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Original Research: Antithrombotic Therapy |

Major Bleeding and Hemorrhagic Stroke With Direct Oral Anticoagulants in Patients With Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials

Bruria Hirsh Raccah, PharmD; Amichai Perlman, PharmD; Haim D. Danenberg, MD; Arthur Pollak, MD; Mordechai Muszkat, MD; Ilan Matok, PhD
Author and Funding Information

Drs Muszkat and Matok contributed equally to this work and jointly directed it.

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

CORRESPONDENCE TO: Ilan Matok, PhD, Pharmacoepidemiology Research Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, POB 12065, Postal Codes 9112001, Jerusalem, Israel


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(6):1516-1524. doi:10.1016/j.chest.2015.12.029
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Background  Direct oral anticoagulants (DOACs) are used as an alternative for traditional antithrombotic therapy. However, the safety profile of DOACs in patients with renal failure (RF) has not been determined.

Methods  A systematic review was performed assessing the reported safety of DOACs compared with vitamin K antagonists (VKAs) in patients with RF and estimated creatinine clearance (eCrCL) < 50 mL/min and eCrCL 50 to 80 mL/min. MEDLINE, EMBASE, Cochrane, and the Clinical Trials Registry (ClinicalTrials.gov) were searched for randomized clinical trials up to November 2015. The data were pooled by using both traditional frequentist and Bayesian random effects models.

Results  Nine trials met the inclusion criteria. Among 94,897 participants, 54,667 (58%) had RF. Compared with VKAs, DOACs were associated with a significantly decreased risk for major bleeding in patients with eCrCL 50 to 80 mL/min (risk ratio, 0.87 [95% CI, 0.81-0.93]) and a nonsignificant decrease in the risk for major bleeding in patients with eCrCL < 50 mL/min (risk ratio, 0.83 [95% CI, 0.68-1.02]); there was evidence of significant heterogeneity. Indirect comparisons, using Bayesian network analysis, indicated that apixaban was associated with a decreased rate of major bleeding compared with other DOACs in patients with eCrCL < 50 mL/min. DOACs were associated with a significant decrease in the risk for hemorrhagic stroke compared with VKAs in patients with eCrCL < 50 mL/min and 50 to 80 mL/min.

Conclusions  As a class, DOACs are associated with a reduced risk for hemorrhagic stroke compared with VKAs in patients with RF. However, DOACs may differ from each other in their relative risk for major bleeding in patients with eCrCL < 50 mL/min.

Trial Registry  PROSPERO registry; No.: CRD42014013730; URL: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014013730

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