A clinical trial of aspirin and simvastatin in pulmonary arterial hypertension (ASA-STAT)

作者：Kawut Steven M^*; Girgis Reda

来源：Circulation, 2011, 123(25).

Pulmonary arterial hypertension (PAH) is characterized by obliteration of the pulmonary vascular bed. Endothelial dysfunction and platelet aggregation cause vasoconstriction, mitogenesis, and thrombosis in the small muscular pulmonary arteries. Right-sided heart failure ensues with severe limitation of exercise and eventual progression to death. This disease most often afflicts young women and is incurable.
The recognition of abnormal eicosanoid metabolism (increased thromboxane A(2) and decreased prostaglandin I-2 production) and increased endothelin-1 (ET-1) levels were major advances in understanding the pathophysiology of PAH. Parenteral prostacyclin analogues and ET-1 receptor antagonists are now the standard of care for PAH. While these therapies intervene on downstream effects of endothelial dysfunction, none adequately addresses the proximal endothelial insult or the platelet response. Patients with PAH presently have a five-year survival of only 60% even with these currentlyapproved treatments.
HMG-CoA reductase inhibitors (statins) and aspirin are very safe, highly-effective cardiovascular therapies used by millions of people. Simvastatin decreases cholesterol, stabilizes the endothelial cell layer, increases the bioavailability of nitric oxide, reduces oxidative stress, and decreases inflammation. Aspirin arrests platelet thromboxane A2 production, inhibiting platelet aggregation. Our pilot studies of simvastatin and aspirin in animal models and humans with PAH have shown very promising results, suggesting that these therapies may have significant clinical benefit when added to traditional PAH medications. We have designed a Phase II trial to initiate the study of these two potentially useful interventions with maximum efficiency.
Our goals are 1) to explore the feasibility of performing an NIH-funded clinical trial of simvastatin and aspirin in PAH, 2) to find treatment-related effect sizes for clinical endpoints in order to plan a Phase III trial, and 3) to study the effects of these therapies on endothelial and platelet function. We propose a randomized, placebo-controlled 2 X 2 factorial trial of simvastatin and aspirin enrolling 92 patients to determine whether these drugs have an effect on the distance walked in six minutes in patients with PAH.

• 出版日期2011-6-28