A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to determine whether aspirin and simvastatin are safe and effective for the treatment of pulmonary arterial hypertension (PAH).

Detailed Description
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PAH is characterized by dyspnea, fatigue, and lower extremity edema as a result of heart failure. In PAH, in situ thrombosis may occur in the lungs, and pulmonary endothelial dysfunction is well-recognized. As aspirin inhibits platelet aggregation, there may be value in using aspirin to treat PAH. Simvastatin has beneficial effects on blood vessels in other types of cardiovascular disease. Therefore, simvastatin may similarly benefit patients with PAH. Participants in this study will be randomly assigned to receive 6 months of daily placebo tablets, daily aspirin and daily placebo, daily simvastatin and daily placebo, or daily aspirin and daily simvastatin in a double-blind fashion. The study will compare the safety and efficacy of aspirin to placebo and simvastatin to placebo.

Official Title
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A Clinical Trial of Aspirin and Simvastatin in Pulmonary Arterial Hypertension

Conditions
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Hypertension, Pulmonary

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Aspirin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mean pulmonary artery pressure greater than 25 mm Hg at rest with a pulmonary capillary wedge pressure less than 16 mm Hg Diagnosis of PAH that is a) idiopathic, b) familial, or c) associated with collagen vascular disease, HIV infection, congenital systemic-to-pulmonary shunt, or former anorexigen use Most recent pulmonary function tests showing FEV1/FVC ratio greater than 50% AND one of the following conditions: a) total lung capacity greater than 70% predicted, or b) total lung capacity between 60% and 70% of predicted value with no more than mild patchy interstitial lung disease on high resolution computerized tomography of the chest Ability to perform six-minute walk testing without limitations in musculoskeletal function or coordination Negative pregnancy test at screening visit for women of childbearing potential If female, willing to use adequate form of birth control Exclusion Criteria: PAH related to other etiologies Diagnosis of sickle cell disease Clinically significant untreated sleep apnea, as diagnosed by polysomnography Left-sided valvular disease (more than moderate mitral valve stenosis or insufficiency or aortic stenosis or insufficiency), pulmonary artery or valve stenosis, or ejection fraction less than 45% on echocardiography Hospitalized or acutely ill Kidney failure Initiation of PAH therapy (prostacyclin analogues, endothelin [ET]-1 receptor antagonists, phosphodiesterase [PDE]-5 inhibitors) within 3 months of study entry Allergy or hypersensitivity to aspirin or simvastatin Absolute indication for aspirin or other anti-platelet therapy Current treatment with statin therapy Inability or unwillingness to avoid non-steroidal, anti-inflammatory medications for 6 months following study entry Current or recent use or planned treatment with one of the following: amiodarone, cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, cimetidine, danazol, large quantities of grapefruit juice (more than 1 quart daily), verapamil, fibrates, or niacin Peptic or duodenal ulcer diagnosed within 1 year of study entry Gastrointestinal bleeding within 6 months prior of study entry Bleeding diathesis History of intracranial bleeding Anemia (hematocrit less than 30%) at screening International normalized ratio (INR) greater than 3.0 at screening Severe thrombocytopenia (less than 75,000/L) at screening Hepatic transaminases greater than twice the upper limit of normal at screening Chronic liver disease (e.g., cirrhosis, chronic hepatitis) with portal hypertension Current or recent (within 6 months of study entry) chronic heavy alcohol consumption History of myositis Creatine phosphokinase (CPK) greater than 1.5 times the upper limit of normal at screening Abnormalities of the arm or hand or past radical mastectomy that might prevent brachial artery ultrasound Pregnant or breastfeeding Current use of another investigational drug for PAH Received a lung transplant

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aspirin 81 mg + Simvastatin 40 mg<br>Simvastatin: Simvastatin 40 mg, taken orally, once a day for 6 months Aspirin: Aspirin 81 mg, taken orally, once a day for 6 months | Drug: Simvastatin<br>* Simvastatin 40 mg, taken orally, once a day for 6 months<br>* Other names: Zocor;Drug: Aspirin<br>* Aspirin 81 mg, taken orally, once a day for 6 months<br>* Other names: acetylsalicylic acid;|
| Active Comparator: Aspirin 81 mg + Placebo<br>Aspirin: Aspirin 81 mg, taken orally, once a day for 6 months Placebo taken orally, once a day for 6 months | Drug: Aspirin<br>* Aspirin 81 mg, taken orally, once a day for 6 months<br>* Other names: acetylsalicylic acid;Drug: Placebo<br>* Placebo, taken orally, once a day for 6 months<br>|
| Active Comparator: Placebo + Simvastatin 40 mg<br>Placebo taken orally, once a day for 6 months Simvastatin: Simvastatin 40 mg, taken orally, once a day for 6 months | Drug: Simvastatin<br>* Simvastatin 40 mg, taken orally, once a day for 6 months<br>* Other names: Zocor;Drug: Placebo<br>* Placebo, taken orally, once a day for 6 months<br>|
| Placebo Comparator: Placebo + Placebo<br>Placebo taken orally, once a day for 6 months Placebo taken orally, once a day for 6 months | Drug: Placebo<br>* Placebo, taken orally, once a day for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distance Walked in Six Minutes |  | Measured at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Clinical Worsening Events (Number of Events) | Defined by the addition of new PAH therapies or dose increases in previously stable PAH therapy, hospitalization for right-sided heart failure, lung transplantation, atrial septostomy, and cardiovascular and all-cause death. | Measured at 6 months | 
| Adverse Events | Please refer to the Adverse Event Tables for specific information | Measured at 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension