Ranolazine is a new antianginal agent believed to reduce oxygen demand through its metabolic action without effects on blood pressure, heart rate or cardiac function. It was evaluated in a randomized, double-blind, placebocontrolled, crossover trial with an extended-period Latin square design (5 one week periods). During a placebo phase, 312 patients with chronic stable angina (≥3 months) receiving multiple antianginals were withdrawn from≥1 antianginal drugs. After their exercise time had shortened by≥1.0 mins they were randomized to receive either ranolazine 267 mg tid, 400 mg bid, 400 mg tid or placebo during each study period. After 1 week of treatment exercise tolerance (Bruce protocol) and plasma ranolazine levels were measured at peak (1 hr after dosing) and at trough (8 [tid] or 12 [bid] hr after dosing).Results at Peak Ranolazine Blood LevelParameter (in sec.)Ranolazine Dose Group minus Placebo Group Responses267 mg tid400 mg bid400 mg tidTime to angina23 (S,38)**19 (4,34)*19 (4,34)*Exercise duration12 (2,23)10 (-06,20)10 (-0.1,20)Time to 1mm ST25 (11,39)**17 (3,31)*22 (8,36)**% with adverse event1.1%-0.3%1.9%Mean (95% CI)*P<0.05**P<0.01, STD=ST Segment DepressionRanolazine significantly increased times to onset of both angina and ST segment depression at all doses tested. All exercise parameters were significantly (P<0.01) improved with ranolazine at peak plasma levels compared with placebo as ranolazine plasma levels ranged from 1,350 to 2,130ng base/mL. No significant differences between ranolazine and placebo were observed at trough with mean ranolazine plasma levels ranging from 235 to 514ng base/mL. No clinically meaningful hemodynamic changes or adverse events occurred with ranolazine compared with placebo. In summary, ranolazine was well tolerated over a wide range of plasma levels. Ranolazine increased exercise times with no detectable effect on cardiac hemodynamics in patients with chronic stable angina taking other antianginal drugs.