Research Article: Non-vitamin K oral anticoagulants are non-inferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: A retrospective register study

Date Published: July 10, 2017

Publisher: Public Library of Science

Author(s): Vilhelm Sjögren, Björn Byström, Henrik Renlund, Peter J. Svensson, Jonas Oldgren, Bo Norrving, Anders Själander, Pablo Garcia de Frutos.


For patients with atrial fibrillation, non-vitamin K oral anticoagulants, or NOACs (dabigatran, rivaroxaban, edoxaban, and apixaban) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, and in risk of haemorrhage. In the pivotal NOAC studies, quality of warfarin treatment was poor with mean time in therapeutic range (TTR) 55–65%, compared with ≥70% in Swedish clinical practice.

We compared NOACs (as a group) to warfarin in non-valvular atrial fibrillation, studying all 12,694 patients starting NOAC treatment within the Swedish clinical register and dosing system Auricula, from July 1, 2011 to December 31, 2014, and matching them to 36,317 patients starting warfarin using propensity scoring. Endpoints were thromboembolic events and major bleedings that were fatal or required hospital care. Outcome data were collected from validated Swedish hospital administrative and clinical registers.

Mean age was 72.2 vs 72.3 years, proportion of males 58.2% vs 57.0%, and mean follow-up time 299 vs 283 days for NOACs and warfarin. Distribution of NOACs was: dabigatran 40.3%, rivaroxaban 31.2%, and apixaban 28.5%. Mean TTR was 70%. There were no significant differences in rates of thromboembolic/thrombotic events or gastrointestinal bleeding. NOAC treated patients had lower rates of major bleeding overall, hazard ratio 0.78 (95% confidence interval 0.67–0.92), intracranial bleeding 0.59 (0.40–0.87), haemorrhagic stroke 0.49 (0.28–0.86), and other major bleeding 0.71 (0.57–0.89).

For patients with atrial fibrillation, NOACs are as effective for stroke prevention as well-managed warfarin but cause fewer major bleedings.

Partial Text

Atrial fibrillation is a strong risk factor for ischaemic stroke. Anticoagulation with vitamin K antagonists, e.g. warfarin, reduces this risk by about two-thirds and mortality by one quarter, but increases the risk of haemorrhage compared to no treatment.[1] Warfarin has been recommended for patients with atrial fibrillation in major guidelines for many years. Since 2011 several non-vitamin K antagonist oral anticoagulants, or NOACs, have been available in clinical practice in Sweden for prevention of stroke and systemic embolism in patients with atrial fibrillation. The term NOAC is used for the direct thrombin inhibitor dabigatran, as well as for direct factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban. In pivotal studies, NOACs have been proven superior or non-inferior to warfarin for both stroke prevention and risk of haemorrhage.[2–5] In a large Danish retrospective study, NOACs were confirmed to be at least as effective and safe as warfarin, but without data on the treatment quality of warfarin.[6]

In this large real-world register study of unselected patients with non-valvular atrial fibrillation starting oral anticoagulation for stroke prevention, we found that NOACs were not superior to warfarin, neither for preventing stroke or systemic embolism, nor for death, stroke, or myocardial infarction. This goes against a meta-analysis of the four pivotal NOAC trials where authors found a risk reduction of stroke and systemic embolism of 19%.[24] In that analysis, NOACs were favourable compared to warfarin with TTR both above and below 66%. Sub-group analyses of two of the NOAC trials indicated reduced benefit of NOACs with higher TTR.[12, 13] The TTR level of 70% in our study could account for some of the reduced benefit in efficacy of NOACs. It is a relatively high TTR for a cohort of newly started warfarin patients, but despite this, the risks of major bleeding, intracranial bleeding, haemorrhagic stroke, and other bleeding were significantly lower with NOACs than with warfarin. The high TTR level and the similar efficacy outcomes indicate that the advantage of NOACs in our study is not due to poor warfarin treatment.

For patients with non-valvular atrial fibrillation, oral anticoagulation with NOACs are as effective as well-managed warfarin for prevention of stroke and systemic embolism, but cause fewer major bleedings.




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