Clinical trial NCT02423265: Efficacy of Ranolazine in Patients With Chronic Total Occlusions of Coronary Arteries
Official title: The Effectiveness of Ranolazine in Reducing Cardiac Ischaemia Induced by Chronic Total Occlusions of Coronary Arteries
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Myocardial Ischemia
Coronary Artery Disease
Arteriosclerosis
Chronic Stable Angina
Keywords: Chronic total coronary occlusions
Ranolazine
Lead sponsor: East Carolina University
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
First posted: 2015-04-22
Enrollment: 0
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cardiac MRI (CMR) strain
timeFrame: 8 weeks
Secondary outcomes:
measure: Dobutamine wall motion scoring index (WMSI)
timeFrame: 8 weeks
measure: Quality of Life/burden of angina
timeFrame: 8 weeks
measure: Treadmill ECG exercise distance
timeFrame: 8 weeks
measure: Time to ECG changes (ST depression) on exercise ECG
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Greenville
country: United States
facility: East Carolina Heart Institute at Vidant Medical Center
state: North Carolina
Study officials:
affiliation: East Carolina University
name: Ashesh N Buch, MB.ChB, M.D.
role: PRINCIPAL_INVESTIGATOR
References: