Clinical Trial Update - VALIANT and EUROPA
In a head-to-head comparison of an angiotensin receptor blocker (ARB), an angiotensin-converting enzyme (ACE) inhibitor, and the combination in patients with acute myocardial infarction (MI) with left ventricular (LV) systolic dysfunction, heart failure, or both, no significant differences were found in the primary end point of death from any cause.

Although ACE inhibitors have been demonstrated to decrease mortality and morbidity after acute MI with LV dysfunction, there have been fewer studies of the efficacy of ARBs in this regard. A recent trial of acute MI, Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL), which evaluated the efficacy of an ARB vs. an ACE inhibitor in acute MI with HF/LV dysfunction, indicated a trend in favor of the ACE inhibitor (p=0.07) for death from any cause and a significant benefit of the ACE inhibitor (p=0.03) for cardiovascular mortality.

Patients with acute MI and heart failure/LV dysfunction (LV ejection fraction <35%/40%) randomly assigned to the three treatment groups: valsartan (up to 160 mg twice daily), captopril (up to 50 mg three times daily), or valsartan plus captopril (up to 80 mg twice a day and 50 mg three times a day, respectively) within 10 days after acute MI and followed for more than 2 years. Primary end point was total mortality. A total of 14,703 participants were evaluated among the three study groups.

In a median follow-up of 24 months, no significant differences were found among the three groups in total mortality (Figure 1). For valsartan vs. captopril, hazard ratio was 1.00 (97.5% confidence interval, 0.89-0.11; p=0.98). For valsartan plus captopril vs. captopril, hazard ratio was 0.98 (97.5% confidence interval, 0.89-1.09; p=0.73). Nonsignificant differences were also found for valsartan vs. captopril in terms of fatal and nonfatal cardiovascular events (Figure 1). Valsartan and captopril were equivalent in terms of effects in high-risk patients after acute MI. In terms of a reference (placebo) population, the hazard ratio for total mortality (0.77) was close to that of three trials of ACE inhibitors in a similar high-risk population (Survival and Ventricular Enlargement [SAVE], Acute Infarction Ramipril Efficacy [AIRE], and Trandolapril Cardiac Evaluation [TRACE]).



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Kaplan-Meier Estimates of A) total mortality and B) the combined cardiovascular end point of cardiovascular death, reinfarction, or hospitalization for heart failure in the Valsartan in Acute Myocardial Infarction Trial (VALIANT). There were no significant differences among the three treatment groups. Reprinted with permission from the Massachusetts Medical Society from N Engl J Med. 2003;349:1893-1906.[1]





Because ARBs block the angiotensin-1 receptor itself, rather than inhibit an enzyme limiting the production of angiotensin II and thereby indirectly decreasing stimulation of the angiotensin-1 receptor, it is reasonable to infer that virtually all of the adverse effects of this receptor relating to inflammatory processes, plaque instability, and cardiac remodeling would be more completely minimized by ARBs. Because the results of the OPTIMAAL trial suggested a mortality benefit of ACE inhibitors vs. ARBs in a high-risk population after MI, the results of the Valsartan in Acute Myocardial Infarction Trial (VALIANT) in a similar population challenge this concept. The OPTIMAAL trial methodology has been criticized because, despite the acronym, an optimal dose of the ARB was not utilized (only 50 mg losartan vs. 150 mg captopril daily). This was not the case with the VALIANT trial. VALIANT utilized statistical analysis to test whether the ARB was or was not inferior to captopril, which had been demonstrated to significantly reduce mortality in high-risk acute MI patients. Statistical analysis was also used to assess the separate group effects on an imputed placebo group of a similar population.

Subgroup comparisons in terms of the primary outcome events evaluating demographic, clinical, and ancillary drug information showed equivalency. There were some differences among groups for various types of side effects. Significantly fewer were taking the drug combination after 1 year than remained on captopril (p=0.007), and more patients were still receiving valsartan than captopril, but this difference was not significant (p=0.07). Hypotension and renal dysfunction were more common with valsartan, and cough, rash, and taste disturbance were more common with captopril. Adverse events were more likely to cause discontinuation of the valsartan plus captopril combination (9%) than captopril (7.7%) or valsartan (5.8%).

These results strengthen the basis of ARB use in high-risk patients with acute MI as an equivalent alternative to ACE inhibitors; however, the extrapolation of these results to other ARBs is conjectural at this time, and it is expected that studies using other members of this class will be assessed. The results allow flexibility in situations in which side effects of ACE inhibitors prevent their use. Balanced against this is the somewhat higher cost of ARBs. There is currently no definitive evidence for a benefit of ARBs in patients with uncomplicated acute MI.