Sildenafil And Atorvastatin Added To Bosentan As Therapy For Pulmonary Hypertension

摘要

Background: The efficacy and safety of combination therapies for pulmonary hypertension are unknown. Methods: Patients with symptomatic pulmonary hypertension on 125 mg bosentan 2 times daily were randomized by a 2:1 randomization to sildenafil 50 mg 3 times daily and atorvastatin 20 mg daily versus placebo. The primary endpoint in the trial was treadmill time. Results: 22 patients age 47.4 ± 14 years were enrolled. Fifteen patients were randomized to receive active therapy, 7 to placebo. After 12 weeks the treadmill time increased from 459± 152 to 623±230 seconds (36%), p =0.004 in those receiving active therapy , largely attributable to the effects in 5 patients. There was an increase in treadmill time from 279±127 to 359±141 seconds (28%), p=0.06 in the placebo group. Conclusions: Although the addition of sildenafil and atorvastatin to bosentan produced beneficial effects in some patients with pulmonary hypertension, the imbalance in baseline treadmill times, and the small sample size makes it difficult to conclude that the combination is favorable. This study was supported by an educational grant from Pfizer. Dr. Gomberg-Maitland has received grant support from Co-Therix, Encysive, Myogen, Pfizer, and United Therapeutics and consulting fees from Co-Therix and United Therapeutics. Dr. McLaughlin has received grant support from Actelion, Co-Therix, Encysive, Myogen, Pfizer and United Therapeutics and has served as a paid consultant, received funding for clinical trials, and/or serves on the speaker's bureau for the following companies: Actelion, CoTherix, Encysive, Myogen, Pfizer, and United Therapeutics. Dr. Rich has received grant support from Actelion, Co-Therix, Encysive, Myogen, Pfizer, and United Therapeutics, and is now a part-time employee of United Therapeutics. Introduction Pulmonary arterial hypertension (PAH) is a disease that previously had few treatment options. Patients now have choices of oral, inhaled, subcutaneous and intravenous treatments. The chronic care of PAH remains challenging, and the morbidity and mortality remain high. The available medications work differently at the cellular level, and it is unknown if combining therapies is safe or if it will improve outcomes. Bosentan, an oral endothelin receptor antagonist, improves exercise tolerance in patients with PAH.1,2As patients with PAH often have elevated endothelin levels,3 it is presumed that blocking receptor stimulation decreases the inflammatory and vasoconstrictive process. Sildenafil is an oral phosphodiesterase 5 (PDE5) inhibitor developed for erectile dysfunction. However, several studies have shown its efficacy in blocking the PDE5 enzyme in the pulmonary circulation resulting in elevation of cyclic GMP levels and a lowering of pulmonary artery pressure.4,5 Atorvastatin is a HMGCoA reductase inhibitor drug that effectively lowers serum cholesterol levels. Recently several studies suggest that the statin drug class improve endothelial cell function and inhibit inflammation, 6,7,8 and in an open label observational study, improved exercise capacity in pulmonary hypertension patients. 9 This trial was initiated at a time when bosentan was the only commercially available oral therapy. Both sildenafil and atorvastatin have favorable records of chronic safety, and offer the possibility of having a beneficial effect in patients with PAH via different mechanisms. Since the action of sildenafil is dependant on an endothelial cell response, and atorvastatin improves endothelial cell function, we reasoned that the combination was rational. Methods The study was approved by the Institutional Review Boards at Rush University Medical Center and at The University of Chicago Hospitals, and all subjects gave written informed consent for their participation. This was a single center double-blind randomized placebo controlled trial testing the combination of atorvastatin 20 mg daily, and sildenafil 50 mg 3 times a day in subjects with PAH on chronic bosenta