Research Article| Volume 19, SUPPLEMENT 1, 92-113, 1997

Safety of calcium antagonists in patients with congestive heart failure

  • Stuart Katz
    Address correspondence to: Stuart Katz, MD, The Heart Failure Center at Columbia—Presbyterian Medical Center, Milstein Hospital Building 5-435, 177 Fort Washington Avenue, New York, NY 10032.
    The Heart Failure Center at Columbia—Presbyterian Medical Center, New York, New York U.S.A.
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      Continuing high morbidity and mortality have spurred an ongoing search for new therapeutic agents for patients with congestive heart failure. Calcium antagonists (CAs) have been under active investigation in patients with heart failure since their introduction into clinical medicine, because their anti-ischemic and vasodilator properties were thought to be of potential benefit in this patient population. However, review of published clinical trials of CAs in patients with heart failure reveals that some of these drugs are associated with detrimental effects, including acute hemodynamic deterioration, increased symptoms of heart failure, and increased mortality. The adverse effects of short-acting CAs in patients with heart failure include negative inotropic effects and neurohormonal activation. Long-acting CAs, such as amlodipine and felodipine, had fewer negative inotropic effects, showed less evidence of neurohormonal activation, and were better tolerated in clinical trials. Amlodipine, in combination with an angiotensin-converting enzyme inhibitor, had a neutral effect in patients with ischemic heart failure and an unexplained benefit in a subgroup of patients with nonischemic cardiomyopathy. Although the preliminary experience with long-acting dihydropyridine CAs in heart failure has been encouraging, safety concerns raised by past trials dictate that no CA can be recommended for the treatment of heart failure at this time.



        • Packer M
        Calcium channel blockers in chronic heart failure: The risks of “physiologically rational” therapy.
        Circulation. 1990; 82: 2254-2257
        • Young J
        • Weiner D
        • Yusuf S
        • et al.
        Patterns of medication use in patients with heart failure: A report from the Registry of Studies of Left Ventricular Dysfunction (SOLVD).
        South Med J. 1995; 88: 514-523
        • Elkayam U
        • Shotan A
        • Mehra A
        • Ostrzega E
        Calcium channel blockers in heart failure.
        J Am Coll Cardiol. 1993; 22 (4 Suppl A): 139A-144A
        • Elkayam U
        • Weber L
        • Torkan B
        • et al.
        Comparison of hemodynamic responses to nifedipine and nitroprusside in severe congestive heart failure.
        Am J Cardiol. 1984; 53: 1321-1329
        • Fifer M
        • Colucci W
        • Lorell B
        • et al.
        Inotropic, vascular and neuroendocrine effects of nifedipine in heart failure: Comparison with nitroprusside.
        J Am Coll Cardiol. 1985; 5: 731-737
        • Factor S
        • Minase T
        • Cho S
        • et al.
        Microvascular spasm in the cardiomyopathic Syrian hamster: A preventable cause of focal myocardial necrosis.
        Circulation. 1982; 66: 342-354
        • Parameshwar J
        • Poole-Wilson P
        The role of calcium antagonists in the treatment of chronic heart failure.
        Eur Heart J. 1993; 14: 38-44
        • Henry P
        Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem.
        Am J Cardiol. 1980; 46: 1047-1058
        • Opie LH
        Calcium channel antagonists in the treatment of coronary artery disease: Fundamental pharmacological properties relevant to clinical use.
        Prog Cardiovasc Dis. 1996; 38: 273-290
        • Braunwald E
        Mechanism of action of calcium-channel-blocking agents.
        NEJM. 1982; 307: 1618-1627
        • Rutledge A
        • Triggle D
        The binding interactions of Ro 40-5967 at the L-type Ca2+ channel in cardiac tissue.
        Eur J Pharmacol. 1995; 290: 155-158
        • Mishra S
        • Hermsmeyer K
        Selective inhibition of T-type Ca2+ channels by Ro 40-5967.
        Circ Res. 1994; 75: 144-148
        • Osterrieder W
        • Holck M
        In vitro pharmacologic profile of Ro 40-5967, a novel Ca2+ channel blocker with potent vasodilator but weak inotropic action.
        J Cardiovasc Pharmacol. 1989; 13: 754-759
        • Freedman D
        • Waters D
        Second generation dihydropyridine calcium antagonists. Greater vascular selectivity and some unique applications.
        Drugs. 1987; 34: 578-598
        • Sun J
        • Triggle D
        Calcium channel antagonists: Cardiovascular selectivity of action.
        J Pharmacol Exp Ther. 1990; 274: 419-426
        • Reicher-Reiss H
        • Barasch E
        Calcium antagonists in patients with heart failure: A review.
        Drugs. 1991; 42: 343-364
        • Piepho R
        Calcium antagonist use in congestive heart failure: Still a bridge too far?.
        J Clin Pharmacol. 1995; 35: 443-453
        • Elkayam U
        • Weber L
        • McKay C
        • Rahimtoola S
        Spectrum of acute hemodynamic effects of nifedipine in severe congestive heart failure.
        Am J Cardiol. 1985; 56: 560-566
        • Packer M
        • Lee W
        • 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; 9: 622-630
        • Packer M
        • Kessler P
        • Lee W
        Calcium-channel blockade in the management of severe chronic congestive heart failure: A bridge too far.
        Circulation. 1987; 75 (Suppl V): V56-V64
        • Packer M
        Pathophysiological mechanisms underlying the adverse effects of calcium channel-blocking drugs in patients with chronic heart failure.
        Circulation. 1989; 80 (Suppl IV): IV59-IV67
        • Barjon J
        • Rouleau J-L
        • Bichet D
        • et al.
        Chronic renal and neurohormonal effects of the calcium entry blocker nisoldipine in patients with severe left ventricular dysfunction.
        J Am Coll Cardiol. 1987; 9: 622-630
        • Elkayam U
        • Amin J
        • Mehra A
        • et al.
        A prospective, randomized, double-blind, crossover study to compare the efficacy of 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: 1954-1961
        • Packer M
        • Nicod P
        • Khandheria B
        • Costello D
        Randomized multi-center double-blind placebo controlled evaluation of amlodipine in patients with mild to moderate heart failure.
        J Am Coll Cardiol. 1991; 17 (Abstract): 274A
        • 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 ischaemic heart disease.
        Eur Heart J. 1990; 11: 200-206
        • de Vries R
        • Queré M
        • Lok D
        • et al.
        Comparison of effects on peak oxygen consumption, quality of life, and neurohormones of felodipine and enalapril in patients with congestive heart failure.
        Am J Cardiol. 1995; 76: 1253-1258
        • Tan L
        • Murray R
        • Littler W
        Felodipine in patients with chronic heart failure: Discrepant hemodynamic and clinical effects.
        Br Heart J. 1987; 58: 122-128
        • Littler W
        • Sheridan D
        Placebo controlled trial of felodipine in patients with mild to moderate heart failure.
        Br Heart J. 1995; 73: 428-433
        • The Multicenter Diltiazem Postinfarction Trial Research Group
        The effect of diltiazem on mortality and reinfarction after myocardial infarction.
        NEJM. 1988; 319: 385-392
        • Goldstein R
        • Boccuzzi S
        • Cruess D
        • Nattel S
        Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction.
        Circulation. 1991; 83: 52-60
        • The Danish Study Group on Verapamil in Myocardial Infarction
        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: 779-785
        • Israeli SPRINT Study Group
        Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT): A randomized intervention trial of nifedipine in patients with acute myocardial infarction.
        Eur Heart J. 1988; 9: 354-364
        • Figulla H
        • Gietzen F
        • Zeymer 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: 346-352
        • Packer M
        • O'Connor C
        • Ghali J
        • et al.
        Effect of amlodipine on morbidity and mortality in severe chronic heart failure.
        NEJM. 1996; 335: 1107-1114
        • Cohn J
        • Ziesche S
        • Loss L
        • Anderson G
        Effect of felodipine on short-term exercise and neurohormone and long-term mortality in heart rate: Results of V-HeFT III.
        Circulation. 1995; 92 (Abstract): I-143
        • Heywood J
        • Graham B
        • Marais G
        • Jutzy K
        Effects of intravenous diltiazem on rapid atrial fibrillation accompanied by congestive heart failure.
        Am J Cardiol. 1991; 67: 1150-1152
        • Goldenberg I
        • Lewis W
        • Dias V
        • et al.
        Intravenous diltiazem for the treatment of patients with atrial fibrillation or flutter and moderate to severe congestive heart failure.
        Am J Cardiol. 1994; 74: 884-889
        • Stauffer J-C
        • Gaasch W
        Recognition and treatment of left ventricular diastolic dysfunction.
        Prog Cardiovasc Dis. 1990; 32: 319-332
        • Nordlander M
        • Abrahamsson T
        • Akerblom B
        • Thalen P
        Vascular versus myocardial selectivity of dihydropyridine calcium antagonists as studied in vivo and in vitro.
        Pharmacol Toxicol. 1995; 76: 56-62
        • Foult J-M
        • Tavolaro O
        • Anthony I
        • Nitenberg A
        Direct myocardial and coronary effects of enalaprilat in patients with dilated cardiomyopathy: Assessment by a bilateral intracoronary infusion technique.
        Circulation. 1988; 77: 337-344
        • Gibbons G
        • Dzau V
        The emerging concept of vascular remodeling.
        NEJM. 1994; 330: 1431-1438
        • Pollman M
        • Yamada T
        • Horiuchi M
        • Gibbons G
        Vasoactive substances regulate vascular smooth muscle cell apoptosis: Countervailing influences of nitric oxide and angiotensin II.
        Circ Res. 1996; 79: 748-756
        • Mancini D
        • LeJemtel T
        • Factor S
        • Sonnenblick E
        Central and peripheral components of cardiac failure.
        Am J Med. 1986; 80: 2-13
        • Naftilan A
        • Oparil S
        The role of calcium in the control of renin release.
        Hypertension. 1982; 4: 670-675
        • Elkayam U
        • Roth A
        • Hsueh W
        • et al.
        Neurohumoral consequences of vasodilator therapy with hydralazine and nifedipine in severe congestive heart failure.
        Am Heart J. 1986; 111: 1130-1138
        • Gheorghiade M
        • Hall V
        • Goldberg A
        • et al.
        Long-term clinical and neurohormonal effects of nicardipine in patients with severe heart failure on maintenance therapy with angiotensin converting enzyme inhibitors.
        J Am Coll Cardiol. 1991; 17 (Abstract): 274A
        • Katz A
        Calcium channel diversity in the cardiovascular system.
        J Am Coll Cardiol. 1996; 28: 522-529
        • Xu X
        • Best P
        Increase in T-type calcium current in atrial myocytes from adult rats with growth hormone-secreting tumors.
        Proc Natl Acad Sci USA. 1990; 87: 4655-4659
        • Nuss H
        • Houser S
        T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes.
        Circ Res. 1993; 73: 777-782
        • Schmitt R
        • Kleinbloesem C
        • Belz G
        • et al.
        Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension.
        Clin Pharmacol Ther. 1992; 52: 314-323
        • Su J
        • Renaud N
        • Carayon A
        • et al.
        Effects of the calcium channel blockers, diltiazem and Ro 40-5967, on systemic haemodynamics and plasma noradrenaline levels in conscious dogs with pacing-induced heart failure.
        Br J Pharmacol. 1994; 13: 395-402
        • Véniant M
        • Clozel J-P
        • Hess P
        • Wolfgang R
        Ro 40-5967, in contrast to diltiazem, does not reduce left ventricular contractility in rats with chronic myocardial infarction.
        J Cardiovasc Pharmacol. 1991; 17: 277-284
        • Ezzaher A
        • Bouanani N
        • Su J
        • et al.
        Increased negative inotropic effect of calcium channel blockers in hypertrophied and failing rabbit heart.
        J Pharmacol Exp Ther. 1991; 257: 466-471
        • Gray G
        • Clozel M
        • Clozel J-P
        • Baumgartner H-R
        Effects of calcium channel blockade on the aortic intima in spontaneously hypertensive rats.
        Hypertension. 1993; 22: 569-576
        • Boulanger C
        • Nakashima M
        • Olmos L
        • et al.
        Effects of the Ca2+ antagonist Ro 40-5967 on endothelium-dependent responses of isolated arteries.
        J Cardiovasc Pharmacol. 1994; 23: 869-876
        • van der Vring J
        • Bernink P
        • van der Wall E
        • et al.
        Evaluating the safety of mibefradil, a selective T-type calcium antagonist, in patients with chronic congestive heart failure.
        Clin Ther. 1996; 18: 1191-1206
        • The SOLVD Investigators
        Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
        NEJM. 1991; 325: 293-302