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). © 2016 the authors.