Efficacy of Ranolazine in Patients With Chronic Total Occlusions of Coronary Arteries

The Effectiveness of Ranolazine in Reducing Cardiac Ischaemia Induced by Chronic Total Occlusions of Coronary Arteries

Anti-anginal drugs relieve ischemia and symptoms by reducing myocardial oxygen demand by reducing heart rate and or contractility (beta-blockers, phenylalkylamine and benzothiazepineate classes of calcium antagonists) or vasodilatation of the venous system (fall in pre-load) and coronary vessels. Late sodium channels remain open for longer in the presence of myocardial ischaemia. Ranolazine, a novel anti-anginal agent, acts by inhibiting the inward late inward sodium current (INaL), reducing intracellular sodium accumulation and consequently intracellular calcium overload via the sodium/calcium exchanger. It is currently thought that this reduction in intracellular calcium reduces diastolic myocardial stiffness and therefore compression of the small coronary vessels. There is considerable animal data to support this theory. There are good theoretical reasons to postulate that patients with chronically occluded vessels may derive less benefit from conventional anti-anginal agents, particularly vasodilators. The ischemic myocardium, subtended by the occluded vessel, will already be subject to significant concentrations of paracrine vasodilators such as adenosine. Ranolazine, therefore, may on the basis of its mechanism of action, provide greater relief of ischemia in such patients than conventional anti-anginal agents.

To test this hypothesis, a randomized study comparing addition of ranolazine to addition of a minimum of 2 conventional anti-anginal agents in patients with chronic total occlusions would be required. To be sufficiently powered, this would require a significant number of patients recruited in a multi-center trial. This study is an initial pilot study with inactive placebo, not addition of a conventional anti-anginal agent, as the control using MRI imaging data as the primary end-point.

The extent of reversibly ischaemic LV myocardium will be assessed using CMR strain at rest and stress

QoL questionnaire based assessment (Seattle Angina Quesstionnaire, SAQ; Duke Activity Status Index, DASI;Medical Outcomes Study-Short Form12 )

If baseline ECG permits, this will allow assessment of impact of treatment on ECG markers of ischemia

Inclusion Criteria: Angiographically proven coronary artery disease with chronic stable angina for at least 3 months. Abnormal stress test (treadmill ECG, nuclear stress test, dobutamine stress echocardiogram or stress perfusion cardiac MRI) ≥ 1 chronically occluded coronary artery of a dominant coronary vessel or the left anterior descending artery and/or ≥ 1 occluded vein graft to chronically occluded native coronary vessel Subjects must be taking a minimum of 2 anti-anginal agents: Exclusion Criteria:• Coronary revascularization in the preceding 2 months LVEF < 40 Terminal illness such as cancer Occluded recessive coronary vessel Hepatic insufficiency, Liver cirrhosis, Prolonged QT interval on ECG, Severe renal failure (see below), Excluding patients with CrCl < 30 Drugs that are strong inhibitors of CYP3A such as, ketoconazole, macrolide antibiotics and HIV protease inhibitors. Limit Ranolazine to 500mg BID in patients on concurrent diltiazem/verapamil Limit concurrent simvastatin to 20 mg/day Limit concurrent metformin to 1700 mg/day Inability to have an MRI scan/known claustrophobia