CARISA Study: Metabolic Modulation of the heart making it more energy efficient

Ranolazine is a potential anti-anginal agent that acts by shifting ATP production away from fatty acid oxidation in favor of glucose oxidation. Because more oxygen is needed to phosphorylate a given amount of ATP during fatty acid oxidation than during carbohydrate oxidation, the ranolazine-induced shift in substrate utilization reduces oxygen demand without decreasing the ability of the tissue to do work.In three placebo controlled studies in angina patients, an immediate release (IR) formulation of ranolazine increased treadmill exercise parameters without associated changes in rest or exercise heart rates or decreases in rest or exercise blood pressures. Statistically significant increases in exercise times were only observed, however, after doses of > 240 mg, when ranolazine plasma concentrations were near their peak. There was no evidence for anti-anginal efficacy 8 or 12 hours after any dose. These studies suggested potential for ranolazine as an anti-anginal drug but indicated that the immediate release formulation was impractical because of the short duration of its effect. They did, however, provide information concerning ranolazine plasma concentrations necessary for an anti-anginal effect. Based on these results, a sustained release (SR) formulation of ranolazine was developed. Another study has shown that subjects treated concomitantly with ranolazine and diltiazem allows the higher ranolazine plasma levels to occur. Both ranolazine SR and IR appear to be safe and well tolerated in short-term, double blind, placebo controlled trials which have included over 1400 patients, most of whom had stable angina.

The CARISA study is a double-blind, randomized, stratified, placebo-controlled, parallel design study of ranolazine in Angina patients. Preliminary data is very promising.