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CLINICAL STATEMENTS AND GUIDELINES

Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 January 2, 2024 e45

Joglar et al 2023 Guideline for the Diagnosis and Management of Atrial Fibrillation

1 A 4 In patients with AF receiving warfarin who develop

life-threatening bleeding, treatment with 4-factor prothrombin complex concentrate (if available) in addition to intravenous vitamin K is recommended to rapidly achieve INR correction over fresh frozen plasma and intravenous vitamin K treatment.8–10

2b B-NR 5 In patients with AF who develop major gastrointestinal

bleeding, resumption of oral anticoagulation therapy may be reasonable after correction of reversible causes of bleeding and reassessment of its long-term benefits and risks with a multidisciplinary team approach during SDM with patients.11,12

*B-NR LOE applies to data on apixaban or rivaroxaban. †C-LD LOE applies to data on edoxaban. Synopsis About 2% to 4% of patients who receive OACs experience major bleeding and require intervention.13 Activated charcoal may be administered up to 6 to 8 hours after the last dose of an OAC.14,15 Hemodialysis may be also considered to eliminate dabigatran but may be challenging and impractical due to coagulopathy and hemodynamic instability.16 The proportion of emergency department visits for bleeding from OACs due to DO- ACs increased from 2.3% in 2011 to 37.9% in 2017 because of the increased use of DOACs over the past decade.17 Some patients may require reversal agents to achieve rapid hemostasis. Failure to achieve effective hemostasis is associated with a >3 times higher risk of death.18 Idarucizumab for dabigatran-induced major bleeding and andexanet alfa for apixaban or rivaroxaban associated major bleeding are US Food and Drug Administration (FDA) approved. Four-factor PCC for DOAC-induced major bleeding was compared with andexanet alfa in retrospective cohort studies, but the comparison has never been investigated in clinical trials.7 For VKA, if life-threatening bleeding cannot be managed with supportive measures, the rapid reversal treatment with 4-factor PCC is preferred over fresh frozen plasma.8–10 Table 15 summarizes reversal agents for OACs. Table 16 describes bleeding events attributable to DOACs in pivotal clinical trials. Recommendation-Supportive Text 1.	 The RE-VERSE AD (Reversal of Dabigatran

Anticoagulant Effect With Idarucizumab) study was a multicenter, prospective cohort study evaluating the use of idarucizumab in patients receiving dabigatran for the management of uncontrolled or life-threatening bleeding or in patients requiring urgent surgery or invasive procedure.1 In patients with uncontrolled or life-threatening bleeding, idarucizumab reversed the dabigatran anticoagulation effect in 100% of patients, and 67.7% had bleeding cessation. Thrombosis events after the reversal agent use was 4.7% within 30 days. However, this study did not have a control group. The post hoc analysis of the RE-VERSE AD study in patients with gastrointestinal bleeding found that 97.5% of patients achieved complete reversal of dabigatran, and bleeding cessation occurred in 76.2% of patients.2 Another post hoc analysis of the same study showed that idarucizumab was effective at reversing dabigatran’s anticoagulation effect, regardless of baseline renal function.3

2 Compared with idarucizumab, the data on PCC for

dabigatran-associated bleeding are very limited. A prospective multicenter cohort study compared the use of activated PCC in 14 patients with dabigatran-associated major bleeding compared with historical matched cases.4 The study was prematurely stopped due to the availability of idarucizumab in the market. The effectiveness of activated PCC was assessed based on the assessment guide rating from good, moderate, and poor. Nine patients (64%) were rated as good, 5 patients (36%) as moderate, and none as poor. No thromboembolic events were found. A randomized, placebocontrolled crossover trial in 12 healthy subjects evaluated the reversal effect of 4-factor PCC on rivaroxaban or dabigatran’s effect.5 It showed 4-factor PCC completely reversed rivaroxaban’s effect based the prothrombin time, but it did not reverse dabigatran’s effect based on the coagulation tests (aPTT, ecarin clotting time, and thrombin time). Four-factor PCC may not be appropriate for dabigatran-associated major bleeding management until further investigation is performed in prospective studies. 3.	 The ANNEXA 4 (Andexanet Alfa, a Novel

Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) trial evaluated the use of andexanet alfa in adult patients with acute major bleeding (safety population, n=254; efficacy population, n=254) receiving factor Xa inhibitors (apixaban 55%, rivaroxaban 36%, edoxaban 3%, and enoxaparin 6%).6 It found that after the bolus administration, the median anti-factor Xa activity decreased by 89%. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79% [95% CI, 64%-89%]); however, thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. Currently, andexanet alfa is FDA-approved for only apixaban- or rivaroxaban-associated lifethreatening or uncontrolled bleeding, because only limited data are available for other factor Xa inhibitors. For 4-factor PCC, a meta-analysis of 22 observational studies compared andexanet alfa (n=438) with PCC (n=1278) in patients with acute bleeding associated with oral factor Xa

Recommendations for Active Bleeding on Anticoagulant Therapy and Reversal Drugs (Continued ) COR LOE Recommendations

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