Reversal Agents for Severe DOAC-Associated Bleeding

Quick Takes

  • Use of 4F-PCC, idarucizumab, and andexanet alpha all achieve a high degree of hemostatic efficacy for reversal in DOAC-associated bleeding.
  • Patients who experience DOAC-related bleeding have a high rate of mortality (17.7%), even with effective drug reversal and hemostasis.
  • Risk of thromboembolism may be elevated among patients who receive andexanet alpha (10.7%) as compared to other reversal medications (4.6%).

Study Questions:

What are the clinical outcomes associated with the use of 4-factor prothrombin complex concentrates (4F-PCC), idarucizumab, or andexanet alpha for reversal of severe direct oral anticoagulant (DOAC)-associated bleeding?


The authors performed a systematic review of the literature for prospective and retrospective studies of reversal agent use in treating severe bleeding associated with DOAC use. Mortality rates, thromboembolic events, and hemostatic efficacy were analyzed using a random-effects model.


Among 60 identified studies inclusive of 4,735 patients with severe DOAC-related bleeding, treatment included 4F-PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet alpha (n = 936). The mortality rate was 17.7% (95% confidence interval [CI], 15.1-20.4%) and was higher among patients with intracranial bleeding (20.2%) than extracranial bleeding (15.4%). Rates of thromboembolism were 4.6% (95% CI, 3.3-6.0%) overall, highest among those who received andexanet alpha (10.7%, 95% CI, 6.5-15.7%). The rate of effective hemostasis was 78.5% (95% CI, 75.1%-81.8%), without significant variation among reversal agents. The rate of rebleeding was 13.2% (95% CI, 5.5%-23.1%) and 78% of rebleeding occurred after resumption of anticoagulation. The risk of death was significantly associated with a failure to achieve effective hemostasis (relative risk, 3.63; 95% CI, 2.56-5.16).


The authors concluded that after severe DOAC-associated bleeding, the risk of death remains high despite a high rate of effective hemostasis with various reversal agents. They also note that thromboembolism risk is particularly high when patients received andexanet alpha.


Management of severe DOAC-associated bleeding has long been a challenge. Even with available “specific” reversal agents, cost, medication availability, and prospective randomized clinical trial data have largely been lacking to guide clinician decision making. This meta-analysis confirms a few key points: 1) Patients with severe DOAC-associated bleeding are at high risk for complications (including death) even when anticoagulant reversal and hemostasis are achieved, 2) recurrent bleeding after resumption of anticoagulation remains an important concern, 3) patients who experience DOAC-associated intracranial bleeding are at particularly high risk for death, and 4) head-to-head trials of DOAC reversal agents are needed. The high rate of thromboembolism with andexanet alpha remains a concern, but the data are dominated by one single-arm trial (ANNEXA-4). An ongoing randomized trial of andexanet alpha versus usual care in patients with intracranial bleeding will provide important safety and efficacy data (NCT03661528). Last, this meta-analysis provides important data on the efficacy and safety of 4F-PCC for DOAC-reversal (especially apixaban and rivaroxaban), a strategy used by many clinicians given the limited availability and high cost associated with andexanet alpha.

Clinical Topics: Anticoagulation Management, Prevention, Novel Agents

Keywords: Antibodies, Monoclonal, Humanized, Anticoagulants, Hemorrhage, Hemostasis, Hemostatics, Primary Prevention, Prothrombin, Risk, Thromboembolism, Vascular Diseases

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