Factor Xa Inhibitor-Related Intracranial Hemorrhage

Abstract

Background: Since the approval of the oral factor Xa inhibitors, there have been concerns regarding the ability to neutralize their anticoagulant effects after intracranial hemorrhage (ICH). Multiple guidelines suggest using prothrombin complex concentrates (PCCs) in these patients on the basis of research that includes a limited number of patients with ICH. Given this, we aimed to evaluate the safety and efficacy of PCCs for factor Xa inhibitor–related ICH in a large, multicenter cohort of patients. Methods: This was a multicenter, retrospective, observational cohort study of patients with apixaban- or rivaroxaban-related ICH who received PCCs between January 1, 2015, and March 1, 2019. The study had 2 primary analysis groups: safety and hemostatic efficacy. The safety analysis evaluated all patients meeting inclusion criteria for the occurrence of a thrombotic event, which were censored at hospital discharge or 30 days after PCC administration. Patients with intracerebral, subarachnoid, or subdural hemorrhages who had at least 1 follow-up image within 24 hours of PCC administration were assessed for hemostatic efficacy. The primary efficacy outcome was the percentage of patients with excellent or good hemostasis on the basis of the modified Sarode criteria. Secondary outcomes included an evaluation of in-hospital mortality, length of stay, infusion-related reactions, and thrombotic event occurrence during multiple predefined periods. Results: A total of 663 patients were included and assessed for safety outcomes. Of these, 433 patients met criteria for hemostatic efficacy evaluation. We observed excellent or good hemostasis in 354 patients (81.8% [95% CI, 77.9–85.2]). Twenty-five (3.8%) patients had a total of 26 thrombotic events, of which 22 occurred in the first 14 days after PCC administration. One patient had documentation of an infusion-related reaction. For the full cohort of patients, in-hospital mortality was 19.0%, and the median intensive care unit and hospital lengths of stay were 2.0 and 6.0 days, respectively. Conclusions: Administration of PCCs after apixaban- and rivaroxaban-related ICH provided a high rate of excellent or good hemostasis (81.8%) coupled with a 3.8% thrombosis rate. Randomized, controlled trials evaluating the clinical efficacy of PCCs in patients with factor Xa inhibitor–related ICH are needed.

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy

“…Therapeutic strategies have included supportive care, antifibrinolytic agents (aminocaproic acid, tranexamic acid), and coagulation factor therapies (prothrombin complex concentrates, plasma, factor VIII inhibitor bypassing activity). Recent reports have described the use of these agents in patients with ICrH, 25 , 26 , 32 , 33 although the mechanistic basis for their effectiveness is controversial. 34 Furthermore, their efficacy may be restricted in the presence of higher anti-FXa levels, 35 and the reports provide limited or no information regarding baseline anti-FXa activity.…”

Clinical Characteristics and Outcomes Associated With Oral Anticoagulant Use Among Patients Hospitalized With Intracerebral Hemorrhage

“…Overall, we observed higher risk profiles in terms of age and comorbidities in patients taking FXa inhibitors than spontaneous ICH without preceding use of OAC. Despite no significant differences in the likelihood of discharge home and functional status at discharge, FXa 17,18 Comparing the impact of various reversal strategies can be difficult because of selection bias and concomitant medication use in ICH, making it hard to disentangle the effectiveness of various treatments. 19 Furthermore, because anticoagulant levels are rarely captured, further research is required to measure clinical outcomes in the context of anticoagulant levels in addition to bleeding size and severity.…”

“…These findings suggest that non-vitamin K OACs may be a better choice than warfarin when combination strategy is warranted.Unlike warfarin-related ICH, the best management strategy for FXa inhibitor-associated ICH remains uncertain. The 2019 European Stroke Organisation Guidelines17,18 recommend andexanet-α in ICH with rivaroxaban or apixaban or prothrombin complex concentrate to normalize coagulation tests if specific reversal agents are not available. However, the quality of evidence is low because of a lack of randomized clinical trials and uncertainty regarding the benefit and harm of the reversal treatment.…”

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding

“…14 4F-PCC contains nonactivated coagulation factors II, VII, IX, and X competing with the effects of FXa inhibitors, increasing thrombin generation, and facilitating clot formation. 14,15 With the exception of Panos et al 16 clinical evaluations of 4F-PCC for reversal of FXa inhibitors are limited to small cohort studies, collectively estimating hemostatic efficacy rates from 60% to 94.7%. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] A meta-analysis of 10 studies evaluating 4F-PCC for FXa-inhibitor reversal found a pooled thrombotic event rate of 4% and a mortality rate of 16%.…”

“…14,15 With the exception of Panos et al 16 clinical evaluations of 4F-PCC for reversal of FXa inhibitors are limited to small cohort studies, collectively estimating hemostatic efficacy rates from 60% to 94.7%. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] A meta-analysis of 10 studies evaluating 4F-PCC for FXa-inhibitor reversal found a pooled thrombotic event rate of 4% and a mortality rate of 16%. 22 Based on the available literature the American Society of Hematology has suggested the use of either 4F-PCC or andexanet alfa for patients with FXa-inhibitor-associated bleeding.…”