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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Myocardial Ischemia, Coronary Artery Disease, Arteriosclerosis, Chronic Stable Angina

Intervention / Treatment
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* Drug: Ranolazine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ranolazine<br>500mg bd ranolazine for 1 week then uptitrated to 1000mg bd to continue for 8 weeks | Drug: Ranolazine<br>* Ranolazine: 500 mg twice day, up-titrated after 1 week to 1000 mg twice a day<br>* Other names: Renexa;|
| Placebo Comparator: Placebo<br>Matching placebo, with up titration after 1 week as in active treatment arm | Drug: Placebo<br>* Matching placebo: up-titration after 1 week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac MRI (CMR) strain | The extent of reversibly ischaemic LV myocardium will be assessed using CMR strain at rest and stress | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dobutamine wall motion scoring index (WMSI) | CMR derived end point | 8 weeks | 
| Quality of Life/burden of angina | QoL questionnaire based assessment (Seattle Angina Quesstionnaire, SAQ; Duke Activity Status Index, DASI;Medical Outcomes Study-Short Form12 ) | 8 weeks | 
| Treadmill ECG exercise distance | Functional capacity assessment | 8 weeks | 
| Time to ECG changes (ST depression) on exercise ECG | If baseline ECG permits, this will allow assessment of impact of treatment on ECG markers of ischemia | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic total coronary occlusions, Ranolazine