Early Comparison of Major Bleeding, Stroke and Associated Medical Costs Among Treatment-Naive Non-Valvular Atrial Fibrillation Patients Initiating Apixaban, Dabigatran, Rivaroxaban or Warfarin

INTRODUCTION: Recent large randomized controlled trials have shown that novel oral anticoagulants (NOACs) are at least as effective as warfarin for risk reduction of stroke or systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and are associated with similar or lower rates of bleeding.^1,2,3,4 The study aimed to compare real-world major bleeding and stroke risk reduction and their related medical costs following initiation of apixaban compared to other oral anticoagulants (OACs) among treatment-naïve NVAF patients.

METHODS: From a large national commercial and Medicare advantage insurance database, adult patients initiating apixaban, dabigatran, rivaroxaban, or warfarin (01/01/2013-12/31/2014) were identified. The OAC prescription date was designated as the index date. Patients were required to have an AF diagnosis (ICD-9-CM: 427.31) and continuous health plan enrollment for 6 months pre-index date. Patients with evidence of mitral valvular heart disease, valve replacement procedures, pregnancy, or OAC claims before the index date were excluded. Patients were classified into four cohorts based on their index prescription: apixaban, dabigatran, rivaroxaban and warfarin. Time-to- first stroke and major bleeding events, identified by the Cunningham algorithm plus additional bleeding sites, were compared using a Cox proportional hazards model. Major bleeding and stroke-related medical costs including those for recurring events were calculated per patient per month (PPPM) and compared using propensity-weighted generalized linear models.

RESULTS: The study included 5,573 apixaban, 4,104 dabigatran, 13,370 rivaroxaban, and 25,978 warfarin patients. Apixaban patients had significantly higher CHA₂DS₂-VASc (3.6) and HAS-BLED (2.4) scores compared to dabigatran (CHA₂DS₂-VASc=3.3, HAS-BLED=2.2; p<0.001) and rivaroxaban (CHA₂DS₂-VASc=3.3, HAS-BLED=2.3; p<0.001) patients but lower scores compared to warfarin patients (CHA₂DS₂-VASc=4.0, HAS-BLED=2.7; p<0.001). After adjusting for baseline characteristics, apixaban patients were significantly less likely to have the first major-bleeding event within 1 year of treatment initiation compared to rivaroxaban (HR=0.71; 95% CI=0.62-0.82), warfarin (HR=0.71; 95% CI=0.62-0.80) patients, and trended towards numerically lower risk compared to dabigatran (HR=0.87; 95% CI=0.74-1.03) patients. Furthermore, apixaban patients were 26% less likely to have the first stroke within 1 year of treatment initiation compared to warfarin patients (HR=0.74; 95% CI=0.68-0.81), and trended towards numerically lower risk compared to rivaroxaban (HR=0.94; 95% CI=0.86-1.04) and dabigatran (HR=0.91; 95% CI=0.81-1.02) patients. Major bleeding-related medical costs were lower in apixaban patients compared to rivaroxaban ($85, p<0.001) and warfarin ($122, p<0.001) patients. The stroke-related medical costs were not significantly different; however, patients treated with apixaban had numerically lower PPPM stroke-related costs ($46) compared to those treated with rivaroxaban ($51) and warfarin ($68).

CONCLUSION: In a large insured population, treatment-naïve NVAF patients treated with apixaban were significantly less likely to have a major bleed compared to those prescribed rivaroxaban or warfarin and less likely to have a stroke compared to those prescribed warfarin. Additionally, patients prescribed apixaban had lower major bleeding costs compared to those prescribed rivaroxaban and warfarin.

¹ Lip GYH, Halperin JL, Petersen P, Rodgers GM, Pall D, Renfurm RW. A phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non-valvular atrial fibrillation: the oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2). J Thrombrosis Haemostasis. 2015;13:1405-13.

² O'Donoghue ML, Ruff CT, Giugliano RP, et al. Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation. Eur Heart J. 2015;36(23):1470-7.

³ Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368(8):699-708.

⁴ Lanssen M, Raskob G, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): A randomized double-blind trial. Lancet 2010;375(9717):807-15.