Aspirin and simvastatin, which have been shown to be beneficial in the treatment of cardiovascular disease, are ineffective at improving functional capacity in patients with pulmonary arterial hypertension (PAH), according to a multicenter study, sponsored by the National Institutes of Health (NIH), presented here at the American Thoracic Society 2011 International Conference.
The study was also published in the May issue of the American Journal of Respiratory and Critical Care Medicine.
In addition to their well-known role in cardiovascular disease, aspirin and simvastatin have demonstrated promising results for symptom relief in PAH, according to lead author Steven Kawut, MD, MS, associate professor of medicine and epidemiology at the University of Pennsylvania School of Medicine in Philadelphia.
"There was a lot of evidence, both from animal models and the human disease of PAH, that inhibiting platelet activation and thromboxane production with aspirin and the endothelial effects of simvastatin would result in benefit in PAH," Dr. Kawut explained.
He noted that each of the drugs' mechanisms were believed to independently improve PAH.
"PAH is characterized by endothelial dysfunction, like many other cardiovascular diseases," he noted. "While simvastatin lowers cholesterol, it is thought to have other beneficial clinical effects . . . through its pleiotropic actions."
"PAH also demonstrates increased platelet activation and increased levels of thromboxane. By inhibiting both, aspirin is thought to have beneficial effects," he added.
In an effort to explore the issue further, Dr. Kawut and his colleagues conducted a double-blind placebo-controlled clinical trial in which patients with PAH were randomized at 4 centers to receive aspirin 81 mg or a matching placebo, or simvastatin 40 mg or a matching placebo.
The primary outcome was 6-minute walk distance (6MWD) after 6 months. The researchers planned to enroll 92 patients in the study; however, the trial was terminated by the Data and Safety Monitoring Board at just 65 patients after an interim analysis showed a significant reduction in 6MWD among those receiving simvastatin.
There was no difference in 6MWD between the 32 patients receiving aspirin and the 33 patients receiving placebo (placebo-corrected difference = –0.5 m; P =.97) or between the 32 patients receiving simvastatin and the 33 patients receiving placebo (with a placebo-corrected difference, –27.6 m; P =.09).
Patients in the aspirin group had more episodes of major bleeding than those in the placebo group (4 vs 1 events; P =.17).
The study is the first NIH-funded randomized clinical trial of PAH. Despite the negative results, it provides a valuable answer to the question clinicians have long asked, said Brett Fenster, MD, a cardiologist from National Jewish Health Center, in Denver, Colorado.
"This study addresses an important question that we've been thinking about for some time, which is — particularly with the statin arm: What can a statin do for pulmonary hypertension?," Dr. Fenster said.
"There's been a lot of anecdotal evidence that it may do some good things, with the idea being that what happens in the pulmonary arteries with PAH in some ways resembles what happens to the coronary arteries or other arteries with atherosclerosis."
Although the results showed no improvement in functional capacity, Dr. Fenster said the drugs should still not be ruled out as possibly offering benefit for mortality in PAH.
"The fact that it's negative in terms of a 6-month look at functional capacity doesn't surprise me too much. I think the bigger question in the longer term is whether there is any change in mortality."
In pulmonary hypertension in general, there appears to be a disconnect between therapies that improve functional capacity and those that improve mortality, with drugs like sildenafil (Revatio, Pfizer) showing improvement in the 6MWD, but not in mortality, Dr. Fenster explained.
"This may go in the opposite direction, ultimately," he said, adding that the study should not be dismissed because of its small sample size.
"With a rare disease like PAH, a sample size of 92 patients is actually pretty good, so this is a decent-sized trial, and the data are compelling. But someone still should still look at the question of what it does for mortality. I think that is certainly a study worth doing."
The study was funded by National Institutes of Health grants R01 HL082895 and HL082895-S1. Dr. Kawut and Dr. Fenster have disclosed no relevant financial relationships.
American Thoracic Society (ATS) 2011 International Conference: Abstract 16864. Presented May 18, 2011.
Am J Respir Crit Care Med. 2011;183:A6126.
這篇研究也登載於5月的美國呼吸道與重症醫學期刊(American Journal of Respiratory and Critical Care Medicine)。
為了進一步探討這個議題，Kawut醫師等人對肺動脈高壓病患進行了一個雙盲安慰劑控制試驗，在4個醫學中心內隨機指派接受阿斯匹靈81 mg或安慰劑，或指定使用simvastatin 40 mg或安慰劑。
服用阿斯匹靈的32名病患和服用安慰劑的33名病患，其6MWD並無差異(安慰劑校正差異= –0.5 m；P=.97)，服用simvastatin的32名病患和服用安慰劑的33名病患之間也沒有差異(安慰劑校正差異= –27.6 m；P=.09)。
阿斯匹靈組的病患發生嚴重出血的事件比安慰劑組多(4件 vs 1件；P=.17)。