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
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): Ranolazine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Ranexa; Placebo pill
Intervention MeSH terms: Ranolazine
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)
Primary purpose: Other
Keywords: type 1 diabetes; type 2 diabetes; exertion angina; suspected CAD; known CAD