Skip to main content
SpringerLink
Log in

The Effect of Mibefradil on Ischemic Episodes With and Without Increase in Heart Rate

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Myocardial ischemia during daily life can be induced by increased demand and by increased coronary tone. The purpose of this study was to assess the mechanism of action of mibefradil, a new T-channel calcium blocker that is a vasodilator with negative chronotropic properties. Included in this study were 114 patients with chronic stable angina pectoris and ischemic episodes during baseline 48-hour ambulatory ECG monitoring (AEM). After a placebo run-in period patients received 50 mg, 100 mg, or 150 mg of mibefradil per day and repeat 48 hours AEM was performed. Ischemic episodes were divided into 2 categories: Type I is those in which an increase in heart rate >10% preceded the development of 1 mm ST depression; Type II is those with ≤10% increase in heart rate. Of the 625 ischemic episodes recorded at baseline, 83% were Type I and 17% were Type II. At 50 mg mibefradil dose, there was a significant decrease in the number of Type I ischemic episodes but not of Type II. At doses of 100 mg and 150 mg/day, there was a significant decrease in frequency of both Types of ischemic episodes. At a low dose of 50 mg/day, mibefradil reduces ischemia predominantly by preventing an increase in heart rate, while at higher doses of 100 mg and 150 mg/day, it also acted as a vasodilator suppressing episodes associated with increased coronary tone.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tzivoni D, Gavish A, Benhorin J, Keren A, Stern S. Myocardial ischemia during daily activities and stress. Am J Cardiol 1986;58:47B-50B.

    Google Scholar 

  2. Banai S, Moriel M, Benhorin J, Gavish A, Stern S, Tzivoni D. Changes in myocardial ischemic threshold during daily activities. Am J Cardiol 1990;66:1403-1406.

    Google Scholar 

  3. Andrews TC, Fenton T, Toyosaki N, et al. Subsets of ambulatory myocardial ischemia based on heart rate activity; circadian distribution and response to anti-ischemic medication. Circulation 1993;88:92-100.

    Google Scholar 

  4. Deedwania PC, Nelson Jr. Pathophysiology of silent myocardial ischemia during daily life. Circulation 1990;82:1296-1304.

    Google Scholar 

  5. Panza JA, Diodati JG, Callahan TS, Epstein SE, Quyyumi AA. Role of increases in heart rate in determining the occurrence and frequency of myocardial ischemia during daily life in patients with stable coronary artery disease. J Am Coll Cardiol 1992;20:1092-1098.

    Google Scholar 

  6. Hinderliter A, Miller P, Bragdon E, Ballenger M, Sheps D. Myocardial ischemia during daily activities: the importance of increased myocardial oxygen demand. J Am Coll Cardiol 1991;18:405-412.

    Google Scholar 

  7. Scrutinio D, Lagioia R, Di Biase M, Rizzon P. Transient myocardial ischemia in patients with chronic angina: relation to heart rate changes and variability in exercise threshold. BAY r 1999 in Chronic Angina Study Group. Int J Cardiol 1995;49:215-223.

    Google Scholar 

  8. Stone PH, Gibson RS, Glasser SP, et al. Comparison of propranolol, diltiazem and nifedipine in the treatment of ambulatory ischemia in patients with stable angina: differential effects on ambulatory ischemia, exercise performance and anginal symptoms. Circulation 1990;82:1962-1972.

    Google Scholar 

  9. Clozel JP, Banken L, Osterrieder W. Effects of Ro-405967, a novel calcium antagonist, on myocardial function during ischemia by lowering coronary perfusion pressure in dogs: comparison with verapamil. J Cardiovasc Pharmacol 1989;14:713-721.

    Google Scholar 

  10. Mirshra SK, Hermsmeyer K. Selective inhibition of T-Type Ca2+ channels by Ro 40-5967. Circ Res 1994;75:144-148.

    Google Scholar 

  11. Clozel JP, Osterrieder W, Kleinbloesem D, et al. Ro 40-5967: a new nondihydropyridine calcium antagonist. Cardiovasc Drug Rev 1991;9:4-17.

    Google Scholar 

  12. Schmitt R, Kleinbloesem D, Belz G, et al. Hemodynamic and humoral effect of the novel calcium antagonist Ro-5967 in patients with hypertension. Clin Pharmacol Ther 1992;52:314-323.

    Google Scholar 

  13. Clozel JP, Véniant M, Osterrieder W. The structurally novel Ca2+ channel blocker Ro 4-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts. Cardiovasc Drugs Ther 1990;4:731-736.

    Google Scholar 

  14. Levin BT, MACH-I Investigators. The design of the mortality assessment in congestive heart failure trial (MACH-1, Mibefradil). Clin Cardiol 1997;20:320-326.

    Google Scholar 

  15. Bernink PJLM, Prager G, Schelling A, Kobrin I. Antihypertensive properties of the novel calcium antagonist mibefradil (Ro 40-5967). Hypertension 1996;27:426-432.

    Google Scholar 

  16. Massie BM, Lacourciere Y, Viskoper R, Woittiez A, Kobrin I. Mibefradil in the treatment of systemic hypertension: comparative studies with other calcium antagonists. Am J Cardiol 1997;80:27C-33C.

    Google Scholar 

  17. Oparil S, Bernink P, Bursztyn M, Carney S, Kobrin I. Antihypertensive effects of mibefradil in the treatment of mild to moderate systemic hypertension. Am J Cardiol 1997;80:12C-19C.

    Google Scholar 

  18. Viskoper RJ, Bernink P, Schelling A, et al. A randomized, double-blind trial comparing mibefradil and amlodipine: two long-acting calcium antagonists with similar efficacy but different tolerability profiles. Mibefradil International Study Group. J Hum Hypertens 1997;11:387-393.

    Google Scholar 

  19. Bakx AL, van der Wall EE, Braun S, Emanuelsson H, Bruschke AV, Kobrin I. Effects of the new calcium antagonist mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: a multicenter, placebocontrolled study. Am Heart J 1995;130:748-757.

    Google Scholar 

  20. Braun S, van der Wall EE, Emanuelsson H, Kobrin I. Effects of the new calcium antagonist mibefradil (Ro 40-5967) on silent ischemia in patients with chronic stable angina pectoris: a multicenter, placebo-controlled study. J Am Coll Cardiol 1996;27:317-333.

    Google Scholar 

  21. Alpert JS, Kobrin I, DeQuattro V, et al. Additional antianginal and anti-ischemic efficacy of mibefradil in patients pretreated with a beta blocker for chronic stable angina pectoris. Am J Cardiol 1997;79:1025-1030.

    Google Scholar 

  22. Frishman WH, Bittar N, Glasser S, Habib G, Smith W, Pordy R. Additional antianginal and anti-ischemic efficacy of mibefradil in patients concomitantly treated with long-acting nitrates for chronic stable angina pectoris. Clin Cardiol 1998;21:483-490.

    Google Scholar 

  23. Alpert JS. Treatment of chronic angina pectoris with combination mibefradil and β blocker therapy. Clin Cardiol 1998;21:129.

    Google Scholar 

  24. Schneeweiss A, Kobrin I, Charlon V, et al. Adding the new calcium antagonist mibefradil to patients receiving long-term β blocker therapy results in improved antianginal and antiischemic therapy. Am Heart J 1998;135272-135280.

  25. Davies GJ, Kobrin I, Caspi A, et al. Long-term antianginal and antiischemic effects of mibefradil, the novel T-Type calcium channel blocker: a multicenter, double-blind, placebocontrolled, randomized comparison with sustained-release Diltiazem. Am Heart J 1997;134:220-228.

    Google Scholar 

  26. Rosseau MG, Harashida W, van Eyll C, et al. Hemodynamic and cardiac effects of the selective T-Type and L-Type calcium channel blocking agent mibefradil in patients with varying degrees of left ventricular systolic dysfunction. J Am Coll Cardiol 1996;28:972-979.

    Google Scholar 

  27. Mulder P, Richard V, Compagnon P, et al. Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure. J Am Coll Cardiol 1997;29:416-421.

    Google Scholar 

  28. Tzivoni D, Kadr H, Braat S, Rutsch W, Ramires JA, Kobrin I. Efficacy of mibefradil compared with amlodipine in suppressing exercise-induced and daily silent ischemia: results of a multicenter, placebo-controlled trial. Circulation 1997;96:2557-2564.

    Google Scholar 

  29. Brixius K, Mohr V, Muller-Ehmsen J, Hoischen S, Munch G, Schwinger RH. Potent vasodilatory with minor cardiodepressent actions of mibefradil in human cardiac tissue. Br J Pharmacol 1998;125:41-48.

    Google Scholar 

  30. Tzivoni D, Medina A, David D, Barzilai Y, Brunel P. Effect of metoprolol in reducing myocardial ischemic threshold during exercise and during daily activity. Am J Cardiol 1998;81:775-777.

    Google Scholar 

  31. Tzivoni D, Medina A, David D, et al. Comparison between metoprolol OROS given once daily and metoprolol twice or thrice daily in suppressing exercise induced and daily myocardial ischemia. Am J Cardiol 1996;78:1362-1368.

    Google Scholar 

  32. Théroux P, Baird M, Juneau M, et al. Effect of diltiazem on symptomatic and asymptomatic episodes of ST segment depression occurring during daily life and during exercise. Circulation 1991;84:15-22.

    Google Scholar 

  33. Portegies MCM, Sijbring P, Göbel EAM, Viersma JW, Lie KI. Efficacy of metoprolol and diltiazem in treating silent myocardial ischemia. Am J Cardiol 1994;74:1095-1098.

    Google Scholar 

  34. Radice M, Giudici V, Albertini A, Mannarini A. Paradoxical effect of long-term treatment of nifedipine on total ischemic load in patients with stable angina pectoris. Clin Cardiol 1992;15:98-102.

    Google Scholar 

  35. El-Tamini H, Davies GJ. Optimal control of myocardial ischemia: the benefit of a fixed combination of atenolol and nifedipine in patients with chronic stable angina. Br Heart J 1992;68:291-295.

    Google Scholar 

  36. Benhorin J, Moriel M, Gavish A, et al. Usefulness of severity of myocardial ischemia on exercise testing in predicting the severity of myocardial ischemia during daily activities. Am J Cardiol 1991;68:176-180.

    Google Scholar 

  37. Egstrup K. Attenuation of circadian variation by combined antianginal therapy with suppression of morning and evening increases in transient myocardial ischemia. Am Heart J 1991;122:648.

    Google Scholar 

  38. SoRelle R. Withdrawal of Posicor from market. Circulation 1998;98:831-832.

    Google Scholar 

  39. Po ALW, Zhang W. What lessons can be learnt from withdrawal of mibefradil from the market? Lancet 1998;351:1829-1830.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Jesselson Heart Center, Shaare Zedek Medical Center, Israel

    Dan Tzivoni

  2. Department of Statistics, Hebrew University, Jerusalem

    Zvi Gilula

  3. Jesselson Heart Center, Shaare Zedek Medical Center, Israel

    Marc W. Klutstein

  4. Barzilai Hospital, Ashkelon

    Leonardo Reisin

  5. Kaplan Hospital, Rehovot

    Shulamit Botvin

  6. F. Hoffmann-LaRoche, Israel

    Isaac Kobrin

Authors
  1. Dan Tzivoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zvi Gilula
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc W. Klutstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leonardo Reisin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shulamit Botvin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isaac Kobrin
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tzivoni, D., Gilula, Z., Klutstein, M.W. et al. The Effect of Mibefradil on Ischemic Episodes With and Without Increase in Heart Rate . Cardiovasc Drugs Ther 14, 503–509 (2000). https://doi.org/10.1023/A:1007889006370

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007889006370

Search

Navigation