Microvascular Assessment of Ranolazine in Non-Obstructive Atherosclerosis (MARINA)

Phase 2

Completed

Conditions: Microvascular Angina

Interventions: Drug: Placebo
Drug: Ranolazine

Registration Number: NCT02147067

Lead Sponsor: Emory University

Brief Summary: The purpose of this study is to look at the effects of the drug Ranolazine compared to Placebo on symptoms of chest pain or chest tightness (known as angina), exercise endurance and ability, and changes in blood flow to the very small arteries of the heart (known as coronary microvascular function) in patients who do not have significant blockages in their major heart arteries. Ranolazine is a drug that is already approved by the FDA for angina, but it may be particularly effective in people with disease in their tiny heart vessels (known as coronary microvascular disease).

This trial aims to enroll 50 patients with angina who undergo baseline bicycle exercise testing with monitoring of the heart's electrical activity and oxygen consumption (known as cardiopulmonary exercise test) and coronary angiogram (taking pictures of the heart arteries through small hollow tubes placed through the wrist or groin). If severe blockages in the main arteries are not found then testing for coronary microvascular function will be performed. Subsequently, participants will then be randomized 50/50 to either Ranolazine or Placebo. After taking the study drug for 12 weeks, they will then repeat the cardiopulmonary exercise test and the coronary angiogram with testing for microvascular function.

Detailed Description: Heart disease is the most common cause of death in the world. Most of our understanding of heart disease has involved the large heart arteries (epicardial arteries); however, disease of the very small heart arteries (coronary microvasculature) likely precedes the development of epicardial disease and represents the "base of the iceberg" of cardiovascular disease. Yet, we do not understand how dysfunctional microvasculature leads to reduced blood flow, symptoms and adverse outcomes.

Coronary microvascular disease results from a combination of structural and functional abnormalities, so it is important to have reliable diagnostic tools that do not rely solely on imaging. The gold-standard for testing involves hemodynamic (blood circulation) measurements such as coronary flow reserve (CFR) and hyperemic microcirculatory resistance (HMR) that take place in the cardiac catheterization laboratory.

Ranolazine is a relatively new U.S Food and Drug Administration-approved medicine to help with angina (chest pain). There are no publications on the effect of Ranolazine on HMR.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

Inclusion Criteria

History of typical angina or effort-induced anginal symptoms and are currently experiencing angina at least once per week
Abnormal stress ECG, exercise stress imaging, or pharmacological stress imaging
Non-obstructive coronary artery disease as defined by lesion stenosis ≤ 50% in any artery as visualized by diagnostic angiography

Exclusion Criteria

Inability to provide informed consent
Active Myocardial Infarction
History of coronary artery bypass grafting
Diagnosis of other specific cardiac disease such as severe valvular heart disease, cardiomyopathy, or variant angina
Left Ventricular Ejection Fraction (LVEF) < 30%
Known renal insufficiency (CrCl < 30 mL/min) or on dialysis
Contraindications to the use of Ranolazine

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo twice daily
Ranolazine	Ranolazine	Ranolazine 1,000 mg twice daily

Primary Outcome Measures

Name	Time	Method
Change in Seattle Angina Questionnaire Score Regarding Angina Frequency	Baseline, Week 12	The change in scores of the angina frequency dimension of the Seattle Angina Questionnaire (SAQ) after 12 weeks therapy with ranolazine or placebo are presented. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. Individual dimensions of the Seattle Angina Questionnaire are transformed to be a score from 0 to 100, where higher scores indicate better health. A positive number for the angina frequency dimension means that the participants are experiencing fewer episodes of angina at week 12 than they were at the baseline visit.

Secondary Outcome Measures

Name	Time	Method
Change in Seattle Angina Questionnaire Score Regarding Physical Limitation	Baseline, Week 12	The change in scores of the physical limitation dimension of the Seattle Angina Questionnaire (SAQ) after 12 weeks therapy with ranolazine or placebo are presented. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. Individual dimensions of the Seattle Angina Questionnaire are transformed to be a score from 0 to 100, where higher scores indicate better health. A positive number for the physical limitation dimension means that the participants are experiencing less limitation at week 12 than they were at the baseline visit.
Change in Seattle Angina Questionnaire Score Regarding Angina Stability	Baseline, Week 12	The change in scores of the angina stability dimension of the Seattle Angina Questionnaire (SAQ) after 12 weeks therapy with ranolazine or placebo are presented. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. Individual dimensions of the Seattle Angina Questionnaire are transformed to be a score from 0 to 100, where higher scores indicate better health. A positive number for the angina stability dimension means that the participants are experiencing fewer changes in their angina at week 12 than they were at the baseline visit.
Change in Seattle Angina Questionnaire Score Regarding Treatment Satisfaction	Baseline, Week 12	The change in scores of the treatment satisfaction dimension of the Seattle Angina Questionnaire (SAQ) after 12 weeks therapy with ranolazine or placebo are presented. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. Individual dimensions of the Seattle Angina Questionnaire are transformed to be a score from 0 to 100, where higher scores indicate better health. A positive number for the treatment satisfaction dimension means that the participants are experiencing greater satisfaction with their treatment at week 12 than they were at the baseline visit.
Change in Peak Rate of Oxygen Consumption (VO2 Max)	Baseline, Week 12	The change in VO2, as measured by cardiopulmonary exercise testing (CPET), after 12 weeks therapy with ranolazine compared with placebo. VO2 max is the maximum amount of oxygen the participants are utilizing during intense treatment. To standardize exercise stress testing, CPET was performed under the guidance of the MET-TEST CPET network in Atlanta, Georgia. The MET-TEST was created in 2003 and is a high-precision stress test with detailed physiological assessment, allowing accurate and reproducible measurements of peak VO2. Individuals may demonstrate an abnormal CPET response before they develop symptoms or present with cardiac events and abnormal CPET results are strong predictors of future adverse outcomes. Higher VO2 values indicate better oxygen utility and positive value for VO2 change means there was improvement from baseline at the week 12 visit. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline.
Change in Seattle Angina Questionnaire Score Regarding Disease Perception	Baseline, Week 12	The change in scores of the disease perception dimension of the Seattle Angina Questionnaire (SAQ) after 12 weeks therapy with ranolazine or placebo are presented. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. Individual dimensions of the Seattle Angina Questionnaire are transformed to be a score from 0 to 100, where higher scores indicate better health. A positive number for the disease perception dimension means that the participants felt that their disease impacted their quality of life less at week 12 than at the baseline visit.
Change in Time to Angina	Baseline, Week 12	Change in time to angina as measured by cardiopulmonary exercise testing after 12 weeks therapy with Ranolazine compared with placebo. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline.
Change in Metabolic Equivalents of Task (METs) at Peak	Baseline, Week 12	Change in exercise was measured as Metabolic Equivalents of Task (METs) at Peak by cardiopulmonary exercise testing (CPET) after 12 weeks therapy with ranolazine compared with placebo. METs are used to describe functional aerobic capacity and harder physical tasks require a higher number of METs. METs at a peak level of exercise was determined for each participant. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. A positive value for change in METs at Peak of exercise indicates that the participant has improved their aerobic capacity from baseline at the week 12 visit.
Change in Coronary Flow Reserve (CFR)	Baseline, Week 12	The changes in Coronary Flow Reserve (CFR) after 12 weeks therapy with ranolazine compared with placebo are presented here. CFR is a measurement of the maximum increase of blood flow through the coronary arteries during exercise. Average peak velocity (APV) was assessed over a 3- to 5-beats period. CFR was defined as the ratio of hyperemic to basal APV. A low CFR is an indication of coronary artery disease. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. A positive value for the change in CFR suggests improvement in coronary artery blood flow between the baseline and week 12 visits.
Change in Hyperemic Microcirculatory Resistance (HMR)	Baseline, Week 12	Change in Hyperemic Microcirculatory Resistance (HMR) after 12 weeks therapy with ranolazine compared with placebo. Average peak velocity (APV) was assessed over a 3- to 5-beats period. HMR was measured as the ratio of distal pressure to APV. Change at 12 weeks was calculated as (Endpoint Value at 12 weeks - Endpoint Value at Baseline)/Endpoint Value at Baseline. Higher HMR is associated with myocardial ischemia and a positive value for change in HMR indicates increased risk for cardiac events at the week 12 visit.
Percent Change in Coronary Blood Flow	Baseline, Week 12	Coronary endothelial function will also be evaluated by measurement of coronary blood flow during infusion of intracoronary acetylcholine. Coronary blood flow (CBF) is defined as diameter (D)2 x APV / 8. Percent change in CBF (%ΔCBF) is calculated by (CBFACh - CBFbaseline) / CBFbaseline x 100%, where a \>50% increase in CBF in response to acetylcholine is considered normal.