Elsevier

American Heart Journal

Volume 190, August 2017, Pages 94-103
American Heart Journal

Clinical Investigation
Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial

https://doi.org/10.1016/j.ahj.2017.06.001Get rights and content

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.

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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