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

Benjamin D. Fox, Osnat Shtraichman, David Langleben, Avi Shimony, Mordechai R. Kramer

Research output: Contribution to journalReview articlepeer-review

47 Scopus citations


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; 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.

Original languageEnglish
Pages (from-to)1520-1530
Number of pages11
JournalCanadian Journal of Cardiology
Issue number12
StatePublished - 1 Dec 2016

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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