New Antiarrhythmic Drugs for the Treatment of Atrial Fibrillation

  • Jörn Schmitt
  • Joachim R. Ehrlich
  • Stefan H. Hohnloser
Article

Abstract

Atrial fibrillation (AF) is the most common arrhythmia requiring medical care, with a prevalence of almost 1% in the adult population. Particularly in the expanding elderly population, pharmacological therapy is and will continue to be the mainstay of AF therapy. Many currently used antiarrhythmic drugs have limited efficacy and cause cardiac and extracardiac toxicity. Thus, there is a continued need for development of new compounds with good efficacy and particularly with a favorable safety profile. Much emphasis is currently given to the development of so-called atrial-selective agents which target ion channels or proteins predominantly expressed in atrial myocardium. The rationale behind these compounds is to avoid unwanted effects on ionic currents on the ventricular site thus avoiding ventricular proarrhythmic effects. Alternatively, more conventional multichannel-blocking drugs are developed, for instance congeners of amiodarone. These molecules are designed to retain the electrophysiological efficacy of the mother compound while avoiding the extracardiac toxicity of this drug. The compounds which are far advanced in their clinical development are vernakalant (“atrial-selective”) and dronedarone (multichannel-blocking). Preclinical and clinical findings of these substances are summarized.

Key Words:

Atrial fibrillation Atrial-selective drugs Vernakalant Dronedarone 

Neue Antiarrhythmika für die Therapie von Vorhofflimmern

Zusammenfassung

Vorhofflimmern ist die häufigste klinisch diagnostizierte Rhythmusstörung mit einer Prävalenz von etwa 1% in der Bevölkerung. Speziell in der stetig wachsenden Gruppe betagter Patienten mit dieser Rhythmusstörung ist die medikamentöse antiarrhythmische Therapie noch immer die wichtigste Behandlungsform. Die eingeschränkte Wirksamkeit und die Toxizität vieler gängiger Antiarrhythmika bedingen die Notwendigkeit, neue Medikamente zu entwickeln. In letzter Zeit werden dabei häufig Substanzen gesucht, die eine relative Selektivität für die Beeinflussung von Ionenkanälen haben, die nur oder überwiegend im Vorhof exprimiert werden. Von diesen sog. atrial selektiven Medikamenten verspricht man sich, dass sie keine ventrikulären Effekte und damit vor allem keine ventrikulären proarrhythmischen Nebenwirkungen hervorrufen. Daneben werden aber auch Medikamente entwickelt, die sich strukturell z.B. am Amiodaronmolekül orientieren; dabei wird versucht, die elektrophysiologischen Effekte und die daraus resultierende Wirksamkeit beizubehalten, die toxischen Effekte aber zu vermeiden. Beispiele für beide Substanzgruppen sind zum einen Vernakalant, zum anderen Dronedaron. Die präklinischen und klinischen Befunde zu diesen Substanzen werden zusammengefasst.

Schlüsselwörter:

Vorhofflimmern Atrial selektive Antiarrhythmika Vernakalant Dronedaron 

References

  1. 1.
    Greenlee RT, Vidaillet H. Recent progress in the epidemiology of atrial fibrillation. Curr Opin Cardiol 2005;20:7–14.PubMedGoogle Scholar
  2. 2.
    Feinberg WM, Blackshear JL, Laupacis A, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–473.PubMedCrossRefGoogle Scholar
  3. 3.
    Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–952.PubMedGoogle Scholar
  4. 4.
    Miyasaka Y, Barnes ME, Bailey KR, et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J Am Coll Cardiol 2007;49:986–992.PubMedCrossRefGoogle Scholar
  5. 5.
    Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation-Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789–1794.PubMedCrossRefGoogle Scholar
  6. 6.
    Van Gelder IC, Hagens VE, Bosker HA, et al., Rate Controlversus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–1840.PubMedCrossRefGoogle Scholar
  7. 7.
    Wyse DG, Waldo AL, DiMarco JP, et al., Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833.PubMedGoogle Scholar
  8. 8.
    Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–2677.PubMedCrossRefGoogle Scholar
  9. 9.
    Kneller J, Kalifa J, Zou R, et al. Mechanisms of atrial fibrillation termination by pure sodium channel blockade in an ionically-realistic mathematical model. Circ Res 2005;96:e35–e47.PubMedCrossRefGoogle Scholar
  10. 10.
    Roy D, Talajic M, Dorian P, et al. Amiodarone to preventrecurrence of atrial fibrillation. N Engl J Med 2000;342:913–920.PubMedCrossRefGoogle Scholar
  11. 11.
    Hohnloser SH, Singh BN. Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications. J Cardiovasc Electrophysiol 1995;6:920–936.PubMedCrossRefGoogle Scholar
  12. 12.
    Dobrzynski H, Marples DD, Musa H, et al. Distribution of the muscarinic K+ channel proteins Kir3.1 and Kir3.4 in the ventricle, atrium, and sinoatrial node of heart. J Histochem Cytochem 2001;49:1221–1234.PubMedGoogle Scholar
  13. 13.
    Atienza F, Almendral J, Moreno J, et al. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism. Circulation 2006;114:2434–2442.PubMedCrossRefGoogle Scholar
  14. 14.
    Dobrev D, Graf E, Wettwer E, et al. Molecular basis of down-regulation of G-protein-coupled inward rectifying K(+) current (I(K,ACh) in chronichuman atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic receptor-mediated shortening of action potentials. Circulation 2001;104:2551–2557.PubMedCrossRefGoogle Scholar
  15. 15.
    Ehrlich JR, Cha TJ, Zhang L, et al. Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium. J Physiol 2004;557:583–597.PubMedCrossRefGoogle Scholar
  16. 16.
    Ehrlich JR, Biliczki P, Hohnloser SH, et al. Atrial-selective approaches for the treatment of atrial fibrillation. J Am Coll Cardiol 2008;51:787–792.PubMedCrossRefGoogle Scholar
  17. 17.
    Mays DJ, Foose JM, Philipson LH, et al. Localization of the Kv1.5 K+ channel protein in explanted cardiac tissue. J Clin Invest 1995;96:282–292.PubMedCrossRefGoogle Scholar
  18. 18.
    Nattel S, Yue L, Wang Z. Cardiacultrarapid delayed rectifiers: a novel potassium current family of functional similarity and molecular diversity. Cell Physiol Biochem 1999;9:217–226.PubMedCrossRefGoogle Scholar
  19. 19.
    Van Wagoner DR, Pond AL, McCarthy PM, et al. Outward K+ current densities and Kv1.5 expression are reduced in chronicatrial fibrillation. Circ Res 1997;80:772–781.PubMedGoogle Scholar
  20. 20.
    Workman AJ, Kane KA, Rankin AC. The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronicatrial fibrillation. Cardiovasc Res 2001;52:226–235.PubMedCrossRefGoogle Scholar
  21. 21.
    Wettwer E, Hala O, Christ T, et al. Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronicatrial fibrillation. Circulation 2004;110:2299–2306.PubMedCrossRefGoogle Scholar
  22. 22.
    Ehrlich JR, Ocholla H, Rütten H, et al. Characterization of AVE1231 block of the human ultrarapid delayed rectifier, Kv1.5. J Cardiovasc Pharmacol 2008;51:380–387.PubMedCrossRefGoogle Scholar
  23. 23.
    Burashnikov A, Antzelevitch C. Can inhibition of IKur promote atrial fibrillation? Heart Rhythm 2008;5:1304–1309.PubMedCrossRefGoogle Scholar
  24. 24.
    Van der Velden HM, Ausma J, Rook MB, et al. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res 2000;46:476–486.PubMedCrossRefGoogle Scholar
  25. 25.
    Gollob MH, Jones DL, Krahn AD, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med 2006;354:2677–2688.PubMedCrossRefGoogle Scholar
  26. 26.
    Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov 2006;5:1034–1049.PubMedCrossRefGoogle Scholar
  27. 27.
    Fedida D. Vernakalant (RSD1235): a novel, atrial-selective antifibrillatory agent. Expert Opin Investig Drugs 2007;16:519–532.PubMedCrossRefGoogle Scholar
  28. 28.
    Fedida D, Orth PM, Chen JY, et al. The mechanism of atrial antiarrhythmic action of RSD1235. J Cardiovasc Electrophysiol 2005;16:1227–1238.PubMedCrossRefGoogle Scholar
  29. 29.
    Orth PM, Hesketh JC, Mak CK, et al. RSD1235 blocks late INa and suppresses early after depolarizations and torsades de pointes induced by class III agents. Cardiovasc Res 2006;70:486–496.PubMedCrossRefGoogle Scholar
  30. 30.
    Roy D, Rowe BH, Stiell IG, et al. A randomized, controlled trial of RSD1235, a novel anti-arrhythmic agent, in the treatment of recent onset atrial fibrillation. J Am Coll Cardiol 2004;44:2355–2361.PubMedCrossRefGoogle Scholar
  31. 31.
    Roy D, Pratt CM, Torp-Pedersen C, et al. Vernakalant hydrochloride for rapid conversion of atrial fibrillation. A phase 3, randomized, placebo-controlled trial. Circulation 2008;117:1518–1525.PubMedCrossRefGoogle Scholar
  32. 32.
    Wegener FT, Ehrlich JR, Hohnloser SH. Dronedarone: an emerging agent with rhythm- and rate-controlling effects. J Cardiovasc Electrophysiol 2006;17:Suppl 2:S17–S20.PubMedCrossRefGoogle Scholar
  33. 33.
    Sun W, Sarma JSM, Singh BN. Electrophysiological effects of dronedarone (SR33589), a non-iodinated benzofuran derivative in the rabbit heart. Comparison with amiodarone. Circulation 1999;100:2276–2283.PubMedGoogle Scholar
  34. 34.
    Sun W, Sarma JSM, Singh BN. Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone. J Cardiovasc Pharmacol 2002;39:677–684.PubMedCrossRefGoogle Scholar
  35. 35.
    Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003;24:1481–1487.PubMedCrossRefGoogle Scholar
  36. 36.
    Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythmin atrial fibrillation or flutter. N Engl J Med 2007;357:987–999.PubMedCrossRefGoogle Scholar
  37. 37.
    Kober L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678–2687.PubMedCrossRefGoogle Scholar
  38. 38.
    Hohnloser SH, Connolly SJ, Crijns HJ, et al. Rationale and design of ATHENA: a placebo-controlled, double-blind, parallel arm trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. J Cardiovasc Electrophysiol 2008;19:69–73.PubMedCrossRefGoogle Scholar

Copyright information

© Urban & Vogel, Muenchen 2008

Authors and Affiliations

  • Jörn Schmitt
  • Joachim R. Ehrlich
  • Stefan H. Hohnloser
    • 1
    • 2
  1. 1.Division of Clinical ElectrophysiologyJ.W. Goethe UniversityFrankfurt/MainGermany
  2. 2.Division of Clinical ElectrophysiologyJ.W. Goethe University HospitalFrankfurtGermany

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