Angina, Pulmonary Arterial Hypertension
Conditions
Keywords
Angina, Right Ventricular Ischemia, Pulmonary Arterial Hypertension, Pulmonary Hypertension
Brief summary
The purpose of the study is to determine if the medication, ranolazine (study drug), can help improve blood flow to your heart, increase your exercise capacity and improve your quality of life (QOL). For this study, you will be asked to perform several tests in order to determine if your heart function, exercise capacity, chest pain and QOL have improved after 3 months of treatment with ranolazine. Ranolazine is approved by the U.S. Food and Drug Administration (FDA) for the treatment of angina.
Detailed description
This study is looking to enroll patients with pulmonary hypertension (PH). PH is abnormally high blood pressure in the arteries of the lungs. It makes the right side of the heart need to work harder than normal and is usually caused by a narrowing of the small arteries of the lung. This narrowing makes it harder for the right side of the heart to circulate the blood to the lungs. Over time, the right side of the heart may become enlarged and symptoms (such as angina \[chest pain\] shortness of breath, fatigue, edema) begin to appear. Ranolazine is a safe, well-tolerated, and FDA-approved medication for the treatment of chronic stable angina. Ranolazine may potentially improve blood flow to the right ventricle (RV), thereby relieving angina while simultaneously improving RV performance and contractility. This latter effect may increase stroke volume and cardiac output which could translate into benefits in exercise capacity and improved quality of life. The purpose of this single center, non-randomized, prospective pilot study is to investigate the effects of 3 months treatment with ranolazine on pulmonary artery hemodynamics, exercise capacity and quality of life in patients with PAH and symptoms of angina or angina equivalent.
Interventions
DRUGRanolazine
ranolazine 1000 mg PO BID for 3 months
Sponsors
Gilead Sciences
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. World Health Organization (WHO) Group 1 PAH, defined as a pulmonary hypertension with mean pulmonary artery pressure \> 25 mmHg, pulmonary capillary wedge pressure \< 15 mmHg, and pulmonary vascular resistance \> 3 Wood units. 2. Right ventricular dysfunction, defined as RV fractional area change \< 32% or RV tricuspid annular plane systolic excursion (TAPSE) \< 15 mm. 3. Symptoms of angina or angina equivalent (exertional dyspnea, exertional epigastric pain, exertional nausea). 4. New York Heart Association functional class II or III symptoms. 5. Stable doses of pulmonary vasodilators (prostacyclins, endothelin receptor antagonists, phosphodiesterase inhibitors), with no new therapy initiation or dose escalation \> 50% in the 4 weeks prior to randomization. 6. Age 18-80 years.
Exclusion criteria
1. Acute coronary syndrome or coronary revascularization within the prior 3 months. 2. Patients with unstable angina. 3. Patients with Class IV congestive heart failure. 4. Planned revascularization, pacemaker or defibrillator placement during the study period. 5. Changes in antianginal medical therapy likely to occur during the study period. 6. Corrected QT interval measurement \>500 ms. 7. Patients with pre-existing QT prolongation (including congenital long QT syndrome) or receiving other QT prolonging drugs (including Class Ia-e.g., quinidine, Class III-e.g., dofetilide, sotalol, antiarrhythmics; antipsychotics (e.g., thioridazine, ziprasidone), or known history of complex ventricular arrhythmias requiring antiarrhythmic medications or ICD implantation. 8. Patients with known history of hepatic dysfunction. 9. Current use of strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir and diltizaem. 10. Patients with pacemakers, cochlear implants, aneurysm clips, who have worked with metal. 11. Patients with metallic hardware, implants, or prostheses will consult with the radiologist/cardiologist prior to the study. 12. Patients with severe or end stage renal disease (an estimated GFR \< 30 mL/min/1.73 m). 13. Women who are pregnant or lactating 14. Any contraindications for the use of a right heart catheter including, but not limited to: * Pulmonic or tricuspid valve stenosis * Prosthetic pulmonic or tricuspid valve * Right atrial or ventricular masses * Previous pneumonectomy * Risk of severe arrhythmias, including left bundle branch block (LBBB) 15. Subjects unable to perform cardiopulmonary exercise testing will be excluded (i.e. extensive musculoskeletal disease)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improve Angina Symptoms | 3 months | Assessed as average improvement in WHO Functional Class. The WHO Functional Class score ranges from 1 to 4, with higher scores indicating more impairment |
| 6-Minute Walk Test | 3 Months | Improve Exercise Capacity measured by 6-Minute Walk Test |
| Improve Quality of Life | 3 Months | The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The scores are averaged and transformed to a range of 0-100, in which higher scores reflect better health status and was performed at the conclusion of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| RV Perfusion on Cardiac MRI | 3 months | The majority of patients did not undergo cardiac MRI because it was difficult for the patients to tolerate the imaging study. Therefore, we were not able to assess change in RV perfusion. |
| Absolute RV Longitudinal Strain | 3 months | Change in absolute right ventricular (RV) longitudinal strain as assessed by exercise stress echocardiography with speckle-tracking echocardiography at baseline and conclusion of the study. An increase in exercise-induced change in RV longitudinal strain between baseline to conclusion of the study is indicative of improved RV function. If absolute RV longitudinal strain increases with exercise, that is a sign that the RV is working well. If absolute RV longitudinal strain decreases with exercise, that is a sign that the RV is not working well. Therefore, between baseline and conclusion of the study, if exercise-induced change in RV strain increases that means that the RV is working better at the conclusion of the study. |
| Right Ventricular Hemodynamics | 3 months | Mean pulmonary artery pressure was assessed invasively by right heart catheterization at the conclusion of the study to estimate right ventricular hemodynamics. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ranolazine 1000 mg PO BID
Ranolazine: ranolazine 1000 mg PO BID for 3 months | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | drug-drug interaction | 1 |
Baseline characteristics
| Characteristic | Ranolazine |
|---|---|
| 6-minute walk test | 383 meters STANDARD_DEVIATION 60 |
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 48 years STANDARD_DEVIATION 13 |
| Exercise stress echocardiography with strain | 63 Ejection Fraction (%) STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 11 participants |
| Right heart catheterization | 48 Mean pulmonary artery pressure (mm Hg) STANDARD_DEVIATION 14 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 11 |
| serious Total, serious adverse events | 1 / 11 |
Outcome results
Primary
6-Minute Walk Test
Improve Exercise Capacity measured by 6-Minute Walk Test
Time frame: 3 Months
Population: Analysis was performed in all participants who completed the study and had a 6-minute walk test at baseline and at the conclusion of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | 6-Minute Walk Test | 419 meters | Standard Deviation 80 |
p-value: 0.09t-test, 2 sided
Primary
Improve Angina Symptoms
Assessed as average improvement in WHO Functional Class. The WHO Functional Class score ranges from 1 to 4, with higher scores indicating more impairment
Time frame: 3 months
Population: Analysis was performed on all participants who completed as average change in WHO Functional class score from baseline to 3 months (Baseline, 3 months)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Improve Angina Symptoms | 1.75 units on a scale | Standard Deviation 0.46 |
p-value: 0.0013t-test, 2 sided
Primary
Improve Quality of Life
The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The scores are averaged and transformed to a range of 0-100, in which higher scores reflect better health status and was performed at the conclusion of the study.
Time frame: 3 Months
Population: Analysis was performed on the 8 participants who completed the KCCQ questionnaire at baseline and at the conclusion of the study (month 3)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Improve Quality of Life | Baseline | 60.3 KCCQ Summary Score | Standard Deviation 19.7 |
| Ranolazine | Improve Quality of Life | Month 3 | 64.2 KCCQ Summary Score | Standard Deviation 17.5 |
p-value: 0.37t-test, 2 sided
Secondary
Absolute RV Longitudinal Strain
Change in absolute right ventricular (RV) longitudinal strain as assessed by exercise stress echocardiography with speckle-tracking echocardiography at baseline and conclusion of the study. An increase in exercise-induced change in RV longitudinal strain between baseline to conclusion of the study is indicative of improved RV function. If absolute RV longitudinal strain increases with exercise, that is a sign that the RV is working well. If absolute RV longitudinal strain decreases with exercise, that is a sign that the RV is not working well. Therefore, between baseline and conclusion of the study, if exercise-induced change in RV strain increases that means that the RV is working better at the conclusion of the study.
Time frame: 3 months
Population: Analysis was performed on all participants who completed exercise stress echocardiography at baseline and conclusion of the study (month 3)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Absolute RV Longitudinal Strain | Baseline | -1.4 percentage | Standard Deviation 0.7 |
| Ranolazine | Absolute RV Longitudinal Strain | Month 3 | 1.0 percentage | Standard Deviation 0.5 |
p-value: 0.037t-test, 2 sided
Secondary
Right Ventricular Hemodynamics
Mean pulmonary artery pressure was assessed invasively by right heart catheterization at the conclusion of the study to estimate right ventricular hemodynamics.
Time frame: 3 months
Population: Analysis was performed on all participants who completed right heart catheterization at the conclusion of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Right Ventricular Hemodynamics | 48 mm Hg | Standard Deviation 6 |
p-value: 0.66t-test, 2 sided
Secondary
RV Perfusion on Cardiac MRI
The majority of patients did not undergo cardiac MRI because it was difficult for the patients to tolerate the imaging study. Therefore, we were not able to assess change in RV perfusion.
Time frame: 3 months