Combination Therapy for Pulmonary Arterial Hypertension: A Systematic Review and Meta-analysis

Background: Combination therapy (CT) for patients with pulmonary arterial hypertension (PAH) has been recommended for many years, despite weak evidence of efficacy over monotherapy (MT). A previous meta-analysis comparing CT vs MT with pulmonary vasodilators failed to demonstrate a clear reduction in clinical worsening events. Methods: We searched for relevant articles in PubMed, EMBASE, the Cochrane Database, and clinicaltrials.gov; we also manually searched review articles and conference abstracts from 1980-December 2015. Target articles were double-blinded studies of 2 or more pulmonary vasodilators given in combination vs monotherapy for treatment of patients with PAH. The principal outcome of interest was "combined clinical worsening" (CCW) events (including but not limited to death or hospitalization). Data on physiological outcomes were also explored. Meta-analysis was performed using the DerSimonian and Laird random-effects model. Results: We extracted data from 18 randomized controlled trials (RCTs) (N = 4162). CT was associated with a significant 38% reduction of risk of CCW (15 RCTs: n = 3906; risk ratio [RR], 0.62; 95% confidence interval [CI], 0.50-0.77). This reduction in risk was driven by a reduction in nonfatal end points (12 RCTs: n = 2611; RR, 0.56; 95% CI, 0.40-0.78) and not by a reduction of mortality (12 RCTs: n = 2717; RR, 0.79; 95% CI, 0.53-1.17). CT was also associated with improvement in 6-minute walking distance (10 RCTs: n = 1553; weighted mean difference [WMD], +23.0 m; 95% CI, 15.9-30.1), improved functional class (9 RCTs: n = 1737; RR, 1.26; 95% CI, 1.05-1.51), and beneficial effects on pulmonary hemodynamics such as cardiac index (WMD, +0.35 L/min/m; 95% CI, 0.14-0.56). Conclusions: In this highly comprehensive meta-analysis, CT reduces the risk of CCW events in patients with PAH and brings physiological improvement.