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Thromb Haemost 2020; 120(09): 1323-1329
DOI: 10.1055/s-0040-1713889
Stroke, Systemic or Venous Thromboembolism

Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?—A Systematic Review

Tim A. C. de Vries 
1   Population Health Research Institute, Hamilton, Ontario, Canada
2   Department of Cardiology, Rijnstate Hospital, Arnhem, Gelderland, The Netherlands
3   Department of Cardiology, Amsterdam University Medical Centers/University of Amsterdam, Amsterdam, North Holland, The Netherlands
,
Jack Hirsh
4   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
5   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Ke Xu
1   Population Health Research Institute, Hamilton, Ontario, Canada
6   Department of Cardiology, Shanghai Jiao Tong University, Shanghai, China
,
Imaad Mallick
1   Population Health Research Institute, Hamilton, Ontario, Canada
,
Vinai C. Bhagirath
4   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
5   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
John W. Eikelboom
1   Population Health Research Institute, Hamilton, Ontario, Canada
4   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
5   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Jeffrey S. Ginsberg
4   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
5   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Paul C. Kruger
1   Population Health Research Institute, Hamilton, Ontario, Canada
7   Department of Haematology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
,
Noel C. Chan
1   Population Health Research Institute, Hamilton, Ontario, Canada
4   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
5   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Abstract

Background Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients.

Objectives To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis.

Results and Discussion We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs.

Conclusion The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

Keywords

anticoagulants - death - hemorrhage - off-label - thromboembolism

Authors' Contributions

T.A.C.V., J.H., V.C.B., J.W.E., J.S.G., P.C.K., and N.C.C. have contributed to the concept and design of the study. T.A.C.V., J.H., and N.C.C. developed the study protocol, designed, and coordinated the study. T.A.C.V., K.X., and N.C.C. developed the search strategy. T.A.C.V. and K.X. tailored the search strategy, performed the literature searches, and extracted the data. T.A.C.V. and K.X. performed the quality assessments, and any disagreement was resolved by N.C.C.. T.A.C.V., J.H., V.C.B., J.S.G., J.W.E., and N.C.C. developed the initial analysis plan. T.A.C.V. and I.M. performed the analysis. T.A.C.V., J.H., and N.C.C. wrote the initial draft and subsequent iterations. All the other authors reviewed the drafts, provided critical comments, and revised the initial draft to produce the final manuscript.


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Publication History

Received: 09 September 2019

Accepted: 17 May 2020

Article published online:
15 July 2020

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