Hypertension, Pulmonary
Conditions
Keywords
Pulmonary Arterial Hypertension
Brief summary
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
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.
Interventions
DRUGSimvastatin
Simvastatin 40 mg, taken orally, once a day for 6 months
DRUGAspirin
Aspirin 81 mg, taken orally, once a day for 6 months
DRUGPlacebo
Placebo, taken orally, once a day for 6 months
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
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
* 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Distance Walked in Six Minutes | Measured at 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Worsening Events (Number of Events) | Measured at 6 months | 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. |
| Adverse Events | Measured at 6 months | Please refer to the Adverse Event Tables for specific information |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aspirin 81 mg + Simvastatin 40 mg Simvastatin: Simvastatin 40 mg, taken orally, once a day for 6 months
Aspirin: Aspirin 81 mg, taken orally, once a day for 6 months | 16 |
| Aspirin 81 mg + Placebo Aspirin: Aspirin 81 mg, taken orally, once a day for 6 months
Placebo: Placebo, taken orally, once a day for 6 months | 16 |
| Placebo + Simvastatin 40 mg Simvastatin: Simvastatin 40 mg, taken orally, once a day for 6 months
Placebo: Placebo, taken orally, once a day for 6 months | 16 |
| Placebo + Placebo Placebo: Placebo, taken orally, once a day for 6 months | 16 |
| Total | 64 |
Baseline characteristics
| Characteristic | Aspirin 81 mg + Simvastatin 40 mg | Total | Placebo + Placebo | Placebo + Simvastatin 40 mg | Aspirin 81 mg + Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 16.6 | 59.6 Years STANDARD_DEVIATION 13.9 | 63.5 Years STANDARD_DEVIATION 14.2 | 58.6 Years STANDARD_DEVIATION 11.7 | 56.75 Years STANDARD_DEVIATION 13.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 8 Participants | 0 Participants | 5 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 56 Participants | 16 Participants | 11 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 13 Participants | 5 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 13 Participants | 45 Participants | 9 Participants | 12 Participants | 11 Participants |
| Region of Enrollment United States | 16 Participants | 64 Participants | 16 Participants | 16 Participants | 16 Participants |
| Sex: Female, Male Female | 11 Participants | 55 Participants | 14 Participants | 15 Participants | 15 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 2 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 33 / 33 | 32 / 32 | 33 / 33 |
| serious Total, serious adverse events | 4 / 32 | 1 / 33 | 0 / 32 | 0 / 33 |
Outcome results
Primary
Distance Walked in Six Minutes
Time frame: Measured at 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aspirin 81 mg | Distance Walked in Six Minutes | 438.0 meters |
| Aspirin Placebo | Distance Walked in Six Minutes | 438.5 meters |
| Simvastatin 40 mg | Distance Walked in Six Minutes | 425.0 meters |
| Simvastatin Placebo | Distance Walked in Six Minutes | 452.7 meters |
Secondary
Adverse Events
Please refer to the Adverse Event Tables for specific information
Time frame: Measured at 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin 81 mg | Adverse Events | 59 events |
| Aspirin Placebo | Adverse Events | 66 events |
| Simvastatin 40 mg | Adverse Events | 66 events |
| Simvastatin Placebo | Adverse Events | 58 events |
Secondary
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.
Time frame: Measured at 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin 81 mg | Time to Clinical Worsening Events (Number of Events) | 2 events |
| Aspirin Placebo | Time to Clinical Worsening Events (Number of Events) | 6 events |
| Simvastatin 40 mg | Time to Clinical Worsening Events (Number of Events) | 4 events |
| Simvastatin Placebo | Time to Clinical Worsening Events (Number of Events) | 4 events |