Published Online
on September 5, 2007

A more recent version of this article appeared on October 9, 2007

This Article Free upon publication Full Text (PDF) CME: Take the course for this article: Circulation: October 9, 2007, Volume 116, Number 15 All Versions of this Article: 116/15/1647    most recent CIRCULATIONAHA.107.724880v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Scirica, B. M. Articles by Braunwald, E. Search for Related Content PubMed PubMed Citation Articles by Scirica, B. M. Articles by Braunwald, E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACETANILIDE Medline Plus Health Information Angina Arrhythmia Heart Attack Related Collections Acute coronary syndromes Arrhythmias, clinical electrophysiology, drugs Electrocardiology Cardiovascular Pharmacology Related Article

Submitted on June 29, 2007
Accepted on August 7, 2007

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

Benjamin M. Scirica MD, MPH^*, David A. Morrow MD, MPH, Hanoch Hod MD, Sabina A. Murphy MPH, Luiz Belardinelli MD, Chester M. Hedgepeth MD, PhD, Peter Molhoek MD, Freek W.A. Verheugt MD, Bernard J. Gersh MBChB, DPhil, Carolyn H. McCabe BS, and Eugene Braunwald MD

From the TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Mass (B.M.S., D.A.M., S.A.M., C.M.H., C.H.M., E.B.); Chaim Sheba Medical Center, Tel Hashomer, Israel (H.H.); CV Therapeutics, Palo Alto, Calif (L.B.); Medisch Spectrum Twente, Enschede, The Netherlands (P.M.); HeartLung Centre, Nijmegen, The Netherlands (F.W.A.V.); and Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (B.J.G.)

^* To whom correspondence should be addressed. E-mail: bscirica{at}partners.org.

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.

Methods and 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 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 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.

Key words: coronary disease • antiarrhythmia agents • tachyarrhythmias

Related Article:

Issue Highlights
Circulation 2007 116: 1643. [Full Text]

This article has been cited by other articles:

				W.-Q. Wang, C. Robertson, A. K. Dhalla, and L. Belardinelli Antitorsadogenic Effects of ({+/-})-N-(2,6-Dimethyl-phenyl)-(4[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine (Ranolazine) in Anesthetized Rabbits J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 875 - 881. [Abstract] [Full Text] [PDF]

				I. Savelieva and J. Camm Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches Europace, June 1, 2008; 10(6): 647 - 665. [Abstract] [Full Text] [PDF]

				M. M. Scheinman and E. Keung The Year in Review of Clinical Cardiac Electrophysiology J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2075 - 2081. [Full Text] [PDF]

				Y. Song, J. C. Shryock, and L. Belardinelli An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2031 - H2039. [Abstract] [Full Text] [PDF]

				L. L. Eckhardt, T. C. Teelin, and C. T. January Is ranolazine an antiarrhythmic drug? Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H1989 - H1991. [Full Text] [PDF]