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

In this issue of THE JOURNAL, Chaitman and colleagues¹ 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.^{2 - 3} In the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial, an earlier placebo-controlled, double-blind trial of the same drug, ranolazine reduced angina and objective evidence of ischemia among patients who were taking no other antianginal medications.⁴ 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.⁵ 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.⁴

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.⁶ 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.

The development of a new antianginal drug also raises the question of the potential role of antianginal medications in an era when percutaneous coronary interventions (PCIs) which are safer than ever, are associated with a much lower restenosis rate than was encountered only a few years ago with balloon angioplasty and approximately 70% lower than was seen with bare (non–drug-eluting) stents.⁷ Coronary artery bypass graft (CABG) surgery has also undergone advances, making this procedure safer and more durable than ever. The role of PCIs against a backdrop of intensive medical therapy is being examined in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial,^{8 - 9} in which patients with coronary disease amenable to PCI are being randomized to receive aggressive medical therapy, risk factor modification, and PCI with stent placement or to receive aggressive medical therapy and risk factor modification alone. To date, more than 2200 patients have been enrolled; enrollment was scheduled to be completed by December 31, 2003, and follow-up will continue until June 2006. The COURAGE study design is more relevant than that of the Atorvastatin Versus Revascularization Treatment Investigators (AVERT) trial, in which, as in the COURAGE trial, patients in one group underwent PCI and those in the other did not.^{9 - 10} But in the AVERT trial, the intensity of medical therapy and risk factor modification was more intense (by study design) in the non-PCI group, many patients were asymptomatic (and <1% had class 3 or 4 angina), and many had a 50% to 70% stenosis (by visual estimate) as their most severe coronary narrowing, narrowings so mild that PCI is usually not recommended.¹⁰

Risk-factor modification is required for all patients with coronary artery disease, regardless of whether a revascularization procedure, PCI or CABG, is performed. An important clinical issue is whether antianginal therapy should be routinely administered to patients if a revascularization procedure, particularly one as well tolerated as PCI, can be performed that would likely eliminate angina entirely. Simply put, there are generally only 2 reasons to perform PCI: (1) if the procedure can be expected to prolong survival or reduce the likelihood of a myocardial infarction, or (2) if the procedure is likely to improve symptoms and quality of life, ie, to make a patient feel better.

The types of patients in whom PCI can be expected to prolong survival or reduce infarction are controversial but likely to include those with ST-wave elevation infarction,¹¹ unstable anginal syndromes and particularly with positive biomarkers,^{12 - 14} with postinfarction angina,¹⁵ and perhaps with multivessel disease and reduced ventricular function.¹⁶ Such patients were shown to live longer after having undergone CABG than having received medical therapy in a study based on data from a time when medical therapy was vastly inferior to that available today.¹⁷ Such patients who underwent PCI had similar survival to those undergoing CABG in the randomized trials comparing PCI and CABG. Enrollment was limited to only those patients whose coronary anatomy was suitable for both PCI and CABG.¹⁶ Such patients comprise a minority of patients undergoing PCI. The second more common indication to perform PCI is when ischemic symptoms are sufficiently severe or troublesome such that they reduce a patient's quality of life. In many such patients, antianginal therapy may obviate the need for a revascularization procedure.

Another important issue is whether to administer medical therapy rather than perform PCI if the revascularization procedure would be likely to entirely eliminate angina and the need for antianginal therapy. Many patients would rather take daily antianginal therapy if doing so would render them less symptomatic or possibly asymptomatic and allow them to avoid the approximate 2% to 3% risk of a significant complication within 30 days associated with PCI (not including the small and often subclinical procedural infarctions that occur in approximately 4%-5% of patients undergoing PCI^{18 - 19} despite medical therapies and procedural measures taken to reduce them). However, medical therapy should be administered to virtually all patients with coronary disease, even those who are completely revascularized and become asymptomatic. Such medical therapy should include aspirin, in most cases a statin, often a β-blocker and an angiotensin-converting enzyme inhibitor, and perhaps clopidogrel.²⁰ These drugs may reduce angina and, perhaps more importantly, reduce the frequency of acute coronary syndromes. Furthermore, many patients who undergo revascularization with PCI or CABG are not rendered asymptomatic and have at least some persistent angina.

The decision is rarely if ever whether to perform revascularization or administer medical therapy, but rather whether to perform PCI and administer medical therapy or to administer medical therapy alone. Furthermore, many patients cannot undergo successful percutaneous or surgical revascularization due to anatomic conditions such as severe distal vessel disease, small-branch vessel disease, or other factors. The therapeutic options for such patients include transmyocardial revascularization, which remains unproved;^{21 - 22} enhanced external counterpulsation, which requires a long course of therapy and is poorly understood²³ ; and angiogenesis, which remains an experimental, unproved approach.²⁴ Thus, the availability of another effective and apparently safe antianginal medication such as ranolazine is particularly important for such patients with angina who are not candidates for revascularization. Use of ranolazine most likely will influence the frequency and timing with which PCI and CABG are performed in the far greater number of patients with angina who are suitable for revascularization procedures.