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Abstract & commentary
Synopsis: Dofetilide has no beneficial effect on total mortality among patients with congestive heart failure.
Source: Torp-Pedersen C, et al. N Engl J Med 1999; 341:857-865.
In this article, torp-pedersen and associates report the results of the Danish Investigations of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure (DIAMOND-CHF) Trial. A total of 1518 patients with advanced heart failure and left ventricular dysfunction were recruited from 34 participating hospitals in Denmark. Patients were randomly assigned to treatment with either dofetilide, a new class III antiarrhythmic drug, or placebo. Patients were hospitalized for the first three days of therapy. The initial dofetilide dose was 500 g bid for patients in sinus rhythm and 250 g bid for patients in atrial fibrillation. After enrollment of 288 patients, the protocol was changed and subsequently the initial dosage was based on creatinine clearance. If the creatinine clearance was greater than 60 mL/min, the dose was 500 g bid. If between 40-60 mL/min, the dose was 250 g bid. If between 20-40 mL/min, a single 250 g daily dose was used. The primary end point was all-cause mortality. In the prespecified atrial fibrillation subgroup, effects of dofetilide conversion rates and hospitalizations were important secondary end points.
Dofetilide had no significant effect on mortality. During a median follow-up of 18 months, 41% of the dofetilide patients and 42% of the placebo patients died. Among the atrial fibrillation patients, dofetilide resulted in conversion to sinus rhythm in 12% vs. 1% on placebo. If patients were either pharmacologically or electrically converted at any time, dofetilide was more effective for maintaining sinus rhythm. New atrial fibrillation developed less frequently during dofetilide therapy. Dofetilide decreased the hospitalization rate among treated patients with both sinus rhythm and atrial fibrillation at baseline.
The only adverse reactions more common during dofetilide treatment were QT prolongation and torsade de pointes. QT prolongation led to discontinuation of study drug in 14 dofetilide patients vs. only three placebo patients. Twenty-five cases of torsade de pointes were noted in the dofetilide group vs. none in the placebo group. Of these, 15 episodes required cardioversion and two were fatal. Nineteen of 25 (76%) occurred during the initial in-hospital loading period. Using the initial unadjusted dose of 500 g bid, the rate of torsade de pointes was 4.8%. After the dosage adjustment was included in the protocol, this rate fell to 2.9%. Female gender and class III or IV heart failure were risk factors for development of proarrhythmia.
Torp-Pedersen et al conclude that dofetilide has no beneficial effect on total mortality among patients with congestive heart failure. However, among patients with heart failure and atrial fibrillation, dofetilide may help restore and maintain sinus rhythm and reduce the need for repeat hospitalization. Although dofetilide may produce torsade de pointes, careful dosage adjustment during initiation of therapy with in-hospital monitoring can lower the risk to the patient.
Comment by John P. DiMarco, MD, PhD
Dofetilide is a new antiarrhythmic drug that has recently been approved by the FDA for use in patients with atrial fibrillation. The data from the DIAMOND-CHF Trial and a similar study in patients with recent myocardial infarction (DIAMOND-MI) provided important evidence in support of this decision.
Atrial fibrillation is common among patients with heart failure and its prevalence increases with heart failure severity. The independent effect of atrial fibrillation on mortality in heart failure is controversial but all agree atrial fibrillation complicates management of heart failure patients. Atrial fibrillation may worsen heart failure in several ways: inappropriate and irregular ventricular rates, loss of atrial contractility, and increased thromboembolic risk. As heart failure worsens, control of ventricular rate and restoration and maintenance of sinus rhythm become more difficult.
Data from studies with class I antiarrhythmic drugs have suggested an increased mortality among patients with atrial fibrillation and heart failure (J Am Coll Cardiol 1992;20:527-532). In a large trial in patients with heart failure, amiodarone resulted in favorable antiarrhythmic effects in patients with atrial fibrillation even though there was no overall survival benefit (Circulation 1998;98:2574-2579). The data in this paper are similar, suggesting a neutral overall effect of dofetilide but some benefit in the atrial fibrillation subgroup.
However, it is important to remember that DIAMOND-CHF was not a trial designed to study the management of atrial fibrillation. An aggressive approach to drug loading and cardioversion was not required by the trial protocol. We can only speculate whether a more systematic attempt to restore and maintain sinus rhythm would have produced greater or lesser benefit.
Like other agents that prolong repolarization, dofetilide can produce torsade de pointes. It appears that careful monitoring of dosage, renal function, and ECG parameters can reduce this risk. However, even the rate of 2.9% seen later in the study is significant and considerable caution will have to be exercised when using dofetilide in high-risk patients.
a. prevented atrial fibrillation.
b. prevented ventricular tachyarrhythmias.
c. prevented torsade de pointes.