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Non-vitamin K oral anticoagulants are non-inferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: a retrospective register study
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e0181000Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2017. Vol. 12, no 7, article id e0181000
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-138422DOI: 10.1371/journal.pone.0181000ISI: 000405544800113PubMedID: 28700711OAI: oai:DiVA.org:umu-138422DiVA, id: diva2:1135518
Available from: 2017-08-23 Created: 2017-08-23 Last updated: 2019-05-22Bibliographically approved
In thesis
1. Oral anticoagulation and stroke risk
Open this publication in new window or tab >>Oral anticoagulation and stroke risk
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: The risk of ischaemic stroke in patients with atrial fibrillation (AF) and mechanical heart valve (MHV) prostheses can be reduced by oral anticoagulation (OAC), which increases the risk of serious bleeding. The aims of this thesis were [1] to find out how effective and safe warfarin is where treatment quality is high, i.e. Sweden, with proportion of time that patients spend within the therapeutic range (TTR) >70%, [2] whether there is evidence for administering low-molecular-weight heparin (LMWH) during temporary interruptions of OAC (bridging therapy), and whether non-vitamin K-dependent oral anticoagulants (NOACs) as a group, [3] or individually, [4] are more effective and safer than warfarin when used for stroke prevention in patients with AF.

Materials and methods: All four studies were retrospective, based on the Swedish anticoagulation register Auricula, and done with merging of data from some or all of the National Patient Register, the Prescribed Drug Register, the Swedish Stroke Register (Riksstroke), and the Cause of Death Register. In studies 2–4, propensity score matching was performed to obtain treatment groups with similar risk profiles. Outcomes were defined as haemorrhages or thromboses requiring specialist care, or death. Haemorrhages were intracranial, gastrointestinal, or other. Thromboses were ischaemic stroke, systemic embolism, myocardial infarction, or venous thromboembolism (VTE).

Study 1 described all patients on warfarin during 2006–2011, which was before the introduction of NOACs. Study 2 was a cohort study of all patients who had a planned interruption of warfarin during the same period. Study 3 included all 49,011 patients starting OAC for stroke prevention due to AF between 1 July 2011 and 31 December 2014, and study 4 all 64,382 patients with the same indication between 1 January 2013 and 31 December 2015.

Results: Study 1 showed that for the 77,423 patients on warfarin with 217,804 treatment years, TTR was 77.4% for patients with AF, 74.5% with MHV, and 75.9% with VTE. Annual rates of intracranial bleeding were 0.38%, 0.51%, and 0.30%. In study 2, with 14,556 warfarin interruptions, the 30-day risk of a bleeding requiring specialist care was 0.64% for LMWH treated and 0.46% for controls. For patients with VTE as indication for OAC, bleeding rate with LMWH was significantly higher at 0.85% vs. 0.16% (hazard ratio 5.24, 95% confidence interval 1.39–19.77), but with no difference for patients with MHV or AF. The incidence of ischaemic complications was higher in the LMWH bridging group overall and for patients with MHV and AF, but not for patients with VTE. In study 3, for the 12,694 patients starting NOAC (10,392 treatment years) or matched warfarin patients (9,835 treatment years, TTR 70%) due to AF, annual incidence of ischaemic stroke and systemic embolism did not differ between the groups (1.35% vs. 1.58%), but risks of major bleedings and intracranial bleedings were significantly lower: 2.76% vs. 3.61% and 0.40% vs. 0.69%. In study 4, patients on individual NOACs (6,574 dabigatran, 8,323 rivaroxaban, 12,311 apixaban) were compared to 37,174 patients starting warfarin (in total 81,176 treatment years). No NOAC showed any difference in risk of ischaemic stroke or systemic embolism, but there were fewer intracranial bleedings, serious bleedings overall, and deaths for dabigatran and apixaban compared to warfarin. For patients starting rivaroxaban the risk of gastrointestinal bleeding was higher than for matched warfarin counterparts, with no significant differences in other bleeding risks, or mortality.

Conclusions: Swedish warfarin treatment shows TTR levels that are high by international standards, correlating to low incidences of ischaemic and haemorrhagic events. LMWH bridging has not been proven beneficial, even for patients with MHV, meaning that bridging in general cannot be recommended. NOACs as a group were safer than high-quality warfarin treatment. Efficacy did not differ, even when comparing individual NOACs to warfarin, but there were fewer bleedings on dabigatran and apixaban. Although not more efficient than warfarin with a high TTR, NOACs should be the recommended first choice for OAC in AF, on the merit of lower bleeding risks.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2017. p. 68
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1930
Keywords
Stroke, warfarin, atrial fibrillation, dabigatran, rivaroxaban, apixaban, low-molecular-weight heparin, bridging
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-141597 (URN)978-91-7601-794-4 (ISBN)
Public defence
2017-12-01, Aulan, Sundsvalls sjukhus, Igeltjärnsvägen 1, Sundsvall, 13:00 (Swedish)
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Supervisors
Note

Finansiär: Forskning och Utveckling, Region Västernorrland

Available from: 2017-11-10 Created: 2017-11-08 Last updated: 2018-06-09Bibliographically approved

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Sjögren, VilhelmSjälander, Anders

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