PURPOSE:An international, multicenter, 3-year, open-label extension study was conducted to describe the long-term safety and tolerability of oral sildenafil for treatment of pulmonary arterial hypertension (PAH).
METHODS:259 of 277 (94%; 4 died, 8 withdrew from double-blind, placebo-controlled [DBPC] phase; 6 refused to enter extension) patients with functional class I–IV enrolled in a 12-week DBPC trial of sildenafil entered this long-term extension study. Sildenafil was titrated to the highest tolerable dose (20, 40, or 80 mg TID) over 12 weeks. Patients were to continue on sildenafil until the last enrolled patient completed 3 years of open-label treatment.
RESULTS:97% of patients were functional class II or III at enrollment. The median duration of sildenafil treatment was 1236 (range, 1–1523) days. 243/259 (94%), 8/259 (%), and 5/259 (2%) patients were titrated to sildenafil 80 mg, 40 mg, and 20 mg TID at week 24, respectively. 213/259 (82%), 27/259 (10%), and 19/259 (7%) patients were receiving sildenafil 80 mg, 40 mg, and 20 mg TID as the last on–extension study dose, respectively. 2.5%, 8.7%, 20%, and 27.8% of patients received a second PAH therapy at 1, 2, and 3 years and end of treatment, respectively.At 3 years, 30% had functional class improvements and 31% were unchanged compared with the DBPC study baseline. 180 (65.0%) patients completed 3 years of treatment. The overall Kaplan-Meier estimated 3-year survival was 79%. Treatment-related adverse events were mostly mild to moderate in severity (16% headache, 10% dyspepsia, 8% diarrhea, and 7% blurred vision). At 3 years, 53 patients had died and 44 had discontinued (including 5 who received lung transplants).
CONCLUSION:Sildenafil 20–80 mg TID was generally well tolerated. At 3 years, Kaplan-Meier survival was 79%, 61% of patients had unchanged or improved functional status, and 20% had a second PAH therapy. This study was funded by Pfizer Inc.
CLINICAL IMPLICATIONS:In this noncontrolled extension study, no significant safety concerns were identified with long-term sildenafil 20–80 mg TID.
DISCLOSURE:Lewis Rubin, Other Consultant/AdvisorScientific Study/Trial InvestigatorPfizer Inc; No Product/Research Disclosure Information