Efficacy and Safety of Direct Oral Anticoagulant Reversal Agents in Intracerebral Hemorrhage: A Systematic Review and Meta-analysis
Omar Abdelkader1, Sai Krishna Vallamchetla2, Karim Borei3, Amr Salem1, Vamsi Reddy Lakkireddy4, Anyna Shine4, Doaa Ramadan2, Ruaa Alsaeed1, Sangharsha Thapa1, Sara Muhammad1, Tomoko Kitago1, Fawaz Al-Mufti1
1Neurology, Westchester Medical Center/New York Medical College, Valhalla, NY, USA, 2Neurology, Mayo Clinic, Florida, USA, 3Neurology, University of Missouri Kansas City, USA, 4Internal Medicine, AIIMS, Bhopal, India
Objective:
To evaluate the efficacy and safety of direct oral anticoagulant (DOAC) reversal agents in patients with intracerebral hemorrhage (ICH).
Background:
Patients on DOACs who develop ICH often receive reversal therapy with agents like 4-factor prothrombin complex concentrate (4F-PCC), andexanet alfa (AA), or idarucizumab. However, data directly comparing the efficacy and safety of these agents remains limited.
Design/Methods:
A systematic search was conducted across PubMed, Embase, Web of Science, and others from inception through February 2025. Eligible studies enrolled adults on DOAC therapy who received a reversal agent for ICH and reported outcomes such as successful hemostatic reversal, all-cause mortality, or thromboembolic events. Meta-analysis was performed using R version 4.5.1.
Results:
A total of 74 studies met inclusion criteria, encompassing 6,664 patients (2,678 receiving 4F-PCC; 3,401 AA; and 585 idarucizumab). The mean age across studies was 76 years (range, 65–85 years), and 56% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 73%–80%; I² = 53%), all-cause mortality 24% (95% CI, 20%–27%; I² = 62%), and thromboembolic events 5% (95% CI, 3%–8%; I² = 44%). For AA, reversal was 81% (95% CI, 77%–85%; I² = 63%), all-cause mortality 17% (95% CI, 13%–22%; I² = 76%), and thromboembolic events 10% (95% CI, 7%–13%; I² = 44%). For idarucizumab, reversal was 80% (95% CI, 33%–97%), all-cause mortality 18% (95% CI, 12%–26%), and thromboembolic events 5% (95% CI, 2%–15%). A direct comparison between 4F-PCC and AA showed no significant differences in anticoagulation reversal, mortality, or thromboembolic events.
Conclusions:
Among patients on DOAC who develop ICH, reversal with 4F-PCC, AA, or idarucizumab achieves high hemostatic success with low to moderate risk of all-cause mortality and thromboembolism. Head-to-head comparisons suggest similar reversal efficacy between AA and 4F-PCC. Findings support the effectiveness of available reversal strategies while underscoring the need for randomized trials to confirm comparative safety and longer-term outcomes.
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