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.
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Giuseppe Cocco - MD, MDS, FESC, Senior Cardiologist; Cardiology Office, Marktgasse 10A, CH-4310 Rheinfelden / SwitzerlandAuthor's disclosures: None declared.
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