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Oral anticoagulation and stroke risk
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.ORCID iD: 0000-0003-0282-8648
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. , 68 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1930
Keyword [en]
Stroke, warfarin, atrial fibrillation, dabigatran, rivaroxaban, apixaban, low-molecular-weight heparin, bridging
National Category
Other Clinical Medicine
Identifiers
URN: urn:nbn:se:umu:diva-141597ISBN: 978-91-7601-794-4 (print)OAI: oai:DiVA.org:umu-141597DiVA: diva2:1155690
Public defence
2017-12-01, Aulan, Sundsvalls sjukhus, Igeltjärnsvägen 1, Sundsvall, 13:00 (Swedish)
Opponent
Supervisors
Note

Finansiär: Forskning och Utveckling, Region Västernorrland

Available from: 2017-11-10 Created: 2017-11-08 Last updated: 2017-11-09Bibliographically approved
List of papers
1. Safety and efficacy of well managed warfarin: a report from the Swedish quality register Auricula
Open this publication in new window or tab >>Safety and efficacy of well managed warfarin: a report from the Swedish quality register Auricula
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2015 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 113, no 6, 1370-1377 p.Article in journal (Refereed) Published
Abstract [en]

The safety and efficacy of warfarin in a large, unselected cohort of warfarin-treated patients with high quality of care is comparable to that reported for non-vitamin K antagonists. Warfarin is commonly used for stroke prevention in atrial fibrillation, as well as for treatment and prevention of venous thromboembolism. While reducing risk of thrombotic/embolic incidents, warfarin increases the risk of bleeding. The aim of this study was to elucidate risks of bleeding and thromboembolism for patients on warfarin treatment in a large, unselected cohort with rigorously controlled treatment. This was a retrospective, registry-based study, covering all patients treated with warfarin in the Swedish national anticoagulation register Auricula, which records both primary and specialised care. The study included 77,423 unselected patients with 100,952 treatment periods of warfarin, constituting 217,804 treatment years. Study period was January 1, 2006 to December 31, 2011. Atrial fibrillation was the most common indication (68%). The mean time in therapeutic range of the international normalised ratio (INR) 2.0-3.0 was 76.5%. The annual incidence of I severe bleeding was 2.24% and of thromboembolism 2.65%. The incidence of intracranial bleeding was 0.37% per treatment year in the whole population, and 0.38% among patients with atrial fibrillation. In conclusion, warfarin treatment where patients spend a high proportion of time in the therapeutic range is safe and effective, and will continue to be a valid treatment option in the era of newer oral anticoagulants.

National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-106015 (URN)10.1160/TH14-10-0859 (DOI)000355776400026 ()25716771 (PubMedID)
Available from: 2015-07-06 Created: 2015-07-03 Last updated: 2017-11-08Bibliographically approved
2. Safety and Efficacy of Bridging With Low-Molecular-Weight Heparin During Temporary Interruptions of Warfarin: A Register-Based Cohort Study
Open this publication in new window or tab >>Safety and Efficacy of Bridging With Low-Molecular-Weight Heparin During Temporary Interruptions of Warfarin: A Register-Based Cohort Study
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2017 (English)In: Clinical and applied thrombosis/hemostasis, ISSN 1076-0296, E-ISSN 1938-2723, Vol. 23, no 8, 961-966 p.Article in journal (Refereed) Published
Abstract [en]

Low-molecular-weight heparin (LMWH) is often recommended as a bridging therapy during temporary interruptions in warfarin treatment, despite lack of evidence. The aim of this study was to see whether we could find benefit from LMWH bridging. We studied all planned interruptions of warfarin within the Swedish anticoagulation register Auricula during 2006 to 2011. Low-molecular-weight heparin bridging was compared to nonbridging (control) after propensity score matching. Complications were identified in national clinical registers for 30 days following warfarin cessation, and defined as all-cause mortality, bleeding (intracranial, gastrointestinal, or other), or thrombosis (ischemic stroke or systemic embolism, venous thromboembolism, or myocardial infarction) that was fatal or required hospital care. Of the 14 556 identified warfarin interruptions, 12 659 with a known medical background had a mean age of 69 years, 61% were males, mean CHADS2 (1 point for each of congestive heart failure, hypertension, age >/=75 years, diabetes, and 2 points for stroke or transient ischemic attack) score was 1.7, and CHA2DS2-VASc score was 3.4. The total number of LMWH bridgings was 7021. Major indications for anticoagulation were mechanical heart valve prostheses 4331, atrial fibrillation 1097, and venous thromboembolism 1331. Bridging patients had a higher rate of thrombotic events overall. Total risk of any complication did not differ significantly between bridging (1.5%) and nonbridging (1.2%). Regardless of indication for warfarin treatment, we found no benefit from bridging. The type of procedure prompting bridging was not known, and the likely reason for the observed higher risk of thrombosis with LMWH bridging is that low-risk procedures more often meant no bridging. Results from randomized trials are needed, especially for patients with mechanical heart valves.

Place, publisher, year, edition, pages
Sage Publications, 2017
Keyword
bridging, dalteparin, enoxaparin, low-molecular-weight heparin, tinzaparin, warfarin
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-141577 (URN)10.1177/1076029617706756 (DOI)000412901900009 ()28468510 (PubMedID)1938-2723 (Electronic) 1076-0296 (Linking) (ISBN)
Note

Sjogren, Vilhelm Grzymala-Lubanski, Bartosz Renlund, Henrik Svensson, Peter J Sjalander, Anders eng 2017/05/05 06:00 Clin Appl Thromb Hemost. 2017 Nov;23(8):961-966. doi: 10.1177/1076029617706756. Epub 2017 May 4.

Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2017-11-09Bibliographically approved
3. Non-vitamin K oral anticoagulants are non-inferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: a retrospective register study
Open this publication in new window or tab >>Non-vitamin K oral anticoagulants are non-inferior for stroke prevention but cause fewer major bleedings than well-managed warfarin: a retrospective register study
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, 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
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-138422 (URN)10.1371/journal.pone.0181000 (DOI)000405544800113 ()28700711 (PubMedID)
Available from: 2017-08-23 Created: 2017-08-23 Last updated: 2017-11-08Bibliographically approved
4. Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillation
Open this publication in new window or tab >>Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillation
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: New oral anticoagulants are non-inferior compared with warfarin regarding stroke prevention in atrial fibrillation, with similar or decreased risk of bleeding. However, it is unclear whether high TTR warfarin is as effective and safe as NOACs. Our objective was to investigate efficacy and safety of apixaban, dabigatran or rivaroxaban compared with warfarin in clinical practice.

Methods: Nationwide retrospective cohort study based on Swedish quality registries. Atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin between 2013-01-01 and 2015-12-31 were included. Main outcomes measures were all-cause stroke and systemic embolism, all-cause stroke, ischemic stroke, hemorrhagic stroke; major bleeding, intracranial bleeding, gastrointestinal bleeding, other bleeding (fatal or requiring hospital care); all-cause mortality; myocardial infarction.

Results: The study included 64382 patients corresponding to 81176 treatment years. Of these, 37174 patients were instituted on warfarin, 6574 on dabigatran, 8323 on rivaroxaban and 12311 on apixaban. In warfarin treated patients, the time in therapeutic range was 71.4 %. After propensity score matching, there was no significant difference in risk of stroke or systemic embolism between NOAC and warfarin treated patients. Hazard ratios for major bleeding events were 0.63(95%CI 0.52-0.75) for apixaban, 0.74(0.62-0.87) for dabigatran and 1.06(0.92-1.23) for rivaroxaban, compared with warfarin.

Conclusions: This study showed no difference between apixaban, dabigatran, or rivaroxaban compared to high TTR warfarin treatment regarding stroke prevention. However, fewer bleeding events were seen for apixaban and dabigatran, but not for rivaroxaban. Further studies are needed on the comparability of individual NOACs with respect to bleeding risks. 

Keyword
Oral anticoagulation, warfarin, apixaban, dabigatran, rivaroxaban, time in therapeutic range, atrial fibrillation, stroke
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-141596 (URN)
Available from: 2017-11-08 Created: 2017-11-08 Last updated: 2017-11-09

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