Targeted Drug Therapies For Pulmonary Arterial Hypertension: A Systematic Review And Meta-analysis

Objective: Endothelin receptor antagonists(ERA), phosphodiesterase type 5 inhibitors(PDE-5), prostacyclin analogs(Prostanoids), Nonprostanoid IP Receptor Agonists, Tyrosine Kinase Inhibition(TKI) and soluble guanylate cyclase stimulators(sGC) were main targeted drug therapies for pulmonary arterial hypertension(PAH). However, the efficacy of treatment is still unclear. We aimed to integrate the available evidence to evaluate the efficacy and tolerability of targeted drug therapies for PAH using meta-analysis.Methods and Results: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials,Chinese Biomedical Literature(CBM), Wanfang Data and Chinese National Knowledge Infrastructure(CNKI) databases to identify relevant randomized controlled trials(RCTs) from inception to January, 2016. RCTs of targeted drug therapies for patients with PAH were eligible. The studies were screened according to the inclusion and exclusion criteria, the data were extracted and the quality of the method of the included studies was assessed. Then, the meta-analysis was performed using the Revman 5.3 software. The primary outcome was mortality, tolerability exercise capacity and clinical worsening. Thirty-one studies, including 6321 participants were finally included. The results of the meta-analysis revealed that, compared with placebo, targeted drug therapies lowers the incidence of mortality(odds ratio(OR) 0.57, 95% confidence interval(CI) 0.42 to 0.77, P=0.0003), prolong patients’ of PAH 6-min walk distance(6WMD) 33.7 meters(95%CI 28.82 to 38.59 meters, P<0.00001), reduce patients’ clinical worsening(OR 0.46, 95%CI 0.30 to 0.71, P<0.00001), mean pulmonary arterial pressure(mean difference(MD)-4.18,95%CI-5.40 to-2.96, P<0.00001), pulmonary vascular resistance(MD-0.71, 95%CI-0.88 to-0.54, P<0.00001) and brog dyspnea score(OR 0.46, 95%CI 0.30 to 0.71, P<0.00001). Further, our analysis found targeted drug therapies had a statistically significantly better tolerability than placebo(OR 0.72, 95%CI 0.60 to 0.85, P=0.003). For subgroup analysis, we found each of targeted drug therapy could increase patients’ 6WMD and decrease patient’s brog dyspnea score, mean pulmonary arterial pressure and pulmonary vascular resistance. Except Nonprostanoid IP Receptor Agonists(OR 0.95, 95%CI 0.55 to 1.63, P=0.85) and TKI(OR 1.16, 95%CI 0.65 to 2.07, P=0.63), each of targeted drug therapy could reduce patients’ clinical worsening. However, only prostanoids(OR 0.52, 95%CI 0.31 to 0.87, P=0.01) could reduce mortality and only ERA(OR 0.68, 95%CI 0.47 to 0.98, P=0.04) had a significant tolerability than placebo among all kinds of targeted drug therapies.Conclusion: The available evidence suggested that targeted drug therapy can significantly improve excise capacity, respiratory function, pulmonary hemodynamics and lowered mortality in patients with PAH.