All antiarrhythmic drugs have the potential to precipitate life-threatening ventricular arrhythmias. In the Stroke Prevention in Atrial Fibrillation (SPAF) study, patients with heart failure and atrial fibrillation had a higher risk of death if they received long-term antiarrhythmic therapy. The probable causes are not only the arrhythmogenicity of these drugs, but also their negative inotropism.
Among the available antiarrhythmic drugs, only amiodarone has been sufficiently studied to determine that it does not increase mortality in patients with heart failure. It converts atrial fibrillation to sinus rhythm and improves the success rate of electrical cardioversion.
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Good response is reported to intravenous amiodarone 5 mg/kg over 10 to 30 minutes followed by the infusion of 500 mg over 24 hours. In the Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy (CHF-STAT), patients in atrial fibrillation on amiodarone were more likely to convert to sinus rhythm, and those in sinus rhythm were less likely to go into atrial fibrillation.
Amiodarone slowed the ventricular rate and maintained sinus rhythm for over 1 year in over 50% of nonresponders to other drugs. In a recent heart failure study, it increased the rate of conversion from atrial fibrillation to sinus rhythm, and the survival rate was higher in patients converting to sinus rhythm than among those in whom atrial fibrillation persisted.
Serious effects can involve the lungs, liver, and thyroid. Concern over actual or perceived toxicity caused drug discontinuation in 41% of patients in the randomized trials. Thus, new and better therapies are needed for restoring and maintaining sinus rhythm.
Dofetilide effectively restored and maintained sinus rhythm in fibrillating heart failure in the Danish Investigations of Arrhythmia and MOrtality oN Dofetilide (DIAMOND) trial. The risk of recurrent atrial fibrillation was reduced by 65% in patients converting to sinus rhythm. In patients known to be in sinus rhythm at baseline, dofetilide reduced the incidence of emergent atrial fibrillation. Safety was suggested by the finding that mortality rates were similar in the dofetilide and placebo groups, but this point requires further assessment.
Dofetilide blocks the rapidly activating component of the delayed rectifier potassium current. Blockade of cardiac potassium currents prolongs the duration of the action potential and hence the QT interval, which can increase the risk of the polymorphic ventricular tachycardia known as torsades de pointes. To mitigate this risk, the study did not include patients with moderate prolongation of the corrected QT interval at baseline, bradycardia, hypokalemia, or severe renal insufficiency. In addition, dose was adjusted to renal function. Patients were hospitalized and monitored continuously for 3 days after starting treatment. Excessive prolongation of the corrected QT interval caused treatment discontinuation in 2% of patients. The risk of torsades de pointes was higher in patients in New York Heart Association class III or IV heart failure at baseline than in those with less severe heart failure. There is a serious potential for drug accumulation and fatal arrhythmia with deteriorating renal function. Dofetilide appears a reasonable alternative to amio-
Drugs: general considerations darone for restoring sinus rhythm, provided renal function is adequate and there are no additional risk factors for torsades de pointes. Patients should be monitored in hospital for at least 3 days after initiating therapy.
Although both dofetilide and amiodarone prevent the emergence of atrial fibrillation in heart failure, routine prophylaxis with either drug is currently unwarranted. In heart failure patients with atrial fibrillation and and/or depressed left ventricular function, antiarrhythmic therapy should be restricted to amiodarone, and, if available, to dofetilide. Warfarin anticoagulation should always be considered in chronic atrial fibrillation unless contraindicated. Until it is known whether strategies to restore and maintain sinus rhythm improve survival in heart failure, therapeutic decisions must remain guided by individual risk-benefit potential.
Levy S. Pharmacologic management of atrial fibrillation: current therapeutic strategies. Am Heart J. 2001 ;141:S15-21.
Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Eur Heart J. 2001 ;22: 1527-1560 Stevenson WG, Stevenson LW. Atrial fibrillation in heart failure. N Engl J Med. 1999;341:910-911.
Torp-Pedersen C, Moller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med. 1999;341:857-865.
Drug; atrial fibrillation; sinus rhythm; antiarrhythmic drug; amiodarone; dofetilide; risk-benefit ratio.