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Defining the Role of Calcium Channel Antagonists in Heart Failure Due to Systolic Dysfunction

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Abstract

Calcium channel antagonists (CCAs) may either be divided into the dihydropyridines (e.g. amlodipine, felodipine, isradipine, lacidipine, nilvadipine, nifedipine, nicardipine etc.), the phenylalkylamines (e.g. verapamil) and the benzothiazepines (e.g. diltiazem) according to their chemical structure, or into first generation agents (nifedipine, verapamil and diltiazem) and second generation agents (subsequently developed dihydropyridine-derivatives). Second generation CCAs are characterized by greater selectivity for calcium channels in vascular smooth muscle cells than the myocardium, a longer duration of action and a small trough-to-peak variation in plasma concentrations.

Heart failure is characterized by decreased cardiac output resulting in inadequate oxygen delivery to peripheral tissues. Although the accompanying neurohormonal activation, leading to vasoconstriction and increased blood pressure, is initially beneficial in increasing tissue perfusion, prolonged activation is detrimental because it increases afterload and further reduces cardiac output. At the level of the myocyte, heart failure is associated with increased intracellular calcium levels which are thought to impair diastolic function. These changes indicate that the CCAs would be beneficial in patients with heart failure.

There has been a strong interest and increasing experience in the use of CCAs in patients with heart failure. Despite potential beneficial effects in initial small trials, findings from larger trials suggest that CCA may have detrimental effects upon survival and cardiovascular events. However, this may not necessarily be a ‘class b’ effect of the CCAs as there is considerable heterogeneity in the chemical structure of individual agents.

Clinical experience with different CCAs in patients with heart failure includes trials that evaluated their effects on hemodynamic parameters, exercise tolerance and on symptomatology. However, the most relevant results are those from randomized clinical trials that assessed mortality as the primary endpoint. First generation CCAs have direct negative inotropic effects and even sustained release formulations have not proved any beneficial effect upon survival. With second generation CCAs, some benefit on hemodynamic parameters has been observed but none on survival, alone or in combination with ACE inhibitors. It is noteworthy that although amlodipine had a neutral effect on morbidity and mortality in large, randomized, placebo-controlled trials in patients with heart failure, the drug was well tolerated. There is no specific indication for CCAs (first or second generation) in patients with systolic heart failure, alone or in combination with ACE inhibitors, but amlodipine may be a considered in the management of hypertension or coronary artery disease in patients with heart failure.

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References

  1. Opie LH. Pharmacological differences between calcium antagonists. Eur Heart J 1997; 18 Suppl. A: 71–9

    Google Scholar 

  2. Mahon N, McKenna WJ. Calcium channels blockers in cardiac failure. Prog Cardiovasc Dis 1998; 41: 191–206

    CAS  PubMed  Google Scholar 

  3. Epstein M. Role of a third generation calcium antagonist in the management of hypertension. Drugs 1999; 57 Suppl. 1: 1–10

    CAS  PubMed  Google Scholar 

  4. Ferrari R. Major differences among the three classes of calcium antagonists. Eur Heart J 1997; 18 Suppl. A: A56–70

    CAS  PubMed  Google Scholar 

  5. Katz S. Safety of calcium antagonists in patients with congestive heart failure. Clin Ther 1997; 19 Suppl. A: 92–113

    CAS  PubMed  Google Scholar 

  6. Bertolet BD. Calcium antagonists in the post-myocardial infarction setting. Drugs Aging 1999; 15(6): 461–70

    CAS  PubMed  Google Scholar 

  7. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a veterans administration cooperative study (V Heft). N Engl J Med 1986; 314: 1547–52

    CAS  PubMed  Google Scholar 

  8. Cohn JN, Johnson G, Ziesche S, et al. A comparison of Enalapril with Hydralazine-Isosorbide Dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–10

    CAS  PubMed  Google Scholar 

  9. Cohn JN. Vasodilators in heart failure: conclusions from VHeft II and rationale for VHeft III. Drugs 1994; 47 Suppl. 4: 47–58

    PubMed  Google Scholar 

  10. Dhein S, Salameh A, Berkels R, et al. Dual mode of action of dihydropyridine calcium antagonists: a role for nitric oxide. Drugs 1999; 58(3): 397–404

    CAS  PubMed  Google Scholar 

  11. Elkayam U. Calcium channel antagonists in heart failure. Cardiology 1998; 89 Suppl. 1:38–46

    CAS  PubMed  Google Scholar 

  12. Pieper JA. Evolving role of calcium channel antagonists in heart failure. Pharmacotherapy 1996; 16 Suppl. 2: 43–9

    Google Scholar 

  13. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part II: causal mechanisms and treatment. Circulation 2002; 105(12): 1503–8

    PubMed  Google Scholar 

  14. Opie LH, Yusuf S, Kubier W. Current status of safety and efficacy of calcium channel antagonists in cardiovascular diseases: a critical analysis based on 100 studies. Prog Cardiovasc Dis 2000; 43: 171–96

    CAS  PubMed  Google Scholar 

  15. de Vries RJ, van Veldhuisen DJ, Dunselman PH. Efficacy and safety of calcium channel antagonists in heart failure: focus on recent trials with second-generation dihydropyridines. Am Heart J 2000; 139: 185–94

    PubMed  Google Scholar 

  16. Iliceto S. Left ventricular dysfunction: which role for calcium antagonists? Eur Heart J 1997; 18 Suppl. A: 87–91

    Google Scholar 

  17. Miller AB. Is there a role for calcium channel antagonists in congestive heart failure? Curr Cardiol Rep 2001; 3: 114–8

    CAS  PubMed  Google Scholar 

  18. Betkowski AS, Hauptman PJ. Update on recent clinical trials in congestive heart failure. Curr Opin Cardiol 2000; 15: 293–303

    CAS  PubMed  Google Scholar 

  19. Cleophas TJ, van Marum R. Meta-analysis of efficacy and safety of second-generation dihydropyridine calcium channel antagonists in heart failure. Am J Cardiol 2001; 87: 487–490, A7-8

    CAS  PubMed  Google Scholar 

  20. Gattis W, O’Connor CM. Calcium antagonists in the treatment of heart failure: re-evaluation of therapeutic strategies. Drugs 2000; 59 Spec No 2: 17–24

    CAS  PubMed  Google Scholar 

  21. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995; 274: 620–5

    CAS  PubMed  Google Scholar 

  22. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31

    CAS  PubMed  Google Scholar 

  23. Kostis JB, Lacy CR, Cosgrove NM, et al. Association of calcium channel blocker use with increased rate of myocardial infarction in patients with left ventricular dysfunction. Am Heart J 1997; 133: 550–7

    CAS  PubMed  Google Scholar 

  24. Hager WD, Davis BR, Riba A, et al. Absence of a deleterious effect of calcium channel antagonists in patients with left ventricular dysfunction after myocardial infarction: the SAVE Study Experience. SAVE Investigators. Survival and Ventricular Enlargement. Am Heart J 1998; 135: 406–13

    CAS  PubMed  Google Scholar 

  25. Walsh RW, Porter CB, Starling MR, et al. Beneficial effects of intravenous and oral diltiazem in severe congestive heart failure. J Am Coll Cardiol 1984; 3: 1044–50

    CAS  PubMed  Google Scholar 

  26. Charlap S, Frishman WH. Calcium antagonists and heart failure. Med Clin North Am 1989; 73: 339–59

    CAS  PubMed  Google Scholar 

  27. Packer M, Lee WH, Medina Y, et al. Comparative inotropic effects of nifedipine and diltiazem in patients with severe left ventricular dysfunction [abstract]. Circulation 1985; 72 Suppl. III: 275

    Google Scholar 

  28. Kulick DL, McIntosh N, Campese VM, et al. Central and hemodynamic effects and hormonal response to diltiazem in severe congestive heart failure. Am J Cardiol 1987; 59: 1138–43

    CAS  PubMed  Google Scholar 

  29. Figulla HR, Gietzezn F, Zeymzer U, et al.. Diltiazem improves cardiac function and exercise capacity in patients with idiopathic dilated cardiomyopathy. Results of the Diltiazem in Dilated Cardiomyopathy Trial. Circulation 1996; 94: 346–52

    CAS  PubMed  Google Scholar 

  30. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988; 319: 385–92

    Google Scholar 

  31. Goldstein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation 1991; 83: 52–60

    CAS  PubMed  Google Scholar 

  32. Anon. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II—DAVIT II). Am J Cardiol 1990; 66: 779-85

  33. Elkayam U, Weber L, McKay C, et al. Spectrum of acute hemodynamic effects of nifedipine in severe congestive heart failure. Am J Cardiol 1985; 56: 560–6

    CAS  PubMed  Google Scholar 

  34. Packer M, Lee WH, Medina N, et al. Prognostic importance of the immediate hemodynamic response to nifedipine in patients with severe left ventricular dysfunction. J Am Coll Cardiol 1987; 10: 1303–11

    CAS  PubMed  Google Scholar 

  35. Elkayam U, Amin J, Mehra A, et al. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990; 82: 1954–61

    CAS  PubMed  Google Scholar 

  36. Agostoni PG, De Cesare N, Doria E, et al. Afterload reduction: a comparison of Captopril and nifedipine in dilated cardiomyopathy. Br Heart J 1986; 55: 391–9

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Israeli SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT): a randomised intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J 1988; 9: 354–64

    Google Scholar 

  38. Mandelzweig L, Goldbourt U, Reicher-Reiss H, et al. Nifedipine does not improve survival in AMI patients without heart failure. The SPRINT Study group [letter]. Cardiovasc Drug Ther 1993; 7: 117–8

    CAS  Google Scholar 

  39. Silvestry FE, St John Sutton MG. Sustained-release calcium channel antagonists in cardiovascular disease: pharmacology and current therapeutic use. Eur Heart J 1998; 19 Suppl. 1:18–14

    Google Scholar 

  40. Kiowski W, Erne P, Pfisterer M, et al. Arterial vasodilator, systemic and coronary hemodynamic effects of nisoldipine in congestive heart failure secondary to ischemic or dilated cardiomyopathy. Am J Cardiol 1987; 59: 1118–25

    CAS  PubMed  Google Scholar 

  41. Thier W, Roewer N, Minderjahn KP, et al. Hemodynamic effects of nisoldipine in chronic congestive heart failure [abstract]. J Am Coll Cardiol 1986; 3: 479

    Google Scholar 

  42. Minderjahn KP, Hanrath P, Bleifeld W. Hemodynamic effects of nisoldipine in chronic congestive heart failure [abstract]. Eur Heart J 1993; Suppl. E, 4: 26

    Google Scholar 

  43. Barjon JN, Rouleau JL, Bichet D, et al. Chronic renal and neurohumoral effects of the calcium-entry blocker nisoldipine in patients with congestive heart failure. J Am Coll Cardiol 1987; 9: 622–30

    CAS  PubMed  Google Scholar 

  44. Lewis BS, Makhoul N, Merdler A, et al. Effect of nisoldipine on exercise performance in heart failure following myocardial infarction. Cardiology 1991; 79: 39–45

    CAS  PubMed  Google Scholar 

  45. Eichstaedt H. Effects of calcium antagonists in patients with coronary disease and heart failure: left ventricular function following nisoldipine measured by radionuclide ventriculography. J Cardiovasc Pharmacol 1992; 29 Suppl. 5: 50–4

    Google Scholar 

  46. DEFIANT Research Group (Doppler Flow and Echocardiography in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy). Improved diastolic function with the calcium antagonist nisoldipine (coat-core) in patients post myocardial infarction: results of the DEFIANT study. Eur Heart J 1992; 13: 1496–505

    Google Scholar 

  47. DEFIANT-II Research Group. Doppler flow and echocardiography in functional cardiac insufficiency assessment of nisoldipine therapy: results of the DEFIANT II study. Eur Heart J 1997; 18: 31–40

    Google Scholar 

  48. Ryman KS, Kubo SH, Lystash J, et al. Effects of nicardipine on rest and exercise hemodynamic in chronic congestive heart failure. Am J Cardiol 1986; 58: 583–8

    CAS  PubMed  Google Scholar 

  49. Lahiri A, Robinson CW, Kohli RS, et al. Acute and chronic effects of nicardipine on systolic and diastolic left ventricular performance in patients with heart failure: a pilot study. Clin Cardiol 1986; 9: 257–61

    CAS  PubMed  Google Scholar 

  50. Lahiri A, Robinson CW, Tovey J, et al. Intravenous nicardipine in patients with chronic congestive heart failure: a nuclear sthetoscope study. Postgrad Med J 1984; 69 Suppl. 4: 35–8

    Google Scholar 

  51. Lahiri A, Rodrigues EA, Carboni GP, et al. Effects of long term treatment with calcium antagonists on left ventricular diastolic function in stable angina and heart failure. Circulation 1990; 81 Suppl. III: 130–8

    Google Scholar 

  52. Gheorghiade M, Cody RJ, Francis GS, et al. Current medical therapy for advanced heart failure. Am Heart J 1998; 135 (6 Pt 2 Su): S231–48

    CAS  PubMed  Google Scholar 

  53. Van den Toren EW, van Veldhuisen DJ, et al. Acute hemodynamic and long-term clinical effects of isradipine in patients with coronary artery disease and chronic heart failure: a double-blind placebo-controlled study. Int J Cardiol 1996; 53: 37–43

    PubMed  Google Scholar 

  54. Neglia D, Sambuceti G, Giorgetti A, et al. Effects of long-term treatment with verapamil on left ventricular function and myocardial blood flow in patients with dilated cardiomyopathy without overt heart failure. J Cardiovasc Pharmacol 2000; 36: 744–50

    CAS  PubMed  Google Scholar 

  55. Smith WB, de Abate AC, Gollub SB, et al. Beneficial long-term hemodynamic and clinical effects of amlodipine in chronic heart failure: results of a multicenter randomised double-blind placebo-controlled dose-ranging study [abstract]. Circulation 1994; 90 Suppl. 1: 602

    Google Scholar 

  56. Packer M, Nicod P, Khandheria RR, et al. Randomised multicenter double-blind placebo-controlled evaluation of amlodipine in patients with mild-to-moderate heart failure [abstract]. J Am Col1 Cardiol 1991; 17: 274 A

    Google Scholar 

  57. Udelson JE, DeAbate CA, Berk M, et al. Effects of amlodipine on exercise tolerance, quality of life, and left ventricular function in patients with heart failure from left ventricular systolic dysfunction. Am Heart J. 2000; 139: 503–10

    CAS  PubMed  Google Scholar 

  58. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure: Prospective Randomized Amlodipine Survival Evaluation Study Group. N Engl J Med 1996; 335: 1107–14

    CAS  PubMed  Google Scholar 

  59. Thackray S, Witte K, Clark AL, et al. Clinical trials update: OPTIME-CHF, PRAISE-2, ALL-HAT. Eur J Heart Fail 2000; 2: 209–12

    CAS  PubMed  Google Scholar 

  60. Timmis AD, Campbell S, Monaghan MJ, et al. Acute and metabolic effects of felodipine in congestive heart failure. Br Heart J 1984; 51: 444–51

    Google Scholar 

  61. Emanuelsson H, Hjalmarson A, Holmberg S, et al. Acute hemodynamic effects of felodipine in congestive heart failure. Eur J Clin Pharmacol 1985; 28: 489–93

    CAS  PubMed  Google Scholar 

  62. Tweddel AC, Hutton J. Felodipine in ventricular dysfunction. Eur Heart J 1986; 7: 54–60

    CAS  PubMed  Google Scholar 

  63. Binetti G, Pancaldi S, Giovanelli N, et al. Hemodynamic effects of felodipine in congestive heart failure. Cardiovasc Drugs Ther 1987; 1: 161–7

    CAS  PubMed  Google Scholar 

  64. Agostini P, Doria E, Riva S, et al. Acute and chronic efficacy of felodipine in congestive heart failure. Int J Cardiol 1991; 30: 89–95

    Google Scholar 

  65. Dunselman P, Kuntze C, van Bruggen A, et al. Efficacy of felodipine in congestive heart failure. Eur Heart J 1989; 10: 354–64

    CAS  PubMed  Google Scholar 

  66. Kassis E, Amtrop O. Cardiovascular and neurohumoral postural responses and baroreceptor abnormalities during a course of adjunctive vasodilatory therapy with felodipine for congestive heart failure. Circulation 1987; 75: 1204–13

    CAS  PubMed  Google Scholar 

  67. Kassis E, Amtrop O. Long-term clinical, hemodynamic, angiographic and neurohumoral responses to vasodilation with felodipine in patients with chronic congestive heart failure. J Cardiovasc Pharmacol 1990; 15: 347–52

    CAS  PubMed  Google Scholar 

  68. Dunselman P, van der Mark T, Kuntze C, et al. Different results in cardiopulmonary exercise tests after long-term treatment with felodipine and enalapril in patients with congestive heart failure due to ischemic heart disease. Eur Heart J 1990; 11:200–6

    CAS  PubMed  Google Scholar 

  69. De Vries R, Querré M, Lok D, et al. Comparison of peak oxygen consumption, quality of life, and neurohormones of felodipine and enalapril in patients with congestive heart failure. Am J Cardiol 1995; 76: 1253–8

    PubMed  Google Scholar 

  70. Tan L, Murray R, Littler W. Felodipine in patients with chronic heart failure: discrepant hemodynamic and clinical effects. Br Heart J 1987; 58: 122–8

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Littler W, Sheridan D. Placebo-controlled trial of felodipine in patients with mild to moderate heart failure. Br Heart J 1995; 73: 428–33

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Cohn JN, Ziesche S, Smith R, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997; 96: 856–63

    CAS  PubMed  Google Scholar 

  73. Hansen JF, Hagerup L, Sigurd B, et al. Cardiac events rates after myocardial infarction in patients treated with verapamil and trandolapril versus trandolapril alone. Am J Cardiol 1997; 79: 738–41

    CAS  PubMed  Google Scholar 

  74. Oparil S, Kobrin I, Abernethy D, et al. Dose-response characteristics of mibefradil, a novel calcium antagonist, in the treatment of essential hypertension. Am J Hypertens 1997; 10: 735–42

    CAS  PubMed  Google Scholar 

  75. Noll G, Luscher TF. Comparative pharmacological properties among calcium channel antagonists: T-channel vs L-channel blockade. Cardiology 1998; 89 Suppl. 1: 10–5

    CAS  PubMed  Google Scholar 

  76. Bakx A, van der Wall EE, Braun S, et al. Effects of the new calcium antagonist mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: a multicenter placebo-controlled study. Am Heart J 1995; 130: 748–57

    CAS  PubMed  Google Scholar 

  77. Tzivoni D, Kadr H, Braat S, et al. Efficacy of mibefradil in comparison to amlodipine in suppressing exercise-induced and daily silent ischemia: results of a multicenter placebo-controlled trial. Circulation 1997; 96: 2557–64

    CAS  PubMed  Google Scholar 

  78. Rousseau MF, Hayashida 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: 972–9

    CAS  PubMed  Google Scholar 

  79. Levine TB, Bernink PJ, Caspi A, et al. Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial. Circulation 2000; 101: 758–64

    CAS  PubMed  Google Scholar 

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  1. Service Médecine A, Hôpital Lariboisière, Paris, France

    Isabelle Mahé, Olivier Chassany, Anne-Sophie Grenard, Charles Caulin & Jean-François Bergmann

  2. Service Medecine A, Hôpital Lariboisière, AP-HP 2 rue Ambroise Paré, Paris, 75010, France

    Isabelle Mahé

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Mahé, I., Chassany, O., Grenard, AS. et al. Defining the Role of Calcium Channel Antagonists in Heart Failure Due to Systolic Dysfunction. Am J Cardiovasc Drugs 3, 33–41 (2003). https://doi.org/10.2165/00129784-200303010-00004

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