Prognostic value of improvement endpoints in pulmonary arterial hypertension trials: A COMPERA analysis
Marius M Hoeper, Christine Pausch, Karen M Olsson, Doerte Huscher, David Pittrow, Ekkehard Grünig, Gerd Staehler, Carmine Dario Vizza, Henning Gall, Oliver Distler, Christian Opitz, J Simon R Gibbs, Marion Delcroix, H Ardeschir Ghofrani, Ralf Ewert, Harald Kaemmerer, Hans-Joachim Kabitz, Dirk Skowasch, Juergen Behr, Katrin Milger, Michael Halank, Heinrike Wilkens, Hans-Jürgen Seyfarth, Matthias Held, Daniel Dumitrescu, Iraklis Tsangaris, Anton Vonk-Noordegraaf, Silvia Ulrich, Hans Klose, Martin Claussen, Stephan Eisenmann, Kai-Helge Schmidt, Stephan Rosenkranz, Tobias J Lange, Marius M Hoeper, Christine Pausch, Karen M Olsson, Doerte Huscher, David Pittrow, Ekkehard Grünig, Gerd Staehler, Carmine Dario Vizza, Henning Gall, Oliver Distler, Christian Opitz, J Simon R Gibbs, Marion Delcroix, H Ardeschir Ghofrani, Ralf Ewert, Harald Kaemmerer, Hans-Joachim Kabitz, Dirk Skowasch, Juergen Behr, Katrin Milger, Michael Halank, Heinrike Wilkens, Hans-Jürgen Seyfarth, Matthias Held, Daniel Dumitrescu, Iraklis Tsangaris, Anton Vonk-Noordegraaf, Silvia Ulrich, Hans Klose, Martin Claussen, Stephan Eisenmann, Kai-Helge Schmidt, Stephan Rosenkranz, Tobias J Lange
Abstract
Background: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated.
Methods: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses.
Results: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools.
Conclusion: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials.
Keywords: clinical trials; endpoints; mortality; pulmonary arterial hypertension; risk; treatment.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed