CAPOTEN IN PATIENTS WITH ASYMPTOMATIC LEFT VENTRICULAR DYSFUNCTION

CAPOTEN IN PATIENTS WITH ASYMPTOMATIC LEFT VENTRICULAR DYSFUNCTION after a heart attack reduces overall mortality by 20% and major cardiovascular events by 21% compared to placebo, according to the results of a study published in the Sept. 1 issue of The New England Journal of Medicine. Called the SAVE trial (Survival and Ventricular Enlargement Trial), the 2,231-patient multi-center, placebo-control study conducted by Pfeffer et al. also showed a 21% risk reduction for death from cardiovascular events in patients taking Bristol-Myers Squibb's Capoten (captopril) and a risk reduction of 37% for development of severe heart failure. The objective of the study, the authors noted, was to determine whether early initiation and long-term administration of an ACE (angiotensin-converting enzyme) inhibitor could achieve further improvement in heart attack patients' long term prognosis when combined with other therapeutic interventions, such as aspirin or beta blockers. The authors concluded that the SAVE results demonstrate "that long-term therapy with captopril in survivors of acute myocardial infarction with depressed left ventricular ejections fractions but without overt heart failure resulted in reductions in both total and cardiovascular mortality, in the frequency of severe congestive heart failure and recurrent myocardial infarction, and in the proportion of patients who either died or survived with marked deterioration in left ventricular ejection fraction." Pfeffer et al. suggested that "these beneficial effects support the study hypothesis that a therapeutic intervention directed at the attenuation of progressive left ventricular dilation and dysfunction would result in an improved clinical outcome." The authors theorized that the long-term benefit seen in the captopril group was due to a direct inhibition of neurohormonal activity, including an effect on angiotensin II, as well as attenuation of ventricular enlargement. Under the study protocol, 2,231 patients with acute myocardial infarction and with left ventricular dysfunction (ejection fraction rate of 40% or less) were randomized to either placebo or Capoten between three and 16 days after the heart attack. The patients in the treatment group were given a starting dose of 12.5 mg with a target dose of 25 mg three-times daily. The dose was gradually escalated to 50 mg t.i.d., if tolerated by the patient. The study followed patients for a minimum of two years with an average follow-up time of 42 months. The Sept. 1 issue of NEJM also includes the results of two other ACE inhibitor trials. The two studies -- the SOLVD (Studies of Left Ventricular Dysfunction) Prevention Trial and the CONSENSUS II (Cooperative New Scandinavian Enalapril Survival Study II) trial -- used Merck's ACE inhibitor Vasotec (enalapril). The final SOLVD Prevention Trial results published in NEJM are consistent with preliminary trial results presented at the American Heart Association annual meeting last November. The 4,228 patient SOLVD Prevention Trial looked at the effect of treating patients with asymptomatic ventricular dysfunction (ejection fraction rates of 35% or less) with enalapril on long-term survival and prevention of future cardiac events. The study showed an 8% risk reduction in all deaths and a 12% risk reduction for cardiovascular death in the treatment group -- neither of which were statistically significant. However, there was a 37% reduction in patients progressing to congestive heart failure in the enalapril group, which was statistically significant. In addition, a subgroup analysis of the SOLVD results shows that the lower a patient's ejection fraction, the more likely that patient could be expected to benefit from enalapril treatment. Patients with ejection fraction rates between .28 and .35 showed no mortality benefit from enalapril, while patients with ejection fraction rates below .28 had a 16% reduction in mortality risk. That trend was consistent when measured for development of CHF, hospitalization for CHF and death, or hospitalization for CHF. The results of the CONSENSUS II trial, which tested the possible benefit of immediate initiation of enalapril treatment following a heart attack, were not so positive. The 6,090-patient placebo-controlled Scandinavian study showed no overall or cardiovascular mortality benefit to patients in the enalapril group at six months. In fact, there were slightly more deaths due to heart failure in the enalapril group than in the placebo group (132 deaths versus 104 deaths). The authors concluded that a treatment period longer than six months "may be necessary to demonstrate whether enalapril benefits patients who have had a myocardial infarction." The authors also suggested that "the lack of an effect of enalapril on mortality could also be the result of a balance between beneficial and adverse effects of the drug during different periods after myocardial infarction." Possibly, the authors speculate, angiotensin II, which is inhibited by ACE inhibitors, "may be important in the healing process" shortly after infarction.