Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD (RAND-CFR)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Brigham and Women's Hospital
Sponsor:
Information provided by (Responsible Party):
Marcelo F. Di Carli, MD, FACC, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT01754259
First received: December 12, 2012
Last updated: July 15, 2014
Last verified: July 2014
  Purpose

Coronary vascular dysfunction is highly prevalent among patients with known or suspected Coronary Artery Disease (CAD)1, increases the severity of inducible myocardial ischemia (beyond the effects of upstream coronary obstruction)2, and identifies patients at high risk for serious adverse events, including cardiac death1, 3-5. Diabetic patients without known CAD with impaired coronary vascular function show a risk of cardiac death comparable to, and possibly higher, than that for non-diabetic patients with known CAD10. In the setting of increased oxygen demand, coronary vasodilator dysfunction can upset the supply-demand relationship and lead to myocardial ischemia, subclinical left ventricular dysfunction (diastolic and systolic), and symptoms.

The significance of microvascular coronary dysfunction is increasingly recognized as invasive and non-invasive (PET) methods of quantifying CFR become available.

Importantly, current treatment strategies for obstructive CAD, such as percutaneous coronary intervention with angioplasty and stenting, are not helpful in microvascular disease. Similarly, mortality-altering treatments for systolic heart failure, such as angiotensin converting enzyme inhibitors, have not been beneficial in treating diastolic dysfunction.


Condition Intervention Phase
Diabetes, Type I
Diabetes, Type II
Angina
Coronary Artery Disease
Drug: Ranolazine
Drug: Placebo Pill
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Patients With Diabetes and Suspected or Known Coronary Artery Disease

Resource links provided by NLM:


Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • Change in post-exercise coronary vasodilator reserve [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in post-exercise coronary vasodilator reserve, as measured by PET imaging at 4 weeks post randomization.


Secondary Outcome Measures:
  • Change in symptoms of exertional angina and/or dyspnea [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change in symptoms of exertional angina and/or dyspnea on the Seattle Angina Questionnaire and Rose Dyspnea Scale Questionnaire at 4 weeks post randomization;

  • Change in left ventricular systolic function [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in left ventricular systolic function, reflected primarily in LV global longitudinal strain, at 4 weeks post randomization

  • Change in post-exercise global myocardial blood flow [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in post-exercise global myocardial blood flow (in mL/min/g) at 4 weeks post randomization

  • Change in post-exercise global coronary vascular resistance [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in post-exercise global coronary vascular resistance (in mm Hg/mL/min/g) at 4 weeks post randomization

  • Change in serum biomarkers of myocardial strain [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change in serum biomarkers of myocardial strain (ultrasensitive troponin I (usTnI), N-terminal pro-B-type natriuretic peptide (NTproBNP), and the interleukin family member (ST2)), as well as glycosylated hemoglobin (A1c) at 4 weeks post randomization

  • Correlation between multimodality imaging parameters [ Time Frame: varies ] [ Designated as safety issue: No ]
    Correlation between multimodality imaging parameters (in PET, echo, and angiography) characterizing extent of coronary vascular reactivity, myocardial dysfunction and patterns of atherosclerotic disease

  • Change in LV diastolic function [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Change (from baseline) in LV diastolic function reflected primarily in mitral annular early diastolic relaxation velocity (E') at 4 weeks post randomization


Estimated Enrollment: 70
Study Start Date: April 2013
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ranolazin
subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
Drug: Ranolazine
Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
Placebo Comparator: Placebo
Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
Drug: Placebo Pill
Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.

Detailed Description:

Ranolazine is a novel anti-anginal agent which inhibits the late sodium current in cardiomyocytes, decreasing sodium and calcium overload. In ischemia, excess of intracellular calcium may impair myocyte relaxation and contribute to ventricular diastolic stiffness, which in turn affects myocardial contractility and perfusion. Ranolazine is FDA-approved for treatment of chronic angina. In three randomized, placebo-controlled trials of patients with stable angina, it was shown to increase exercise time free of angina and ST-segment depression, increase exercise capacity and decrease angina when used in combination with established antianginal agents including diltiazem, amlodipine or atenolol, and reduce the frequency of angina on patients on maximum doses of amlodipine.Similarly, in a large population of patients with acute coronary syndromes, ranolazine also decreased exertional angina symptoms and incidence of arrhythmias, with no effect on mortality. Interestingly, in this same study, it significantly improved hemoglobin A1c and recurrent ischemia in patients with diabetes mellitus, and reduced the incidence of increased hemoglobin A1c in patients without known prior hyperglycemia.

Although the anti-ischemic effect of ranolazine is thought to be mediated in part by increased myocardial blood flow,there is currently limited evidence for such an effect on tissue perfusion. A previous study in women without overt CAD did not detect improved myocardial blood flow after treatment with ranolazine. In that study, however, coronary hyperemia was elicited with adenosine (which uncouples blood flow from cardiac work, and reflects predominantly endothelial-independent vasodilation) rather than exercise, which triggers a more complex interplay between metabolic demand, coronary hemodynamics, and vasodilator response. Thus, there is a need for additional investigation of whether the beneficial effects of ranolazine on exertional symptoms are directly related to improved global tissue perfusion. Such evidence would support the use of ranolazine as an anti-ischemic therapy in the challenging population of symptomatic patients with evidence of microvascular dysfunction without obstructive CAD.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. type 1 or 2 diabetes mellitus
  2. anginal symptoms and/or exertional dyspnea;
  3. ability to exercise and achieve an exercise tolerance of at least 3 METS but not higher than 9 METS either on a treadmill or bicycle exercise tolerance test;
  4. perfusion sum stress score (SSS) ≤ 6, as assessed by initial PET

Exclusion Criteria

  1. patients not fulfilling inclusion criteria
  2. patients with evidence of unprotected left main coronary artery stenosis >50%
  3. patients with evidence of new obstructive CAD not on optimal medical therapy
  4. evidence of angiographic disease and/or inducible myocardial ischemia on stress testing planning to undergo revascularization within the following 3 months
  5. history of cardiomyopathy (LVEF <40%) or significant valvular heart disease
  6. uncontrolled hypertension (SBP >180 mm Hg at screening)
  7. gait instability, lower extremity amputations preventing exercise

9. significant liver dysfunction (LFTs >3x upper limits of normal), including cirrhosis 10. prolonged QT (QTc >450 and >470 ms for men and women, respectively) or concomitant use of drugs that prolong QT interval (including methadone and antiarrhythmics such as sotalol, amiodarone, and quinidine) 11. use of drugs that inhibit CYP3A such as ketoconazole, itraconazole, fluconazole, clarithromycin, erythromycin, diltiazem, verapamil, nefazodone, nelfinavir, ritonavir, lopinavir, ritonavir, indinavir, and saquinavir 12. use of drugs that induce CYP3A such rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort 13. atrial fibrillation / inability to hold breath for ≥ 10 seconds (in patients in whom CTA will be performed) 14. eGFR < 50 ml/min or end stage renal disease on dialysis 15. allergy to intravenous contrast 16. pregnant or lactating women, or women of childbearing potential not using an acceptable form of birth control (negative pregnancy test also required) 17. inability to fit safely in PET/CT scanner

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01754259

Contacts
Contact: Marcelo Di Carli, MD 617-525-8322 mdicarli@partners.org
Contact: Masha Gaber, ALM 617-732-4237 mgaber@partners.org

Locations
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
Investigators
Principal Investigator: Marcelo Di Carli, MD Brigham and Women's Hospital
  More Information

No publications provided

Responsible Party: Marcelo F. Di Carli, MD, FACC, Chief, Division of Nuclear Medicine-PET, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01754259     History of Changes
Other Study ID Numbers: 2012P002537
Study First Received: December 12, 2012
Last Updated: July 15, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Brigham and Women's Hospital:
type 1 diabetes
type 2 diabetes
exertion angina
suspected CAD
known CAD

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Diabetes Mellitus
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Ranolazine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014