Chest
Volume 135, Issue 1, January 2009, Pages 122-129
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Original Research
Pulmonary Arterial Hypertension
Ambrisentan Therapy in Patients With Pulmonary Arterial Hypertension Who Discontinued Bosentan or Sitaxsentan Due to Liver Function Test Abnormalities

https://doi.org/10.1378/chest.08-1028Get rights and content

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.

Section snippets

Patients

Patients 12 to 75 years of age with IPAH, familial PAH (FPAH), or PAH associated (APAH) with connective tissue disease, congenital systemic-to-pulmonary shunts, anorexigen use, or HIV infection who had previously discontinued bosentan or sitaxsentan therapy, or both, due to serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) concentrations more than three times the ULN (LFT result abnormalities) were eligible for this study. Patients were required to have normal (less

Study Population

Forty-two patients were screened for participation in the study, and 6 patients failed screening: transaminase levels more than one times the ULN (3 patients), inability to obtain baseline laboratory values (1 patient), lack of inclusion diagnosis (1 patient), and death (1 patient). A total of 36 patients were enrolled into the study between May and October 2005. Patient demographic and disease characteristics are summarized in Table 1. The majority were female (86.1%) and white (77.8%), and

Discussion

Although considerable progress has been made in developing new agents for treating patients with PAH, an unmet need remains for conveniently administered therapeutics with sustained safety profiles. In this context, an ongoing concern with ERAs is the potential for clinically significant and sometimes serious liver toxicity.

The mechanisms by which sulfonamide-based ERAs induce liver toxicity are not well established. Preclinical evidence suggests that elevations in aminotransferase

Acknowledgment

We thank the investigators and institutions who participated in this multicenter study, without whom this work would not have been possible: E. Gabbay, Royal Perth Hospital, Perth, Australia; J. Klinger, Rhode Island Hospital, Providence, RI; A. Vonk Noordegraaf, Vrije Universiteit Medical Center, Amsterdam, the Netherlands; J. Carroll, University of Iowa Hospitals and Clinics, Iowa City, IA; H. Garcia, Mount Sinai Medical Center, Miami Beach, FL; A. Keogh, St. Vincent's Hospital, Darlinghurst,

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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.

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 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.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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