Association of oral endothelin receptor antagonists with risks of cardiovascular events and mortality: meta-analysis of randomized controlled trials

Background: Endothelin receptor antagonists (ERAs) are widely used in a variety of disorders, including pulmonary artery hypertension, systemic sclerosis, diabetic and kidney diseases, and several tumors. However, reported adverse events, especially increased risks of cardiovascular disease (CVD) morbidity and mortality, have cast doubt on their potential clinical application. Therefore, we conducted this meta-analysis to confirm whether ERAs increased CVD risk and mortality.

Methods: We systematically searched PubMed (1966-2015), EMBASE (1974-2015), ClinicalTrials.gov, and the Cochrane Controlled Clinical Trials Register Database for randomized controlled trials published between Jan 1, 1990 and Mar 18, 2015. Inclusion criteria included a study duration of more than 3 weeks, the use of a randomized control group receiving an oral ERA or placebo, and the availability of outcome data for cardiovascular events and all-cause death.

Results: A total of 33 trials met the inclusion criteria. There were 8098 cases in the ERA group and 5074 cases in the placebo group. Compared with the control group, the risk ratio (RR) for all-cause death in the ERA group was 0.983 [95% confidence interval (CI), 0.883 to 1.094, P = 0.754]. The summary RR for cardiovascular events was 1.651 in the ERA group (95% CI, 1.164 to 2.34, P = 0.005). The pooled results showed that ERAs treatment could lead to more edema, anemia, and abnormal transaminase levels. Also, there was an increased proportion of discontinued therapy in the ERA treatment because of side effects (RR = 1.322, 95% CI, 1.036 to 1.686, P = 0.025). There were no significant differences in the experienced episodes of headache and dyspnea between the active therapy and control groups.

Conclusions: ERAs therapy is not significantly associated with increased all-cause death, but there are more cardiovascular events and edema or fluid retention, anemia, and liver enzymes disorder. Large clinical randomized controlled studies are needed to further confirm the safety of the clinical application of ERAs.