Clinician Article

Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis.

  • Chaudhary R
  • Singh A
  • Chaudhary R
  • Bashline M
  • Houghton DE
  • Rabinstein A, et al.
JAMA Netw Open. 2022 Nov 1;5(11):e2240145. doi: 10.1001/jamanetworkopen.2022.40145. (Review)
PMID: 36331504
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  • Hemostasis and Thrombosis
    Relevance - 6/7
    Newsworthiness - 6/7
  • Hospital Doctor/Hospitalists
    Relevance - 6/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Emergency Medicine
    Relevance - 6/7
    Newsworthiness - 5/7
  • Neurology
    Relevance - 6/7
    Newsworthiness - 3/7


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.

Clinical Comments

Emergency Medicine

This systematic review and meta-analysis evaluated anticoagulation reversal in patients on DOACs with ICH. The primary outcome was proportion with anticoagulation reversed. Primary safety end points were all-cause mortality and thromboembolic events after reversal. 36 studies with 1832 patients were included. Importantly, reversal agents for those with ICH on DOACs appeared similar. Reversal using 4-factor PCC occurred in 77%, with 26% all-cause mortality, and 8% thromboembolic events. Andexanet alfa reversed 75% of patients, with 24% mortality and 14% thromboembolic events. Idarucizumab reversed 82%, with 11% mortality and 5% thromboembolic events. There are limitations (e.g., inclusion of retrospective studies, inclusion of traumatic and non traumatic ICH, and heterogeneity), but this systematic review provides important information.

Emergency Medicine

As an Internist, I found this information very useful for my everyday clinical practice.

Hemostasis and Thrombosis

Andexanet Alpha is not available.

Hospital Doctor/Hospitalists

This is an important study showing that 4-factor prothrombin complex concentrate, andexanet alfa, and idarucizumab had simillar safety profiles and outcomes. I think every physician should know this.


This study is flawed. Although the title suggests "anticoagulant reversal" and the "primary outcome was the successful reversal of anticoagulation," the actual outcome is stability of intracranial hemorrhage at follow-up scan. Most patients have stable hematomas at follow-up imaging in this and other observational data, so it is unclear how much, if any, the agents effected "reversal." To the casual reader, if no reversal agents were given, the "reversal" would be 0%. But the outcome is stability and most patients are stable. Hemorrhage stability is no different among the agents tested, but it is unclear whether the study was powered to answer the question.


The superiority of andexanet over prothrombin complex concentrate is still unproven.

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