Antianginal under review has unique mechanism of action

Cardiology Review® Online, March 2004, Volume 21, Issue 3

An antianginal drug under review by the Food and Drug Administration increases exercise capacity and reduces the frequency of angina in patients who remain symptomatic despite therapy with standard antianginal medications. The agent, called ranolazine, is thought to work by partially inhibiting fatty acid oxidation and reciprocally increasing glucose oxidation during periods of myocardial stress.

As reported in JAMA (2004;291

[3]:309-316), ranolazine was studied in 823 patients with severe chronic angina who were already taking standard doses of atenolol, amlodipine, or diltiazem. The study was a three-group, parallel, double-blind trial of patients with symptomatic chronic angina who were randomized to twice-daily placebo or 750 mg or 1,000 mg of ranolazine for 12 weeks. Treadmill exercise at trough levels (12 hours) and peak levels (4 hours) was assessed after 2, 6 (trough only), and 12 weeks of treatment.

Treadmill exercise duration was increased with each of the ranolazine doses at trough (P = .03) and at peak (P < .02) compared with placebo. The trough exercise duration increased by 115.6 seconds from baseline in the ranolazine groups (pooled analysis) versus 91.7 seconds in the placebo group (P = .01).

The mean number of anginal attacks per week decreased from

3.3 (placebo group) to 2.5 in the

750-mg ranolazine group (P < .01), and to 2.1 in the 1,000-mg ranolazine group (P < .001). Ranolazine also significantly reduced nitroglycerin consumption with a similar dose response.

Consistent with its mechanism of action, ranolazine does not have clinically significant effects on heart rate or blood pressure. It may therefore be a good choice in patients with lower heart rates or blood pressures who have angina despite therapy with a beta blocking agent or calcium antagonist, and in whom increasing the dosage of the beta blocker or calcium antagonist would have unwanted hemodynamic effects, said lead author of the study Bernard R. Chaitman, MD, professor of medicine and director of cardiovascular research, St. Louis University.

A previous double-blind clinical trial showed it to be effective as monotherapy, he said. Patients who continue to experience symptoms after a revascularization procedure will be candidates for ranolazine as well, said Dr. Chaitman. About one fourth of patients still experience anginal attacks despite both revascularization and drug therapy. In addition, many patients are not candidates for a revascularization procedure because of anatomic conditions, such as severe distal disease, small-branch vessel disease, or other factors.

“In some patients in whom a revascularization procedure is being considered for the purpose of symptom relief, ranolazine may be able to increase the bar enough so that the patient would have an acceptable lifestyle without requiring angioplasty or bypass surgery,” said Dr. Chaitman.

In an accompanying editorial, Peter Berger, MD, Duke University, Durham, North Carolina, discusses the potential role of new antianginal drugs in the era of percutaneous coronary intervention (PCI). PCI is most commonly performed when ischemic symptoms interfere with quality of life. “In many such patients, antianginal therapy may obviate the need for a revascularization procedure,” he writes. Many patients would rather take antianginal medication if it relieves symptoms than undergo PCI with its 2% to 3% risk of a significant complication within 30 days. He adds, “the availability of another effective and apparently safe antianginal medication such as ranolazine is particularly important for such patients with angina who are not candidates for revascularization.”