A Study of Aspirin and Simvastatin in Pulmonary Arterial Hypertension

A Clinical Trial of Aspirin and Simvastatin in Pulmonary Arterial Hypertension

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

Study Overview

• Status: Terminated
• Conditions: Hypertension, Pulmonary
• Intervention / Treatment: Drug: Simvastatin; Drug: Aspirin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02110
      • Tufts University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: Simvastatin; Simvastatin 40 mg, taken orally, once a day for 6 months; Other Names: Zocor; Drug: Aspirin; Aspirin 81 mg, taken orally, once a day for 6 months; Other Names: acetylsalicylic acid
Active Comparator: Aspirin 81 mg + Placebo; Aspirin: Aspirin 81 mg, taken orally, once a day for 6 months Placebo taken orally, once a day for 6 months	Drug: Aspirin; Aspirin 81 mg, taken orally, once a day for 6 months; Other Names: acetylsalicylic acid; Drug: Placebo; Placebo, taken orally, once a day for 6 months
Active Comparator: Placebo + Simvastatin 40 mg; Placebo taken orally, once a day for 6 months Simvastatin: Simvastatin 40 mg, taken orally, once a day for 6 months	Drug: Simvastatin; Simvastatin 40 mg, taken orally, once a day for 6 months; Other Names: Zocor; Drug: Placebo; Placebo, taken orally, once a day for 6 months
Placebo Comparator: Placebo + Placebo; Placebo taken orally, once a day for 6 months Placebo taken orally, once a day for 6 months	Drug: Placebo; Placebo, taken orally, once a day for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: David J Lederer, MD, MS, Columbia University; Principal Investigator: Reda E Girgis, MB, BCh, Johns Hopkins University; Principal Investigator: Kari E Roberts, MD, Tufts University

Publications and helpful links

General Publications

• 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. doi: 10.1161/CIRCULATIONAHA.110.015693. Epub 2011 May 18.
• Al-Naamani N, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Roberts KE, Tracy RP, Hassoun PM, Girgis RE, Shimbo D, Post WS, Kawut SM; ASA-STAT Study Group. Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. Ann Am Thorac Soc. 2016 Jan;13(1):25-30. doi: 10.1513/AnnalsATS.201508-543OC.
• Matura LA, Ventetuolo CE, Palevsky HI, Lederer DJ, Horn EM, Mathai SC, Pinder D, Archer-Chicko C, Bagiella E, Roberts KE, Tracy RP, Hassoun PM, Girgis RE, Kawut SM. Interleukin-6 and tumor necrosis factor-alpha are associated with quality of life-related symptoms in pulmonary arterial hypertension. Ann Am Thorac Soc. 2015 Mar;12(3):370-5. doi: 10.1513/AnnalsATS.201410-463OC.
• 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. doi: 10.1016/j.cct.2010.12.005. Epub 2010 Dec 10.

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: September 30, 2006
• First Submitted That Met QC Criteria: October 5, 2006
• First Posted (Estimate): October 6, 2006

Study Record Updates

• Last Update Posted (Actual): July 21, 2017
• Last Update Submitted That Met QC Criteria: July 18, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Aspirin; Simvastatin
• Other Study ID Numbers: 458; R01HL082895-01 (U.S. NIH Grant/Contract)