACE inhibitor captopril. Previous investigations have proven that captopril 50 mg tid is effective in post-myocardial infarction patients at high risk of mortality or further morbidity.

Investigators enrolled 14,703 patients from 931 sites in 24 countries. Investigators ascertained vital status in 14,564 patients, or 99.05%.

All patients had experienced a myocardial infarction within the past 10 days. All patients had acute heart failure, left ventricular dysfunction, or both. Randomization was to valsartan 160 mg bid, captopril 50 mg tid, or the combination of valsartan 80 mg bid plus captopril 50 mg tid.

The primary endpoint of the study was all-cause mortality, and secondary endpoints included cardiovascular death, myocardial infarction and heart failure. Investigators also looked at safety and tolerability.

Results showed that valsartan was as effective as the proven dose of captopril in reducing risk of death. At the median follow-up of 24.7 months, there were 979 deaths in the valsartan group and 958 deaths in the captopril group (hazard ratio 1.00; 97.5% confidence interval 0.90-1.11). There were 941 deaths in the group of patients that received the valsartan/captopril combination (hazard ratio of 0.98 compared to the captopril group, 97.5% confidence interval 0.89-1.09). There were no statistically significant differences in death between the 3 groups.

Investigators conducted a non-inferiority test with regard to mortality. For valsartan versus captopril, the upper limit of the one-sided 97.5% confidence interval was within the prespecified margin for non-inferiority (p = 0.004). Valsartan was also non-inferior to captopril for the combined endpoint of fatal and nonfatal cardiovascular events (p < 0.001). According to Dr. Pfeffer, valsartan preserves 99.6% of the mortality benefit seen with captopril.

For a variety of mortality/morbidity endpoints, valsartan was as effective as captopril, Dr. Pfeffer said. These endpoints included cardiovascular death, cardiovascular death or myocardial infarction, cardiovascular death or heart failure, and the combination of cardiovascular death, myocardial infarction and heart failure.

Combining valsartan with the proven dose of captopril did not provide any further reduction in mortality, Dr. Pfeffer reported. On the other hand, the combination of valsartan and captopril did increase risk of adverse drug effects.

These results suggest that valsartan is a clinically effective alternative to the ACE inhibitor captopril in post-myocardial infarction patients at high risk of a subsequent event or mortality. Dr. Pfeffer said clinicians now have an ARB dosing regimen that is as effective in preserving lives and reducing morbidity in this patient population.

Full results of the Valiant Trial are now available in the New England Journal of Medicine (November 13, 2003, p. 1893).