Mortality Assessment in Congestive Heart Failure Trial - MACH-1
MACH-1 compared mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, with placebo as adjunct to usual therapy in CHF patients.
Mibefradil would show a 17% mortality risk reduction over a 2- to 3-year period.
Patients Screened: not reported
Patients Enrolled: 2590
NYHA Class: Class III placebo 63.7% mibefradil 64.8%; class IV placebo 11.0% mibefradil 9.2%
Mean Follow Up: 3 years
Mean Patient Age: not reported
Mean Ejection Fraction: Baseline EF = 24%
Stable CHF; NYHA class II to IV; left ventricular ejection fraction <35%; and use of clinically optimal doses of loop diuretics and ACE inhibitors with or without vasodilators and/or digitalis.
Scheduled cardiac procedure or transplant; a myocardial infarction, CABG, or coronary angioplasty within 1 month; second- or third-degree AV block without a pacemaker; clinically significant arrhythmias; heart rate <55 bpm; blood pressure >160/100 mm Hg or systolic <90 mm Hg; a cerebrovascular accident within 3 months; or any clinically significant disease other than CHF.
All-cause mortality over a 2- to 3-year period.
Cardiovascular mortality; Combined cardiovascular morbidity/mortality; Change in NYHA class.
After a 2-week placebo run-in, patients were randomized to placebo or 50 mg/d mibefradil (single tablet). After 1 month, all patients were uptitrated to 2 tablets once daily (placebo or 100 mg mibefradil). Patients with intolerable adverse events were returned to the lower dose.
Patients continued their usual medications except calcium antagonists.
Total mortality was similar between mibefradil- and placebo-treated patients (27.0% vs 24.6%, p=0.151). Mortality at 3 months was increased 14% with mibefradil, although not statistically significant (p=0.093). Treatment groups had similar cardiovascular mortality (24.0% vs 22.2%, p=0.246), cardiovascular morbidity/mortality (51.6% vs 53.4%, p=0.783), and reasons for death or hospitalization. Mibefradil with concomitant digoxin or antiarrhythmics (class I or III), including amiodarone, was associated with a significantly increased risk of death.
Mibefradil as adjunct therapy for the treatment of congestive heart failure did not reduce mortality or morbitity, and instead resulted in a trend toward increased early mortality. Given the increased mortality risk in mibefradil patients treated with concomitant antiarrhythmics, the drug-drug interactions between mibefradil and other medications may have played a significant role in the poor outcomes seen early in the study.
Keywords: Risk Reduction Behavior, Digoxin, Calcium Channels, T-Type, Mibefradil, Sodium Potassium Chloride Symporter Inhibitors, Vasodilator Agents, Calcium Channel Blockers, Drug Interactions, Benzimidazoles, Heart Failure, Digitalis, Stroke Volume
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