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Original Research |

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

Michael D. McGoon, MD, FCCP*; Adaani E. Frost, MD, FCCP; Ronald J. Oudiz, MD; David B. Badesch, MD, FCCP; Nazzareno Galie, MD; Horst Olschewski, MD, FCCP; Vallerie V. McLaughlin, MD, FCCP; Michael J. Gerber, MD; Chris Dufton, PhD; Darrin J. Despain, MS; Lewis J. Rubin, MD, FCCP
Author and Funding Information

*From the Mayo Clinic (Dr. McGoon), Rochester, MN; Baylor College of Medicine (Dr. Frost), Houston, TX; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (Dr. Oudiz), Torrence, CA; University of Colorado (Dr. Badesch), Denver, CO; University of Bologna (Dr. Galie), Bologna Italy; Medical University-Graz (Dr. Olschewski), Austria; University of Michigan (Dr. McLaughlin), MI; Gilead Sciences (Drs. Gerberm, Dufton, and Mr. Despain), Westminster, CO; and University of California-San Diego (Dr. Rubin), La Jolla, CA.

Correspondence to: Michael D. McGoon, MD, Cardiovascular Diseases, Pulmonary Hypertension Clinic, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: mmcgoon@mayo.edu

*Data are presented as mean ± SD or No. (%).

†Prostanoid therapies included epoprostenol and treprostinil. No subject was receiving inhaled iloprost.

*Data are presented as No. or No. (%).

†Three patients discontinued both bosentan and sitaxsentan.

The following disclosures apply: Dr. McGoon is and investigator and consultant for Myogen/Gilead, LungRx, and Actelion. Dr. Frost received funds for conduct of Food and Drug Administration-approved studies in pulmonary hypertension from Gilead/Myogen, Encysive, and Actelion; is on the speaker's bureau for Gilead/Myogen, Pfizer, and Actelion; and has received honoraria for lectures in pulmonary hypertension from Encysive. Dr. Oudiz is an investigator and consultant for Myogen/Gilead. Dr. Badesch has received consultant fees from GlaxoSmithKline, Actelion, Myogen/Gilead, Encysive, CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, Biogen IDEC, PR Pharmaceuticals, Forrest Labs, Scios, Amgen, Biovale Pharmaceuticals/Clarus Health, and Johnson & Johnson; and is on the speaker's bureau for GlaxoSmithKline, Actelion, Encysive, Myogen/Gilead, CoTherix, United Therapeutics, and Pfizer; is on advisory committees for GlaxoSmithKline, Actelion, Myogen/Gilead, Encysive, CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, Biogen IDEC; and is on the Pulmonary Hypertension Association Board of Directors, and the American Thoracic Society Board of Directors. Dr. Galie is an investigator and consultant for Myogen/Gilead. Dr. Olschewski is an investigator and consultant for Myogen/Gilead. Dr. McLaughlin has received grants from Actelion, Encysive, Pfizer, and Lung Rx/United Therapeutics; and is a consultant/speaker/advisory board for Actelion, Gilead, Pfizer, and Caremark. Dr. Gerber is a former Gilead employee. Dr. Dufton is a Gilead employee. Dr. Despain is a Gilead employee. Dr. Rubin is an investigator and consultant for Myogen/Gilead.

This work was performed at the following institutions: 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 and Clinic, Temple, TX; Erasme Hospital, Bruxelles, Belgium; Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

This work was funded by Myogen (now Gilead Sciences, Inc), Westminster, CO. The authors have financial relationships with Myogen, the sponsor of this study. These relationships include consultancy, membership on steering committees, support for work as investigators, or employee.


The following disclosures apply: Dr. McGoon is and investigator and consultant for Myogen/Gilead, LungRx, and Actelion. Dr. Frost received funds for conduct of Food and Drug Administration-approved studies in pulmonary hypertension from Gilead/Myogen, Encysive, and Actelion; is on the speaker's bureau for Gilead/Myogen, Pfizer, and Actelion; and has received honoraria for lectures in pulmonary hypertension from Encysive. Dr. Oudiz is an investigator and consultant for Myogen/Gilead. Dr. Badesch has received consultant fees from GlaxoSmithKline, Actelion, Myogen/Gilead, Encysive, CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, Biogen IDEC, PR Pharmaceuticals, Forrest Labs, Scios, Amgen, Biovale Pharmaceuticals/Clarus Health, and Johnson & Johnson; and is on the speaker's bureau for GlaxoSmithKline, Actelion, Encysive, Myogen/Gilead, CoTherix, United Therapeutics, and Pfizer; is on advisory committees for GlaxoSmithKline, Actelion, Myogen/Gilead, Encysive, CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, Biogen IDEC; and is on the Pulmonary Hypertension Association Board of Directors, and the American Thoracic Society Board of Directors. Dr. Galie is an investigator and consultant for Myogen/Gilead. Dr. Olschewski is an investigator and consultant for Myogen/Gilead. Dr. McLaughlin has received grants from Actelion, Encysive, Pfizer, and Lung Rx/United Therapeutics; and is a consultant/speaker/advisory board for Actelion, Gilead, Pfizer, and Caremark. Dr. Gerber is a former Gilead employee. Dr. Dufton is a Gilead employee. Dr. Despain is a Gilead employee. Dr. Rubin is an investigator and consultant for Myogen/Gilead.

The following disclosures apply: Dr. McGoon is and investigator and consultant for Myogen/Gilead, LungRx, and Actelion. Dr. Frost received funds for conduct of Food and Drug Administration-approved studies in pulmonary hypertension from Gilead/Myogen, Encysive, and Actelion; is on the speaker's bureau for Gilead/Myogen, Pfizer, and Actelion; and has received honoraria for lectures in pulmonary hypertension from Encysive. Dr. Oudiz is an investigator and consultant for Myogen/Gilead. Dr. Badesch has received consultant fees from GlaxoSmithKline, Actelion, Myogen/Gilead, Encysive, CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, Biogen IDEC, PR Pharmaceuticals, Forrest Labs, Scios, Amgen, Biovale Pharmaceuticals/Clarus Health, and Johnson & Johnson; and is on the speaker's bureau for GlaxoSmithKline, Actelion, Encysive, Myogen/Gilead, CoTherix, United Therapeutics, and Pfizer; is on advisory committees for GlaxoSmithKline, Actelion, Myogen/Gilead, Encysive, CoTherix, Pfizer, United Therapeutics, Mondo-Biotech, Biogen IDEC; and is on the Pulmonary Hypertension Association Board of Directors, and the American Thoracic Society Board of Directors. Dr. Galie is an investigator and consultant for Myogen/Gilead. Dr. Olschewski is an investigator and consultant for Myogen/Gilead. Dr. McLaughlin has received grants from Actelion, Encysive, Pfizer, and Lung Rx/United Therapeutics; and is a consultant/speaker/advisory board for Actelion, Gilead, Pfizer, and Caremark. Dr. Gerber is a former Gilead employee. Dr. Dufton is a Gilead employee. Dr. Despain is a Gilead employee. Dr. Rubin is an investigator and consultant for Myogen/Gilead.

This work was performed at the following institutions: 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 and Clinic, Temple, TX; Erasme Hospital, Bruxelles, Belgium; Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

This work was performed at the following institutions: 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 and Clinic, Temple, TX; Erasme Hospital, Bruxelles, Belgium; Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

This work was funded by Myogen (now Gilead Sciences, Inc), Westminster, CO. The authors have financial relationships with Myogen, the sponsor of this study. These relationships include consultancy, membership on steering committees, support for work as investigators, or employee.

This work was funded by Myogen (now Gilead Sciences, Inc), Westminster, CO. The authors have financial relationships with Myogen, the sponsor of this study. These relationships include consultancy, membership on steering committees, support for work as investigators, or employee.


Chest. 2009;135(1):122-129. doi:10.1378/chest.08-1028
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Background:  Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving 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, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point 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 level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd 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 result abnormalities.

Trial registration:  Clinicaltrials.gov Identifier NCT00423592.

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