Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD
Condition: Diabetes, Type I; Diabetes, Type II; Angina; Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus
Intervention: Ranolazine; Placebo
Intervention description: 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.; 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 MeSH terms: Ranolazine
Phase: Phase 3
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 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.
Masking: Double (Participant, Investigator)
Enrollment: 47.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: type 1 diabetes; type 2 diabetes; exertion angina; suspected CAD; known CAD

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.
    

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

        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