Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Diabetic Patients and CAD
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Angina, Angina, Peripheral Vascular Disease, Cardiology, Diabetes |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 90 |
| Updated: | 4/21/2016 |
| Start Date: | April 2013 |
| End Date: | December 2015 |
Effects of Ranolazine on Coronary Flow Reserve in Symptomatic Patients With Diabetes and Suspected or Known Coronary Artery Disease
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.
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.
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.
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.
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
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