Ziad Hijazi1, Jonas Oldgren2, Ulrika Andersson3, Stuart J Connolly4, John W Eikelboom4, Michael D Ezekowitz5, Paul A Reilly6, Salim Yusuf4, Agneta Siegbahn7, Lars Wallentin2. 1. Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden; Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. Electronic address: ziad.hijazi@ucr.uu.se. 2. Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden; Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. 3. Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. 4. Population Health Research Institute, Hamilton, Canada. 5. Thomas Jefferson Medical College and the Heart Center, Wynnewood, PA. 6. Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT. 7. Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
Abstract
OBJECTIVE: To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial. METHODS:GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1, <1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3, >1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment. RESULTS:GDF-15concentrations were <1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and >1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P < .0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P < .0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores. CONCLUSIONS: In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.
RCT Entities:
OBJECTIVE: To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial. METHODS:GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1, <1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3, >1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment. RESULTS:GDF-15 concentrations were <1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and >1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P < .0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P < .0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores. CONCLUSIONS: In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.
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Authors: Ziad Hijazi; Paolo Verdecchia; Jonas Oldgren; Ulrika Andersson; Gianpaolo Reboldi; Giuseppe Di Pasquale; Giovanni Mazzotta; Fabio Angeli; John W Eikelboom; Michael D Ezekowitz; Stuart J Connolly; Salim Yusuf; Lars Wallentin Journal: J Am Heart Assoc Date: 2019-01-22 Impact factor: 5.501
Authors: Tymon Pol; Ziad Hijazi; Johan Lindbäck; John H Alexander; M Cecilia Bahit; Raffaele De Caterina; J W Eikelboom; Michael D Ezekowitz; Bernard J Gersh; Christopher B Granger; Elaine M Hylek; Renato Lopes; Agneta Siegbahn; Lars Wallentin Journal: Open Heart Date: 2021-03