MERLIN TIMI-36: Antianginal agent ranolazine shown to be antiarrhythmic

September 05, 2007

Vienna, Austria - New data presented this week has shown that the novel antianginal agent ranolazine (Ranexa, CV Therapeutics, Palo Alto, CA), an inhibitor of the late phase of the sodium current, is safe, with investigators finding no evidence of an excess risk of arrhythmia or sudden cardiac death, according to an analysis of the MERLIN TIMI 36 study. In fact, despite prolonging the QT interval, the drug actually appears to have antiarrhythmic effects, with patients treated with ranolazine having fewer episodes of ventricular tachycardia, supraventricular tachycardia, and ventricular pauses.

The results, say investigators who presented the MERLIN analysis here at the European Society of Cardiology Congress 2007 today, suggest that further studies designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.

"I think, right now, that the drug has an important role in the treatment of patients with chronic angina. I think from MERLIN TIMI-36, the drug has not been shown to modify disease, meaning it doesn't reduce death, it doesn't reduce myocardial infarction, but it does reduce ischemia in a larger population than had been previously studied with the drug," lead investigator Dr Ben Scirica (Brigham and Women's Hospital, Boston, MA) told heartwire . "I think this new data from the Holter monitoring suggest that the safety observed in the overall MERLIN trial was certainly emphasized, and second, I think this is an intriguing and hopefully new avenue to evaluate a potential antiarrhythmic drug."

Commenting on the results of the study during the clinical-trials update, Dr John Camm (St George's Hospital Medical School, London, UK) said that while the MERLIN study was primarily a study of patients with ACS, the documentation of arrhythmias was an important secondary end point

"The results of this trial suggest that ranolazine is antiarrhythmic rather than proarrhythmic," said Camm. "It certainly doesn't have proarrhythmic tendencies. It is not associated in this trial with an excess of sudden cardiac death or cardiovascular death, but neither has it been shown to reduce such end points. . . . This trial is very impressive and seriously adds to the convincing safety database with ranolazine."

Prolongation of the QT interval

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. With that, its indication has been limited to second-line therapy in patients who continue to experience angina despite treatment with another class of antianginal medication.

The MERLIN-TIMI 36 investigators originally enrolled 6560 non-ST-elevation-ACS patients within 48 hours of ischemic symptoms. Patients were treated with ranolazine or placebo and followed up for a median of 348 days. 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. The primary efficacy end point was a composite of cardiovascular death, MI, or recurrent ischemia through the end of the study. As reported previously by heart wire , there was no significant difference in the primary end point among those treated with ranolazine or placebo, nor was there a difference in other major composite outcome end points. There was, however, a significant reduction in recurrent ischemia in the ranolazine group.

Because of concerns about the prolongation of the QT interval with ranolazine—the interval is prolonged 2 to 6 ms at approved doses—investigators also conducted a large safety assessment, in which 97% of the original cohort underwent continuous seven-day Holter monitoring to gauge the risk of clinically significant arrhythmia. In terms of the primary arrhythmic end points, including ventricular tachycardia, supraventricular tachycardia, and bradycardia, complete heart block, or ventricular pause, investigators observed a significant reduction in arrhythmic events with ranolazine.

"When we went back and analyzed these patients, we found out that not only was there no problem, but treatment with ranolazine actually resulted in significant decreases in many types of arrhythmias—in particular, ventricular tachycardia, including those lasting longer than eight beats, as well as reductions in supraventricular tachycardia," said Scirica.

Primary arrhythmia end points

Arrhythmic end point Ranolazine (%) Placebo (%) p
Ventricular tachycardia >3 beats 52.0 60.6 <0.001
Ventricular tachycardia >8 beats 5.3 8.3 <0.001
Supraventricular tachycardia >4 beats 44.7 55.0 <0.001
New-onset atrial fibrillation 1.7 2.4 0.08
Bradycardia <45 beat per minute, complete heart block, or pause >2.5 sec 39.8 46.6 <0.001
Pause >3 sec 3.1 4.3 0.01

A subgroup analysis looking at high-risk patients, including those with heart failure and those with QT intervals exceeding 450 ms, also showed the drug to be effective as an antiarrhythmic. Among those with ejection fractions <40% and those with a baseline QT interval >450 ms, there was a significant 47% reduction in the incidence of ventricular tachycardia lasting eight beats or longer. The incidence of sudden cardiac death was not significantly different between the two study groups at one year.

"Looking at sudden cardiac death, with an average follow-up of about one year, we found no statistical difference, but there was a lower numerical rate of sudden cardiac death among patients treated with ranolazine," said Scirica. "I think, together with the Holter data, this gives us very important safety information for people who are treating patients with angina or with high-risk coronary disease."

Asked why a drug that prolongs the QT interval actually appears to be antiarrhythmic, Scirica told heartwire that some basic science studies in animal models have shown that ranolazine suppresses some of the triggers and substrates that make the heart susceptible to arrhythmia. Scirica said this new data warrant further study of the drug in patients at high risk for arrhythmias, a trial that would determine whether the drug reduced not only the risk of arrhythmias but also adverse clinical outcomes resulting from these rhythm disorders.

MERLIN's magic not clear

During the clinical-trials update, Camm said the most "noteworthy and impressive" finding in the study was the reduction in ventricular tachycardia lasting eight beats or more, particularly in patients with depressed left ventricular function. The incidence of this arrhythmia is essentially cut in half with ranolazine, he noted.

QT prolongation with antiarrhythmic drugs remains a concern, particularly a regulatory concern, since the incidence of torsades de pointes is very small. With the incidence so small, said Camm, randomized, controlled clinical trials "cannot completely rule out the possibility of torsades." However, he said this new data should move ranolazine up as a first-line agent, as the drug cannot seriously be considered proarrhythmic.

Camm added that the mechanism of action of ranolazine is not quite clear, as the effects might be related to the agent's anti-ischemic properties or to a specific antiarrhythmic effect, such as the inhibition of the slow sodium current. CV Therapeutics is expected to return to the Food and Drug Administration to ask for an updated label for the drug, in the hopes of making it an option as a first-line agent in the treatment of angina.

The MERLIN TIMI-36 study was sponsored by CV Therapeutics. Scirica reports receiving honoraria for educational presentations from CV Therapeutics. Camm also reports conflicts of interest pertaining to a number of pharmaceutical companies, including CV Therapeutics.

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