MERLIN: No Role for Ranolazine in ACS but First-Line Indication in Stable Angina Now Likely

March 27, 2007

March 27, 2007 (New Orleans, LA) - The new antianginal drug ranolazine (CV Therapeutics) has no role in ACS patients, according to the results of the MERLIN TIMI-36 trial. But the study has provided reassurance about the drug’s safety profile in stable angina patients.

Ranolazine was approved in 2006 for use in treating angina pain, but because the drug increases the QT interval, there has been some concern that it might have proarrhythmic effects, and its indication has therefore been limited to second-line therapy in patients who continue to experience angina despite treatment with another class of antianginal medication. Following the reassuring safety data from this trial, it is expected that the drug will gain a first-line indication for the treatment of stable angina.

Lead investigator Dr David Morrow (Brigham and Women’s Hospital, Boston, MA) explained that the MERLIN trial was conducted to investigate three issues: whether ranolazine had a role in the new indication of ACS; whether the drug had disease-modifying effects in stable patients; and to gain more data on its long-term safety profile. Although the first two objectives were not met, the trial did successfully address safety concerns with the drug, showing no adverse trend in death or arrhythmia and suggesting that, if anything, it might have antiarrhythmic effects.

The trial enrolled 6560 non-ST-elevation ACS patients who were all treated with standard of care and randomized to ranolazine or placebo. Ranolazine was administered as a 200-mg IV infusion given over one hour, followed by an 80-mg/h infusion for up to 96 hours. Oral treatment (1000 mg twice daily) was then given for approximately 12 months. Results showed no difference between the two groups in the primary end point of cardiovascular death/MI/recurrent ischemia. On further analysis, it was found that the drug had no effect on cardiovascular death or MI, so did not have disease-modifying effects, but its antianginal effect was confirmed, with a significant reduction in recurrent ischemia.

MERLIN: Main efficacy results

End point Placebo (n=3281) Ranolazine (n=3279) HR p
CV death/recurrent ischemia* 23.5 21.8 0.92 0.11
CV death/MI 10.5 10.4 0.99 0.87
Recurrent ischemia 16.1 13.9 0.87 0.030

*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.

MERLIN: Main safety results

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 >3 beats, supraventricular tachycardia >120 bpm, new atrial fibrillation, brady <45 bpm, complete heart block or pause >2.5 s

Morrow commented: “These results support the safety of ranolazine in a much larger population than previously studied. There were concerns that this drug may have been proarrhythmic, but our results actually suggest the opposite--that it could be antiarrhythmic. This has also been suggested in experimental studies, and it warrants additional investigation in further clinical trials.”

Cochair of the late-breaking clinical-trial session at which the MERLIN study was presented, Dr Salim Yusuf (McMaster University, Hamilton, ON), agreed that the results supported the use of ranolazine in stable disease. Continuing his campaign against the use of angioplasty in stable coronary disease patients, he quipped: “Ranolazine actually looks as good as PCI in this indication.”

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