Effect of Combination Therapy of Endothelin Receptor Antagonist and Phosphodiesterase-5 Inhibitor on Clinical Outcome and Pulmonary Haemodynamics in Patients with Pulmonary Arterial Hypertension: A Meta-Analysis

Background The combination of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor having different biological targets has become an integral part of the treatment of pulmonary arterial hypertension; however, several clinical studies have reported conflicting results. Objective The objective of this meta-analysis was to evaluate the effect of an endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination in pulmonary arterial hypertension. Methods After performing a comprehensive literature search in MEDLINE, Cochrane and the International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from seven relevant articles (publications till December 2018). PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed in the selection, analysis and reporting of findings. The odds ratio and mean difference were calculated to estimate the difference in clinical worsening, 6-minute walking distance, pulmonary vascular resistance and N-terminal pro-brain natriuretic peptide between the groups. Quality assessment was performed using the risk of bias assessment tool and a meta-regression for probable variables affecting effect size. Results The random-effect model analysis revealed an odds ratio of 0.56 [95% confidence interval (CI) 0.41-0.76; p = 0.0002] for clinical worsening, mean difference of 15.64 (95% CI 2.67-28.61; p = 0.02) for 6-minute walking distance, - 1.66 (95% CI - 3.82 to 0.50; p = 0.13) for pulmonary vascular resistance and - 21.04 (95% CI - 26.87 to - 15.22; p < 0.00001) for N-terminal pro-brain natriuretic peptide. The meta-regression showed no statistically significant association between the dose and duration of treatment and outcomes (odds ratio of clinical worsening and mean difference of 6-minute walking distance). Conclusions In pulmonary arterial hypertension, endothelin receptor antagonist and phosphodiesterase-5 inhibitor combination therapy significantly improved 6-minute walking distance, clinical worsening and N-terminal pro-brain natriuretic peptide compared with the monotherapy but did not offer any advantage in improving pulmonary vascular resistance. PROSPERO Registration No CRD42018091133.