A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension

• Platelet markers [ Time Frame: Measured at 6 months ] [ Designated as safety issue: No ]
• Endothelial function [ Time Frame: Measured at 6 months ] [ Designated as safety issue: No ]
• World Health Organization (WHO) functional class [ Time Frame: Measured at 6 months ] [ Designated as safety issue: No ]
• Addition of PAH medication [ Time Frame: Measured at 6 months ] [ Designated as safety issue: No ]
• Time to clinical events [ Time Frame: Measured at 6 months ] [ Designated as safety issue: Yes ]
• Adverse events [ Time Frame: Measured at 6 months ] [ Designated as safety issue: Yes ]

• Platelet markers
• Endothelial function
• World Health Organization (WHO) functional class
• Use of PAH medication
• Time to clinical events
• Adverse events (all measured at Month 7)

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

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.

• Drug: Simvastatin
  Simvastatin 40 mg, taken orally, once a day for 6 months
  Other Name: Zocor
• Drug: Aspirin
  Aspirin 81 mg, taken orally, once a day for 6 months
• Drug: Placebo
  Placebo, taken orally, once a day for 6 months

• Active Comparator: 1
  Aspirin 81 mg + Simvastatin 40 mg
  Interventions:

  • Drug: Simvastatin
  • Drug: Aspirin
• Active Comparator: 2
  Aspirin 81 mg + Placebo
  Interventions:

  • Drug: Aspirin
  • Drug: Placebo
• Active Comparator: 3
  Placebo + Simvastatin 40 mg
  Interventions:

  • Drug: Simvastatin
  • Drug: Placebo
• Placebo Comparator: 4
  Placebo + Placebo
  Intervention: Drug: Placebo

• Kawut SM, Bagiella E, Lederer DJ, Shimbo D, Horn EM, Roberts KE, Hill NS, Barr RG, Rosenzweig EB, Post W, Tracy RP, Palevsky HI, Hassoun PM, Girgis RE; ASA-STAT Study Group. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation. 2011 Jun 28;123(25):2985-93. Epub 2011 May 18.
• Kawut SM, Bagiella E, Shimbo D, Lederer DJ, Al-Naamani N, Roberts KE, Barr RG, Post W, Horn EM, Tracy R, Hassoun P, Girgis R; ASA-STAT Study Group. Rationale and design of a phase II clinical trial of aspirin and simvastatin for the treatment of pulmonary arterial hypertension: ASA-STAT. Contemp Clin Trials. 2011 Mar;32(2):280-7. Epub 2010 Dec 10.

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