Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis

J Cardiovasc Pharmacol. 2012 Oct;60(4):342-6. doi: 10.1097/FJC.0b013e318262a793.


Background: Clinical studies on combination therapy in patients with pulmonary arterial hypertension (PAH) revealed mixed results.

Aims: The aim of the present meta-analysis was to evaluate the effect of combination therapy on exercise capacity [measured with 6-minute walk distance (6MWD)] and clinical worsening in PAH patients.

Methods: We identified trials of importance from the Cochrane Library, EMBASE, and PUBMED databases, reviews, and reference lists of relevant articles. We calculated risk ratios for dichotomous data and weighted mean differences, with 95% confidence intervals (CIs), for net changes in 6MWD.

Results: Seven trials with a total of 768 patients (386 patients in the combination treatment group and 382 patients in the monotherapy group) were included in the meta-analysis. Compared with the monotherapy group, combination therapy increased 6MWD by 21.59 meters (weighted mean difference 21.59 m, 95% CI of 13.25-29.93; P < 0.001) and reduced the risk of clinical worsening (risk ratio: 0.43, 95% CI: 0.26-0.72, P = 0.001). For both outcomes, no significant heterogeneity and publication bias were found.

Conclusion: Compared with monotherapy, combination therapy improves exercise capacity and reduces the risk of clinical worsening in PAH patients. In future studies, more large randomized controlled trials should be designed to adequately assess the efficacy and safety of combination therapy.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use*
  • Drug Therapy, Combination
  • Endothelin Receptor Antagonists
  • Exercise Tolerance / drug effects*
  • Familial Primary Pulmonary Hypertension
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / physiopathology
  • Phosphodiesterase 5 Inhibitors / administration & dosage
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • Prostaglandins / administration & dosage
  • Prostaglandins / pharmacology
  • Prostaglandins / therapeutic use


  • Antihypertensive Agents
  • Endothelin Receptor Antagonists
  • Phosphodiesterase 5 Inhibitors
  • Prostaglandins