Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension - ASA-STAT

May 30, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
National Institutes of Health. Aspirin provided by Bayer HealthCare, LLC, and simvastatin by Merck & Co., Inc.
Date Published:
01/01/2011
Date Updated:
05/30/2011
Original Posted Date:
05/30/2011
References

Description:

By targeting platelet activation and endothelial dysfunction, aspirin and statins have the potential to improve outcomes in patients with pulmonary arterial hypertension (PAH). The current trial was a phase II trial designed to study the feasibility of the use of aspirin and simvastatin in patients with PAH.

Hypothesis:

Aspirin and statin would each be safe and efficacious compared with placebo in patients with PAH.

Study Design

  • Blinded
  • Factorial
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Mean pulmonary artery pressure >25 mm Hg at rest with a pulmonary capillary wedge pressure <16 mm Hg
  • Diagnosis of PAH that is idiopathic, familial, or 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 >50% AND one of the following conditions: a) total lung capacity >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 6-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

    Number of screened applicants: 712
    Number of enrollees: 65
    Duration of follow-up: 6 months (mean)
    Mean patient age: 50.5 years
    Percentage female: 86%

Exclusions:

  • 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 <45% on echocardiography
  • Hospitalized or acutely ill
  • Kidney failure
  • Initiation of PAH therapy (prostacyclin analogues, endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors) within 3 months of study entry
  • Allergy or hypersensitivity to aspirin or simvastatin
  • Absolute indication for aspirin or other antiplatelet therapy
  • Current treatment with statin therapy
  • Inability or unwillingness to avoid nonsteroidal 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 to study entry
  • Bleeding diathesis
  • History of intracranial bleeding
  • Anemia (hematocrit <30%) at screening
  • INR >3.0 at screening
  • Severe thrombocytopenia (<75,000/L) at screening
  • Hepatic transaminases >2x the upper limit of normal (ULN) 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 >1.5 times the ULN at screening
  • Abnormalities of the arm or hand or past radical mastectomy that might prevent brachial artery ultrasound
  • Received a lung transplant 

Primary Endpoints:

  • 6MWD at 6 months

Secondary Endpoints:

  • Platelet markers at 6 months
  • Endothelial function at 6 months
  • WHO functional at 6 months
  • Addition of PAH medication at 6 months
  • Time to clinical events
  • Adverse events at 6 months

Drug/Procedures Used:

In a 2x2 factorial design, patients with PAH were randomized to either aspirin 81 mg daily or matching placebo, or simvastatin 40 mg daily or matching placebo. The randomization scheme was stratified by type of PAH (idiopathic/heritable vs. other) and center.

Concomitant Medications:

Ambrisentan (28%), bosentan (28%), epoprostenol (23%), inhaled iloprost (14%), sildenafil (64%), combination therapy (62%), and warfarin (79%)

Principal Findings:

A total of 65 patients were randomized from the planned sample size of 92, when the trial was terminated early by the Data Safety and Monitoring Board due to futility. At this point, 32 patients had been randomized each to aspirin and simvastatin, and 33 in the respective placebo arms. The major etiologies of PAH were idiopathic (52%), systemic sclerosis (18%), and other connective disuse diseases (14%). The median right ventricular systolic pressure by echocardiography was about 60 mm Hg, and the majority of patients had either World Health Organization (WHO) class II (63%) or III (29%) symptoms, with a mean 6-minute walk distance (6MWD) of about 430 m. The median post-walk Borg dyspnea score was 3.

Aspirin versus placebo: There was no difference in 6MWD between aspirin and placebo groups at 6 months after adjustment for baseline 6MWD (least squares means: 438.0 m vs. 438.5 m, p = 0.97). Median post-walk Borg dyspnea scales were also similar. Aspirin reduced serum thromboxane (Tx) B2 levels by 93% compared with placebo. However, there were no differences in soluble P-selectin, beta-thromboglobulin, or N-terminal probrain natriuretic peptide (NT-proBNP) levels between the groups. Adverse events were similar, although there was a trend toward higher major bleeding in the aspirin arm.

Simvastatin versus placebo: There was no difference in 6MWD between simvastatin and placebo groups at 6 months after adjustment for baseline 6MWD (least squares means: 425.0 m vs. 452.7 m, p = 0.09). The placebo-corrected difference was -27.6 m (95% confidence interval -59.6 to 4.3 m), which indicates that simvastatin may have reduced the 6MWD. Median post-walk Borg dyspnea scales were also similar. As expected, simvastatin had a favorable effect of the lipid profile, but no differences in levels of von Willebrand factor, C-reactive protein, or NT-proBNP or in flow-mediated dilation between the groups. Adverse events were similar.

Interpretation:

This small phase II trial in patients with PAH randomized to either aspirin or simvastatin vs. placebo demonstrated no improvement in 6MWD or post-walk Borg dyspnea scale, despite an improvement in laboratory parameters. This illustrates the importance of carefully conducted clinical trials with clinical outcomes assessment versus reliance on surrogate markers alone. One limitation is that routine hemodynamic measurements were not conducted in this trial, which may have demonstrated some favorable impact in this relatively short-term follow-up trial.

References:

Kawut SM, Bagiella E, Lederer DJ, et al. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation 2011;May 18:[Epub ahead of print].

Keywords: Total Lung Capacity, Pulmonary Wedge Pressure, beta-Thromboglobulin, Blood Pressure, HIV Infections, von Willebrand Factor, Lung Diseases, Interstitial, Contraception, Thromboxane B2, Hypertension, Pulmonary, Natriuretic Peptide, Brain, Echocardiography, Outcome Assessment, Health Care, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Vascular Diseases, Dyspnea, Simvastatin, Respiratory Function Tests, P-Selectin, C-Reactive Protein, Peptide Fragments, Platelet Activation, Scleroderma, Systemic


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