ABC | Volume 113, Nº1, July 2019

Statement Statement on Antiplatelet Agents and Anticoagulants in Cardiology – 2019 Arq Bras Cardiol. 2019; 113(1):111-134 Table 10 – Recommendations on the use of NOAC antidotes Indications Grade of recommendation Level of evidence The use of idarucizumab in patients receiving dabigatran is indicated at a dose of 5 g intravenous, when emergency intervention or surgery are necessary in patients who cannot wait the time it takes to metabolize the anticoagulant or in the event of life-threatening or uncontrollable bleeding episodes IIa B In the event of surgeries or procedures which are elective or for which it is possible to wait the NOAC clearance time, controlled bleeding events, or anticoagulant overdoses without bleeding, the use of antidotes should not be indicated III C NOAC: new oral anticoagulant. Table 9 – Reversal of NOAC anticoagulant effects 8 NOAC Specific antidote Alternative therapeutic options Dabigratan Idarucizumab 5 g IV (divided in 2 doses of 2.5 g) • PCC 50 IU/kg IV • RFVIIa 90 mcg/kg IV every 2 hours • Tranexamic acid 15 to 30 mg/kg IV • Hemodialysis Rivaroxaban Anti-factor Xa (e.g., Andexanet alfa – not approved) • PCC 50 IU/kg IV • RFVIIa 90 mcg/kg IV every 2 hours • Tranexamic acid 15 to 30 mg/kg IV Apixaban Anti-factor Xa (e.g., Andexanet alfa – not approved) • PCC 50 IU/kg IV • RFVIIa 90 mcg/kg IV every 2 hours • Tranexamic acid 15 to 30 mg/kg IV Edoxaban Anti-factor Xa (e.g., Andexanet alfa – not approved) • PCC 50 IU/kg IV • RFVIIa 90 mcg/kg IV every 2 hours • Tranexamic acid 15 to 30mg/kg IV IV: intravenous; NOAC: new oral anticoagulant; PCC: prothrombin complex concentrates; rFVIIa: recombinant activated factor VII. • Need for emergency surgical intervention in patients with high risks of bleeding who cannot wait the time it takes to metabolize NOAC. The use of antidotes does not seem to be necessary in patients who have received the last dose of NOAC more than 24 hours prior and who have creatinine clearance > 60 mL/min. In the event of elective surgeries or procedures, patients who may wait the time it takes to metabolize the NOAC, controlled bleeding, or anticoagulant overdose with no bleeding, antidote use does not need to be indicated. 47 4.3. Idarucizumab Idarucizumab is a monoclonal antibody fragment that neutralizes the anticoagulant effect of dabigatran by direct binding . Dabigatran, idarucizumab, and dabigatran- idarucizumab are eliminated by the kidneys. The phase III Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD) study has shown that the intravenous use of 5 g of idarucizumab (2 consecutive doses of 2.5 g at 15-minute intervals) reverted the anticoagulant effect of dabigatran with normalization of thrombin time in more than 98% of patients, leading to early hemostasis in patients with major bleedings and low rates of hemorrhagic events in patients undergoing urgent surgery. 48 4.3.1. Andexanet alfa Andexanet alfa is a recombinant factor Xa protein that binds to direct and indirect factor Xa inhibitors, removing them from circulation. Phase II studies in healthy elderly patients have demonstrated that this drug, administered via intravenous bolus with subsequent continuous 2-hour infusion, reverted more than 90% of rivaroxaban and apixaban’s anti-Xa factor activity. 49 The phase III Ability of Andexanet Alfa to Reverse the Anticoagulant Activity-4 study, which is currently underway, will evaluate the efficacy and safety of andexanet in controlling hemostasis in patients receiving rivaroxaban, apixaban, and edoxaban who have major bleedings. Interim analysis of the study with 67 patients showed a reduction in anti-Xa factor activity in 89% and 93% of patients using rivaroxaban and apixaban, with 70% clinical hemostasis. 50 4.4. Alternative Therapies Fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), recombinant activated factor VII, and tranexamic acid are suggested as alternative therapies for patients receiving NOAC who have life-threatening hemorrhagic events or who need to undergo urgent procedures in the absence of a specific antidote (Table 9). 46 121