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

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).