Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure - The MACH-1 study

Background-Calcium antagonists have proved disappointing in long-term conge stive heart failure (CHF) studies. Mibefradil, a new calcium antagonist tha t selectively blocks T-type calcium channels, has been shown to be an effec tive antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. Methods and Results-This multicenter, randomized, double-blind study compar ed mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg d aily dose of mibefradil was uptitrated to 100 mg after 1 month and continue d up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05), Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was s imilar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not s tatistically significant (P=0.093). Treatment groups had similar cardiovasc ular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a signific antly increased risk of death. Substudies demonstrated no significant diffe rences between treatments. Conclusions-When used as adjunct therapy, mibefradil did not affect the usu al outcome of CHF. The potential interaction with antiarrhythmic drugs, esp ecially amiodarone, and drugs associated with torsade de pointes may have c ontributed to poor outcomes early in the study.