ESC: On Second Go-Round, MERLIN Finds Arrhythmia Magic in Ranolazine

VIENNA, Sept. 6 -- The anti-anginal drug ranolazine (Ranexa) may reduce episodes of ventricular tachycardia and supraventricular tachycardia, researchers reported here.
The potential benefit was detected in a pre-specified analysis of Holter monitor data from MERLIN-TIMI 36 -- a failed trial of ranolazine for treatment of acute coronary syndrome.
Yet the analysis showed that ranolazine reduced the number of ventricular tachycardia episodes by 37% (P<0.001) and reduced supraventricular tachycardia by 19% (P<0.001). Benjamin M. Scirica, M.D., M.P.H. of Brigham and Women's Hospital in Boston, reported at the European Society of Cardiology meeting. The study was published online simultaneously in Circulation, Journal of the American Heart Association.
Dr. Scirica said the drug also tended to reduce occurrence of new onset atrial fibrillation by 27%, but that difference was not statistically significant (P=0.08).
When the MERLIN-TIMI 36 data were reported last spring, the drug failed to demonstrate benefit as a treatment for acute coronary syndrome. But because the drug had previously been associated with prolonged QT interval continuous ECG monitoring (Holter or cECG) was conducted on all patients for the first seven days after randomization.
Analysis of those of thousands of hours of ECG data revealed the antiarrhythmic potential, Dr. Scirica said.
Ranolazine is a piperazine derivative that reduces ischemia via inhibition of the inward sodium current during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload.
In MERLIN, 6,560 patients with non-ST elevation acute coronary syndrome were randomized to ranolazine or placebo on top of standard therapy. Of those, 6,351 had ECG recordings evaluable for analysis.
The primary endpoints were a set of prespecified clinically significant arrhythmias that were evaluated by a blinded core laboratory. Those arrhythmias included ventricular tachycardia, defined as at least three beats in length, any supraventricular tachycardia greater than 120 beats per minute and lasting at least four beats, new onset atrial fibrillation, an episode of bradycardia of less than 45 beats per minute lasting at least four beats, complete heart block, or ventricular pause greater than 2.5 seconds.
Those arrhythmias were further classified and included ventricular tachycardias, categorized according to current guidelines -- at least four beats, at least eight beats, and sustained for more than 30 seconds -- as well as any supraventricular tachycardia greater than 120 beats per minute and lasting at least four beats, and new onset atrial fibrillation. Also included were episodes of bradycardia of less than 45 beats per minute lasting at least four beats, complete heart block, and ventricular pause greater than 2.5 seconds.
Among the findings:
Fewer patients had an episode of ventricular tachycardia lasting more than eight beats (166 versus 265, P<0.001).
Supraventricular tachycardia occurred in 1,752 patients in the control group versus 1,413 in the active treatment arm (P<0.001).
New onset atrial fibrillation was reported in 55 ranolazine patients versus 75 placebo patients.
Pauses of more than three seconds occurred in 97 ranolazine patients versus 136 placebo patients (P<0.001).
Dr. Scirica concluded that studies are warranted specifically designed to evaluate the potential role of ranolazine as an anti-arrhythmic agent.
The study was funded by CV Therapeutics and Dr. Scirica said he had received modest honoraria from CV Therapeutics. Additional source: European Society of CardiologySource reference: Scirica, BM et al "The effect of ranolazine, a novel anti-anginal agent with electrophysiologic properties, on the incidence of tachyarrhythmias: results from the MERLIN-TIMI 36 randomised controlled trial." Clinical Trial Update II September 5, 2007