Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan.
BACKGROUND
Bosentan, an oral ET(A)/ET(B) receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH). However, some patients discontinue bosentan because of hepatotoxicity or inadequate efficacy. Sitaxsentan, an oral, ET(A)-selective endothelin antagonist currently under investigation, may be an alternative treatment option. In this study we evaluate the safety and efficacy of sitaxsentan in patients discontinuing bosentan.


METHODS
Forty-eight patients with idiopathic PAH or PAH associated with connective-tissue disease or congenital heart disease were randomized (double-blind) to a single daily dose of either 50 mg or 100 mg sitaxsentan. Thirty-five of the 48 patients discontinued bosentan because of inadequate efficacy, as judged by the investigator, and 13 discontinued bosentan for safety concerns. Study end-points included change in 6-minute walk distance (6MWD), change in World Health Organization (WHO) functional class, time to clinical worsening, and change in Borg dyspnea score (Borg) from baseline to Week 12.


RESULTS
With 100 mg sitaxsentan, 5 of 15 patients (33%) who discontinued bosentan because inadequate efficacy improved, demonstrating a >15% increase in 6MWD, vs 2 of 20 patients (10%) treated with 50 mg sitaxsentan. Fifteen percent and 20% of these patients had a >15% decrease in 6MWD in the 50- and 100-mg groups, respectively. Similar results were seen for the Borg and WHO functional class. Of the 12 patients discontinuing bosentan because of hepatotoxicity, 1 developed elevated liver enzymes at 13 weeks of sitaxsentan therapy. Overall, sitaxsentan was well tolerated.


CONCLUSIONS
Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing bosentan.
Benza
Raymond L
RL
Division of Cardiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0006, USA. rbenza@uab.edu
Mehta
Sanjay
S
Keogh
Anne
A
Lawrence
E Clinton
EC
Oudiz
Ronald J
RJ
Barst
Robyn J
RJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D002648:Child; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D013449:Sulfonamides; D013876:Thiophenes; C106276:sitaxsentan; D000077300:Bosentan