Ranolazine and Other Antianginal Therapies in the Era of the Drug-Eluting Stent

Abstract

IN THIS ISSUE OF THE JOURNAL, CHAITMAN AND COLleagues report the results of the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial, an important study evaluating ranolazine, a new antianginal drug. Ranolazine is the first member of a new class of drugs believed to reduce angina by partially inhibiting fatty acid oxidation, thereby increasing glucose oxidation and generating more ATP (adenosine triphosphate) per molecule of oxygen consumed. In the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial, an earlier placebocontrolled, double-blind trial of the same drug, ranolazine reduced angina and objective evidence of ischemia among patients who were taking no other antianginal medications. In CARISA, ranolazine reduced the frequency and severity of angina and improved exercise duration in patients with stable angina receiving other antianginal therapy, specifically those taking a standard dose of either atenolol, amlopidine, or diltiazem. This well-designed, well-conducted clinical trial in which patients were randomized to receive either 1 of 2 doses of ranolazine or placebo showed that both doses of ranolazine were more effective than placebo at reducing symptoms and improving exercise capacity when added to conventional doses of atenolol, diltiazem, or amlopidine. The CARISA trial answers many questions about this promising drug, which currently is under review by the US Food and Drug Administration for approval. Among patients with stable angina taking standard medical therapy, ranolazine reduced angina frequency to a clinically and statistically significant degree when compared with placebo, from 3.3 episodes per week among patients taking placebo to 2.1 to 2.5 episodes per week among patients taking ranolazine; it improved exercise capacity 26 to 34 seconds more in the treatment groups than in the placebo group for an exercise test performed during peak levels, and 24 seconds more with treatment than placebo for an exercise test performed during trough levels. This reduction in symptoms and improvement in exercise capacity was achieved with few apparent adverse effects from either dose of ranolazine. The most frequently reported adverse effects—constipation, nausea, asthenia, and dizziness—each occurred in fewer than 6.2% more patients taking ranolazine than placebo. The only potentially serious adverse effect reported was syncope, which occurred in 5 patients, all of whom were taking 1000 mg of ranolazine twice daily. Although no patients were injured by the syncopal event, the exact mechanism of the syncope is apparently unknown. None of the episodes appeared to be due to ventricular arrhythmia or torsades de pointes, even though ranolazine did prolong the QT interval by no more than 10 milliseconds. However, the CARISA trial raises other questions, both about ranolazine and its role in the treatment of patients with symptomatic coronary artery disease. For example, when reviewing the benefits and adverse effects of ranolazine in the CARISA trial, the data suggest that the lower dose (750 mg of ranolazine twice daily), which had no episodes of syncope, might be the preferred doses. A dose response was not apparent with the 2 doses studied (750 mg and 1000 mg twice daily) when administered in addition to the one other antianginal medication. However, in the MARISA trial, a clear dose response was observed between 500 mg, 1000 mg, and 1500 mg of ranolazine twice daily. The mechanism of the 5 cases of syncope among patients receiving the 1000 mg dose is not known. Four patients who had syncope were also taking diltiazem, and all 5 with syncope were also taking an angiotensin-converting enzyme inhibitor, suggesting that the syncope may have been due to postural hypotension. Although the lack of an observed blood pressure-lowering effect of the drug might appear to argue otherwise, phase 2 studies of ranolazine did reveal a hypotensive effect with doses greater than 1000 mg twice daily. However, if syncope was due to orthostatic hypotension, an important issue is whether high doses of ranolazine would be as well tolerated (as they were in the CARISA trial) when administered to patients with persistent angina despite truly maximal doses of other antianginal medications.