Dofetilide

Dofetilide, azimilide promise greater safety.

SNOWMASS, COLO. -- New antiarrhythmic drugs offer a reasonably good chance of keeping patients with atrial fibrillation in sinus rhythm long-term, Dr. Roger A. Winkle said at a conference sponsored by the American College of Cardiology

Marketing approval was recently granted for dofetilide, a "pure" class III antiarrhythmic agent and is anticipated this year for azimilide, a similar agent.

Dofetilide and azimilide have caused Dr. Winkle to reconsider his long-held preference for rate control over antiarrhythmic agents for maintaining sinus rhythm.

Treatment before these drugs "has generally been a decision to use somewhat dangerous or relatively ineffective antiarrhyrhmic drugs or rate control. That's all going to change this year," predicted Dr. Winkle, director of the cardiac surveillance unit and electrophysiology laboratory at Sequoia Hospital in Redwood City, Calif.

"Dofetilide and azimilide may be more efficacious than previous drugs and will probably get widespread use when marketed. Your patients are going to bombard you with newspaper articles, at least until we see what the true dangers are. Then things will fall into their proper places. But they are very promising drugs," he added.

Dofetilide (Tikosyn), a twice-daily Pfizer drug, and azimilide, a once-daily drug from Procter & Gamble Pharmaceuticals, share key properties. Dr. Winkle largely confined his comments to dofetilide because it was recently approved and he considers it to have the more extensive safety data to date. He said that he has no financial interest or relationship with the makers of either drug.

Pure class III drugs such as dofetilide and azimilide prolong depolarization by blocking potassium channels. They have no effect upon heart rate, QRS duration, or P-R interval.

In addition, dofetilide does not cause peripheral vasodilation or influence myocardial contractility, making it well suited for use in atrial fibrillation (AF) patients with congestive heart failure. Dofetilide does not interact with digoxin, warfarin, or propranolol, another real prescribing plus for heart failure patients.

In multiple randomized clinical trials, about 70% of dofetilide-treated patients with supraventricular arrhythmias have remained in sinus rhythm at 6 months' follow-up, compared with 25% of patients on placebo.

In the 1,518-patient Danish Investigators of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure (DIAMOND-CHF) study, 60% of dofetilide-treated patients with AF at baseline were in sinus rhythm at 2 years, compared with 30% on placebo.

Compare that with the performance of sotalol, which in recent years has been one of the most widely prescribed antiarrhythmic agents for AF. In a well-conducted study in which 253 AF patients were randomized to placebo or to one of three sotalol doses, freedom from AF at 1 year was 28% with placebo and 30% with 80 mg b.i.d. of sotalol, the dosage that most physicians use in clinical practice, according to Dr. Winkle.

Even at the highest dosage studied--160 mg b.i.d.--only 45% of patients remained free of AF at 1 year. And at that dosage, 29% of patients discontinued therapy, compared with 6% on placebo (Am. J. Cardiol. 84[3]:270-77, 1999).

But dofetilide can induce torsades de pointes, which occurred in 3.3% of heart failure patients on the drug and none on placebo in DIAMOND-CHF. Both fatalities and 76% of the total incidents occurred during the first 72 hours of therapy. That's the rationale for the emphatic recommendation that patients be hospitalized for Q-T monitoring during the first 3 days on dofetilide.

Yet despite this proarrhythmic effect, all-cause, cardiac, and arrhythmic mortality did not differ between dofetilide and placebo at 36 months. The drug's proarrhythmic effect may be offset by protection against other ventricular arrhythmias or perhaps by a small survival benefit derived by maintaining normal sinus rhythm in the face of heart failure, Dr. Winkle said.

Other cautions to keep in mind are that the dosage needs to be adjusted for renal function, from 0.5 mg b.i.d. in patients with normal renal function down to as low as 0.25 mg daily for those with slowed renal function, and it will be important to exclude from treatment patients who were not included in the clinical trials--those with low heart rates, preexisting prolonged Q-T intervals, and hypokalemia.

ICDs vs. Antiarrhythmics

Implantable cardioverter-defibrillators are more effective than antiarrhythmic drugs in preventing arrhythmic cardiac death, but they do not affect rates of death from other cardiac causes. Moreover, arrhythmic death still accounts for many of the cardiac deaths among patients who have an ICD.

These are the findings of the AVID (Antiarrhythmics Versus Implantable Defibrillators) trial, a multicenter comparison of the two treatment approaches involving more than 1,000 patients who survived an initial episode of ventricular fibrillation or sustained ventricular tachycardia (J. Am. Coll. Cardiol. 34[5]: 1552-59, 1999).

More deaths (122) occurred in patients randomly assigned to receive antiarrhythmic agents than in those treated with an ICD (80 deaths), so the ICD clearly is an effective strategy. But despite the benefit, 38% of cardiac deaths in patients who had an ICD still appeared to be arrhythmic, the investigators said.

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