Haematological Management of Major Bleeding Associated with Direct Oral Anticoagulants - UK Experience

Background: The lack of antidotes for direct-oral-anticoagulants (DOACs) means that management of bleeding on DOACs will consist largely of existing therapies. This study aimed to: a) examine the relative frequency of DOAC-related major bleeding in relation to DOAC prescriptions over study period; b) describe the presentation and haematological management of DOAC-related major bleeding; and c) evaluate the association between use of prothrombin-complex-concentrate (PCC) and in-hospital mortality. Methods: Over a three-year period (2013-2016) 32 UK hospitals submitted routine data on haematological management of DOAC-related bleeding. Findings: Data consisted of 421 episodes (67%, 21%, 11% and 1% on rivaroxaban, apixaban, dabigatran and edoxaban respectively) of major bleeding on DOACs. The proportion of major bleeds on DOAC and DOAC prescriptions increased throughout the study. Overall, 44% and 37% of patients presented with gastrointestinal bleeding and intracranial-haemorrhage (ICH) respectively. Factor-specific assays were seldom performed. PCC was the most common treatment (39%) and was more likely to be given for ICH and factor-Xa inhibitor DOACs. Compared to no PCC, receiving ≥3000 IU of PCC was associated with over twofold increase in adjusted cumulative incidence of death (subdistribution hazard ratio: 2.56; 95%CI: 1.46-4.47; p=0.001); there were no statistically significant associations with lower doses. The in-hospital thromboembolic event rate was 1.9% and was not associated with PCC use. Interpretation: There was no evidence of benefit associated with PCC use for major bleeding DOAC patients in terms of in-hospital mortality, and higher doses were associated an increased incidence of death; PCC effects should be further investigated. Funding: The study was funded by the British Society for Haematology Early Stage Researcher Fellowship awarded to Dr Laura Green. Declaration of Interest: All authors declare the following: LG, JT, JM, NC, TE and SS have no conflicts of interest to disclose. AS has received honorarium from from Bayer Healthcare, Daiichi Sankyo, and Portola, outside the submitted work. RA has received honorarium from Bayer, Daiichi-Sankyo, Boehringer Ingelheim and BMS/Pfizer. KS has received honorarium from Bayer, BMS/Pfizer and Boehringer Ingelheim. CT has received honoraria and/or support to attend scientific meetings from Bayer, Pfizer, NovoNordisk, Shire, Sobi, CSL Behring and Daiichi-Sankyo. PM has served as a speaker for Bayer and Daiichi-Sankyo, as a consultant for Daiichi-Sankyo, and has received travel support from Boehringer Ingelheim. Ethical Approval: Ethics approval was obtained for the study from the National Health Service, Health Research Authority (East of England- Cambridge South Research Ethics Committee, reference: 12/EE/0431)