The effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation: a Belgian nationwide cohort study

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek, FWO). BACKGROUND: Although non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management, direct head-to-head comparisons are lacking and the long-term effectiveness and safety are less well established in real life. PURPOSE: We aimed to investigate the risk-benefit profiles of dabigatran, rivaroxaban, apixaban and edoxaban in direct head-to-head comparisons with VKAs and between NOACs. METHODS: Using two Belgian nationwide healthcare databases, AF patients ≥45 years old initiating anticoagulation between January 1st, 2013 and January 1st, 2019 were included. Outcomes were identified using International Classification of Diseases-coded hospital discharge diagnoses (e.g. cerebral infarction) and medical procedure codes in hospital care (e.g. intracranial mechanical thrombectomy). Patients were followed from anticoagulant initiation until the first occurrence of the investigated outcome, discontinuation or switch of treatment, death, emigration or end of the study period, whichever came first (on-treatment analysis). Inverse probability of treatment weighted Cox regression was used to investigate effectiveness and safety outcomes. RESULTS: A total of 254,478 newly-treated AF patients were included during a mean follow-up of 1.3 ± 1.5 years (328,796 person-years of on-treatment follow-up). Before weighting, the 193,072 NOAC and 61,406 VKA users were on average 76.3 ± 10.1 and 70.9 ± 12.1 years old, and had a mean CHA2DS2-VASc score of 3.6 ± 1.8 and 3.2 ± 2.0, respectively. After multivariable adjustment, NOACs were associated with significantly lower risks of stroke or systemic embolism (stroke/SE) (hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.64-0.72)), all-cause mortality (HR 0.76, 95%CI (0.74-0.79)), major or clinically relevant non-major bleeding (MB/CRNMB) (HR 0.94, 95%CI (0.91-0.98)) and intracranial hemorrhage (HR 0.73, 95%CI (0.66-0.79)), but non-significantly different risks of myocardial infarction, gastrointestinal and urogenital bleeding compared to VKAs. Despite similar stroke/SE risks, dabigatran and apixaban were associated with significantly lower MB/CRNMB risks compared to rivaroxaban (HR 0.86, 95%CI (0.83-0.90); HR 0.86, 95%CI (0.83-0.89), respectively) and edoxaban (HR 0.91, 95%CI (0.83-0.99); HR 0.86, 95%CI (0.81-0.91), respectively), and apixaban with significantly lower major bleeding risks compared to dabigatran (HR 0.86, 95%CI (0.80-0.92)) and edoxaban (HR 0.79, 95%CI (0.72-0.86)). However, higher mortality risks were observed with apixaban in some risk groups including patients with diabetes or concomitantly using digoxin, compared to dabigatran and edoxaban, respectively. CONCLUSION: NOACs had better long-term risk-benefit profiles than VKAs. While effectiveness was comparable, apixaban was associated with a more favorable safety profile for most patients, followed by dabigatran.