Clinical research: coronary artery disease
Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina

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Abstract

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

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

Cited by (0)

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.