BACKGROUND Ranolazine modulates the metabolism of ischemic myocardial cells and improves the efficiency of oxygen use. This study was conducted to evaluate the antianginal and anti-ischemic effects and safety of different doses of ranolazine administered three times daily (tid) compared with placebo in patients with stable angina pectoris. RESULTS Patients with stable angina pectoris took part in the study. Previous antianginal drugs were discontinued under medical supervision. Three hundred nineteen patients received single-blind placebo for up to 18 days, and 318 stopped exercise because of angina of moderate severity, had evidence of myocardial ischemia (> or = 1-mm ST segment depression), and were randomized to one of four study groups in a double-blind manner: ranolazine 30 mg tid (n = 81), ranolazine 60 mg tid (n = 81), ranolazine 120 mg tid (n = 78), and placebo tid (n = 79). After the 4-week double-blind phase, symptom-limited exercise tests were repeated at 1 hour (peak test) and 8 hours (trough test) after the study medication was administered. In addition, patients kept an angina diary throughout the study and wore a Holter monitor for 48 hours. Total exercise duration at baseline (+/- SEM) was 5.9 +/- 0.2 minutes for the placebo group and 6.4 +/- 0.3, 5.9 +/- 0.3, and 6.6 +/- 0.2 minutes for the ranolazine 30-, 60-, and 120-mg groups, respectively (P = NS). After 4 weeks of double-blind therapy, compared with baseline values, at 1 hour after the study medication was administered (peak effect), total exercise duration (+/- SEM) increased by 0.45 +/- 0.2 minutes in the placebo group and by 0.3 +/- 0.2, 0.6 +/- 0.2, and 0.5 +/- 0.2 minutes in the ranolazine 30-, 60-, and 120-mg groups, respectively (placebo versus ranolazine, P = NS). Times to 1-mm ST segment depression at baseline were similar in the four groups and, after 4 weeks of therapy in each group, increased significantly by similar magnitudes at 1 hour after the administration of the medications. Similar changes were seen for the time to onset of angina. Eight hours after administration (trough effect), no differences in total exercise time or any other exercise variables were observed between the placebo and the ranolazine groups. Compared with the baseline values, the number of anginal attacks per week and the number and duration of ischemic episodes per 48 hours during Holter monitoring decreased significantly by similar magnitudes in the placebo and ranolazine groups. CONCLUSIONS Therapy with ranolazine 30, 60, and 120 mg tid was not superior to placebo. Our study does not support the published beneficial effects of similar doses of ranolazine on either myocardial ischemia or exercise performance or on anginal attacks during daily life in patients with angina pectoris.