DOUBLE-BLIND EFFICACY AND SAFETY STUDY OF A NOVEL ANTIISCHEMIC AGENT,RANOLAZINE, VERSUS PLACEBO IN PATIENTS WITH CHRONIC STABLE ANGINA-PECTORIS

Background Ranolazine modulates the metabolism of ischemic myocardial cells and improves the efficiency of oxygen use. This study was conduc ted to evaluate the antianginal and anti-ischemic effects and safety o f different doses of ranolazine administered three times daily (rid) c ompared with placebo in patients with stable angina pectoris. Methods and Results Patients with stable angina pectoris took part in the stud y. Previous antianginal drugs were discontinued under medical supervis ion. 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 (greater than or equal to 1-mm ST segment depression), and were randomized to one of four stu dy groups in a double-blind manner: ranolazine 30 mg tid (n=81), ranol azine 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) af ter 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 minu tes for the placebo group and 6.4+/-0.3, 5.9+/-0.3, and 6.6+/-0.2 minu tes for the ranolazine 30-, 60-, and 120-mg groups, respectively (P=NS ). After 4 weeks of double-blind therapy, compared with baseline value s, 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 0.51+/-0.2 minutes in the ranolazine 30-, 60-, and 120-mg groups, respectively (placebo v ersus ranolazine, P=NS), Times to 1-mm ST segment depression at baseli ne were similar in the four groups and, after 4 weeks of therapy in ea ch group, increased significantly by similar magnitudes at 1 hour afte r 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 dur ing Holter monitoring decreased significantly by similar magnitudes in the placebo and ranolazine groups. Conclusions Therapy with ranolazin e 30, 60, and 120 mg tid was not superior to placebo. Our study does n ot support the published beneficial effects of similar doses of ranola zine on either myocardial ischemia or exercise performance or on angin al attacks during daily life in patients with angina pectoris.