Long-term bleeding risk prediction in ‘real world’ patients with atrial fibrillation: Comparison of the HAS-BLED and ABC-Bleeding risk scoresThe Murcia Atrial Fibrillation Project
12 July 2017
Accepted after major revision: 24 July 2017
08 November 2017 (online)
Risk scores in patients with atrial fibrillation (AF) based on clinical factors alone generally have only modest predictive value for predicting high risk patients that sustain events. Biomarkers might be an attractive prognostic tool to improve bleeding risk prediction. The new ABCBleeding score performed better than HAS-BLED score in a clinical trial cohort but has not been externally validated. The aim of this study was to analyze the predictive performance of the ABC-Bleeding score compared to HAS-BLED score in an independent “real-world” anticoagulated AF patients with long-term follow-up. We enrolled 1,120 patients stable on vitamin K antagonist treatment. The HAS-BLED and ABC-Bleeding scores were quantified. Predictive values were compared by c-indexes, IDI, NRI, as well as decision curve analysis (DCA). Median HAS-BLED score was 2 (IQR 2–3) and median ABC-Bleeding was 16.5 (IQR 14.3–18.6). After 6.5 years of follow-up, 207 (2.84%/year) patients had major bleeding events, of which 65 (0.89%/year) had intracranial haemorrhage (ICH) and 85 (1.17%/year) had gastrointestinal bleeding events (GIB). The c-index of HAS-BLED was significantly higher than ABC-Bleeding for major bleeding (0.583 vs 0.518; p=0.025), GIB (0.596 vs 0.519; p=0.017) and for the composite of ICH-GIB (0.593 vs 0.527; p=0.030). NRI showed a significant negative reclassification for major bleeding and for the composite of ICH-GIB with the ABC-Bleeding score compared to HAS-BLED. Using DCAs, the use of HAS-BLED score gave an approximate net benefit of 4% over the ABC-Bleeding score. In conclusion, in the first “real-world” validation of the ABC-Bleeding score, HAS-BLED performed significantly better than the ABC-Bleeding score in predicting major bleeding, GIB and the composite of GIB and ICH.
Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief.
Supplementary Material to this article is available online at www.thrombosis-online.com.
* Joint senior authors.
- 1 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: 857-867.
- 2 Lip GYH, Lane DA, Buller H, Apostolakis S. Development of a novel composite stroke and bleeding risk score in patients with atrial fibrillation: the AMADEUS Study. Chest 2013; 144: 1839-1847.
- 3 Pisters R, Lane DA, Nieuwlaat R. et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138: 1093-1100.
- 4 Lip GYH. Assessing Bleeding Risk With the HAS-BLED Score: Balancing Simplicity, Practicality, and Predictive Value in Bleeding-Risk Assessment. Clin Cardiol 2015; 38: 562-564.
- 5 Lip GYH, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011; 57: 173-180.
- 6 Apostolakis S, Lane DA, Guo Y. et al. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol 2012; 60: 861-867.
- 7 Marín F, Roldán V. Biomarkers: GDF-15 and risk stratification in atrial fibrillation. Nat Rev Cardiol 2015; 12: 8-9.
- 8 Lip GYH, Lane D, Van Walraven C, Hart RG. Additive role of plasma von Willebrand factor levels to clinical factors for risk stratification of patients with atrial fibrillation. Stroke J Cereb Circ 2006; 37: 2294-2300.
- 9 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37: 2893-2962.
- 10 Wallentin L, Hijazi Z, Andersson U. et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 130: 1847-1858.
- 11 Hijazi Z, Lindbäck J, Alexander JH. et al. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation, Eur Heart J. 2016 Epub ahead of print.
- 12 Hijazi Z, Oldgren J, Andersson U. et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation 2012; 125: 1605-1616.
- 13 Granger CB, Alexander JH, McMurray JJV. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
- 14 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
- 15 Hijazi Z, Oldgren J, Lindbäck J. et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387: 2302-2311.
- 16 Lip GYH, Nieuwlaat R, Pisters R. et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010; 137: 263-272.
- 17 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 03: 692-694.
- 18 Levey AS, Stevens LA, Schmid CH. et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604-612.
- 19 DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44: 837-845.
- 20 Pencina MJ, D’Agostino RB, D’Agostino RB, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008; 27: 157-172. discussion 207-212
- 21 Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models. Med Decis Mak Int J Soc Med Decis Mak 2006; 26: 565-574.
- 22 Vickers AJ, Cronin AM, Elkin EB, Gonen M. Extensions to decision curve analysis, a novel method for evaluating diagnostic tests, prediction models and molecular markers. BMC Med Inform Decis Mak 2008; 08: 53.
- 23 Lip G, Freedman B, De Caterina R, Potpara TS. Stroke prevention in atrial fibrillation: Past, present and future Comparing the guidelines and practical decision-making. Thromb Haemost 2017; 117: 1230-1239.
- 24 Roldán V, Marín F, Fernández H. et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a “real-world” population with atrial fibrillation receiving anticoagulant therapy. Chest 2013; 143: 179-184.
- 25 Kooiman J, van Hagen N, Iglesias Del Sol A. et al. The HAS-BLED Score Identifies Patients with Acute Venous Thromboembolism at High Risk of Major Bleeding Complications during the First Six Months of Anticoagulant Treatment. PloS One 2015; 10: e0122520.
- 26 Omran H, Bauersachs R, Rübenacker S. et al. The HAS-BLED score predicts bleedings during bridging of chronic oral anticoagulation Results from the national multicentre BNK Online bRiDging REgistRy (BORDER). Thromb Haemost 2012; 108: 65-73.
- 27 Smith JG, Wieloch M, Koul S. et al. Triple antithrombotic therapy following an acute coronary syndrome: prevalence, outcomes and prognostic utility of the HAS-BLED score. EuroIntervention J Eur Collab Work Group Interv Cardiol Eur Soc Cardiol 2012; 08: 672-678.
- 28 Lip GYH, Lane DA. Assessing bleeding risk in atrial fibrillation with the HAS-BLED and ORBIT scores: clinical application requires focus on the reversible bleeding risk factors. Eur Heart J 2015; 36: 3265-3267.
- 29 Lip GYH, Lane DA. Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. J Thromb Haemost 2016; 14: 1711-1714.
- 30 Hijazi Z, Oldgren J, Andersson U. et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation 2012; 125: 1605-1616.
- 31 Hijazi Z, Aulin J, Andersson U. et al. Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation. Heart Br Card Soc 2016; 102: 508-517.
- 32 Hijazi Z, Oldgren J, Andersson U. et al. Importance of persistent elevation of cardiac biomarkers in atrial fibrillation: a RE-LY substudy. Heart Br Card Soc 2014; 100: 1193-1200.
- 33 Banerjee A, Fauchier L, Vourc’h P. et al. A prospective study of estimated glomerular filtration rate and outcomes in patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project. Chest 2014; 145: 1370-1382.
- 34 Olesen JB, Lip GYH, Kamper A-L. et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367: 625-635.
- 35 Westenbrink BD, Alings M, Granger CB. et al. Anemia is associated with bleeding and mortality, but not stroke, in patients with atrial fibrillation: Insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am Heart J 2017; 185: 140-149.
- 36 Wallentin L, Hijazi Z, Andersson U. et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 130: 1847-1858.
- 37 Hijazi Z, Oldgren J, Andersson U. et al. 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. Am Heart J 2017; 190: 94-103.
- 38 Griffiths HR, Lip GYH. New biomarkers and risk stratification in atrial fibrillation: simplicity and practicality matter. Circulation 2014; 130: 1837-1839.
- 39 Montoro-García S, Hernández-Romero D, Jover E. et al. Growth differentiation factor-15, a novel biomarker related with disease severity in patients with hypertrophic cardiomyopathy. Eur J Intern Med 2012; 23: 169-174.
- 40 Ban N, Siegfried CJ, Lin JB. et al. GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients. JCI Insight. 2017 Epub ahead of print.
- 41 Freedman B, Lip GYH. “Unreal world” or “real world” data in oral anticoagulant treatment of atrial fibrillation. Thromb Haemost 2016; 116: 587-589.
- 42 Carmo J, Moscoso Costa F, Ferreira J, Mendes M. Dabigatran in real-world atrial fibrillation Meta-analysis of observational comparison studies with vitamin K antagonists. Thromb Haemost 2016; 116: 754-763.
- 43 Martinez C, Katholing A, Wallenhorst C, Freedman SB. Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC A cohort study. Thromb Haemost 2016; 115: 31-39.
- 44 Wilson MR, Parakramawansha R, Quinn TJ, Tait RC. Quality and predictors of anticoagulant control with vitamin K antagonist for stroke prevention in atrial fibrillation. Thromb Haemost 2016; 116: 578-580.
- 45 Beyer-Westendorf J, Camm AJ, Coleman CI, Tamayo S. Rivaroxaban real-world evidence: Validating safety and effectiveness in clinical practice. Thromb Haemost 2016; 116 (Suppl. 02) S13-S23.
- 46 Roldán V, Marín F, Muiña B. et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57: 2496-2504.
- 47 García-Fernández A, Roldán V, Rivera-Caravaca JM. et al. Does von Willebrand factor improve the predictive ability of current risk stratification scores in patients with atrial fibrillation?. Sci Rep 2017; 07: 41565.
- 48 Beinema M, Brouwers JRBJ, Schalekamp T, Wilffert B. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 2008; 100: 1052-1057.
- 49 Lip GYH. Stroke prevention in Atrial Fibrillation. Eur Heart J 2017; 38: 4-5.