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.

Study Design

Study Design:

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
Female: 20
Mean Ejection Fraction: Baseline EF = 24%

Patient Populations:

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.

Primary Endpoints:

All-cause mortality over a 2- to 3-year period.

Secondary Endpoints:

Cardiovascular mortality; Combined cardiovascular morbidity/mortality; Change in NYHA class.

Drug/Procedures Used:

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.

Concomitant Medications:

Patients continued their usual medications except calcium antagonists.

Principal Findings:

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.


Circulation. 2000;101:758-764.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, EP Basic Science, Lipid Metabolism, Novel Agents, Acute Heart Failure

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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