Efficacy and Safety of a Metabolic Modulator Drug in Chronic Stable Angina: Review of Evidence from Clinical Trials

Abstract

A number of newer antianginal agents, including nicorandil, trimetazidine, and ivabradine, have been synthesized in recent years, but ranolazine, a piperazine derivative that partially inhibits fatty acid oxidation and the late INa current in animal models, is of particular interest mechanistically. Earlier clinical trials with immediate-release ranolazine led to the current sustained-release version tested in the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) (n = 193) and Combination Assessment of Ranolazine In Stable Angina (CARISA) trials (n = 823) of patients with chronic angina and severe limitation of exercise capacity (ie, < 5 metabolic equivalents). MARISA was a placebo-controlled, randomized trial that compared ranolazine monotherapy (500 mg, 1000 mg, and 1500 mg, twice daily) to placebo. CARISA was a placebo-controlled trial that randomized patients on background 1-blocker or calcium antagonist therapy to placebo or ranolazine (750 mg or 1000 mg, twice daily). Both studies showed a significant increase in total exercise duration, time to angina onset, and time to 1 mm ST segment depression. The average magnitude of increase in exercise duration over placebo was 29 to 56 seconds at peak and 24 to 46 seconds at trough with the 3 doses tested in MARISA, and 24 to 34 seconds greater than placebo with the 2 doses used in CARISA. The beneficial effect was achieved without clinically important changes in rest or exercise heart rate or blood pressure. Weekly angina attack frequency and nitroglycerin usage were significantly reduced in a dose-dependent manner in the 12-week CARISA trial. Reported adverse effects were similar in MARISA and CARISA and consisted of asthenia, nausea, constipation, and dizziness. Syncope, reported in 8 patients at doses of 1000 mg twice daily or more may be related to attenuation of α-1 receptor activity. The mean QTc interval increased with dose and was less than 10 msec on ranolazine at 1000 mg twice daily. The mortality rates at 1 and 2 years in MARISA and CARISA open-label run-on studies were 2% and less than 5%, acceptable for this high-risk population with limited exercise capacity. In conclusion, clinical trial evidence with ranolazine to date is consistent with its proposed mechanism of action and demonstrates an effective antianginal profile that may benefit patients with severe chronic angina.