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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina

Bernard R. Chaitman, MD, FACC^*,*, Sandra L. Skettino, MD, John O. Parker, MD, FACC, Peter Hanley, MD, FACC, Jaroslav Meluzin, MD, PhD^||, Jerzy Kuch, MD, PhD^¶, Carl J. Pepine, MD, FACC^#, Whedy Wang, PhD, Jeanenne J. Nelson, PhD^**, David A. Hebert, PhD^**, Andrew A. Wolff, MD, FACC MARISA Investigators

^* Saint Louis University School of Medicine, St. Louis, Missouri, USA
CV Therapeutics, Palo Alto, California, USA
Kingston General Hospital, Kingston, Canada
Medical Group of Fort Wayne, Fort Wayne, Indiana, USA
^|| St. Anna Hospital, Brno, Czech Republic
^¶ Medical Academy Hospital, Warsaw, Poland
^# The University of Florida, Gainesville, Florida, USA
^** Quintiles, Inc., Research Triangle Park, North Carolina. USA.

Manuscript received September 16, 2003; revised manuscript received November 6, 2003, accepted November 13, 2003.

^* Reprint requests and correspondence: Dr. Bernard R. Chaitman, St. Louis University Core ECG Laboratory, 1034 S. Brentwood Boulevard, Suite 1550, St. Louis, Missouri 63117, USA.
chaitman{at}slu.edu

OBJECTIVES: The primary objective of the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial was to determine the dose-response relationship of ranolazine, a potentially new anti-anginal compound, on symptom-limited exercise duration.

BACKGROUND: Fatty acids rise precipitously in response to stress, including acute myocardial ischemia. Ranolazine is believed to partially inhibit fatty acid oxidation, shift metabolism toward carbohydrate oxidation, and increase the efficiency of oxygen use.

METHODS: Patients (n = 191) with angina-limited exercise discontinued anti-anginal medications and were randomized into a double-blind four-period crossover study of sustained-release ranolazine 500, 1,000, or 1,500 mg, or placebo, each administered twice daily for one week. Exercise testing was performed at the end of each treatment during both trough and peak ranolazine plasma concentrations.

RESULTS: Exercise duration at trough increased with ranolazine 500, 1,000, and 1,500 mg twice daily by 94, 103, and 116 s, respectively, all greater (p < 0.005) than the 70-s increase on placebo. Dose-related increases in exercise duration at peak and in times to 1 mm ST-segment depression at trough and peak and to angina at trough and peak were also demonstrated (all p < 0.005). Ranolazine had negligible effects on heart rate and blood pressure. One year survival rate combining data from the MARISA trial and its open-label follow-on study was 96.3 ± 1.7%.

CONCLUSIONS: In chronic angina patients, ranolazine monotherapy was well tolerated and increased exercise performance throughout its dosing interval at all doses studied without clinically meaningful hemodynamic effects. One-year survival was not lower than expected in this high-risk patient population. This metabolic approach to treating myocardial ischemia may offer a new therapeutic option for chronic angina patients.

Abbreviations and Acronyms   ANOVA = analysis of variance   BP = blood pressure   CARISA = Combination Assessment of Ranolazine In Stable Angina trial   ECG = electrocardiogram/electrocardiographic   ETT = exercise treadmill test   HR = heart rate   MARISA = Monotherapy Assessment of Ranolazine In Stable Angina trial   SR = sustained release

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