Author + information
- Received September 16, 2003
- Revision received November 6, 2003
- Accepted November 13, 2003
- Published online April 21, 2004.
- 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
- ↵*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.
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.
☆ A complete listing of the MARISA investigators is found in the online Appendix. This study was supported by CV Therapeutics, Inc., Palo Alto, California. Drs. Chaitman and Pepine: grant support for research, CME, consultant and/or speaker's bureau program; Drs. Skettino, Wang, and Wolff: full-time employees of study sponsor CV Therapeutics and hold company stocks; Dr. Parker: consultant to study sponsor CV Therapeutics; Drs. Hanley, Kuch, and Meluzin: participating investigators on behalf of study sponsor CV Therapeutics.
- Received September 16, 2003.
- Revision received November 6, 2003.
- Accepted November 13, 2003.
- American College of Cardiology Foundation