Ranolazine and Pulmonary Hypertension

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Ranolazine in Patients With Angina Due to Right Ventricular Ischemia in Pulmonary Arterial Hypertension

Conditions
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Angina, Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Ranolazine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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. Right ventricular dysfunction, defined as RV fractional area change < 32% or RV tricuspid annular plane systolic excursion (TAPSE) < 15 mm. Symptoms of angina or angina equivalent (exertional dyspnea, exertional epigastric pain, exertional nausea). New York Heart Association functional class II or III symptoms. 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. Age 18-80 years. Exclusion criteria: Acute coronary syndrome or coronary revascularization within the prior 3 months. Patients with unstable angina. Patients with Class IV congestive heart failure. Planned revascularization, pacemaker or defibrillator placement during the study period. Changes in antianginal medical therapy likely to occur during the study period. Corrected QT interval measurement >500 ms. 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. Patients with known history of hepatic dysfunction. Current use of strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir and diltizaem. Patients with pacemakers, cochlear implants, aneurysm clips, who have worked with metal. Patients with metallic hardware, implants, or prostheses will consult with the radiologist/cardiologist prior to the study. Patients with severe or end stage renal disease (an estimated GFR < 30 mL/min/1.73 m). Women who are pregnant or lactating 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) Subjects unable to perform cardiopulmonary exercise testing will be excluded (i.e. extensive musculoskeletal disease)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranolazine<br>1000 mg PO BID | Drug: Ranolazine<br>* ranolazine 1000 mg PO BID for 3 months<br>* Other names: Ranexa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 3 months | 
| 6-Minute Walk Test | Improve Exercise Capacity measured by 6-Minute Walk Test | 3 Months | 
| 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. | 3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 months | 
| 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. | 3 months | 
| 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. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angina, Right Ventricular Ischemia, Pulmonary Arterial Hypertension, Pulmonary Hypertension