Ranolazine as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by, or intolerant of, first-line anti-anginal therapies such as ß-blockers and/or calcium antagonists.

The mechanism of action of ranolazine is still largely unknown. However, it is thought to exert some anti-anginal effects through inhibition of the late sodium current in cardiac cells, thereby reducing intracellular sodium accumulation and subsequently decreasing intracellular calcium overload. This reduction in cellular calcium overload is expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness.1 The anti-anginal actions of ranolazine do not depend upon changes in heart rate, blood pressure or vasodilation.1

The effects of ranolazine on treadmill exercise performance at peak and trough ranolazine plasma concentrations were assessed in a four-period double-blind cross-over study involving 191 patients with effort angina responding to beta-blockers, calcium antagonists and/or long-acting nitrates randomised to receive sustained-release ranolazine 500mg, 1000mg or 1500mg or placebo taken twice daily for one week.2 Anti-anginal therapy was discontinued, with the exception of sublingual glyceryl trinitrate (GTN) used as needed.

Patients receiving ranolazine at all doses had significantly improved total exercise duration, time to angina and time to 1mm ST-segment depression at both the trough and peak time points compared with those receiving placebo. At trough, 71.8, 67.2, 60.3 and 56.8 per cent of patients receiving placebo or ranolazine 500mg, 1000mg or 1500mg, respectively, stopped exercising because of angina.

In another placebo-controlled trial (n=823) ranolazine was found to reduce both angina frequency and GTN consumption in patients with symptomatic chronic angina experiencing exercise-induced myocardial ischaemia at low workloads despite treatment with standard doses of atenolol (50mg daily), amlodipine (5mg daily), or diltiazem (180mg once daily).3 Patients in the trial were randomised to receive sustained-release ranolazine 750mg or 1000mg or placebo twice daily for 12 weeks while continuing treatment with atenolol, amlodipine or diltiazem.

Treadmill exercise duration was significantly increased in patients receiving ranolazine at both trough and peak ranolazine plasma concentrations compared with placebo, an effect that was sustained throughout the 12-week study at both dosage levels. Similar results were observed for times to angina and to ECG ischaemia. Anti-anginal background therapy did not significantly modify the response to ranolazine. In addition, ranolazine was found to reduce the mean number of angina attacks per week from 3.3 for placebo to 2.5 for ranolazine 750mg and 2.1 for ranolazine 1000mg and to significantly reduce GTN consumption.

No clinically significant changes in rest or exercise heart rates or blood pressures were observed in either trial.2,3 In both of these trials, small, dose-related increases in Bazett’s QTc interval were observed for ranolazine compared with placebo.2,3 The most common dose-related adverse effects in both trials were constipation, dizziness, nausea and asthenia.2,3

The safety of ranolazine was also assessed in a large outcome study involving 6,560 patients with non-ST-elevation acute coronary syndromes.4 No difference was observed between ranolazine and placebo in the risk of all-cause mortality, sudden cardiac death or the frequency of symptomatic documented arrhythmias when added to standard medical therapy.

The recommended maximum dose of Ranexa is 750mg twice daily.1

View Ranexa drug record

1. Ranexa, Summary of Product Characteristics.
2. Chaitman BR, Skettino SL, Parker JO et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina.
3. J Am Coll Cardiol 2–4; 43: 1375–82.
4. Chaitman BR, Pepine CJ, Parker JO et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina. JAMA 2004; 291: 309–16.
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: the MERLIN-TIMI 36 randomised trial. JAMA 2007: 297: 1775–83.

Further information: A. Menarini Pharma

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