Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial.
BACKGROUND
Ranolazine is a novel antianginal agent that reduces ischemia in patients with chronic angina but has not been studied in patients with acute coronary syndromes (ACS).


OBJECTIVE
To determine the efficacy and safety of ranolazine during long-term treatment of patients with non-ST-elevation ACS.


METHODS
A randomized, double-blind, placebo-controlled, multinational clinical trial of 6560 patients within 48 hours of ischemic symptoms who were treated with ranolazine (initiated intravenously and followed by oral ranolazine extended-release 1000 mg twice daily, n = 3279) or matching placebo (n = 3281), and followed up for a median of 348 days in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial between October 8, 2004, and February 14, 2007.


METHODS
The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or recurrent ischemia through the end of study. The major safety end points were death from any cause and symptomatic documented arrhythmia.


RESULTS
The primary end point occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83-1.02; P = .11). The major secondary end point (cardiovascular death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96; 95% CI, 0.86-1.08; P = .50). Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85-1.15; P = .87). Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76-0.99; P = .03). 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 ranolazine (99 [3.0%]) and placebo (102 [3.1%]) groups (P = .84). No difference in total mortality was observed with ranolazine compared with placebo (172 vs 175; HR, 0.99; 95% CI, 0.80-1.22; P = .91).


CONCLUSIONS
The addition of ranolazine to standard treatment for ACS was not effective in reducing major cardiovascular events. Ranolazine did not adversely affect the risk of all-cause death or symptomatic documented arrhythmia. Our findings provide support for the safety and efficacy of ranolazine as antianginal therapy.


BACKGROUND
clinicaltrials.gov Identifier: NCT00099788.
Morrow
David A
DA
TIMI Study Group, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass 02115, USA. dmorrow@partners.org
Scirica
Benjamin M
BM
Karwatowska-Prokopczuk
Ewa
E
Murphy
Sabina A
SA
Budaj
Andrzej
A
Varshavsky
Sergei
S
Wolff
Andrew A
AA
Skene
Allan
A
McCabe
Carolyn H
CH
Braunwald
Eugene
E
D000083:Acetanilides / Q000008:administration & dosage / Q000627:therapeutic use*; D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy*; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy*; D017202:Myocardial Ischemia / Q000188:drug therapy; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D000069458:Ranolazine; D012008:Recurrence
D000083:Acetanilides; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D000069458:Ranolazine