Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas

Abstract

Objectives: Growth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions.

Methods: Data were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region.

Results: GDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (p<0.0001). Similarly, GDF-15 and the ABC-AF-death score were associated with all-cause mortality in both trials across regions (p<0.0001). Overall, the association between GDF-15, the ABC-AF-bleeding score and ABC-AF-death risk score with major bleeding and death was consistent across regions in both ARISTOTLE and the RE-LY trial cohorts. The ABC-AF-bleeding and ABC-AF-death risk scores were consistent regarding discriminative ability when comparing geographic regions in both trial cohorts. The C-indices ranged from 0.649 to 0.760 for the ABC-AF-bleeding and from 0.677 to 0.806 for the ABC-AF-death score by different geographic regions.

Conclusions: In patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions.

Trial registration number: ClinicalTrials.gov Registry NCT00412984 and NCT00262600.

Keywords: atrial fibrillation; biomarkers; global health.

Conflict of interest statement

Competing interests: TP reports institutional research grants from Bristol-Myers Squibb/Pfizer. ZH reports lecture and consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer and Roche Diagnostics; consulting fees from Bristol-Myers Squibb, Meda, Merck Sharp & Dohme, Pfizer and Roche Diagnostics and research grants from the Swedish Society for Medical Research (S17-0133) and the Swedish Heart-Lung Foundation (20170718). JL reports institutional research grants from Boehringer Ingelheim and Bristol-Myers Squibb/Pfizer. JHA reports institutional research grants and consulting fees/honoraria from Bayer, Bristol-Myers Squibb, CryoLife and XaTek and consulting fees/honoraria from Pfizer and Portola. MCB reports consulting fee/honoraria from Pfizer, MSD and CSL Behring. RDC reports fees, honoraria and research funding from Sanofi-Aventis, Amgen, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Novartis, Portola and Roche. JWE reports institutional research grants and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Janssen Pharmaceuticals, AstraZeneca, Eli Lilly, GlaxoSmithKline and Sanofi Aventis. MDE reports research grants and consulting fees from Pfizer, Bristol-Myers Squibb and Boehringer Ingelheim, consulting fees from Anthos Therapeutic, Alta Therapeutics and Boston Scientific. BJG has received other research support (DSMB) from Boston Scientific, Cardiovascular Research Foundation, Duke Clinical Research Institute, Duke University, Icahn School of Medicine at Mount Sinai, Janssen Research & Development, Kowa Research Institute, Medtronic, Mount Sinai St. Luke’s, Teva Pharmaceutical Industries and MyoKardia and consulting fees from Coretherapix SLU, Janssen Scientific Affairs and Sirtex Medical. CBG reports research grants and consulting/speaker fees from Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals and Pfizer; research grants from AstraZeneca, Daichii Sankyo, AKROS, Apple, GlaxoSmithKline, Medtronic Foundation, Novartis Pharmaceutical Company and US Food & Drug Administration and consulting/speaker fees from Bayer Corporation, USA, Boston Scientific Corporation, Abbvie, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic, Merck, National Institutes of Health, NovoNordisk, Roche Diagnostics and Rhoshan Pharmaceuticals. EMH reports research grant from Janssen; consulting/advisory board fees and honoraria from Boehringer Ingelheim; consulting/advisory board fees from Medtronic and Roche and honoraria from Bristol-Myers Squibb/Pfizer. RL reports institutional research grants and consulting fees from Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Medtronic PLC and Sanofi and consulting fees from Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck and Portola. AS reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics and consultancy fees from Olink Proteomics. LW reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics and Merck & Co; consulting fees from Abbott and holds two patents involving growth differentiation factor 15 licensed to Roche Diagnostics (EP2047275B1 and US8951742B2).

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Relative hazard of major bleeding (top panels) and death (bottom panels) in relation to levels of GDF-15 among patients from different regions in the ARISTOTLE (left panels) and RE-LY (right panels) trials. An arbitrary reference point is set at a GDF-15 value of 1500 ng/L in Europe. The p value in each panel is for a test of no interaction between region and GDF-15. ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; GDF-15, growth differentiation factor 15; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy.

Figure 2

Relative hazard of major bleeding (top panels) and death (bottom panels) in relation to predicted ABC-AF-bleeding (top) and ABC-AF-death (bottom) 1-year risks among patients from different regions in the ARISTOTLE (left panels) and RE-LY (right panels) trials. An arbitrary reference point is set at a predicted ABC-AF-risk value of 0.02 in Europe. The p value in each panel is for a test of no interaction between region and predicted ABC-AF-risk. ABC-AF bleeding score is age, biomarkers (troponin-hs, haemoglobin, and GDF-15 or renal function), clinical history (previous bleeding). ARISTOTLE, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; RE-LY, Randomized Evaluation of Long-Term Anticoagulation Therapy.