Ranolazine for ACS

Abstract & Commentary

By John P. DiMarco, MD, PhDProfessor of Medicine, Division of Cardiology, University of Virginia, CharlottesvilleDr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.

Source: Scirica BM, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non-ST-segment-elevation acute coronary syndrome. Results from the metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndrome-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007;116:1647-1652.

This report from the merlin-timi 36 investigators describes the effects of ranolazine on spontaneous arrhythmias in patients with acute coronary syndrome (ACS). The MERLIN-TIMI 36 trial was designed to assess the effects of ranolazine on cardiovascular deaths and recurrent ischemic events in patients who presented with ACS. The primary end point results for the trial showed trends in favor of ranolazine therapy that were not statistically significant and that had not been previously reported (JAMA. 2007;297:1775-1783). The MERLIN-TIMI 36 trial included continuous days of ECG monitoring during the first 7 days of therapy.

In MERLIN-TIMI 36, patients with a non-ST elevation ACS were randomized to intravenous followed by oral ranolazine vs placebo, in addition to standard medical therapy. Patients underwent continuous ECG (cECG) monitoring during the first 7 days of therapy. Satisfactory cECG data were available from 6351 patients. Several observations were reported. Ranolazine therapy resulted in a significant reduction in the frequency of nonsustained ventricular tachycardia. Analyses were performed for nonsustained episodes of ≥ 3, 4, or 8 beats duration, and the relative risks associated with ranolazine were 0.86, 0.71, and 0.63, respectively. Sustained VT was uncommon (0.44%), and there was no difference between the ranolazine and control groups. New onset atrial fibrillation was also less frequent in the ranolazine group, but the difference between groups was not statistically significant (1.7% vs 2.4%, P = 0.08). The incidence of sudden cardiac death during the first year of therapy was not significantly affected by ranolazine, with 56 sudden deaths (1.7%) in the ranolazine group vs 65 (1.8%) in the placebo group.

Scirica and colleagues concluded that ranolazine has an overall beneficial effect on cardiac arrhythmias in patients with ACS.

Commentary

Ranolazine was recently introduced for treatment of angina. During the drug's clinical development, it was shown to produce mild prolongation of the QT interval. Subsequent studies showed that ranolazine inhibits both the delayed rectifier potassium current (IKr) and the late inward sodium current (INa). The IC50 for INa inhibition is lower (6 µmol/L) than the IC50 for IKr (12 µmol/L). In experimental preparations, this combination of effects has been shown to have antiarrhythmic rather than proarrhythmic effects. Due to the question of QT prolongation, a long-term safety study in a moderate- to moderate-to-high-risk population was required for final approval of the drug. The MERLIN-TIMI 36 study design included systematic prolonged ECG monitoring to assess the effect of ranolazine on spontaneous arrhythmias in such a population. The data in this report. show that ranolazine does not result in proarrhythmia. Further studies will be needed to see if ranolazine's electrophysiologic actions can lead to its use as an antiarrhythmic drug. Based on the limited data available now, the effects seen on arrhythmias may only be due to a modest improvement in myocardial ischemia.