Emerging clinical role of ranolazine in the management of angina

Abstract

Chronic stable angina is an exceedingly prevalent condition with tremendous clinical, social, and financial implications. Traditional medical therapy for angina consists of beta-blockers, calcium channel blockers, and nitrates. These agents decrease myocardial oxygen demand and ischemia by reducing heart rate, lowering blood pressure, and/or optimizing ventricular loading characteristics. Unique in its mechanism of action, ranolazine is the first new antianginal agent approved for use in the US for chronic angina in over 25 years. By inhibiting the late inward sodium current (I(Na)), ranolazine prevents pathologic intracellular calcium accumulation that leads to ischemia, myocardial dysfunction, and electrical instability. Ranolazine has been proven in multiple clinical trials to reduce the symptoms of angina safely and effectively and to improve exercise tolerance in patients with symptomatic coronary heart disease. These benefits occur without reduction in heart rate and blood pressure or increased mortality. Although ranolazine prolongs the QT(c), experimental data indicate that ranolazine may actually be antiarrhythmic. In a large acute coronary syndrome clinical trial, ranolazine reduced the incidence of supraventricular tachycardia, ventricular tachycardia, new-onset atrial fibrillation, and bradycardic events. Additional benefits of ranolazine under investigation include reductions in glycosylated hemoglobin levels and improved left ventricular function. Ranolazine is a proven antianginal medication in patients with symptomatic coronary heart disease, and should be considered as an initial antianginal agent for those with hypotension or bradycardia.

Keywords: antianginal; chronic angina; myocardial ischemia; pharmacotherapy; ranolazine; sodium current.

Figure 1

Ionic disturbances in ischaemia and heart failure, and their consequences. Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late (sustained/persistent) sodium current: a potential drug target to reduce intracellular sodium-dependent calcium overload and its detrimental effects on cardiomyocyte function. Eur Heart J. 2004;6 (Suppl I):13–17. By permission Oxford University Press, copyright © 2004.

Figure 2

Relation between peak and late sodium current and ventricular action potential (AP) and contraction (tracings are not actual recordings). Panels A and B illustrate a normal and an increased late INa (due to impaired inactivation of Na+ channel), respectively. The enhanced late INa is accompanied by delayed ventricular repolarization (longs APs, and occasional early after depolarization) and abnormal twitch (contraction composed of a phasic and tonic component.) Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late (sustained/persistent) sodium current: a potential drug target to reduce intracellular sodium-dependent calcium overload and its detrimental effects on cardiomyocyte function. Eur Heart J. 2004;6(Suppl I):13–17. By permission Oxford University Press, copyright © 2004.

Figure 3

Sites of action of anti-ischemia medication. Reprinted from Stone P. Ranolazine: new paradigm for management of myocardial ischemia, myocardial dysfunction, and arrhythmias. Cardiol Clin. 2008;26:603–614. Copyright © 2008, with permission from Elsevier.

Figure 4

Symptom-limited exercise duration: dose and plasma concentration relationships. A) Exercise duration versus ranolazine dose. Data are shown at trough (solid bars, primary end point) and peak (lined bars). Statistically significant increases were observed on each ranolazine dose versus placebo (*P < 0.005 vs placebo; **P < 0.001 vs. placebo). A dose-response relationship was evident with greater increases at peak than at trough. B) Exercise duration versus ranolazine plasma concentration. Mean exercise duration increases with mean plasma ranolazine concentrations. From left to right, values on each treatment at trough and peak, respectively, are represented by diamonds (placebo), squares (500 mg twice daily), circles (1,000 mg twice daily), and triangles (1,500 mg twice daily). Dotted lines represent the 95% confidence intervals around the fitted curve. Reprinted from Chaitman BR, Skettino SL, Parker JO, et al. MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–1382. Copyright © 2004, with permission from Elsevier.

Figure 5

Change in treadmill exercise duration from baseline at trough ranolazine levels over time. Reprinted with permission from Chaitman BR, Pepine CJ, Parker J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with chronic severe angina: a randomized controlled trial. JAMA. 2004;291:309–316. Copyright © 2004 American Medical Association. All rights reserved. Data are least square means (SE). P values are for comparisons of each ranolazine group vs placebo.

Figure 6

Change in treadmill exercise duration by background antianginal treatment. Reprinted with permission from Chaitman BR, Pepine CJ, Parker J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with chronic severe angina: a randomized controlled trial. JAMA. 2004;291:309–316. Copyright © 2004 American Medical Association. All rights reserved. Data are least square means (SE). Treatment × background interaction P = 0.63, indicating no statistical evidence of differential treatment effects among background strata.

Figure 7

Number of weekly angina attacks (A) and number of weekly nitroglycerin uses (B), excluding patients with weekly angina rate in the top 2% and bottom 2% of each treatment group (trimmed mean). SE = standard error of the trimmed mean. Reprinted from Stone P, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (efficacy of ranolazine in chronic angina) trial. J Am Coll Cardiol. 2006;48:566–575. Copyright © 2006, with permission from Elsevier.

Figure 8

Kaplan–Meier Estimated Rates of Cardiovascular Death or MI and Recurrent Ischemia. Reprinted with permission from Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes. JAMA. 2007;297:1775–1783. Copyright © 2007 American Medical Association. All rights reserved. Abbreviations: MI, myocardial infarction; HR, hazard ratio; CI, confidence interval.

Figure 9

Summary of concentration-response relationships for effect of ranolazine to inhibit inward and outward ion channel currents in canine ventricular myocytes. Numbers inside parentheses are IC₅₀ values for effect of ranolazine to inhibit rapidly activating delayed rectifier potassium current (I_Kr), late sodium current (late I_Na), peak calcium current (I_Ca), late I_Ca, and sodium–calcium exchange current (I_Na − I_Ca). Reprinted with permission from Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110:904–910. Copyright © 2004 Wolters Kluwer Health.