Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide

Abstract

Background: The arrhythmogenic potential of short QT intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-interval prolongation is a known risk factor for ventricular tachyarrhythmias. However, reports on drug-induced QT-interval shortening are rare and proarrhythmic effects remain unclear.

Objective: Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT intervals in patients with difficult-to-treat epilepsies.

Methods: Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 ± 12 years). QRS, QT, and T(peak)-T(end) intervals were analyzed before and during rufinamide treatment.

Results: The mean QT interval shortened significantly following rufinamide administration (QT interval 349 ± 23 ms vs 327 ± 17 ms; corrected QT interval 402 ± 22 ms vs 382 ± 16 ms; P = .002). T(peak)-T(end) intervals were 79 ± 17 ms before and 70 ± 20 ms on treatment (P = .07). The mean reduction of the corrected QT interval was 20 ± 18 ms. During follow-up (3.04 ± 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed.

Conclusion: QTc-interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations notwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings.

Figure 1

QTc intervals (a) before and (b) during rufinamide treatment of 19 patients. For better visualization, QTc-interval scale (left) starts with 340 ms.

Figure 2

Electrocardiogram (ECG) of drug-induced QTc-interval shortening during rufinamide treatment of a 63-year-old woman with drug-refractory focal epilepsy since 60 years. A: Before rufinamide treatment: heart rate of the preceding RR interval 74 beats/min (arrow); QT interval 381 ms; corrected QTc interval 424 ms; anti-epileptic comedication clonazepam (2 mg/d), zonisamide (500 mg/d), and lam-otrigine (400 mg/d). B: During rufinamide treatment: heart rate of the preceding RR interval 67 beats/min (arrow); QT interval 365 ms; QTc interval 385 ms, and thus QTc-interval shortening of −39 ms; rufinamide (2400 mg/d) with comedication lamotrigine (325 mg/d) and pregabalin (375 mg/d) (paper speed 50 mm/s).