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

University of North Carolina System

Status and phase

Withdrawn

Phase 4

Conditions

Coronary Artery Disease

Myocardial Ischemia

Arteriosclerosis

Chronic Stable Angina

Treatments

Drug: Placebo

Drug: Ranolazine

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02423265

IN-US-259-0172 Buch ISR

UMCIRB 13-001574 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Sex

All

Ages

21+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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