Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta#x2010;Analysis of 4894 Patients From 24 Randomized Double#x2010;Blind Placebo#x2010;Controlled Clinical Trials

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 randomor 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.