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Ranolazine

A Review of its Use in Chronic Stable Angina Pectoris

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An Erratum to this article was published on 01 July 2011

Summary

Abstract

Extended-release ranolazine (ranolazine ER) [Ranexa®] is a piperazine derivative with a novel mechanism of action that was recently approved in the EU for use as add-on therapy in patients with stable angina pectoris. Ranolazine ER achieves its antianginal effect without affecting heart rate or blood pressure (BP) to a clinically significant extent. Results of well designed, placebo-controlled, short-term studies demonstrate that add-on therapy with ranolazine ER in patients with chronic stable angina improves exercise performance, and reduces anginal frequency and nitroglycerin use. Although longer-term therapy with ranolazine ER did not reduce the incidence of major cardiovascular events in patients with non-ST-elevation acute coronary syndromes, it did reduce the incidence of recurrent ischaemia. Ranolazine ER is a generally well tolerated antianginal agent. Although it is associated with modest dose-related increases in the corrected QT (QTc) interval, ranolazine ER does not appear to be associated with an excess of arrhythmias. Thus, ranolazine ER is a useful new option for patients with chronic stable angina whose symptoms are not controlled with first-line antianginal therapy or who do not tolerate first-line antianginal agents.

Pharmacological Properties

The proposed mechanism of action for ranolazine is inhibition of the late inward sodium current in cardiac cells. Ranolazine also inhibits the rapidly activating component of the delayed rectifier potassium current (IKr). Ranolazine has antianginal activity, but does not affect heart rate or BP to a clinically significant extent. Despite modestly increasing the QTc interval, ranolazine appears to lack the proarrhythmic activity typically associated with drugs that inhibit IKr and even demonstrated antiarrhythmic activity in preclinical and clinical trials. Ranolazine ER improved glycaemic control in patients with diabetes mellitus and chronic stable angina or non-ST-elevation acute coronary syndromes.

Steady-state pharmacokinetics are usually reached within 3 days with twice-daily administration of ranolazine ER. The drug is primarily metabolized by cytochrome P450 (CYP) 3A, with a lesser contribution from CYP2D6. In the EU, contraindications to ranolazine ER include its use in patients with moderate or severe hepatic impairment and its concomitant administration with potent CYP3A inhibitors.

Therapeutic Efficacy

The efficacy of ranolazine ER in patients with chronic stable angina was examined in three randomized, double-blind, placebo-controlled, multicentre trials of up to 12 weeks' duration: the crossover MARISA trial (examining ranolazine ER monotherapy) and the parallel-group CARISA and ERICA trials (examining addon therapy with ranolazine ER).

In the MARISA trial, monotherapy with ranolazine ER 500, 1000 or 1500 mg twice daily increased the total exercise duration at trough (primary endpoint) and peak drug concentrations, the time to onset of angina at trough and peak, and the time to 1 mm ST-segment depression at trough and peak to a significantly greater extent than placebo.

In the CARISA trial, the addition of ranolazine ER 750 or 1000 mg twice daily to background therapy comprising atenolol, diltiazem or amlodipine increased exercise duration at trough (primary endpoint) and peak, and the time to onset of angina at trough and peak to a significantly greater extent than placebo. The time to 1 mm ST-segment depression was increased to a significantly greater extent with ranolazine ER 750 or 1000 mg twice daily than with placebo only at peak ranolazine concentrations. Angina frequency and nitroglycerin use were significantly lower with ranolazine ER 750 or 1000 mg twice daily than with placebo.

In the ERICA trial, angina frequency (primary endpoint) and nitroglycerin use were significantly lower with ranolazine ER 1000 mg twice daily plus amlodipine than with placebo plus amlodipine. The mean Seattle Angina Questionnaire score for the angina frequency dimension improved to a significantly greater extent with ranolazine ER 1000 mg twice daily than with placebo.

MERLIN-TIMI 36 was a randomized, double-blind, placebo-controlled, multinational trial examining the efficacy of ranolazine ER in patients with non-ST-elevation acute coronary syndromes who were at moderate to high risk of death or recurrent ischaemic events (median duration of follow-up 348 days). The incidence of the composite primary endpoint (cardiovascular death, myocardial infarction or recurrent ischaemia) did not significantly differ between ranolazine ER and placebo recipients at study end. However, patients receiving ranolazine ER were significantly less likely than those receiving placebo to experience recurrent ischaemia.

Tolerability

Ranolazine ER was generally well tolerated in short-term trials (CARISA, MARISA, ERICA) and in the longer-term ROLE extension trial (mean duration of follow-up 2.8 years) in patients with chronic stable angina. The most commonly occurring adverse events included dizziness, nausea, asthenia and constipation. In the MARISA, CARISA and ROLE trials, ranolazine ER was associated with modest dose-related increases in the QTc interval.

In the MERLIN-TIMI 36 trial, there was no significant difference between patients receiving ranolazine ER and those receiving placebo in the incidence of death from any cause at months 6, 12 or 18; death or any cardiovascular hospitalization; sudden cardiac death; or symptomatic documented arrhythmia. In addition, the incidence of clinically significant arrhythmias during Holter monitoring over the first 7 days of the trial was significantly lower in ranolazine ER than in placebo recipients.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand

    Gillian M. Keating

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Gillian M. Keating

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Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: J. Abrams, Division of Cardiology, Department of Internal Medicine, The University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA; J-P. Bassand, Department of Cardiology, University Hospital Jean Minjoz, Besançon, France; G. Cocco, Cardiology Office, Rheinfelden, Switzerland; H. Hod, Intensive Cardiac Care Unit, Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, Israel; L.S. Maier, Department of Cardiology and Pneumology, Georg-August-Universität Göttingen, Göttingen, Germany; C.J. Pepine, Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida, USA; B.M. Scirica, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘ranolazine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘ranolazine’ and ‘angina pectoris’. Searches were last updated 20 October 2008.

Selection: Studies in patients with chronic stable angina pectoris who received ranolazine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Ranolazine, angina pectoris, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

An erratum to this article is available at http://dx.doi.org/10.2165/11595790-000000000-00000.

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Keating, G.M. Ranolazine. Drugs 68, 2483–2503 (2008). https://doi.org/10.2165/0003495-200868170-00006

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