Skip to main content
PMC home page
Clinical Cardiology logoLink to Clinical Cardiology
. 2006 Dec 5;28(4):165–173. doi: 10.1002/clc.4960280403

Carvedilol's antiarrhythmic properties: Therapeutic implications in patients with left ventricular dysfunction

Gerald V Naccarelli 1,✉, Mary Ann Lukas 2
PMCID: PMC6653935  PMID: 15869048

Abstract

Carvedilol is a beta‐and alpha‐adrenergic‐blocking drug with clinically important antiarrhythmic properties. It possesses anti‐ischemic and antioxidant activity and inhibits a number of cationic channels in the cardiomyocyte, including the HERG‐associated potassium channel, the L‐type calcium channel, and the rapid‐depolarizing sodium channel. The electrophysiologic properties of carvedilol include moderate prolongation of action potential duration and effective refractory period; slowing of atrioventricular conduction; and reducing the dispersion of refractoriness. Experimentally, carvedilol reduces complex and repetitive ventricular ectopy induced by ischemia and reperfusion.

In patients, carvedilol is effective in controlling the ventricular rate response in atrial fibrillation (AF), with and without digitalis, and is useful in maintaining sinus rhythm after cardioversion, with and without amiodarone. In patients with AF and heart failure (HF), carvedilol reduces mortality risk and improves left ventricular (LV) function. Large‐scale clinical trials have demonstrated that combined carvedilol and angiotensin‐converting enzyme inhibitor therapy significantly reduces sudden cardiac death, mortality, and ventricular arrhythmia in patients with LV dysfunction (LVD) due to chronic HF or following myocardial infarction (MI).

Despite intensive neurohormonal blockade, mortality rates remain relatively high in patients with post‐MI and nonischemic LVD. Recent trials of implantable cardioverter‐defibrillators added to pharmacologic therapy, especially beta blockers, have shown a further reduction in arrhythmic deaths in these patients.

Keywords: carvedilol, antiarrhythmic drugs, left ventricular dysfunction, atrial fibrillation, ventricular arrhythmias, sudden cardiac death

Full Text

The Full Text of this article is available as a PDF (88.1 KB).

References

  • 1. Kannel WB, Plehn JF, Cupples LA: Cardiac failure and sudden death in the Framingham Study. Am Heart J 1988; 115: 869–875 [DOI] [PubMed] [Google Scholar]
  • 2. Hynes BJ, Luck JC, Wolbrette DL, Boehmer J, Naccarelli GV: Arrhythmias in patients with heart failure. Curr Treat Options Cardiovasc Med 2002; 4: 467–485 [DOI] [PubMed] [Google Scholar]
  • 3. Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW: Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: A retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1998; 32: 695–703 [DOI] [PubMed] [Google Scholar]
  • 4. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349–1355 [DOI] [PubMed] [Google Scholar]
  • 5. Reiter MJ, Reiffel JA: Importance of beta blockade in the therapy of serious ventricular arrhythmias. Am J Cardiol 1998; 82: 91–191 [DOI] [PubMed] [Google Scholar]
  • 6. Packer M: Beta‐adrenergic blockade in chronic heart failure: Principles, progress, and practice. Prog Cardiovasc Dis 1998; 41: 39–52 [DOI] [PubMed] [Google Scholar]
  • 7. Bristow MR, Roden RL, Lowes BD, Gilbert EM, Eichhorn EJ: The role of third‐generation beta‐blocking agents in chronic heart failure. Clin Cardiol 1998; 21: 13–113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Hjalmarson A: Cardioprotection with beta‐adrenoceptor blockers. Does lipophilicity matter? Basic Res Cardiol 2000; 95 (suppl 1): I41–I45 [DOI] [PubMed] [Google Scholar]
  • 9. Cheng J, Niwa R, Kamiya K, Toyama J, Kodama I: Carvedilol blocks the re‐polarizing K+ currents and the L‐type Ca2+ current in rabbit ventricular myocytes. Eur J Pharmacol 1999; 376: 189–201 [DOI] [PubMed] [Google Scholar]
  • 10. Karle CA, Kreye VA, Thomas D, Rockl K, Kathofer S, Zhang W, Kiehn J: Antiarrhythmic drug carvedilol inhibits HERG potassium channels. Cardiovasc Res 2001; 49: 361–370 [DOI] [PubMed] [Google Scholar]
  • 11. Maltsev VA, Sabbab HN, Undrovinas AI: Down‐regulation of sodium current in chronic heart failure: Effect of long‐term therapy with carvedilol. Cell Mol Life Sci 2002; 59: 1561–1568 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Morganroth J: Antiarrhythmic effects of beta‐adrenergic blocking agents in benign or potentially lethal ventricular arrhythmias. Am J Cardiol 1987; 60: 10D–14D [DOI] [PubMed] [Google Scholar]
  • 13. Senior R, Muller‐Beckmann B, DasGupta P, van der DR, Lahiri A: Effects of carvedilol on ventricular arrhythmias. J Cardiovasc Pharmacol 1992; 19 (suppl1): S117–S121 [DOI] [PubMed] [Google Scholar]
  • 14. Cheng J, Kamiya K, Kodama I: Carvedilol: Molecular and cellular basis for its multifaceted therapeutic potential. Cardiovasc Drug Rev 2001; 19: 152–171 [DOI] [PubMed] [Google Scholar]
  • 15. Basu S, Senior R, Raval U, van der Does R, Bruckner T, Lahiri A: Beneficial effects of intravenous and oral carvedilol treatment in acute myocardial infarction: A placebo‐controlled, randomized trial. Circulation 1997; 96: 183–191 [DOI] [PubMed] [Google Scholar]
  • 16. Chiamvimonvat N, Kargacin ME, Clark RB, Duff HJ: Effects of intracellular calcium on sodium current density in cultured neonatal rat cardiac myocytes. J Physiol 1995; 483 (Pt2): 307–318 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Vassallo JA, Cassidy DM, Kindwall KE, Marchlinski FE, Josephson ME: Nonuniform recovery of excitability in the left ventricle. Circulation 1988; 78: 1365–1372 [DOI] [PubMed] [Google Scholar]
  • 18. Buja G, Miorelli M, Turrini P, Melacini P, Nava A: Comparison of QT dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. Am J Cardiol 1993; 72: 973–976 [DOI] [PubMed] [Google Scholar]
  • 19. Bonnar CE, Davie AP, Caruana L, Fenn L, Ogston SA, McMurray JJ, Struthers AD: QT dispersion in patients with chronic heart failure: Beta blockers are associated with a reduction in QT dispersion. Heart 1999; 81: 297–302 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Yildirir A, Sade E, Tokgozoglu L, Oto A: The effects of chronic carvedilol therapy on QT dispersion in patients with congestive heart failure. Eur J HeartFail 2001; 3: 717–721 [DOI] [PubMed] [Google Scholar]
  • 21. Piccirillo G, Quaglione R, Nocco M, Naso C, Moise A, Lionetti M, Di Carlo S, Marigliano V: Effects of long‐term beta‐blocker (metoprolol or carvedilol) therapy on QT variability in subjects with chronic heart failure secondary to ischemic cardiomyopathy. Am J Cardiol 2002; 90: 1113–1117 [DOI] [PubMed] [Google Scholar]
  • 22. Horio T, Ito S, Aoyama M, Takeda Y, Suzumura H, Nakata K, Yamada Y, Suzuki S, Fukutomi T, Itoh M: Effect of carvedilol on atrioventricular conduction in the ischemic heart. Eur J Pharmacol 2001; 4: 145–153 [DOI] [PubMed] [Google Scholar]
  • 23. Feuerstein GZ, Poste G, Ruffolo RR: Carvedilol update III: Rationale for use in congestive heart failure. Drugs Today 1995; 31: 307–326 [Google Scholar]
  • 24. Takusagawa M, Komori S, Matsumura K, Osada M, Kohno I, Umetani K, Ishihara T, Sawanobori T, Ijiri H, Tamura K: The inhibitory effects of carvedilol against arrhythmias induced by coronary reperfusion in anesthetized rats. J Cardiovasc Pharmacol Ther 2000; 5: 105–112 [DOI] [PubMed] [Google Scholar]
  • 25. Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA: Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 2001; 104: 174–180 [DOI] [PubMed] [Google Scholar]
  • 26. Coumel P: Neurogenic and humoral influences of the autonomic nervous system in the determination of paroxysmal atria fibrillation In The Atrium in Health and Disease, p. 213–232 (Eds. Attuel P, Coumel P, Janse MJ.). Mount Kisco, NY: Futura Publishing, 1989. [Google Scholar]
  • 27. Farshi R, Kistner D, Sarma JS, Longmate JA, Singh BN: Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: A crossover open‐label study of five drug regimens. J Am Coll Cardiol 1999; 33: 304–310 [DOI] [PubMed] [Google Scholar]
  • 28. Olshansky B, Rosenfeld LE, Warner AL, Solomon AJ, O'Neill G, Sharma A, Platia E, Feld GK, Akiyama T, Brodsky MA, Greene HL, and the AFFIRM Investigators : The atrial fibrillation follow‐up investigation of rhythm management (AFFIRM) study. Approaches to control rate in atrial fibrillation. J Am Coll Cardiol 2004; 43: 1201–1208 [DOI] [PubMed] [Google Scholar]
  • 29. CIBIS‐II Investigators : The Cardiac Insufficiency Bisoprolol Study II (CIBIS‐II): A randomised trial. Lancet 1999; 353: 9–13 [PubMed] [Google Scholar]
  • 30. MERIT‐HF Investigators : Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF). Lancet 1999; 353: 2001–2007 [PubMed] [Google Scholar]
  • 31. Digitalis Investigation Group : The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997; 336: 525–533 [DOI] [PubMed] [Google Scholar]
  • 32. Packer M, Colucci WS, Sackner‐Bernstein JD, Liang CS, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH: Double‐blind, placebo‐controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation 1996; 94: 2793–2799 [DOI] [PubMed] [Google Scholar]
  • 33. Lechat P, Hulot JS, Escolano S, Mallet A, Leizorovicz A, Werhlen‐Grandjean M, Pochmalicki G, Dargie H: Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation 2001; 103: 1428–1433 [DOI] [PubMed] [Google Scholar]
  • 34. Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG: Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol 2003; 42: 1944–1951 [DOI] [PubMed] [Google Scholar]
  • 35. Kuhlkamp V, Schirdewan A, Stangl K, Honberg M, Ploch M, Beck OA: Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation. Arandomized, double‐blind, placebo‐controlled study. J Am Coll Cardiol 2000; 36: 139–146 [DOI] [PubMed] [Google Scholar]
  • 36. Katritsis DG, Panagiotakos DB, Karvouni E, Giazitzoglou E, Korovesis S, Paxinos G, Anagnostopoulos CE, Camm AJ: Comparison of effectiveness of carvedilol versus bisoprolol for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. Am J Cardiol 2003; 92: 1116–1119 [DOI] [PubMed] [Google Scholar]
  • 37. Merritt JC, Niebaur M, Tarakji K, Hammer D, Mills RM: Comparison of effectiveness of carvedilol versus metoprolol or atenolol for atrial fibrillation appearing after coronary artery bypass grafting or cardiac valve operation. Am J Cardiol 2003; 92: 735–736 [DOI] [PubMed] [Google Scholar]
  • 38. Kanoupakis EM, Manios EG, Mavrakis HE, Tzerakis PG, Mouloudi HK, Vardas PE: Comparative effects of carvedilol and amiodarone on conversion and recurrence rates of persistent atrial fibrillation. Am J Cardiol 2004; 94: 659–662 [DOI] [PubMed] [Google Scholar]
  • 39. McMurray J, Kober I, Robertson M, Dargie H, Colucci W, Lopez‐Sendon J, Remmew W, Sharpe DN, Ford I: Antiarrhythmic effect of carvedilol after acute myocardial infarction. Results of the carvedilol post‐infarct survival control in left ventricular dysfunction (CAPRICORN) trial. J Am Coll Cardiol 2005; 45: 525–530 [DOI] [PubMed] [Google Scholar]
  • 40. Panidis IP, Morganroth J: Sudden death in hospitalized patients: Cardiac rhythm disturbances detected by ambulatory electrocardiographic monitoring. J Am Coll Cardiol 1983; 2: 798–805 [DOI] [PubMed] [Google Scholar]
  • 41. Bayes DL, Coumel P, Leclercq JF: Ambulatory sudden cardiac death: Mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989; 117: 151–159 [DOI] [PubMed] [Google Scholar]
  • 42. Gradman A, Deedwania P, Cody R, Massie B, Packer M, Pitt B, Goldstein S: Predictors of total mortality and sudden death in mild to moderate heart failure. Captopril‐Digoxin Study Group. J Am Coll Cardiol 1989; 14: 564–570 [DOI] [PubMed] [Google Scholar]
  • 43. Brophy JM, Joseph L, Rouleau JL: Beta‐blockers in congestive heart failure. ABayesianmeta‐analysis. Ann Intern Med 2001; 134: 550–560 [DOI] [PubMed] [Google Scholar]
  • 44. Doval HC, Nul DR, Grancelli HO, Varini SD, Soifer S, Corrado G, Dubner S, Scapin O, Perrone SV: Nonsustained ventricular tachycardia in severe heart failure: Independent marker of increased mortality due to sudden death. GESICA‐GEMAInvestigators. Circulation 1996; 94: 3198–3203 [DOI] [PubMed] [Google Scholar]
  • 45. Bigger JT Jr, Fleiss JL, Kleiger R, Miller JP, Rolnitzky LM: The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984; 69: 250–258 [DOI] [PubMed] [Google Scholar]
  • 46. Cice G, Tagliamonte E, Ferrara L, Iacono A: Efficacy of carvedilol on complex ventricular arrhythmias in dilated cardiomyopathy: Double‐blind, randomized, placebo‐controlled study. Eur Heart J 2000; 21: 1259–1264 [DOI] [PubMed] [Google Scholar]
  • 47. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner‐Bernstein JD, Young ST, Holcslaw TL, Lukas MA: Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation 1996; 94: 2800–2806 [DOI] [PubMed] [Google Scholar]
  • 48. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–1658 [DOI] [PubMed] [Google Scholar]
  • 49. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amanns‐Zalan I, DeMets DL: Effect of carvedilol on the morbidity of patients with severe chronic heart failure: Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation 2002; 106: 2194–2199 [DOI] [PubMed] [Google Scholar]
  • 50. Amiodarone Trials Meta‐Analysis Investigators : Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: Meta‐analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta‐Analysis Investigators. Lancet 1997; 350: 1417–1424 [PubMed] [Google Scholar]
  • 51. Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, Simon P: Randomised trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet 1997; 349: 667–674 [DOI] [PubMed] [Google Scholar]
  • 52. Janse MJ, Malik M, Camm AJ, Julian DG, Frangin GA, Schwartz PJ: Identification of post acute myocardial infarction patients with potential benefit from prophylactic treatment with amiodarone: A substudy of EMIAT (the European Myocardial Infarct Amiodarone Trial). Eur Heart J 1998;: 85–95 [DOI] [PubMed]
  • 53. Nagele H, Bohlmann M, Eck U, Petersen B, Rodiger W: Combination therapy with carvedilol and amiodarone in patients with severe heart failure. Eur J Heart Fail 2000; 2: 71–79 [DOI] [PubMed] [Google Scholar]
  • 54. Poole‐Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp‐Pedersen C, Scherhag A, Skene AM: Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): Randomised controlled trial. Lancet 2003; 362: 7–13 [DOI] [PubMed] [Google Scholar]
  • 55. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: 1309–1321 [DOI] [PubMed] [Google Scholar]
  • 56. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M: Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335: 1933–1940 [DOI] [PubMed] [Google Scholar]
  • 57. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML: Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346: 877–883 [DOI] [PubMed] [Google Scholar]
  • 58. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G: A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999; 341: 1882–1890 [DOI] [PubMed] [Google Scholar]
  • 59. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp‐Channing N, Davidson‐Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH, for the Sudden Cardiac Death in Heart Failure Trial (SCD‐HeFT) Investigators : Amiodarone or an implantable cardioverter‐defibrillator for congestive heart failure. N Engl J Med 2005; 352 (3): 225–237 [DOI] [PubMed] [Google Scholar]
  • 60. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NAM, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH, the Defibrillator in Non‐Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators : Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004; 350: 2151–2158 [DOI] [PubMed] [Google Scholar]
  • 61. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, de Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM: Cardiac resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350: 2140–2150 [DOI] [PubMed] [Google Scholar]
  • 62. Bigger JT Jr: Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary‐artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med 1997; 337: 1569–1575 [DOI] [PubMed] [Google Scholar]
  • 63. Hohnloser SG, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, Fain E, Gent M, Connolly SJ, on behalf of the DINAMIT Investigators : Prophylactic use of an implantable cardioverter‐defibrillator after acute myocardial infarction. N Engl J Med 2004; 351: 2481–2488 [DOI] [PubMed] [Google Scholar]
  • 64. CAPRICORN Investigators : Effect of carvedilol on outcome after myocardial infarction in patients with left‐ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001; 357: 1385–1390 [DOI] [PubMed] [Google Scholar]

Articles from Clinical Cardiology are provided here courtesy of Wiley

RESOURCES