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

Coronary Artery Disease Clinical Trial

— RAND-CFR  

Official title:

Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Patients With Diabetes and Suspected or Known Coronary Artery Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01754259
• Other study ID #: 2012P002537
• Status: Completed
• Phase: Phase 3
• First received: December 12, 2012
• Last updated: August 25, 2016
• Start date: April 2013
• Est. completion date: December 2015

Study information

• Verified date: August 2016
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: December 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator)

Related Conditions & MeSH terms

• Angina
• Coronary Artery Disease
• Coronary Disease
• Diabetes Mellitus
• Diabetes, Type I
• Diabetes, Type II
• Myocardial Ischemia

Intervention

Drug:
• Ranolazine
Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
• Placebo Pill
Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Brigham and Women's Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in post-exercise coronary vasodilator reserve	Change (from baseline) in post-exercise coronary vasodilator reserve, as measured by PET imaging at 4 weeks post randomization.	4 weeks	No
Secondary	Change in symptoms of exertional angina and/or dyspnea	Change in symptoms of exertional angina and/or dyspnea on the Seattle Angina Questionnaire and Rose Dyspnea Scale Questionnaire at 4 weeks post randomization;	4 weeks	No
Secondary	Change in left ventricular systolic function	Change (from baseline) in left ventricular systolic function, reflected primarily in LV global longitudinal strain, at 4 weeks post randomization	4 weeks	No
Secondary	Change in post-exercise global myocardial blood flow	Change (from baseline) in post-exercise global myocardial blood flow (in mL/min/g) at 4 weeks post randomization	4 weeks	No
Secondary	Change in post-exercise global coronary vascular resistance	Change (from baseline) in post-exercise global coronary vascular resistance (in mm Hg/mL/min/g) at 4 weeks post randomization	4 weeks	No
Secondary	Change in serum biomarkers of myocardial strain	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	4 weeks	No
Secondary	Correlation between multimodality imaging parameters	Correlation between multimodality imaging parameters (in PET, echo, and angiography) characterizing extent of coronary vascular reactivity, myocardial dysfunction and patterns of atherosclerotic disease	varies	No
Secondary	Change in LV diastolic function	Change (from baseline) in LV diastolic function reflected primarily in mitral annular early diastolic relaxation velocity (E') at 4 weeks post randomization	4 weeks	No