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Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is a condition that leads to progressive right heart failure and death unless recognized and treated early. Endothelin, a potent endogenous vasoconstrictor, has been identified as an important mediator of PAH. Endothelin receptor antagonists (ERAs) have been associated with an improvement in exercise capacity and time to clinical worsening in patients with Group 1 PAH, and three different ERAs are currently approved for use in this population: bosentan, ambrisentan, and macitentan. While all three ERAs are generally well-tolerated, they each have important adverse effects that need to be recognized and monitored. In particular, they may cause anemia, peripheral edema, and mild cardiac, respiratory, neurologic, and gastrointestinal adverse effects to varying degrees. Although bosentan increases a patient’s risk of developing liver transaminitis, ambrisentan and macitentan do not appear to confer the same risk of hepatotoxicity at this time. Important drug–drug interactions, particularly involving other drugs metabolized via the cytochrome P450 pathway, are important to recognize when prescribing ERAs. In this review, we provide a brief overview of the current state of knowledge as it relates to the adverse effect profiles, tolerability, and drug–drug interactions of this class of medication as informed by the results of randomized clinical trials, drug surveillance programs, and regulatory agencies.

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Acknowledgments

No sources of funding were used to assist in the preparation of this review. Meghan Aversa and Sandra Porter have no conflicts of interest that are directly relevant to the content of this review. John Granton is an investigator in trials in pulmonary hypertension sponsored by Actelion Pharmaceuticals Ltd, Eli Lilly and Co., and GlaxoSmithKline Inc., a member of a data safety monitoring committee for Actelion Pharmaceuticals Ltd, and receives consultant fees from Actelion Pharmaceuticals Ltd, Eli Lilly and Co., and GlaxoSmithKline Inc. that are payable to the University Health Network Foundation. Actelion Pharmaceuticals Ltd has supported the University Health Network Foundation to help provide education and research in pulmonary hypertension.

Meghan Aversa, Sandra Porter, and John Granton were responsible for writing and reviewing all drafts of the manuscript and approving the final draft.

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  1. Toronto General Hospital, 11-124 Munk building, 585 University Ave, Toronto, Ontario, Canada

    Meghan Aversa, Sandra Porter & John Granton

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  1. Meghan Aversa
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Correspondence to John Granton.

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Aversa, M., Porter, S. & Granton, J. Comparative Safety and Tolerability of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension. Drug Saf 38, 419–435 (2015). https://doi.org/10.1007/s40264-015-0275-y

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