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Ambrisentan Therapy in Patients with Pulmonary Arterial Hypertension Who Discontinued Bosentan or Sitaxsentan Due to Liver Function Test Abnormalities.

McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, McLaughlin VV, Gerber MJ, Dufton C, Despain DJ, Rubin LJ

Institutions at which the work was performed: University of Colorado Health Sciences Center, Denver, CO; Columbia University College of Physicians and Surgeons, New York, NY; UCSD Medical Center, Thornton Hospital, La Jolla, CA; Virginia Commonwealth University Health System, Richmond, VA; University of Connecticut Health Center, Farmington, CT; Baylor College of Medicine, Houston, TX; Mount Sinai Medical Center, Miami Beach, FL; St. Vincent's Hospital, Darlinghurst, Australia; Rhode Island Hospital, Providence, RI; University of Iowa Hospitals and Clinics, Iowa City, IA; Mayo Clinic, Rochester, MN; Harbor-UCLA Medical Center, Torrance, CA; Massachusetts General Hospital, Boston, MA; Beth Israel Medical Center, New York, NY; Royal Perth Hospital, Perth, Australia; Scott and White Memorial Hospital & Clinic, Temple, TX; Erasme Hospital, Bruxelles, Belgium; Vrije Universiteit Medical Center, Amsterdam, The Netherlands.

Background Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) abnormalities. However, ambrisentan has an incidence of serum aminotransferases >3 times the upper limit of normal (ULN) similar to that observed in PAH patients who are not taking ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population. Methods Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan at 2.5mg once daily for 4 weeks followed by 5mg for 8 weeks. The primary endpoint was the incidence of aminotransferases >3xULN considered by the investigator to be related to ambrisentan and resulted in drug discontinuation. Secondary endpoints included aminotransferases >5xULN requiring drug discontinuation and >3xULN requiring dose reduction, as well as changes in 6-minute walk distance (6MWD), Borg dyspnea index (BDI), WHO functional class, and SF-36((R)) Health Survey score. Patients continued treatment beyond the 12-week endpoint with monthly monitoring of LFTs. Results Thirty-six patients who previously discontinued bosentan (n=31), sitaxsentan (n=2), or both (n=3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase >3xULN that required ambrisentan discontinuation. One patient had a transient aminotransferase >3xULN that resolved following a temporary dose reduction. No additional aminotransferases >3xULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg once daily in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed. Conclusions Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT abnormalities.

Published 24 September 2008 in Chest.
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