Microvascular Angina
Conditions
Keywords
microvascular angina, coronary microvascular disease, coronary physiology, ranolazine
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.
Interventions
DRUGRanolazine
Ranolazine 1,000 mg twice daily
DRUGPlacebo
Placebo
Sponsors
Gilead Sciences
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from Emory University Hospital in Atlanta, Georgia. Participant enrollment began in September 2014 and all study procedures were completed in June 2018.
Participants by arm
| Arm | Count |
|---|---|
| Ranolazine Participants receiving 500mg twice a day for 2 weeks then 1000mg twice daily of ranolazine for 10 weeks | 11 |
| Placebo Participants receiving a placebo to match the ranolazine dose for 12 weeks | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Ranolazine | Placebo |
|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 12 | 54.6 years STANDARD_DEVIATION 12.3 | 51.9 years STANDARD_DEVIATION 13.9 |
| Hypertension | 16 Participants | 8 Participants | 8 Participants |
| Prior myocardial infarction | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized African American | 5 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 15 Participants | 8 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 22 participants | 11 participants | 11 participants |
| Sex: Female, Male Female | 16 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 0 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
Change in Seattle Angina Questionnaire Score Regarding Angina Frequency
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Seattle Angina Questionnaire Score Regarding Angina Frequency | 0.70 score on a scale | Standard Deviation 1.26 |
| Placebo | Change in Seattle Angina Questionnaire Score Regarding Angina Frequency | 0.27 score on a scale | Standard Deviation 0.62 |
Secondary
Change in Coronary Flow Reserve (CFR)
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Coronary Flow Reserve (CFR) | 0.38 ratio of hyperemic to basal APV | Standard Deviation 0.85 |
| Placebo | Change in Coronary Flow Reserve (CFR) | 0.09 ratio of hyperemic to basal APV | Standard Deviation 0.3 |
Secondary
Change in Hyperemic Microcirculatory Resistance (HMR)
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Hyperemic Microcirculatory Resistance (HMR) | 0.14 mmHg/cm/s | Standard Deviation 0.5 |
| Placebo | Change in Hyperemic Microcirculatory Resistance (HMR) | -0.04 mmHg/cm/s | Standard Deviation 0.42 |
Secondary
Change in Metabolic Equivalents of Task (METs) at Peak
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Metabolic Equivalents of Task (METs) at Peak | 0.00 3.5ml of oxygen/kg per min | Standard Deviation 0.2 |
| Placebo | Change in Metabolic Equivalents of Task (METs) at Peak | 4.42 3.5ml of oxygen/kg per min | Standard Deviation 14.45 |
Secondary
Change in Peak Rate of Oxygen Consumption (VO2 Max)
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Peak Rate of Oxygen Consumption (VO2 Max) | -0.03 L/min | Standard Deviation 0.23 |
| Placebo | Change in Peak Rate of Oxygen Consumption (VO2 Max) | 0.06 L/min | Standard Deviation 0.11 |
Secondary
Change in Seattle Angina Questionnaire Score Regarding Angina Stability
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Seattle Angina Questionnaire Score Regarding Angina Stability | 0.00 score on a scale | Standard Deviation 0.79 |
| Placebo | Change in Seattle Angina Questionnaire Score Regarding Angina Stability | 0.50 score on a scale | Standard Deviation 1.16 |
Secondary
Change in Seattle Angina Questionnaire Score Regarding Disease Perception
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Seattle Angina Questionnaire Score Regarding Disease Perception | 0.89 score on a scale | Standard Deviation 1.49 |
| Placebo | Change in Seattle Angina Questionnaire Score Regarding Disease Perception | 1.00 score on a scale | Standard Deviation 0.99 |
Secondary
Change in Seattle Angina Questionnaire Score Regarding Physical Limitation
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Seattle Angina Questionnaire Score Regarding Physical Limitation | -0.09 score on a scale | Standard Deviation 0.25 |
| Placebo | Change in Seattle Angina Questionnaire Score Regarding Physical Limitation | 0.27 score on a scale | Standard Deviation 0.68 |
Secondary
Change in Seattle Angina Questionnaire Score Regarding Treatment Satisfaction
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.
Time frame: Baseline, Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Change in Seattle Angina Questionnaire Score Regarding Treatment Satisfaction | 1.17 score on a scale | Standard Deviation 3.92 |
| Placebo | Change in Seattle Angina Questionnaire Score Regarding Treatment Satisfaction | 0.28 score on a scale | Standard Deviation 0.49 |
Secondary
Change in Time to Angina
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.
Time frame: Baseline, Week 12
Population: Data for this outcome measure was not collected.
Secondary
Percent Change in Coronary Blood Flow
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.
Time frame: Baseline, Week 12
Population: Data for this outcome measure was not collected.