Ranolazine: a new antiarrhythmic agent for patients with non-ST-segment elevation acute coronary syndromes?


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Abstract

SYNOPSISBACKGROUNDRanolazine is a novel antianginal agent that has also been shown to have electrophysiological properties in laboratory models. This is the first clinical evaluation of the antiarrythmic effects of ranolazine.OBJECTIVETo compare the incidence of cardiac arrhythmias in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) receiving ranolazine with that in patients receiving placebo.DESIGN AND INTERVENTIONThis was a subanalysis of the international, randomized, double-blind, placebo-controlled MERLIN-TIMI 36 trial, which was conducted from 8 October 2004 to 24 May 2006. Patients with NSTE ACS and at moderate to high cardiovascular risk were enrolled within 48 h of their last ischemic symptoms. A detailed description of the inclusion and exclusion criteria has previously been published. Patients were randomized to receive ranolazine (intravenous followed by oral administration) or matching placebo, alongside standard medication and interventional therapy. All patients underwent continuous electrocardiographic (cECG; Holter) monitoring for the first 7 days after randomization.OUTCOME MEASUREThe primary end point was the incidence of clinically significant arrhythmia (supraventricular tachycardia >120 beats per min lasting at least four beats, ventricular tachycardia of at least three beats, ventricular pause >2.5 s, new-onset atrial fibrillation [AF], or complete heart block).RESULTSA total of 6,560 patients were enrolled in the trial, of whom 6,351 (97%) had interpretable cECG recordings (ranolazine = 3,162; placebo = 3,189). The baseline characteristics were similar in both groups. The mean age was 63 years and around a third of patients were female. Approximately 4% of patients in each group had a prior ventricular arrhythmia, approximately 34% in each had a prior myocardial infarction, and the majority of patients had a Thrombolysis in Myocardial Infarction (TIMI) risk score of 3-4. The median time from symptom onset to randomization was 23.9 h in the ranolazine group and 23.3 h in the placebo group. Overall, the mean duration of cECG monitoring was 6.8 days, after which time significantly fewer patients in the ranolazine group than in the placebo group had experienced ventricular tachycardia lasting for more than three (52.1% vs 60.6%, risk ratio [RR] 0.86, 95% CI 0.82-0.90; P <0.001), four (20.9% vs 29.5%, RR 0.71, 95% CI 0.60-0.78; P <0.001), or eight (5.3% vs 8.3%, RR 0.63, 95% CI 0.52-0.76; P <0.001) beats. Similarly, ranolazine was associated with a lower incidence of supraventricular tachycardias than was placebo (44.7% vs 55.0%, RR 0.81, 95% CI 0.77-0.85; P <0.001). There were only two cases of torsade depointes, one in each group. There was also a trend towards a lower rate of new-onset AF in the ranolazine group, although the difference was not significant (P = 0.08).CONCLUSIONRanolazine is associated with reduced incidences of ventricular and supraventricular arrhythmia in moderate-to-high-risk patients with NSTE ACS.

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