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Mr Giuseppe Cocco,
Ranolazine is an anti-ischaemic agent that does not reduce heart rate nor blood pressure. It is approved as add-on therapy to conventional agents for the symptomatic treatment of patients with stable angina pectoris in whom conventional drugs have failed. Here, the author will describe its approved indications and studies and present its off-label use with a focus on the benefit ranolazine in a case of angina in the absence of coronary artery disease.
Ischaemic heart disease (IHD) - reduced blood supply to the heart usually caused by coronary artery disease - is the leading cause of death and morbidity in America and Europe and is expected to be so by the year 2020 in emerging countries as well (1-3).
Percutaneous coronary intervention, coronary artery bypass grafting and medical therapy have had an outstanding impact to help reduce the burden of IHD, nonetheless, certain patients may continue to have angina symptoms and will experience:
Ranolazine, an anti-ischaemic agent with additional electrophysiological properties can help in the above-described situations and is different from conventional agents (4) in that it does not reduce heart rate nor blood pressure.
Ranolazine is, like trimetazidine, a piperazine derivative - piperazine itself was introduced in 1953 as an anthelmintic - a drug to expel parasitic worms in the body. Ranolazine was developed in the late 1990s and has been approved as a anti-anginal medicine subsequently. Unlike trimetazidine, another antianginal drug which is also a piperazine derivative for which the European Medicines Agency (EMEA) has recommended in 2012 to restrict the use of to second-line therapy, Ranolazine has been approved as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies such as beta-blockers and/or calcium antagonists by both the Federal Drug Administration (FDA) in 2006 and by the EMEA in 2008 and as first-line therapy by the FDA in the treatment of chronic angina in 2012.The main studies carried out with Ranolazine in angina were:
Regarding the mechanisms of ranolazine, reduced diastolic myofilament activation is one mechanism of ranolazine which has been demonstrated - this action is achieved at therapeutic levels which have been determined at 375-750 mg twice a day, through inhibition of the cardiac late Na+ current (INa+) and reduction of the Ca2+ overload. Cross-bridge kinetics of the cardiomyocytes are ameliorated as a result (9-11) and thereby assuming a prodiastolic dysfunction. Some researchers believe that reduced diastolic myofilament activation's net result is reduced oxygen consumption and reduced wall tension thereby improving microvascular blood flow however its value with regard to its antianginal and anti-ischaemic mechanism remains speculative. Additionally, ranolazine has been found to inhibit the IKr-current (12) which is what might explain its electrophysiological effects.Ranolazine also prolongs the QTc-interval, but shortens repolarization in type-3 long-QT-syndrome (13). It is not indicated however to treat patients with cardiac arrhythmias or for lowering haemoglobin A1c in diabetic patients (4). It was also confirmed not to promote sudden death in patients with long-QT syndrome (14). Ranolazine is used today in its extended-release formulation only (15).
A recent review and its accompanying editorial analyse the present knowledge on ranolazine in cardiac diseases and put forward that ranolazine is indicated in patients with stable IHD and refractory angina pectoris (4,16) added to a β-blocker and/or calcium channel blocker in patients without a background of long-acting organic nitrates who remain symptomatic despite treatment with these agents. Furthermore, it is thought that ranolazine should be used as initial antianginal therapy (instead of treatment with a β-blocker, or a calcium-channel blocker, or a nitrate preparation) when an absolute or a relative contraindication to treatment with these agents is present, and if there is a concern regarding low blood pressure or low heart rate.
There are plenty of studies regarding ranolazine in very diverse areas of cardiology however the most numerous are those regarding ischaemic heart disease, angina and myocardial disease together with those regarding rhythmology of which, the HARMONY trial - A Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination in Patients With Paroxysmal Atrial Fibrillation and the RAFFAELLO trial - Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion (headed by J.Camm) which are both due for preliminary results this year.
Cardiac ischaemia with angina pectoris can exist in the absence of significant coronary artery disease, possibly due to microcoronary dysfunction (up to 10% of patients of which a majority of women). Conventional anti-ischaemic drugs may be disappointing in the therapy of this condition and ranolazine may be a particularly interesting approach in these patients.
1. Recent trends in acute coronary heart disease: mortality, morbidity, medical care, and risk factors. McGovern PG et al. N Engl J Med. 1996;334:884–8901. 2. Report From the American Heart Association.Lloyd-Jones D et al on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2010) Heart Disease and Stroke Statistics-2010 Update. Circulation. 121:e46-e215.3. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study.Murray CJ, Lopez AD. Lancet 1997;349:1498–1504.4. Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris?Thadani U. A critical appraisal. Expert Opin Pharmacol 2012;13(17):2555-635. MARISAChaitman Br et al. J Am Coll Cardiol. 2006 Aug 1;48(3):566-75. Epub 2006 Jun 15.6. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trialAssessment of Ranolazine In Stable Angina (CARISA) Investigators. Chaitman Br et al. JAMA. 2004 Jan 21;291(3):309-16.7. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial.Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators.J Am Coll Cardiol. 2006 Aug 1;48(3):566-75. Epub 2006 Jun 15.8. Metabolic efficiency with ranolazine for less ischemia in non-ST elevation acute coronary syndromes (MERLIN TIMI-36) study.Expert Rev Cardiovasc Ther. 2008 Jan;6(1):9-16.Melloni C, Newby LK.9. Inhibition of the late sodium current as a potential cardioprotective principle effect of the late sodium current inhibitor ranolazine.Belardinelli L, shyrock JC, Fraser H, et al. Heart 2006;92:iv6-1410. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non-ST-segment –elevation acute coronary syndrome. Scirica BM, Morrow DA, Hod H, et al. Circulation 2007;116:1647-5211. Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity.Lovelock JD, Monasky MM, Jeong EM, et al. Circ Res 2012;110:841-50 PMID:2234371112. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Circulation 2004;110:904-1013. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT-syndrome.Moss AJ, Zareba W, Schwarz KQ, et al. J Cardiovasc Electrophysiol 2008;19:1289-9314. The risk of sudden cardiac death in patients with non-ST elevation acute coronary syndrome and prolonged QTc interval: effect of ranolazine.Europace. 2013 Mar;15(3):429-36. doi: 10.1093/europace/eus400. Epub 2012 Dec 19.15. Ranolazine FDA regularatory information16. Management of myocardial ischemia. Is ranolazine needed? For all or some patients with myocardial ischemia? Cocco G. Expert Opinion On Pharmacotherapy 2012; Early on line: 1-4. doi: 10.1517/ 14656566.2012.741599217. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes.Timmis AD, Chaitman BR, Crager M. Eur Heart J 2006;27:42-818. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI randomised controlled trial.Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Circulation 2009;119:2032-919. Modulating fatty acid oxidation in heart failure.Lionetti V, Stanley WC, Recchia FA. Cardiovasc Res 2011;90:202-920. The use of oral ranolazine to convert new or paroxysmal atrial fibrillation: a review of experience with implications for possible "Pill in the pocket" approach to atrial fibrillation. Murdock DK, Kersten M, Kaliebe J, et al. Indian Pacing Electrophysiol J 2009;9:260-721. Rhythm control strategies and the role of antiarrhythmic drugs in the management of atrial fibrillation: focus on clinical outcomes.Straube F. J Gen Intl Med 2011;5:531-722. Antiarrhythmic drug therapy for atrial fibrillation.Zimetbaum P. Circulation 2012;125:381-9Cocco G, Chu D: 23. Stress induced cardiomyopathy, a review. Cocco C. Eur. J Int. Med 2007;18:369-379
Giuseppe Cocco - MD, MDS, FESC, Senior Cardiologist; Cardiology Office, Marktgasse 10A, CH-4310 Rheinfelden / SwitzerlandAuthor's disclosures: None declared.