Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD

NCT ID: NCT01754259

Last Updated: 2017-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-04-30
• Study Completion Date: 2015-12-31

Brief Summary

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.

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.

Conditions

Diabetes, Type I; Diabetes, Type II; Angina; Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Ranolazine

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Group Type: EXPERIMENTAL

Ranolazine

Intervention Type: DRUG

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Placebo

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Interventions

Ranolazine

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Intervention Type: DRUG

Placebo

Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. Each patient will receive both ranolazine and placebo for 4 weeks, but both the investigator and subject are blinded to the order.

Intervention Type: DRUG

Other Intervention Names

Ranexa; Placebo pill

Eligibility 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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Marcelo F. Di Carli, MD, FACC

Chief, Nuclear Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marcelo Di Carli, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

References

Shah NR, Cheezum MK, Veeranna V, Horgan SJ, Taqueti VR, Murthy VL, Foster C, Hainer J, Daniels KM, Rivero J, Shah AM, Stone PH, Morrow DA, Steigner ML, Dorbala S, Blankstein R, Di Carli MF. Ranolazine in Symptomatic Diabetic Patients Without Obstructive Coronary Artery Disease: Impact on Microvascular and Diastolic Function. J Am Heart Assoc. 2017 May 4;6(5):e005027. doi: 10.1161/JAHA.116.005027.

Reference Type: DERIVED

PMID: 28473401 (View on PubMed)

Other Identifiers

2012P002537

Identifier Type: -

Identifier Source: org_study_id