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Are hemodynamics surrogate end points in pulmonary arterial hypertension?

ABSTRACT: 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).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.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.

SUBMITTER: Ventetuolo CE

PROVIDER: S-EPMC4146736 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Are hemodynamics surrogate end points in pulmonary arterial hypertension?

Ventetuolo Corey E CE Gabler Nicole B NB Fritz Jason S JS Smith K Akaya KA Palevsky Harold I HI Klinger James R JR Halpern Scott D SD Kawut Steven M SM

Circulation 20140620 9

<h4>Background</h4>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).<h4>Methods and results</h4>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 ...[more]

PMID: 24951771

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Project description:BackgroundAlthough many predictors have been evaluated, a set of strong independent prognostic mortality indicators has not been established in children with pediatric pulmonary arterial hypertension (PAH). The aim of this study was to identify a combination of clinical and molecular predictors of survival in PAH.MethodsThis single-center, retrospective cohort study was performed from children with PAH between 2001 and 2008 at Children's Hospital Colorado. Blood samples from 83 patients (median age of 8.3 years-old) were obtained. We retrospectively analyzed 46 variables, which included 27 circulating proteins, 7 demographic variables and 12 hemodynamic and echocardiographic variables for establishing the best predictors of mortality. A data mining approach was utilized to evaluate predictor variables and to uncover complex data structures while performing variable selection in high dimensional problems.ResultsThirteen children (16%) died during follow-up (median; 3.1 years) and survival rates from time of sample collection at 1 year, 3 years and 5 years were 95%, 85% and 79%, respectively. A subset of potentially informative predictors were identified, the top four are listed here in order of importance: Tissue inhibitors of metalloproteinases-1 (TIMP-1), apolipoprotein-AI, RV/LV diastolic dimension ratio and age at diagnosis. In univariate analysis, TIMP-1 and apolipoprotein-AI had significant association with survival time (hazard ratio [95% confidence interval]: 1.25 [1.03, 1.51] and 0.70 [0.54-0.90], respectively). Patients grouped by TIMP-1 and apolipoprotein-AI values had significantly different survival risks (p<0.01).ConclusionImportant predictors of mortality were identified from a large number of circulating proteins and clinical markers in this cohort. If confirmed in other populations, measurement of a subset of these predictors could aid in management of pediatric PAH by identifying patients at risk for death. These findings also further support a role for the clinical utility of measuring circulating proteins.

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Are hemodynamics surrogate end points in pulmonary arterial hypertension?

Publications

Are hemodynamics surrogate end points in pulmonary arterial hypertension?

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