Non-Specific Hemostatic Agents (PCC, aPCC, rVIIa) for Reversal of Direct Oral Anticoagulant Effect in Patients with Major Bleeding Complications: A Retrospective Review
Authors: Siegal Deborah M. , Movilla Ron , Siddiqui Reda , Barty Rebecca , Crowther Mark A. , Heddle Nancy M 
Published: October 2019

Abstract
Direct oral anticoagulants (DOACs) are used for the prevention and treatment of thromboembolism in a variety of clinical settings. Although rates of DOAC-associated major bleeding are similar to, or lower than that of warfarin, there are currently no antidotes available to reverse DOAC anticoagulant effect. In the absence of specific reversal agents a variety of strategies have evolved to overcome DOAC-induced coagulation inhibition. Widely used agents to treat bleeding in DOAC treated patients include prothrombin complex concentrate (PCC), activated PCC (aPCC, FEIBA) or recombinant activated factor VII (rVIIa); these agents are used despite a known risk of thrombosis and a lack of evidence of efficacy.
We present preliminary results of a retrospective review of patients treated with PCC, aPCC and/or rVIIa for DOAC-associated major bleeding at Hamilton Health Sciences, Hamilton, Ontario, Canada to (i) characterize utilization of these agents and (ii) describe the clinical course and complications after administration in this setting.
Eligible patients were adults (≥ 18 yrs) treated with PCC, aPCC and/or rVIIa for major DOAC-associated bleeding between 2010 and 2013. After screening 503 patients with anticoagulant associated major bleeding (661 cases), 11 patients (12 cases) were eligible for inclusion with the remainder excluded as they were treated with warfarin. Median age was 81 years (interquartile range [IQR] 74-86) with 64% male. Patients were treated with dabigatran (73%) or rivaroxaban (27%). The majority of patients were treated for atrial fibrillation (91%) with a median CHADS2 score of 3 (IQR 2-3). Bleeding events occurred within 12 hours of DOAC administration in 9 patients (82%) or 13-24 hours in 2 patients (18%). Intracranial hemorrhage was the most common site of bleeding (54%) followed by gastrointestinal (27%), ocular (9%) and body cavity (9%). APCC and PCC were administered to 6 patients (54%) and 5 patients (46%), respectively. Six patients (54%) were admitted to the intensive care unit with median length of stay 2.5 days (IQR 2-4). Three patients (27%) underwent surgical procedures. Median length of hospital admission for the cohort was 10 days (IQR 4-29). There were no thromboembolic complications. In-hospital mortality was 18%.
This case series demonstrates that PCC and aPCC are used "off-label" for reversal of DOAC anticoagulant effect in the setting of major bleeding. Our observed mortality rate was generally higher than that reported in the clinical trials leading to DOAC approval; this is likely explained by the severity of bleeding complications of which the majority were intracranial hemorrhage. Our failure to observe thromboembolic complications is reassuring; however, the small sample size does not allow us to confidently rule out even high frequency toxic events. Our results confirm the need for rigorous studies comparing strategies for DOAC reversal in patients with major or life-threatening bleeding.

Disclosures
Siegal: Daiichi Sankyo: Other: participated in an advisory board; Boerhinger Ingelheim: Other: participated in an advisory board; Portola Pharmaceuticals: Other: participated in an advisory board; Interactive Forums Inc.: Other: created educational slides. Off Label Use: We conducted a chart review of the off-label use of prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant factor VIIa for direct oral anticoagulant reversal..