New Data Supports Safety of Anti-anginal Drug but Not Its Effectiveness in Reducing Recurrent Major Cardiac Events in Patients with Acute Coronary Syndromes

CHICAGO, April 25, 2007—The anti-anginal medication ranolazine was shown to be safe in regard to certain outcomes but did not reduce the risk of major cardiovascular events such as death, heart attack or recurrent ischemia following acute coronary syndromes, according to a study in the April 25 issue of JAMA.

Despite advances in the treatment of acute coronary syndromes (ACS), the risk of recurrent events remains substantial. The medication ranolazine is used for patients with chronic angina, but because of an association between ranolazine and prolongation of the QT interval (a certain measurement on an electrocardiogram), there is a need for additional safety information to guide its use in patients with coronary artery disease. The effectiveness and safety of the drug had not previously been studied in patients with ACS or for secondary prevention of major cardiovascular events in patients with established coronary artery disease, according to background information in the article.

David A. Morrow, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues with the MERLIN (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes)-TIMI 36 trial evaluated the efficacy and safety of ranolazine as a new treatment to reduce cardiovascular death, heart attack or recurrent ischemia in moderate- to high-risk patients with non–ST-elevation (a certain pattern on an electrocardiogram) ACS. The randomized, multinational clinical trial included 6,560 patients who within 48 hours of ischemic symptoms were treated with ranolazine (initiated intravenously and followed by oral ranolazine extended-release 1,000 mg twice daily, n = 3,279) or matching placebo (n = 3,281), and followed up for a midpoint of 348 days.

The primary end point (cardiovascular death, heart attack, or recurrent ischemia) occurred in 21.8 percent of the patients in the ranolazine group, compared with 23.5 percent of the patients in the placebo group. The major secondary end point (cardiovascular death, heart attack, or severe recurrent ischemia) occurred in 18.7 percent of the patients in the ranolazine group compared with 19.2 percent of the patients in the placebo group. Failure of therapy (including cardiovascular death, heart attack, recurrent ischemia, hospitalization for new or worsening heart failure) occurred at similar rates in both groups. The risk of recurrent ischemia was reduced in the ranolazine group (13.9 percent) compared with the placebo group (16.1 percent). Symptomatic documented arrhythmias did not differ between the two groups. There was little difference in the total number of deaths between the ranolazine and placebo groups (172 vs. 175, respectively).

"The results of this robustly powered, randomized 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 [heart attack]. However, 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," the authors write. "These findings, together with the observed favorable overall profile of safety, provide additional evidence to guide the use of ranolazine as antianginal therapy in patients with chronic angina."
(JAMA. 2007;297:1775-1783. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

EDITORIAL: DOES RANOLAZINE HAVE A PLACE IN THE TREATMENT OF ACUTE CORONARY SYNDROMES?

In an accompanying editorial, L. Kristin Newby, M.D., M.H.S., and Eric D. Peterson, M.D., M.P.H., of Duke University Medical Center, Durham, N.C., examine the findings concerning the use of ranolazine in patients with ACS.

"...the MERLIN-TIMI 36 trial offers several important messages. First, ranolazine does not significantly improve acute or downstream prognosis; therefore, it should not be routinely added to treatment following an acute coronary event. Second, in terms of antianginal agents, beta-blockers and nitrates should still be considered initial therapies. The enhanced safety information and supportive antianginal data suggest that ranolazine may offer a back-up option for intensification of antianginal treatment if these first-line agents fail. And finally, with the modern redefinition of the central role of medical therapy in the management of chronic ischemic heart disease, the MERLIN-TIMI 36 trial presages development of additional novel therapeutic agents in an attempt to optimize both symptom management and clinical outcomes."
(JAMA. 2007;297:1823-1826. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc.

For More Information: Contact the JAMA/Archives Media Relations Department at 312/464-JAMA (5262) or email: mediarelations@jama-archives.org .

Posted: April 2007


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