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CLINICAL STATEMENTS AND GUIDELINES

January 2, 2024 Circulation. 2024;149:e1–e156. DOI: 10.1161/CIR.0000000000001193 e46

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

inhibitors.7 It showed that mean hemostatic effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours versus 88% at 12 hours and 76% at 24 hours for PCC. Mean 30-day venous thromboembolism rate was 5.0% in the andexanet alfa group versus 1.9% in the PCC group. However, the meta-analysis had more significant methodological issues than the ANNEXA 4 trial. Thus, the level of evidence for the 4-factor PCC use was downgraded. 4 A meta-analysis of 13 studies (5 randomized trials

and 8 observational studies) compared 4-factor PCC with fresh frozen plasma for warfarin-associated bleeding or urgent surgery/procedure.8 Four-factor PCC use was significantly associated with lower risk of all-cause mortality (25.1% versus 28.8%; OR, 0.56 [95% CI, 0.37-0.84]), higher probability to achieve INR correction (60.6% versus 12.8%; OR, 10.8 [95% CI, 6.12-19.07]), shortened time to INR correction (–6.5 h [95% CI, –9.75 h to –3.24 h]),

Table 15.  Reversal Agents for Oral Anticoagulants

Idarucizumab Andexanet alfa 4-Factor PCC Activated PCC

Class Humanized monoclonal antibody fragment binding to dabigatran and neutralizing anticoagulation effects A recombinant modified human factor Xa protein binding and sequestering the factor Xa inhibitors PCC: coagulation factors II, VII, IX, and X Anticoagulation proteins C and S Nonactivated factors II, IX, and X Activated VII FDA indications Reversal of dabigatran effects For emergency surgery/

urgent procedures Life-threatening or

uncontrolled bleeding Reversal of apixaban or rivaroxaban For life-threatening or

uncontrolled bleeding The urgent reversal for acute major bleeding or need for an urgent surgery/invasive procedure in patients receiving VKAs Control and prevention of bleeding episodes, perioperative management, prophylaxis to prevent or reduce bleeding frequency in patients with hemophilia A and B

Off-label indications N/A Edoxaban-associated life-threatening bleeding Reversal of factor Xa inhibitors in patients requiring urgent procedure or with life-threatening bleeding Dabigatran-associated life-threatening bleeding Dosing 5-g (2 separate vials of 2.5 g/ vial) intravenous infusion over 5 min. Additional 5 g may be given if reappearance of bleeding with elevated coagulation parameters have been observed or patients require second emergency surgery/ procedure and elevated coagulation parameters Low-dose regimen: 400-mg bolus at a target rate of 30 mg/min followed by 4 mg/min for up to 120 min High-dose regimen: 800-mg bolus at a target rate of 30 mg/min followed by 8 mg/min for up to 120 min The recommended dosing is based on apixaban or rivaroxaban, dose, and time since the patient’s last dose of apixaban or rivaroxaban Warfarin reversal based on pretreatment INR (units of factor IX): 1.	INR 2–<4: 25 units/kg |(up to 2500 units) 2.	INR 4–6: 35 units/kg (up to 3500 units) 3.	INR >6: 50 units/kg (up to 5000 units) Oral factor Xa inhibitors: 2000 units once or 25 to 50 units/kg Dabigatran-associated life-threatening bleeding: 50 units/kg once Onset Within 5 min Within 2 min Within 10 min Within 30 min Duration 12-24 h 2 h 8 h 12 h Monitoring Coagulation parameters (aPTT, diluted thrombin time, or ecarin clotting time) between 12 and 24 h to assess redistribution of dabigatran from peripheral to plasma Current commercial anti-Xa activity assays are unsuitable for measuring factor Xa activities after andexanet alfa use Warfarin reversal: Repeat INR within 30 min after the administration N/A Others Risk of serious reactions (hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure) in patients with hereditary fructose intolerance (due to sorbitol excipient 4 g in each 5 g of idarucizumab) No procoagulant effect based on endogenous thrombin potential No FDA indication for other factor Xa inhibitors other than apixaban or rivaroxaban Andexanet alfa may interfere with the anticoagulation effect of heparin US black box warning: Serious and life-threatening adverse events (arterial and venous thromboembolism, myocardial infarction, ischemic stroke, cardiac arrest, sudden deaths) May not be indicated for patients with thromboembolic events in the previous 3 mo It includes heparin Administer intravenous vitamin K 10 mg over 10-20 min in addition to 4-factor PCC It does not include heparin Coagulation parameters do not correlate with the drug’s efficacy Not effective to reverse factor Xa inhibitors Information in table was obtained from manufacturer package inserts. aPTT indicates activated partial thromboplastin time; FDA, US Food and Drug Administration; PCC, prothrombin complex concentrate; and VKA, vitamin K antagonists.

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