title: Use of outcome measures in pulmonary hypertension clinical trials.
abstract: OBJECTIVE
  To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice.
  
  
  BACKGROUND
  Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined.
  
  
  METHODS
  We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014.
  
  
  RESULTS
  Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients).
  
  
  CONCLUSIONS
  The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures.
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Kishan S
authors.initials: KS
authors.lastname: Parikh
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC; Center for Pulmonary Vascular Diseases, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Rajagopal
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Kristine
authors.initials: K
authors.lastname: Arges
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sivak
authors.affiliation: Division of Cardiology, University of North Carolina, Chapel Hill, NC.
authors.forename: Prashant
authors.initials: P
authors.lastname: Kaul
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC.
authors.forename: Svati H
authors.initials: SH
authors.lastname: Shah
authors.affiliation: Center for Pulmonary Vascular Diseases and Venous Thromboembolism, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Victor
authors.initials: V
authors.lastname: Tapson
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Clinical Research Institute, Durham, NC.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Velazquez
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC; Duke Clinical Research Institute, Durham, NC.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Douglas
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC. Electronic address: zainab.samad@gmail.com.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Samad
mesh_terms: D002986:Clinical Trials as Topic; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D017063:Outcome Assessment, Health Care