Elsevier

The Lancet

Volume 387, Issue 10035, 4–10 June 2016, Pages 2302-2311
The Lancet

Articles
The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study

https://doi.org/10.1016/S0140-6736(16)00741-8Get rights and content

Summary

Background

The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation.

Methods

We developed and internally validated a new biomarker-based risk score for major bleeding in 14 537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with ClinicalTrials.gov, numbers NCT00412984 and NCT00262600, respectively.

Findings

The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0·68 [95% CI 0·66–0·70] vs 0·61 [0·59–0·63] vs 0·65 [0·62–0·67], respectively; ABC-bleeding vs HAS-BLED p<0·0001 and ABC-bleeding vs ORBIT p=0·0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0·71 [95% CI 0·68–0·73] vs 0·62 [0·59–0·64] for HAS-BLED vs 0·68 [0·65–0·70] for ORBIT; ABC-bleeding vs HAS-BLED p<0·0001 and ABC-bleeding vs ORBIT p=0·0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores.

Interpretation

The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The ABC-bleeding score performed better than HAS-BLED and ORBIT scores and should be useful as decision support on anticoagulation treatment in patients with atrial fibrillation.

Funding

BMS, Pfizer, Boehringer Ingelheim, Roche Diagnostics.

Introduction

Atrial fibrillation is an important risk factor for stroke and systemic embolism.1 Oral anticoagulants substantially reduce the risk of thromboembolic events although with an inherent increased bleeding risk.2 The benefit of oral anticoagulation in atrial fibrillation is therefore based on a balance between reduction in ischaemic stroke and increase in major bleeding events.3, 4 At present, there are several clinically based and one biomarker-based score for evaluation of the risk of stroke in patients with atrial fibrillation.3, 5 The risk of bleeding in patients on oral anticoagulation can currently be assessed by the HAS-BLED6 and ORBIT7 scores, which are based on clinical risk factors. In recent years, several biomarkers have been shown to provide incremental information about the risk of bleeding in patients with atrial fibrillation during anticoagulation: these factors include growth differentiating factor-15 (GDF-15), a marker of oxidative stress; cardiac troponin measured with high-sensitivity assays (cTn-hs), indicating myocardial injury; cystatin C or estimated glomerular filtration rate (eGFR), markers of renal function; and haemoglobin or haematocrit, markers of anaemia.7, 8, 9, 10, 11, 12, 13, 14 Also, biomarkers reflecting coagulation and inflammatory activity such as D-dimer, C-reactive protein (CRP), and interleukin 6 have shown associations with the risk of bleeding, but are less reliable as independent biomarkers of bleeding risk because of non-specificity and several reasons for large intraindividual variability.15, 16, 17

The biomarkers GDF-15, cTn-hs, cystatin C (or eGFR), haemoglobin, and haematocrit were therefore selected as candidate biomarkers for assessment in combination with clinical risk factors and the stroke risk biomarker NT-proBNP5, 18 to develop a new biomarker-based risk score for bleeding (the ABC-bleeding score). We aimed to derive and internally validate the novel score in one large cohort of patients with atrial fibrillation included in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and to externally validate the findings in another large cohort of similar patients from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.19, 20, 21, 22 The clinical use was compared with the HAS-BLED and the ORBIT bleeding risk scores.6, 7 The analyses were done in accordance with the TRIPOD statement.23

Research in context

Evidence before this study

Bleeding risk scores are important clinical instruments to balance the risk of bleeding events against the risk of stroke during anticoagulant treatment in atrial fibrillation. However, current guideline recommended bleeding scores only have a modest predictive ability. During the past years, several biomarkers reflecting cardiovascular and renal physiology, coagulation, and inflammatory activity have shown association with risk of major bleeding in patients with atrial fibrillation. A risk score for major bleeding in atrial fibrillation using both clinical risk factors and prognostic biomarkers could improve the risk assessment and clinical usefulness.

We have previously reviewed data for biomarkers and risk of cardiovascular events in patients with atrial fibrillation. We updated our review of this topic with added focus on risk of major bleeding. We searched PubMed without language or date restrictions for publications up to February, 2016, about bleeding risk in atrial fibrillation and biomarkers of renal and cardiovascular physiology as well as biomarkers of coagulation and inflammatory activity, included free-text search terms such as “atrial fibrillation”, “biomarkers”, “major bleeding”, “renal function”, “cystatin C”, “cardiac biomarkers”, “troponin”, “GDF-15, “, “coagulation”, “D-dimer”, “inflammation”, “CRP”, and “IL-6” in various combinations. No language or date restrictions were enabled. Several of these biomarkers were associated with major bleeding risk in patients with atrial fibrillation on oral anticoagulation. In particular, GDF-15, cardiac troponin, and markers of renal dysfunction showed robust associations with the outcome. However, development and validation of a risk score including the prognostically most important biomarkers and clinical characteristics for major bleeding risk in atrial fibrillation has not previously been done.

Added value of this study

In this study, a novel risk score for prediction of major bleeding events using age, history of bleeding, and the level of three biomarkers (GDF-15, cTn-hs, and haemoglobin) was developed and internally and externally validated and was calibrated in two large cohorts of patients with atrial fibrillation treated with oral anticoagulation. The ABC-bleeding score, containing the variables (age, biomarkers, clinical history [previous bleeding]), showed better discrimination and use than the HAS-BLED score. Although the study also provided external validation of the superiority of the recently presented ORBIT bleeding score in comparison to the HAS-BLED score in both these large cohorts, the ABC-bleeding score also did better than the ORBIT score. The ABC score should therefore be useful as decision support regarding indications for and selection of treatment with oral anticoagulation treatment in patients with atrial fibrillation.

Importantly, the biomarkers included in the score, cardiac troponin, GDF-15, or cystatin C, and haemoglobin or haematocrit, are already, or will be (GDF-15), generally available in many parts of the world, which enables a wide clinical use of the new score. Furthermore, and by contrast with previous scores, which use mainly irreversible risk factors, the proposed ABC-bleeding score contains continuous biomarker concentrations, which over time might increase or decrease reflecting changes in the patient's cardiovascular condition and therefore provides additional unique features for personalised risk assessment.

Implications of all the available evidence

This study brings new insights to clinical physicians by providing a fundamentally new and improved model to predict the risk of bleeding in atrial fibrillation and could accordingly provide improved decision support in these patient populations.

Section snippets

Study design and participants

The ARISTOTLE trial22 randomly assigned 18 201 patients with atrial fibrillation and an increased risk of stroke to warfarin or apixaban. Biomarker samples were available from 14 537 participants. The median length of follow-up was 1·7 years. The RE-LY trial20 randomly assigned 18 113 patients with atrial fibrillation to dabigatran or warfarin. The median length of follow-up was 1·9 years for the 8468 participants with biomarker samples available. Details on both cohorts are presented in the

Results

14 537 patients in the ARISTOTLE derivation cohort and 8468 from the RE-LY validation cohort had plasma samples for biomarker determinations available at baseline. Baseline demographics and median concentrations for the assessed biomarkers GDF-15, cystatin C, eGFR cTnT-hs, cTnI-hs, haemoglobin, haematocrit, and NT-proBNP are shown in table 1. The results showed few major differences in these variables between the derivation and validation cohort.

The new biomarker-based bleeding risk score was

Discussion

This study developed and validated, internally and externally, a new biomarker-based risk score for major bleeding in patients with atrial fibrillation treated with oral anticoagulation therapy. The new ABC-bleeding, based on the five variables; age, previous bleeding, haemoglobin, cTn-hs, and GDF-15, contained 91·3% of the prognostic information provided by all included clinical and biomarker variables. This score showed good discriminative ability in two large cohorts and in clinically

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