title: Dual therapy in IPAH and SSc-PAH. A qualitative systematic review.
abstract: BACKGROUND
  Use of endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogues has resulted in improved outcomes in idiopathic pulmonary arterial hypertension (IPAH) and systemic sclerosis-associated PAH (SSc-PAH) patients. However, patients often deteriorate on monotherapy. The objective of this study is to evaluate the effect of dual therapy on outcomes in IPAH and SSc-PAH.
  
  
  METHODS
  A systematic review of MEDLINE (1950-2011), EMBASE (1980-2011) and CINAHL (inception-2011) was conducted to identify studies that evaluated the effect of any dual combination of ERA, PDE-5 inhibitors or prostaglandin analogues on 6-min walk distance (6MWD), functional class (FC), haemodynamics, quality-of-life (QoL) or time-to-clinical-worsening in IPAH or SSc-PAH. A standardized form was used to abstract design, sample size, aetiology, outcome and treatment effect.
  
  
  RESULTS
  Twenty-six observational studies and 6 randomized trials were identified. Using combination PDE-5 inhibitor and prostaglandin analogues, 6/7 studies reported improvement in 6MWD, 6/8 studies reported improvement in FC, 6/6 studies reported improvement in haemodynamics and 1 trial demonstrated improvement in QoL and time-to-clinical-worsening. Using combination ERA and prostaglandin analogues, 4/6 studies and 1 trial reported improvement in 6MWD, 3/3 studies and 1 trial reported improvement in FC, 4/5 studies and 1 trial reported improvement in PAP. Using combination ERA and PDE-5 inhibitor, 4/7 studies reported an improvement in 6MWD, and 2/6 report improvement in FC.
  
  
  CONCLUSIONS
  The evidence suggests a beneficial effect of dual therapy in IPAH and SSc-PAH, particularly those who are deteriorating on monotherapy. Research should focus on subsets of patients to identify the optimal timing and combination of dual therapy.
authors.affiliation: University Health Network, Pulmonary Hypertension Programme, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. Sindhu.Johnson@uhn.on.ca
authors.forename: Sindhu R
authors.initials: SR
authors.lastname: Johnson
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Brode
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mielniczuk
authors.forename: John T
authors.initials: JT
authors.lastname: Granton
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use; D011465:Prostaglandins, Synthetic / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000150:complications*; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D058986:Phosphodiesterase 5 Inhibitors; D011465:Prostaglandins, Synthetic