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Published on: October 15, 2021
Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and
Rahul Chaudhary1, Amteshwar Singh2, Rohit Chaudhary3
1Division of Cardiology, Department of Medicine, University of Pittsburgh Heart and Vascular Institute, Pittsburgh, Pennsylvania.
Insights
Direct oral anticoagulant reversal agents show similar safety and efficacy for intracranial hemorrhage. Factors like cost and availability may influence agent selection in clinical practice.
Area of Science:
- Neurology
- Pharmacology
- Clinical Medicine
Background:
- Direct oral anticoagulants (DOACs) are increasingly used but associated with high morbidity and mortality in intracranial hemorrhage (ICH).
- Limited data exists on the safety and effectiveness of DOAC reversal agents in patients with ICH.
Approach:
- A systematic review and meta-analysis was conducted, searching multiple databases through April 2022.
- Included were 36 studies with 1832 adult patients with ICH receiving DOAC reversal agents.
- Data on anticoagulation reversal, mortality, and thromboembolic events were pooled using a random-effects model.
Key Points:
- Anticoagulation reversal rates were 77% for 4-factor prothrombin complex concentrate (4F-PCC), 75% for andexanet alfa (AA), and 82% for idarucizumab.
- All-cause mortality rates were 26% for 4F-PCC, 24% for AA, and 11% for idarucizumab.
- Thromboembolic event rates were 8% for 4F-PCC, 14% for AA, and 5% for idarucizumab.
Conclusions:
- Available DOAC reversal agents demonstrate similar rates of anticoagulation reversal, mortality, and thromboembolic events in ICH management.
- Randomized clinical trials are lacking for direct comparisons.
- Choice of reversal agent may be influenced by cost, formulary status, and availability, especially in smaller hospitals.
Importance:
Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited.
Objective:
To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH.
Data Sources:
PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022.
Study Selection:
The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded.
Data Extraction And Synthesis:
Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model.
Main Outcomes And Measures:
The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent.
Results:
A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events.
Conclusions And Relevance:
In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.
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