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Safety and Efficacy of Bridging With Low-Molecular-Weight Heparin During Temporary Interruptions of Warfarin: A Register-Based Cohort Study
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. (Sundsvall Research Unit)ORCID iD: 0000-0003-0282-8648
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. (Sundsvall Research Unit)
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2017 (English)In: Clinical and applied thrombosis/hemostasis, ISSN 1076-0296, E-ISSN 1938-2723, Vol. 23, no 8, p. 961-966Article 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. Vol. 23, no 8, p. 961-966
Keywords [en]
bridging, dalteparin, enoxaparin, low-molecular-weight heparin, tinzaparin, warfarin
National Category
Hematology
Identifiers
URN: urn:nbn:se:umu:diva-141577DOI: 10.1177/1076029617706756ISI: 000412901900009PubMedID: 28468510ISBN: 1938-2723 (Electronic) 1076-0296 (Linking) OAI: oai:DiVA.org:umu-141577DiVA, id: diva2:1155684
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: 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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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, VilhelmGrzymala-Lubanski, BartoszSjälander, Anders

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