Exaggerated QT Prolongation After Cardioversion
October 1, 1999 3 minutes read
Exaggerated QT Prolongation After Cardioversion
Abstract & commentary
Synopsis: Dofetilide produced greater QT interval increases in sinus rhythm than during atrial fibrillation. Monitoring of rhythm and QT changes after restoration of sinus rhythm is required until steady state has been reached.
Source: Choy AMJ, et al. J Am Coll Cardiol 1999;34: 396-401.
Choy and colleagues measured the effects of intravenous dofetilide on QT intervals during both atrial fibrillation and sinus rhythm. Twelve patients with hypertension and atrial fibrillation or flutter who were scheduled for elective cardioversion were recruited for the study. Atrial fibrillation or flutter had been present for between 24 hours and 12 months. Patients received either 5.25 g/kg or 8 g/kg intravenous dofetilide over 100 minutes. QT intervals were measured in leads V2 and V3, with the mean volume for five consecutive beats reported. Only one patient was converted to sinus rhythm with intravenous dofetilide. Electrical cardioversion was attempted in the remaining 11 patients. Three patients failed electrical cardioversion and their data were excluded. The remaining nine patients were scheduled to receive a second identical dofetilide infusion the following day. In four patients, however, the infusion was terminated before its completion because of QT prolongation to greater than 500 msec in two ECG leads. The nine study patients were divided into two groups: group I (infusion terminated early) and group II (infusion completed). During atrial fibrillation in all nine patients, dofetilide produced a modest increase in QT that was not significant (baseline and 100 min infusion values: 386 ± 49 and 420 ± 60 msec, P = NS). The four group I patients showed an exaggerated QT response during sinus rhythm. After only 20 minutes, QT had increased from 432 ± 15 at baseline to 580 ± 63 msec (P < 0.01). Among the five group II patients, dofetilide produced a change in QT from 412 ± 52 at baseline to 459 ± 62 msec at end infusion (P = NS). One patient in group I developed asymptomatic, recurrent runs of torsades de pointes that lasted for 10 minutes after stopping the infusion. Plasma dofetilide concentrations were similar on both infusion days. Heart rate was slower in sinus rhythm, with the slowest heart rates noted in the four group I patients. Atrial natriuretic peptide and plasma norepinephrine levels fell after cardioversion in both groups.
Choy et al conclude that the IKr blocker, dofetilide, produced greater QT interval increases in sinus rhythm than during atrial fibrillation. Monitoring of rhythm and QT changes after restoration of sinus rhythm is required until steady state has been reached.
Comment by John P. DiMarco, MD, PhD
Dofetilide is a new type III antiarrhythmic drug that has recently received FDA approval for use in patients with atrial fibrillation. Dofetilide blocks the rapidly acting, outward potassium current, IKr, and prolongs repolarization and the QT interval. Unlike sotalol, dofetilide has no beta-blocking activity and does not result in bradycardia. Unlike amiodarone, dofetilide results in only rare extracardiac toxicity. Dofetilide has no major negative inotropic effects and has been used safely in patients with heart failure. The major toxicity observed during clinical trials with dofetilide has been QT prolongation and torsades de pointes.
In this paper, Choy et al report that dofetilide produces more QT prolongation and toxicity during sinus rhythm than during atrial fibrillation. This would be consistent with the clinical observation made with other QT-prolonging drugs that serious arrhythmias occur most commonly in the period immediately after cardioversion. Unfortunately, the mechanism for this increased response is unexplained. In this study, patients were to receive identical infusions of dofetilide, yet QT prolongation was more marked when the patients were in sinus rhythm. It is hard to know if the changes in heart rate, the small residual concentrations of dofetilide still present from the first infusion, or some electrophysiologic changes in the ventricles after restoration of sinus rhythm were responsible. The small number of patients in this study also limits our ability to interpret the data since mean QT changes of up to 10-15% did not reach statistical significance.
Dofetilide will be marketed with strict guidelines for administration. Dosage adjustment based on renal function and initiation of therapy during in-hospital monitoring will be recommended. The data presented in this paper support this conservative approach.
The major adverse effect of dofetilide, a new type III antiarrhythmic agent, is:
a. beta blockade.
b. extra cardiac toxicity.
c. negative inotropic effect.
d. QT prolongation and torsades de pointes.
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