Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial.
BACKGROUND
Ranolazine, a piperazine derivative, reduces ischemia via inhibition of the late phase of the inward sodium current (late I(Na)) during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload. Increased intracellular calcium leads to both mechanical dysfunction and electric instability. Ranolazine reduces proarrhythmic substrate and triggers such as early afterdepolarization in experimental models. However, the potential antiarrhythmic actions of ranolazine have yet to be demonstrated in humans.


RESULTS
The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome (MERLIN)-Thrombolysis in Myocardial Infarction (TIMI) 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non-ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG (Holter) recording was performed for the first 7 days after randomization. A prespecified set of arrhythmias were evaluated by a core laboratory blinded to treatment and outcomes. Of the 6560 patients in MERLIN-TIMI 36, 6351 (97%) had continuous ECG recordings that could be evaluated for arrhythmia analysis. Treatment with ranolazine resulted in significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting > or = 8 beats (166 [5.3%] versus 265 [8.3%]; P<0.001), supraventricular tachycardia (1413 [44.7%] versus 1752 [55.0%]; P<0.001), or new-onset atrial fibrillation (55 [1.7%] versus 75 [2.4%]; P=0.08). In addition, pauses > or = 3 seconds were less frequent with ranolazine (97 [3.1%] versus 136 [4.3%]; P=0.01).


CONCLUSIONS
Ranolazine, an inhibitor of late I(Na), appears to have antiarrhythmic effects as assessed by continuous ECG monitoring of patients in the first week after admission for acute coronary syndrome. Studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.
Scirica
Benjamin M
BM
TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. bscirica@partners.org
Morrow
David A
DA
Hod
Hanoch
H
Murphy
Sabina A
SA
Belardinelli
Luiz
L
Hedgepeth
Chester M
CM
Molhoek
Peter
P
Verheugt
Freek W A
FW
Gersh
Bernard J
BJ
McCabe
Carolyn H
CH
Braunwald
Eugene
E
D000083:Acetanilides / Q000009:adverse effects* / Q000627:therapeutic use*; D000208:Acute Disease; D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000453:epidemiology*; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000453:epidemiology; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010879:Piperazines / Q000009:adverse effects* / Q000627:therapeutic use*; D010919:Placebos; D000069458:Ranolazine; D013610:Tachycardia / Q000453:epidemiology; D015912:Thrombolytic Therapy