This Article Free upon publication Full Text 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 Citation Map 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. Related Collections Cardiovascular Pharmacology Electrocardiology Acute coronary syndromes Arrhythmias, clinical electrophysiology, drugs Related Article

(Circulation. 2007;116:1647-1652.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

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; 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.).

Correspondence to Benjamin M. Scirica, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail bscirica{at}partners.org

Received June 29, 2007; accepted August 7, 2007.

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.

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