This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Levine, T. B. Articles by Lindberg, E. Search for Related Content PubMed PubMed Citation Articles by Levine, T. B. Articles by Lindberg, E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure Related Collections Congestive Cardiovascular Pharmacology

(Circulation. 2000;101:758.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Effect of Mibefradil, a T-Type Calcium Channel Blocker, on Morbidity and Mortality in Moderate to Severe Congestive Heart Failure

The MACH-1 Study

T. Barry Levine, MD; Peter J. L. M. Bernink, MD; Abraham Caspi, MD; Uri Elkayam, MD; Edward M. Geltman, MD; Barry Greenberg, MD; William J. McKenna, MD; Jalal K. Ghali, MD; Thomas D. Giles, MD; Alon Marmor, MD; Leonardo H. Reisin, MD; Susan Ammon, RN; Elisabet Lindberg, MD

Correspondence to T. Barry Levine, MD, Michigan Institute for Heart Failure and Transplant Care, Botsford General Hospital, 28050 Grand River Ave, Farmington Hills, MI 48336.

Background—Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective 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 compared 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 daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued 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 (=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular 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 significantly increased risk of death. Substudies demonstrated no significant differences between treatments.

Conclusions—When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.

Key Words: mibefradil • calcium channels • heart failure

This article has been cited by other articles:

				H. Arima, R. G. Hart, S. Colman, J. Chalmers, C. Anderson, A. Rodgers, M. Woodward, S. MacMahon, B. Neal, and for the PROGRESS Collaborative Group Perindopril-Based Blood Pressure-Lowering Reduces Major Vascular Events in Patients With Atrial Fibrillation and Prior Stroke or Transient Ischemic Attack Stroke, October 1, 2005; 36(10): 2164 - 2169. [Abstract] [Full Text] [PDF]

				T. Izumi, Y. Kihara, N. Sarai, T. Yoneda, Y. Iwanaga, K. Inagaki, Y. Onozawa, H. Takenaka, T. Kita, and A. Noma Reinduction of T-Type Calcium Channels by Endothelin-1 in Failing Hearts In Vivo and in Adult Rat Ventricular Myocytes In Vitro Circulation, November 18, 2003; 108(20): 2530 - 2535. [Abstract] [Full Text] [PDF]

				R.A de Boer and D.J van Veldhuisen Polypharmacy in chronic heart failure: practical issues regarding the use of angiotensin-converting enzyme inhibitors, beta-blockers and other drugs Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D111 - D116. [Abstract] [PDF]

				G. C. Fonarow Quality Indicators for the Management of Heart Failure in Vulnerable Elders Ann Intern Med, October 16, 2001; 135(8_Part_2): 694 - 702. [Full Text] [PDF]

				B. Darpo Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K70 - K80. [Abstract] [PDF]

				T. Meinertz Mibefradil -- a drug which may enhance the propensity for the development of abnormal QT prolongation Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K89 - K92. [Abstract] [PDF]