Physicians' Academy for Cardiovascular Education

NOACs are generally safe and effective alternatives to warfarin in a clinical care setting

Larsen TB, et al., BMJ 2016

Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study

Larsen TB, Skjøth F, Nielsen PB, et al.
BMJ. 2016 Jun 16;353:i3189


The four currently available non-vitamin K oral anticoagulants (NOACs) are rivaroxaban, apixaban, dabigatran and edoxaban [1-4]. A meta-analysis showed that NOACs at standard dose have a favourable risk-benefit profile compared to warfarin; significant reductions in stroke, systemic embolism, intracranial haemorrhage and mortality were observed but the major bleeding profile was comparable to warfarin, apart from increased gastrointestinal bleeding [5].
However, only large scale real world comparisons of a single NOAC versus warfarin have been published or presented and evidence relating to the comparative effectiveness and safety of all oral anticoagulant drugs used in clinical practice is currently lacking.
This study therefore assessed and compared the effectiveness and safety of dabigatran (12,701 patients), rivaroxaban (7,192 patients) and apixaban (6,349 patients), compared with warfarin (35,436 patients) in clinical practice, thereby using the nationwide Danish cohort (prescription registry) of patients with atrial fibrillation (AF) and who were naïve to oral anticoagulants (average follow-up 1.9 yrs).

Main results

  • There were significant baseline differences between treatment groups. The inverse probability of treatment weighted method corrected for these differences.
  • All treatments were more, or less often prescribed in particular patient groups.  
  • During the first year, 1,702 ischemic stroke or systemic embolism events occurred. Rivaroxaban was associated with lower rates compared with warfarin (after first year HR: 0.83, 95% CI: 0.69-0.99, after 2.5 yrs HR: 0.80, 95% CI: 0.69-0.94). This trend was similar when the analysis was restricted to patients with hospital-diagnosed AF (HR: 0.86, 95% CI: 0.70-1.07) or when stratified according to age (<65 yr HR: 0.79, 95% CI: 0.53-1.19, >65 yrs HR: 0.82, 95% CI: 0.67-1.00) or primary (HR: 0.85, 95% CI: 0.65-1.11) or secondary stroke protection (HR: 0.80, 95% CI: 0.63-1.00), but non-significant. No differences were observed for apixaban and dabigatran.
  • When restricted to ischemic stroke only, no significant differences were evident for NOACs compared with warfarin across strata.
  • The incidence of ‘any bleeding’ was significantly lower for apixaban and dabigatran, compared to warfarin (apixaban HR: 0.63, 95% CI: 0.53-0.76 and dabigatran HR: 0.61, 95% CI: 0.51-0.74). This was still significant after 2.5 yrs. This was comparable to when the analysis was restricted to patients with hospital-diagnosed AF or when stratified according to age or secondary stroke protection, though non-significant for secondary stroke protection.
  • After 1 year, the incidence of intracranial bleeding was lower for dabigatran (HR: 0.40, 95% CI: 0.25-0.65) and rivaroxaban (HR: 0.56, 95% CI: 0.34-0.90). This was comparable after 2.5 yrs.
  • After 1 year, death rates were significantly lower for apixaban (HR; 0.65, 95% CI: 0.56-0.75) and dabigatran (HR: 0.63, 95% CI: 0.48-0.82), which remained significant when stratified on subgroups.
  • Combining all endpoints (ischemic stroke, systemic embolism and death) showed a lower relative risk for all NOACs compared to warfarin, with general consistency in the entire cohort and patients admitted to the hospital. This was still notable after 2.5 yrs.


In this large multicentre effectiveness and safety analysis comparing 3 different NOACs with warfarin, it was shown that there were no significant differences for ischemic stroke between NOACs and warfarin. However, the risks for death, any bleeding or major bleeding were significantly lower for apixaban and dabigatran compared with warfarin. This means that rivaroxaban, apixaban and dabigatran are good alternatives for warfarin in clinical practice.
Find this article online at BMJ


1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. doi:10.1056/NEJMoa0905561.
2 Patel MR, Mahaffey KW, Garg J, et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. doi:10.1056/NEJMoa1009638.
3 Granger CB, Alexander JH, McMurray JJV, et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92. doi:10.1056/
4 Giugliano RP, Ruff CT, Braunwald E, et al. ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104. doi:10.1056/
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