Ranolazine Improves Exercise Tolerance in Chronic Angina

Laurie Barclay, MD

January 20, 2004

Jan. 20, 2004 -- Ranolazine improves exercise tolerance in patients with chronic angina already receiving standard doses of other medications, according to the results of a randomized, double-blind trial published in the Jan. 21 issue of The Journal of the American Medical Association. The editorialist calls this an important trial for this drug, which is currently under review by the U.S. Food and Drug Administration.

"Many patients with chronic angina experience anginal episodes despite revascularization and antianginal medications," write Bernard R. Chaitman, MD, from St. Louis University School of Medicine in Missouri, and colleagues. "In a previous trial, antianginal monotherapy with ranolazine, a drug believed to partially inhibit fatty acid oxidation, increased treadmill exercise performance."

From July 1999 to August 2001, 823 adults with symptomatic chronic angina who were treated at 118 participating outpatient practice settings in several countries were enrolled in the Combined Assessment of Ranolazine In Stable Angina (CARISA) trial. Participants were randomized to receive twice-daily placebo or 750 mg or 1,000 mg of ranolazine. Follow-up through Oct. 31, 2002, included treadmill testing at 12 hours (trough levels) and four hours (peak levels) after dosing and assessed after 2, 6, and 12 weeks of treatment.

After 12 weeks of ranolazine therapy, exercise duration increased by 115.6 seconds at trough compared with 91.7 seconds in the placebo group ( P = .01). The ranolazine groups also fared better in terms of time to angina and to electrocardiographic ischemia.

Compared with the placebo group, the decrease in angina attacks was slightly less than one per week for those in the 750-mg ranolazine group and somewhat more than one per week for those in the 1,000-mg ranolazine group ( P < .02). There were no major adverse long-term survival consequences for ranolazine during one to two years of therapy in a long-term open-label study.

"We report the first evidence that ranolazine can reduce both angina frequency and nitroglycerin consumption when added to a standard dose of one of three frequently prescribed antianginal drugs: atenolol, amlodipine or diltiazem," the authors write. "It may be particularly useful in patients who cannot tolerate the initiation or upward titration of currently available antianginal drugs because of their depressive effects on blood pressure and heart rate."

CV Therapeutics, Inc., supported this study and has financial arrangements with several of its authors, who also report financial disclosures concerning other pharmaceutical companies.

In an accompanying editorial, Peter Berger, MD, from Duke University Medical Center in Durham, North Carolina, discusses current options in treatment of coronary artery disease, including revascularization, medical therapy, and percutaneous coronary intervention (PCI) alone or in combination.

"The availability of another effective and apparently safe antianginal medication such as ranolazine is particularly important for...patients with angina who are not candidates for revascularization," he writes. "Use of ranolazine most likely will influence the frequency and timing with which PCI and coronary artery bypass graft are performed in the far greater number of patients with angina who are suitable for revascularization procedures."

Dr. Berger has various financial arrangements with Bristol-Myers Squibb/Sanofi, Cordis/Johnson & Johnson, Genentech, Merck and Co., Aventis, and the Medicines Co.

JAMA. 2004;291:309-316, 365-366

Reviewed by Gary D. Vogin, MD