To address safety concerns also raised by the FDA and in an attempt to broaden the indications for ranolazine, CV Therapeutics performed a study to test the efficacy of ranolazine in patients with acute coronary syndrome to reduce cardiovascular death or recurrent ischemia. The study was titled the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes: TIMI-36) trial, and its initial results were released before the ACC meeting on 7 February 2007 because it failed to meet its primary endpoint:
|End point||Placebo (n=3281)||Ranolazine (n=3279)||HR||p|
|CV death/recurrent ischemia*||23.5||21.8||0.92||0.11|
*primary end point
Safety results showed no difference between the two groups in death from any cause or sudden cardiovascular death. In addition, there was a reduction in clinically significant arrhythmia on Holter monitoring.
What was not known (until today) was the results of the safety data with this trial, especially as it relates to the potential for proarrhythmia:
|End point||Placebo (n=3273)||Ranolazine (n=3268)||HR||p|
|Death—any cause (number of patients)||175||172||0.99||0.91|
|Sudden cardiac death (number of patients)||65||56||0.87||0.43|
|Symptomatic documented arrhythmia (number of patients)||102||99||0.97||0.84|
|Clinically significant arrhythmia on Holter* (% of patients)||83.1||73.1||0.89||<0.001|
*ventricular tachycardia greater than 3 beats, supraventricular tachycardia >120 bpm, new atrial fibrillation, brady less than 45 bpm, complete heart block or pause greater than 2.5 s
The reduction in arrhythmic events was surprising and warrants further evaluation - how many of these were supraventricular versus ventricular arrhythmias? Could ranolazine act in a similar mechanism to amiodarone (another effective anti-arrhythmic that prolongs QT interval) as an anti-arrhythmic medication? The data, as presented, are incomplete but offer an unexpected finding that should provide a niche for this drug in the use of patients with chronic stable refractory angina. While the company's special protocol assessment agreement with the U.S. Food and Drug Administration (FDA) could support expansion of the existing Ranexa® (ranolazine extended-release tablets) indication to include first line angina, the MERLIN trial did not address the use of this drug in heart failure patients. As such caution should be exercised applying these findings more generally to patients with the potential for hepatic dysfunction from any cause, including congestive heart failure.