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Review
. 2016 Oct 26;5(11):e003896.
doi: 10.1161/JAHA.116.003896.

Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials

Anhua Wei  1 , Zhichun Gu  2   3 , Juan Li  1 , Xiaoyan Liu  2 , Xiaofan Wu  4 , Yi Han  5 , Jun Pu  6
Affiliations
Review

Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials

Anhua Wei et al. J Am Heart Assoc. .

Abstract

Background: Evidence of the clinical safety of endothelin receptor antagonists (ERAs) is limited and derived mainly from individual trials; therefore, we conducted a meta-analysis.

Methods and results: After systematic searches of the Medline, Embase, and Cochrane Library databases and the ClinicalTrials.gov website, randomized controlled trials with patients receiving ERAs (bosentan, macitentan, or ambrisentan) in at least 1 treatment group were included. All reported adverse events of ERAs were evaluated. Summary relative risks and 95% CIs were calculated using random- or fixed-effects models according to between-study heterogeneity. In total, 24 randomized trials including 4894 patients met the inclusion criteria. Meta-analysis showed that the incidence of abnormal liver function (7.91% versus 2.84%; risk ratio [RR] 2.38, 95% CI 1.36-4.18), peripheral edema (14.36% versus 9.68%; RR 1.44, 95% CI 1.20-1.74), and anemia (6.23% versus 2.44%; RR 2.69, 95% CI 1.78-4.07) was significantly higher in the ERA group compared with placebo. In comparisons of individual ERAs with placebo, bosentan (RR 3.78, 95% CI 2.42-5.91) but not macitentan (RR 1.17, 95% CI 0.42-3.31) significantly increased the risk of abnormal liver function, whereas ambrisentan (RR 0.06, 95% CI 0.01-0.45) significantly decreased that risk. Bosentan (RR 1.47, 95% CI 1.06-2.03) and ambrisentan (RR 2.02, 95% CI 1.40-2.91) but not macitentan (RR 1.08, 95% CI 0.81-1.46) significantly increased the risk of peripheral edema. Bosentan (RR 3.09, 95% CI 1.52-6.30) and macitentan (RR 2.63, 95% CI 1.54-4.47) but not ambrisentan (RR 1.30, 95% CI 0.20-8.48) significantly increased the risk of anemia. ERAs were not found to increase other reported adverse events compared with placebo.

Conclusions: The present meta-analysis showed that the main adverse effects of treatment with ERAs were hepatic transaminitis (bosentan), peripheral edema (bosentan and ambrisentan), and anemia (bosentan and macitentan).

Keywords: adverse drug event; endothelin; endothelin receptor antagonists; meta‐analysis.

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Figures

Figure 1
Figure 1
Flow diagram for the selection of eligible randomized controlled trials. RCT indicates randomized controlled trial.
Figure 2
Figure 2
Risk of bias summary: review of authors’ judgments about each risk of bias item for each included study. + indicates low risk; −, high risk; ?, unclear risk.
Figure 3
Figure 3
Forest plot with meta‐analysis of the risk of abnormal liver function. Risk ratios and 95% CIs for the risk of abnormal liver function with endothelin receptor antagonist treatment. The size of data markers indicates the weight of each trial.
Figure 4
Figure 4
Forest plot with meta‐analysis of the risk of peripheral edema. Risk ratios and 95% CIs for the risk of peripheral edema with endothelin receptor antagonist treatment. The size of data markers indicates the weight of each trial.
Figure 5
Figure 5
Forest plot with meta‐analysis for the risk of anemia. Risk ratios and 95% CIs for the risk of anemia with endothelin receptor antagonist treatment. The size of data markers indicates the weight of each trial.
Figure 6
Figure 6
Funnel plot to assess publication bias. Funnel plot of studies included in the meta‐analysis of the risk of (A) abnormal liver function, (B) peripheral edema, and (C) anemia. RR indicates risk ratio.
See this image and copyright information in PMC

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