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Ranolazine Safe But Adds No Benefit for Non-ST Elevation ACS


BOSTON -- The anti-angina drug ranolazine (Ranexa) is safe in patients with non-ST elevation acute coronary syndromes (ACS), but it doesn't reduce the occurrence of cardiovascular events.

BOSTON, April 25 -- The anti-angina drug ranolazine (Ranexa) is safe in patients with non-ST elevation acute coronary syndromes (ACS), but it doesn't reduce the occurrence of cardiovascular events.

In more than 6,500 patients with non-ST elevation acute coronary syndromes treated within 48 hours of the onset of ischemic symptoms, ranolazine (Ranexa) added to standard care did not reduce the occurrence of a composite endpoint of cardiovascular death, MI, or recurrent ischemia, reported David A. Morrow, M.D., M.P.H., of Brigham and Women's Hospital here and colleagues in the MERLIN-TIMI 36 trial.

The findings, reported in the April 25 issue of the Journal of the American Medical Association, dashed hopes that ranolazine might have a disease-modifying effect in some patients, suggested L. Kristin Newby, M.D., M.H.S., and Eric D. Peterson, M.D., M.P.H., of Duke University Medical Center in Durham, N.C., in an accompanying editorial.

"Ranolazine does not significantly improve acute or downstream prognosis; therefore, it should not be routinely added to treatment following an acute coronary event," they wrote. "Second, in terms of anti-anginal agents, ?-blockers and nitrates should still be considered initial therapies. The enhanced safety information and supportive anti-anginal data suggest that ranolazine may offer a back-up option for intensification of anti-anginal treatment if these first-line agents fail."

Ranolazine has been shown in randomized studies to be effective at reducing angina symptoms and increasing exercise time to angina or to ST-segment depression when compared with standard agents such as atenolol, diltiazem, and amlodipine.

Unlike other agents, however, ranolazine does not have significant adverse effects on heart rate or blood pressure, although it has been associated with prolongation of the QT interval, raising questions about its safety, the authors noted.

To determine whether the drug could be safe and effective in patients with non-ST elevation ACS, the authors conducted a randomized, double-blind, placebo-controlled, multinational clinical trial. It was known as the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Acute Myocardial Infarction-36) trial.

The MERLIN-TIMI 36 investigators enrolled 6,560 patients with non-ST elevation ACS within 48 hours of ischemic symptoms, and assigned them to placebo (3,281 patients) or to intravenous ranolazine followed by oral ranolazine extended-release 1,000 mg twice daily (3,279 patients). They followed the patients for a median of 348 days.

"The primary efficacy endpoint of the trial was the first occurrence of any element of the composite of cardiovascular death, MI, or recurrent ischemia," they wrote. "The major secondary end point was the first occurrence of a major cardiovascular event defined by the composite of cardiovascular death, MI, or severe recurrent ischemia."

The safety endpoints were death from any cause, and symptomatic documented arrhythmia.

They found that there was no significant between-group difference in the primary composite endpoint, with 21.8% of patients in the ranolazine groups and 23.5% of controls having at least one of the elements of the composite endpoint (hazard ratio 0.92, 95% confidence interval, 0.83-1.02; P=0.11).

The major secondary endpoint (any cardiovascular event) occurred in 18.7% of patients on ranolazine and 19.2% of patients on placebo (hazard ratio 96, 95% CI, 0.86-1.08 P=0.50).

In each group, about 10.5% of patients suffered cardiovascular death or MI (hazard ratio, 0.99, 95% CI, 0.85-1.15, P=0.87).

Ranolazine was, however, associated with a significant reduction in recurrent ischemia compared with placebo, with 13.9% of patients on the active drug having a recurrence compared with 16.1 of controls (0.87, 95% CI, 0.76-0.99 P=0.03).

Prolongation of the QT interval (corrected for heart rate) requiring a reduction in the intravenous drug dose occurred in 0.9% of patients randomized to ranolazine, compared with 0.3% of controls (P value not shown). There was no difference in the occurrence of symptomatic documented arrhythmias, which occurred in 3.0% of patients on ranolazine and 3.1% of those on placebo (P=0.84).

There was also no difference in total mortality, with deaths occurring in 172 patients on ranolazine and 175 controls (hazard ratio 0.99; 95% CI, 0.80-1.22. P=0.91).

While they did not find a benefit for ranolazine in patients with non-ST elevation ACS, the evidence does appear to support the use of ranolazine in patients with intractable angina, both the authors and the editorialists said.

"Although there were non-significant reductions in admissions for ischemia and ischemia leading to revascularization, the reduction in recurrent ischemia among patients treated with ranolazine was predominantly due to lower rates of worsening angina (HR, 0.77; 95% CI, 0.62-0.96) and the need to titrate anti-anginal therapy (HR, 0.81; 95% CI, 0.69-0.94)," Drs. Newby and Peterson wrote. "This appeared to be particularly evident among patients with prior angina and among women, subgroup findings from the MERLIN-TIMI 36 trial that warrant further formal exploration in appropriately designed studies."

The evidence suggests that ranolazine may be an option for intensification of anti-anginal therapy if first-line therapies fail, they noted, a point of agreement with the MERLIN-TIMI 36 trialists.

"The observed reduction in recurrent ischemia in a broad population of patients with established coronary artery disease is consistent with previous evidence in selected patients with chronic angina," Dr. Morrow and colleagues wrote. "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."

They acknowledged that the study was limited by the use of prespecified efficacy analyses, which precluded additional analyses that might have seen a greater difference in clinical endpoints.

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