title: Are hemodynamics surrogate end points in pulmonary arterial hypertension?
abstract: BACKGROUND
  Although frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate end point for clinical events in pulmonary arterial hypertension (PAH).
  
  
  RESULTS
  We performed a patient-level pooled analysis of 4 randomized, placebo-controlled trials to determine whether treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, or escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 years (37-59 years), and 23% were men. A total of 656 patients (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure, mean pulmonary artery pressure, and pulmonary vascular resistance and increased cardiac output and index (P<0.01 for all). Changes in hemodynamic values (except for right atrial pressure and mean pulmonary artery pressure) were significantly associated with the risk of a clinical event (P<0.02 for all). Although active treatment approximately halved the odds of a clinical event compared with placebo (P<0.001), changes in hemodynamics accounted for only 1.2% to 13.9% of the overall treatment effect.
  
  
  CONCLUSIONS
  Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate end points for short-term events in PAH clinical trials.
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Corey E
authors.initials: CE
authors.lastname: Ventetuolo
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Gabler
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Fritz
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: K Akaya
authors.initials: KA
authors.lastname: Smith
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Harold I
authors.initials: HI
authors.lastname: Palevsky
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Halpern
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep, Department of Medicine (C.E.V., J.R.K.) and Department of Health Services, Policy, and Practice (C.E.V.), Alpert Medical School of Brown University, Providence, RI; Center for Clinical Epidemiology and Biostatistics (N.B.G., S.D.H., S.M.K.), Department of Medicine (J.S.F., K.A.S., H.I.P., S.D.H., S.M.K.), Penn Cardiovascular Institute (S.D.H., S.M.K.), and Leonard Davis Institute of Health Economics (S.D.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. kawut@upenn.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kawut
mesh_terms: D000328:Adult; D015415:Biomarkers; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic
chemical_list: D015415:Biomarkers
keywords: hemodynamics; hypertension, pulmonary; pulmonary heart disease; trials