title: Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials.
abstract: Evidence of the clinical safety of endothelin receptor antagonists (ERAs) is limited and derived mainly from individual trials; therefore, we conducted a meta-analysis.
  
  
  
  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.
  
  
  
  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).
authors.affiliation: Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Anhua
authors.initials: A
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhichun
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacy, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Geriatric ICU, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China pujun310@hotmail.com hanyi79@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Cardiology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China pujun310@hotmail.com hanyi79@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
mesh_terms: D000740:Anemia / Q000139:chemically induced; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004311:Double-Blind Method; D004487:Edema / Q000139:chemically induced; D065128:Endothelin Receptor Antagonists / Q000009:adverse effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D065128:Endothelin Receptor Antagonists
keywords: adverse drug event; endothelin; endothelin receptor antagonists; meta‐analysis