Presented by Renato D. Lopes, MD, PhD, Duke Clinical Research Institute, Duke University, USA for the ARISTOTLE investigators. Efficacy and Safety of Apixaban Compared with Warfarin According to Patient Risk of Stroke and Bleeding in Atrial Fibrillation

Disclosures for Renato D. Lopes Institutional research grants from: Bristol-Myers Squibb Advisory board or consultancy for: Boehringer Ingelheim and Bristol-Myers Squibb

Background Warfarin is very effective at preventing stroke in patients with atrial fibrillation (AF), but it has several limitations. The need to assure optimal benefit given the known bleeding risks of warfarin has led to the development of risk scores for thromboembolism and bleeding in patients with AF. Scores are important tools to predict the risk of stroke and bleeding in patients with AF and to inform decisions regarding the use of antithrombotic therapy. The value of these scores in guiding decision making in patients with AF receiving apixaban, a novel oral factor Xa inhibitor, is uncertain.

Warfarin (target INR 2-3) Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Primary outcome: stroke or systemic embolism Randomize double blind, double dummy (n = 18,201) Inclusion risk factors  Age ≥ 75 years  Prior stroke, TIA or SE  HF or LVEF ≤ 40%  Diabetes mellitus  Hypertension Inclusion risk factors  Age ≥ 75 years  Prior stroke, TIA or SE  HF or LVEF ≤ 40%  Diabetes mellitus  Hypertension Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Exclusion Exclusion  Mechanical prosthetic valve  Severe renal insufficiency  Need for aspirin plus thienopyridine Exclusion Exclusion  Mechanical prosthetic valve  Severe renal insufficiency  Need for aspirin plus thienopyridine Atrial Fibrillation with at Least One Additional Risk Factor for Stroke

Main Trial Results 21% RRR 31% RRR ISTH major bleedingStroke or systemic embolism Median TTR 66% Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P=0.011 Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60–0.80); P<0.001

Objectives We conducted this analysis of the ARISTOTLE population to assess the efficacy and safety of apixaban compared with warfarin according to CHADS 2 and HAS-BLED scores in patients with AF. Pre-specified outcomes: – Stroke or systemic embolism (primary efficacy outcome). – ISTH Major bleeding (primary safety outcome). – Mortality. Post-hoc explored outcomes: – Intracranial bleeding. – Net clinical benefit (the composite of stroke, systemic embolism, major bleeding, and all-cause mortality).

Methods The efficacy, safety, and balance of efficacy and safety of apixaban and warfarin were compared across patient risk categories classified by: 1. CHADS 2 (low risk: 0-1, medium risk: 2, high risk: ≥3) and 2. HAS-BLED (low risk: 0-1, medium risk: 2, high risk: ≥3) scores.

Statistical Analysis Efficacy analyses included all randomized patients (18201 subjects). The analyses of bleeding events included all patients who received at least one dose of study drug (18140 subjects). Analyses based on interactions between treatment and categories of CHADS 2 and HAS-BLED were performed using a Cox proportional hazards model.

Baseline Characteristics

Correlation between CHADS 2 and HAS-BLED scores Data presented at number (%).

Stroke/Systemic Embolism

ISTH Major Bleeding

Intracranial Bleeding

All-cause Mortality

Net Clinical Benefit: Stroke, Systemic Embolism, Major Bleeding, or All-cause Mortality

Limitations The absence of patients with CHADS 2 score of 0 does not permit an assessment of the benefit / risk profile of apixaban in this low-risk group of patients with AF. We calculated labile INR based on one single INR value among warfarin-experienced patients at baseline and this is different from how labile INR was initially described (TTR less than 60%). Our results were derived from a large clinical trial population that differs from an unselected clinical patient population.

Conclusion The benefits of apixaban compared with warfarin in reducing stroke or systemic embolism, all-cause mortality, and causing less bleeding are consistent across AF patients with a wide range of stroke and bleeding risks as assessed by the CHADS 2 and HAS-BLED scores. Patients with AF and at the highest risk of bleeding may have the greatest reduction (both relative and absolute) in intracranial bleeding with apixaban as compared with warfarin.

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