title: Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL Registry analysis.
abstract: BACKGROUND
  Time to clinical worsening has been proposed as a primary end point in clinical trials of pulmonary arterial hypertension (PAH); however, neither standardized nor validated definitions of clinical worsening across PAH trials exist. This study aims to evaluate a proposed definition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy).
  
  
  METHODS
  We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults with hemodynamically defined PAH (N = 3,001). Freedom from clinical worsening was defined as freedom from worsening functional class (FC), a ≥ 15% reduction in 6-min walk distance (6MWD), all-cause hospitalization, or the introduction of parenteral prostacyclin analog therapy.
  
  
  RESULTS
  In the 2 years of follow-up, 583 patients died. Four hundred twenty-six died after a documented clinical worsening event, including FC worsening (n = 128), a ≥ 15% reduction in 6MWD (n = 118), all-cause hospitalization (n = 370), or introduction of a prostacyclin analog (n = 91). Patients who experienced clinical worsening had significantly poorer subsequent 1-year survival postworsening than patients who did not worsen (P &lt; .001).
  
  
  CONCLUSIONS
  Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary end point in clinical trial design.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.
authors.affiliation: Baylor College of Medicine, Houston, TX. Electronic address: frost@bcm.tmc.edu.
authors.forename: Adaani E
authors.initials: AE
authors.lastname: Frost
authors.affiliation: University of Colorado Health Sciences Center, Denver, CO.
authors.forename: David B
authors.initials: DB
authors.lastname: Badesch
authors.affiliation: ICON Late Phase & Outcomes Research, San Francisco, CA.
authors.forename: Dave P
authors.initials: DP
authors.lastname: Miller
authors.affiliation: Allegheny General Hospital, Pittsburgh, PA.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.affiliation: Actelion Pharmaceuticals US, Inc, South San Francisco, CA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Meltzer
authors.affiliation: Mayo Clinic, Rochester, MN.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McGoon
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use; D019468:Disease Management; D018450:Disease Progression; D011464:Epoprostenol / Q000627:therapeutic use*; D005080:Exercise Test; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012042:Registries; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D014481:United States / Q000453:epidemiology
chemical_list: D000959:Antihypertensive Agents; D011464:Epoprostenol