MERLIN-TIMI 36 published: Role of ranolazine clarified

April 24, 2007

Boston, MA - The MERLIN TIMI-36 trial, which showed no effect of ranolazine (Ranexa, CV Therapeutics) on outcomes in non-ST-elevation-ACS patients but did provide reassuring safety and efficacy data on its use in stable angina, has now been published in the April 25, 2007 issue of the Journal of the American Medical Association[1]. The trial was first presented at last month's American College of Cardiology meeting.

MERLIN-TIMI 36 enrolled 6560 non-ST-elevation-ACS patients within 48 hours of ischemic symptoms who were treated with ranolazine or placebo and followed up for a median of 348 days. The primary efficacy end point was a composite of cardiovascular death, MI, or recurrent ischemia through the end of the study. This was not significantly different between the two groups. There was also no difference in other major composite outcome end points, but there was a significant reduction in recurrent ischemia in the ranolazine group.

MERLIN TIMI-36 outcomes

End point Ranolazine (%) Placebo (%) HR (95% CI) p
Primary end point 21.8 23.5 0.92 (0.83-1.02) 0.11
CV death/MI/recurrent ischemia 18.7 19.2 0.96 (0.86-1.08) 0.50
CV death/MI 10.4 10.5 0.99 (0.85-1.15) 0.87
Recurrent ischemia 13.9 16.1 0.87 (0.76-0.99) 0.03

The other main focus of the trial was safety, given that ranolazine is associated with prolongation of the QT interval. In the trial, QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%) receiving ranolazine, compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the two groups, and there was also no difference in total mortality. And there was actually a significant reduction in arrhythmias detected on Holter monitoring during the first seven days of treatment with ranolazine.

Because of concerns over the prolongation of the QT interval, ranolazine was initially approved only for the treatment of selected patients with chronic angina who have persistent symptoms despite treatment with beta blockers, calcium-channel blockers, or nitrates. The authors of the paper, led by Dr David Morrow (Brigham and Women's Hospital, Boston, MA), state that the results of the MERLIN trial "do not support the use of ranolazine for acute management of ACS or as disease-modifying therapy for secondary prevention of cardiovascular death or MI." But they add: "Our findings suggest a benefit of ranolazine as antianginal therapy in a substantially more broad population of patients with established ischemic heart disease than previously studied." Noting that previous smaller studies of the drug have pointed to a possible diminished treatment effect of ranolazine on exercise performance in women, the researchers note that, in the MERLIN trial, "the reduction in recurrent ischemia with ranolazine was certainly not less in women than in men."

Adverse-effect profile

On the adverse effects of the drug, Morrow et al note that while there was no excess of arrhythmias with ranolazine, there was a higher rate of discontinuation due to adverse events in the ranolazine group, with the most common adverse events being dizziness, nausea, and constipation. "This tolerability profile, along with the higher proportion of patients with syncope, should be considered by the clinician in assessing the potential risks vs benefits of treatment with ranolazine," they write.

They add that the reduction in arrhythmias detected on Holter monitoring with ranolazine provides the first clinical evidence for the potential relevance of experimental data showing suppression of markers of proarrhythmia and provides some reassurance with respect to arrhythmia as a potential cause for syncope. They note that the possible antiarrhythmic effects of ranolazine warrant additional investigation.

Ranolazine: A good backup option

In an accompanying editorial, Drs Kristin Newby and Eric Peterson (Duke University Medical Center, Durham, NC) say that beta blockers and nitrates should still be considered initial therapies for angina, but that the enhanced safety information and supportive antianginal data from MERLIN suggest that ranolazine may offer a backup option for intensification of antianginal treatment if these first-line agents fail[2].

Press telebriefing: MERLIN and COURAGE together show broader role for ranolazine

A press telebriefing sponsored by CV Therapeutics gathered together MERLIN investigators, one of the JAMA editorialists, and Dr William Boden, the chief investigator of the landmark COURAGE trial, which showed no benefit of PCI over optimal medical therapy in preventing future events in patients with stable coronary disease.

Chairing the briefing, Dr Eugene Braunwald, senior author of the MERLIN-TIMI 36 trial, noted that the recent COURAGE trial has highlighted the role of medical therapy, rather than PCI, as first-line treatment of stable angina and that despite the availability of many different antianginal therapies, there are still many millions of patients who remain symptomatic.

Confirming this, Boden noted that, even after five years of aggressive medical therapy in the COURAGE study, around 25% of patients still had symptoms, regardless of whether they had undergone PCI or not. "This highlights the need for new medical treatments, and the MERLIN trial is therefore welcome news in that it supports the safety and benefits of ranolazine, the first new antianginal in 35 years," he said. He suggested that ranolazine may be particularly appropriate for older patients, who tend to be less tolerant of multiple drugs that affect heart rate and blood pressure, as ranolazine does not have any such effects. And older patients tend to have worse renal function and are therefore more susceptible to adverse effects from the dye used in angiography, which is another reason not to rush to PCI in this group, he added.

The editorialist, Newby, described the COURAGE and MERLIN studies as "a tremendous pair of trials" that help frame the current treatment approach to patients with chronic heart disease. "COURAGE showed that PCI does not extend life and does not add much to best medical therapy but can be used as a backup. But even with best medical therapy, patients were still having symptoms and events, and the door is wide open for new therapies. Ranolazine can therefore be regarded as another treatment in our arsenal now that the safety concerns have been addressed. While I still think beta blockers should be used first, as they have a proven outcome benefit, many patients have side effects with beta blockers, and other treatments are often necessary on top of beta blockers, so it's nice to know we now have another option to further intensify therapy," she commented.

 

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