Clinical InvestigationGrowth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial
Section snippets
Study population and trial design
The study organization, trial design, patient characteristics, and outcomes of the RE-LY study have been published previously.11., 12. Patients were recruited from 967 centers in 44 countries between November 2005 and December 2007. A total of 18,113 patients with AF who had at least 1 additional risk factor for stroke were randomized in a 1:1:1 fashion to receive fixed doses of dabigatran—110 or 150 mg twice daily—or adjusted-dose warfarin (target international normalized ratio 2.0-3.0).12 The
Baseline characteristics and distribution levels of GDF-15
The median age in this cohort was 72.0 years and 5,372 (63.4%) were men. The GDF-15 distribution was according to the following: mean 1,893 and median 1,514 (25th percentile 1,108, 75th percentile 2,190) ng/L in the total population without any differences between the randomized treatment groups. GDF-15 levels were <1,200 ng/L, the 90th percentile of healthy subjects of similar age in 2,647 (31.2%). A total of 2,704 (31.9%) had GDF-15 concentrations between 1,200 and 1,800 ng/L, and 3,123 (36.9%)
Discussion
The present biomarker substudy in anticoagulated patients with AF from the RE-LY trial showed that the GDF-15 level was independently and consistently associated with risk of major bleeding and all-cause mortality, but not with stroke or systemic embolic events. Thus, although GDF-15 was correlated with clinical risk factors, comorbidities, and several other biomarkers, GDF-15 level still provided incremental information on the risk of major bleeding and total mortality. In a direct comparison,
Conclusions
In patients with AF, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but without any significant independent association with the risk of stroke. Therefore, GDF-15 seems to be useful in specifically assessing bleeding risk in patients with AF on oral anticoagulant treatment. The benefits of dabigatran as compared with warfarin were more pronounced in patients with low GDF-15 concentrations.
Disclosure statements
Dr Hijazi: lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb (BMS), and Pfizer; consulting fees from Merck Sharp & Dohme, Bristol-Myers Squibb, and Pfizer. GDF-15 assays supported by Roche
Dr Oldgren: consulting and lecture fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, and Pfizer
Mrs Andersson: institutional research grants from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer.
Dr Connolly: consulting fees, speaker fees, and research grants from Boehringer Ingelheim,
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Multiplex protein screening of biomarkers associated with major bleeding in patients with atrial fibrillation treated with oral anticoagulation
2021, Journal of Thrombosis and HaemostasisWhat is the role of growth-differentiation factor-15 in biomarker-based prediction of mortality in patients with atrial fibrillation?
2021, European Journal of Internal MedicineGrowth differentiation factor-15 predicts major adverse cardiac events and all-cause mortality in patients with atrial fibrillation
2021, European Journal of Internal MedicineCitation Excerpt :The good predictive accuracy of GDF-15 in cardiovascular diseases (e.g. chronic coronary artery disease, acute coronary syndrome, and heart failure) as well as for cardiovascular events (e.g. myocardial infarction, stroke, hospitalization for heart failure, and cardiac death) was reported previously. [23-31] In patients with AF included in two clinical trials, the association of GDF-15 with increased risk of stroke and myocardial infarction did not prevail after adjustment for baseline characteristics and other biomarkers (cystatin-C, Troponin I, and NT-proBNP). [12,32] Major bleeding, on the other hand, was independently associated with higher GDF-15 levels in these two studies and also in another study of patients with acute coronary syndrome [33].
Circulating Levels of Biomarkers of Cerebral Injury in Patients with Atrial Fibrillation
2019, American Journal of CardiologyCitation Excerpt :An elevated level of circulating S100B is also a marker for neurological stress or BBB disruption; however, there are reports that S100B might be lacking in specificity and sensitivity due to its extracerebral presence.17 GDF15 is a member of the TGF-β superfamily, and is a proven marker of oxidative stress and inflammation, and is a risk predictive marker for bleeding and all-cause mortality in AF patients.18 GDF15 is expressed in various tissues, is elevated in response to brain injury, and also is associated with both cognitive decline and Alzheimer's dementia (AD) when significant white matter hyperintensities are detected.19,20
Clinical Trial Registration: www.clinicaltrials.gov, NCT00262600.