Angina, Coronary Artery Disease, Diabetes, Type I, Diabetes, Type II
Conditions
Keywords
type 1 diabetes, type 2 diabetes, exertion angina, suspected CAD, known CAD
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.
Interventions
DRUGRanolazine
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.
DRUGPlacebo
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.
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Post-exercise Coronary Vasodilator Reserve | 4 weeks | Change (from baseline) in post-exercise coronary vasodilator reserve, as measured by PET imaging at 4 weeks post randomization. Per-patient global coronary flow reserve (CFR) was calculated as the ratio of absolute MBF at stress over rest for the entire left ventricle. Quantitation of MBF was performed by two operators blinded to patient, treatment period and treatment order. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in LV Diastolic Function | 4 weeks | Change (from baseline) in LV diastolic function reflected primarily in mitral annular early diastolic relaxation velocity (E') at 4 weeks post randomization. LV end-diastolic and end-systolic volumes (used to calculate LVEF), left atrial volume, septal and lateral peak early diastolic tissue velocity (e'), septal and lateral peak systolic tissue velocity (s'), and mitral inflow velocity (E) were all measured in accordance with ASE guidelines. |
Countries
United States
Participant flow
Pre-assignment details
The order of ranolazine and placebo exposure was randomly assigned in a 1:1 ratio by the Investigational Drug Service at BWH. During the 28-day treatment periods, ranolazine and matching placebo were administered as 500 mg by mouth twice daily for 1 week and increased to 1000 mg by mouth twice daily for 3 weeks, as tolerated.
Participants by arm
| Arm | Count |
|---|---|
| Ranolazine subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor.
Ranolazine: Subject will receive labeled bottles containing tablets with ranolazine 500 mg or a matching placebo provided by the sponsor. | 23 |
| Placebo 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. | 24 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Ranolazine |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 28 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 19 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 6 Participants | 10 Participants | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 18 Participants | 34 Participants | 16 Participants |
| Race/Ethnicity, Customized Indian | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 24 Participants | 47 Participants | 23 Participants |
| Sex: Female, Male Female | 13 Participants | 24 Participants | 11 Participants |
| Sex: Female, Male Male | 11 Participants | 23 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 12 / 23 | 2 / 24 |
| serious Total, serious adverse events | 0 / 23 | 1 / 24 |
Outcome results
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. Per-patient global coronary flow reserve (CFR) was calculated as the ratio of absolute MBF at stress over rest for the entire left ventricle. Quantitation of MBF was performed by two operators blinded to patient, treatment period and treatment order.
Time frame: 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Change in Post-exercise Coronary Vasodilator Reserve | -4 % change |
| Placebo | Change in Post-exercise Coronary Vasodilator Reserve | 2 % change |
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. LV end-diastolic and end-systolic volumes (used to calculate LVEF), left atrial volume, septal and lateral peak early diastolic tissue velocity (e'), septal and lateral peak systolic tissue velocity (s'), and mitral inflow velocity (E) were all measured in accordance with ASE guidelines.
Time frame: 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Change in LV Diastolic Function | 1 % change |
| Placebo | Change in LV Diastolic Function | -2 % change |