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

March 10, 2023 updated by: Dr Ashesh N. Buch, East Carolina University

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Greenville, North Carolina, United States, 27834
        • East Carolina Heart Institute at Vidant Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

East Carolina University

Collaborators

Gilead Sciences

Investigators

  • Principal Investigator: Ashesh N Buch, MB.ChB, M.D., East Carolina University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2015

Primary Completion (Anticipated)

December 1, 2016

Study Completion (Anticipated)

March 1, 2017

Study Registration Dates

First Submitted

April 12, 2015

First Submitted That Met QC Criteria

April 17, 2015

First Posted (Estimate)

April 22, 2015

Study Record Updates

Last Update Posted (Actual)

March 13, 2023

Last Update Submitted That Met QC Criteria

March 10, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IN-US-259-0172 Buch ISR
  • UMCIRB 13-001574 (Other Identifier: Institutional Review Board (IRB))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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