title: Combination therapy in the management of pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a progressive disease without a cure, which can lead to right heart failure and death. Over the past decades, several therapeutic advances have been developed for the management of PAH. Although these agents have demonstrated clinical safety and efficacy, some patients may require additional drug therapy due to a lack of response or disease progression.
  
  
  OBJECTIVE
  The purpose of this review was to evaluate the safety and efficacy of various combination PAH therapies.
  
  
  METHODS
  A systematic search was conducted using the MEDLINE database (1966 and June 2012) for relevant clinical studies. Searches were limited to English, human and clinical trial using the terms sildenafil, tadalafil, vardenafil, phosphodiesterase inhibitor, prostacyclin, prostaglandin, epoprostenol, treprostinil, iloprost, beraprost, endothelin receptor antagonist, bosentan, ambrisentan, sitaxsentan and pulmonary hypertension.
  
  
  RESULTS
  Overall, 22 studies met inclusion criteria. Overall, the majority of trials demonstrated clinical efficacy in improving functional class, reducing pulmonary pressure, or increasing exercise capacity. Most trials were uncontrolled with small sample sizes investigating the acute effects of combination therapy and lacking long-term clinical outcomes. Adjunctive therapy was well tolerated by most patients.
  
  
  CONCLUSIONS
  Overall, combination therapy is relatively safe and well tolerated. Published guidelines provide evidence-based recommendations for monotherapy. However, suggestions for combination therapy in refractory PAH patients are lacking. Several studies evaluating several combination therapies have been published. The preferred combination treatment among several PAH drug therapies remain controversial. Therefore, clinicians should consider ease of administration, cost, and tolerability when choosing specific combination therapies.
  
  
  CONCLUSIONS
  Combination therapy appears promising for patients who are refractory to treatment or whose disease progression is not well controlled with monotherapy. An optimal combination drug therapy regimen remains debatable and should be customized for individual PAH patients. Further studies are needed to determine the optimal combination therapy in PAH based upon efficacy, safety and cost.
authors.affiliation: Department of Pharmacy, Banner Good Samaritan Medical Center, Phoenix, AZ 85006, USA. mitchell.buckley@bannerhealth.com
authors.forename: M S
authors.initials: MS
authors.lastname: Buckley
authors.forename: R L
authors.initials: RL
authors.lastname: Staib
authors.forename: L M
authors.initials: LM
authors.lastname: Wicks
mesh_terms: D000959:Antihypertensive Agents / Q000145:classification / Q000494:pharmacology; D019468:Disease Management; D018450:Disease Progression; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination / Q000379:methods; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000959:Antihypertensive Agents