Identifying patients with atrial fibrillation and "truly low" thromboembolic risk who are poorly characterized by CHA2DS2-VASc: Superior performance of a novel machine-learning tool in GARFIELD-AF Keith A.A. Fox, Joseph E. Lucas, Karen S. Pieper, Jean-Pierre Bassand, A. John Camm, David A. Fitzmaurice, Werner Hacke, Gloria Kayani, Ali Oto, Ajay K. Kakkar for the GARFIELD-AF Investigators

Background and Context The role of anticoagulation for patients with AF and ≥ 1 risk factor for stroke/systemic embolism is defined by trial evidence and guidelines Between 2010-2011 and 2014-2015, anticoagulation usage rose from 57% to 71% of patients with AF However, the balance of risk and benefit is poorly defined for “low risk’ AF Camm AJ et al. Heart 2016 (in press)

How are low and high risk AF patients managed in practice? Contrary to international guideline recommendations, 28% high-risk patients (CHA2DS2-VASc ≥2) are not anticoagulated 51% of very low-risk patients (CHA2DS2-VASc 0) are anticoagulated CHA2DS2-VASc 1 ≥2 Factors beyond those in current risk scores appear to influence prescribing decisions on anticoagulation, including risk of bleed Camm AJ et al. Heart 2016 (in press)

Purpose: To provide accurate estimates of risk as the basis of decisions on prescribing or withholding anticoagulation Aim: To derive and validate a more accurate and user-friendly method of stratifying patients according to risks of death, stroke and bleeding

Statistical Methods: The GARFIELD Score A “machine learning” approach to risk modelling Coalescent regression avoids the need to specify levels of relatedness in the statistical model, it allows joint modeling of all outcomes. Models were based on 38984 patients in GARFIELD 2010 to 2015 for: all-cause mortality, ischaemic stroke/thromboembolism, and haemorrhagic stroke/major bleed that occurred within 1-year of enrolment into GARFIELD­AF. Also, a simplified model was also derived to facilitate web applications The performance of both models were compared with CHA2DS2-VASc in all patients and those with a low risk of stroke External validation was undertaken using an independent contemporary registry ORBIT-AF Note on a coalescent regression approach : This approach avoids the need to specify levels of relatedness in the statistical model and allows the modelling of related events, for example major bleeding and death, to each influence the model

Number of events in low- and higher-risk patients at 1 year Number of events determined using one year Kaplan-Meier rates Event Low risk* (n=7 861; 20.2%) Higher risk (n=31 123) All-cause mortality 94 (1.4%) 1387 (4.9%) Ischaemic stroke/ Systemic embolism 35 (0.5%) 396 (1.4%) Haemorrhagic stroke/ Major bleed 26 (0.4%) 295 (1.1%) Low risk patients (defined as CHA2DS2-VASc 0 or 1 for men and 1 or 2 for women) represent 20.2% of overall cohort Total number of patients: 38,984 enrolled between March 2010 and July 2015

GARFIELD Score performance characteristics in all patients Ischaemic stroke / Systemic embolism Haemorrhagic stroke / Major bleed All-cause mortality C statistic: 0.78 C statistic: 0.63 C statistic: 0.67

Comparison of GARFIELD Score with CHA2DS2-VASc in all patients Performance measure Event GARFIELD Score CHA2DS2-VASc C statistic   All-cause mortality 0.78 0.66 Ischaemic stroke / systemic embolism 0.63 Haemorrhagic stroke / major bleed 0.67 0.61

Comparison of GARFIELD Score with CHA2DS2-VASc in low-risk patients CHA2DS2-VASc 0 or 1 for men and 1 or 2 for women Performance measure Events GARFIELD Score CHA2DS2-VASc C statistic   All-cause mortality 0.72 0.56 Ischaemic stroke / Systemic embolism 0.62 Haemorrhagic stroke / Major bleed 0.57

Performance of the new simplified GARFIELD Score in patients enrolled in GARFIELD-AF and ORBIT-I Population Endpoint C Statistic (95% CI) Events (n / N) GARFIELD-AF Ischaemic stroke/SE 0.70 (0.68, 0.73) 438 / 38,607 ORBIT-I Any stroke/SE 0.69 (0.64, 0.75) 91 / 9,743 Haemorrhagic stroke/major bleed 0.68* (0.64, 0.72) 187 / 12,249 1 Major bleed 0.61 (0.58-0.64) 625 / 7,442 *C statistic for HAS-BLED is 0.64 (95% CI 0.59, 0.68) 1. Evaluation of a subset of patients who were prescribed oral anticoagulants in countries where at least 1% bleeding rate was recorded

Conclusions Performance of GARFIELD Score was superior to CHA2DS2-VASc in predicting ischaemic stroke or major bleed in all patients, and those with a low­ risk of stroke This integrated risk tool has the potential for incorporation in routine electronic systems

Next steps A simplified GARFIELD Score, validated using data from ORBIT-AF, is being developed, with web-based and mobile device applications* The GARFIELD Score may help physicians assess the appropriateness of anticoagulation in low-risk patients *http://colab-sbx-322.oit.duke.edu:3338/

BLEEDING SCORE 20% Risk of major bleed in 1 year