EFFECTS OF A NEW METABOLIC MODULATOR, RANOLAZINE, ON EXERCISE TOLERANCE IN ANGINA-PECTORIS PATIENTS TREATED WITH BETA-BLOCKER OR DILTIAZEM

Ranolazine (RS 43285) is a new piperazine derivative with anti-ischemic properties attributed to a modulation of myocardial metabolism. Its antianginal action was assessed in 104 patients recruited in a double-blind, crossover, randomized study comparing placebo with a single dose of ranolazine (10, 60, 120, and 240 mg). All patients had chronic stable angina pectoris and remained symptomatic (at least 0.1 mV ST-segment depression and angina during prestudy exercise testing) despite treatment with a beta-blocker or with diltiazem. No significant effects of ranolazine on exercise duration or time to angina were observed after the dose of 10, 60, and 120 mg. After the 240 mg dose, however, significant improvement in exercise duration (+ 13.1% in the combined group, two-tailed p = 0.002; + 14.3% in the beta-blocker group, p = 0.009; + 11.9% in the diltiazem group, p = 0.06), in time to angina (+ 56.8 s, p = 0.008), and in time to 1 mm ST-segment depression was observed. The cumulative proportion of patients who improved their time to angina by at least 30 s above placebo were 25, 42, 50, and 72% with the doses of 10, 60, 120, and 240 mg, respectively. Sixty-seven percent of the patients with ranolazine plasma levels above 500 ng/ml improved their time to angina against 40% at plasma levels below 500 ng/ml and summed ST-segment depression during exercise and recovery was also significantly reduced at these plasma concentrations. Both heart rate and arterial pressure at rest and at peak exercise were unchanged after ranolazine, 240 mg. It is concluded that a single dose of 240 mg of ranolazine exerts a significant antianginal action in patients already treated with a beta-blocker or diltiazem and that the lack of hemodynamic changes supports the hypothesis of a novel mode of action for ranolazine. Further studies are warranted to determine the optimal dosing interval and the maximum effective dose.