Letter to the Editor on Nagendran et al
To the Editor:
In their article entitled “Endothelin Axis is Upregulated in Human and Rat Right Ventricular Hypertrophy,”1 Nagendran et al erroneously characterize the US label information for approved endothelin receptor antagonist (ERA) antagonists including ambrisentan (Letairis), an endothelin receptor-A-selective antagonist. Specifically, Nagendran et al1 stated the following findings.
Although this seems to be a class effect, additional postmarketing reports of edema to the Food and Drug Administration (at times requiring hospitalization for decompensated heart failure) within a few weeks from ambrisentan initiation led to a black box warning for significant edema in ERA labels.
In contrast to this statement by Nagendran et al,1 the Food and Drug Administration did not include a black box warning for edema in any ERA label, including the one for ambrisentan. Edema was recognized as an adverse event in the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (phase 3 ambrisentan studies), and postmarketing experience has not uncovered additional concerns. Meanwhile, a post hoc analysis of these studies demonstrated that study subjects who developed edema attributed to ambrisentan still benefitted from this oral therapeutic for their pulmonary arterial hypertension.2 In addition, there is evidence supporting volume expansion rather than right ventricular dysfunction as the cause of edema.3 There is no suggestion that the edema is because of a clinical maladaptive effect on right ventricular function.
The Food and Drug Administration did issue black box warnings for the 3 commercially available ERAs at the time of regulatory approval. The current black box and risk evaluation and management programs for ambrisentan, bosentan, and macitentan state that none should be administered to a pregnant woman because they may cause fetal harm. Bosentan carries a black box for hepatotoxicity, and macitentan carries a warning related to hepatotoxicity.
I congratulate the authors on their original research and look forward to future translational work that might bridge these preclinical observations to clinical practice.
Howard M. Lazarus
Gilead Sciences, Inc.
Foster City, CA
Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.
- © 2014 American Heart Association, Inc.
- Nagendran J,
- Sutendra G,
- Paterson I,
- Champion HC,
- Webster L,
- Chiu B,
- Haromy A,
- Rebeyka IM,
- Ross DB,
- Michelakis ED
- et al