Reversal agents for oral anticoagulant-associated major or life-threatening bleeding

Abstract

Oral anticoagulants (OA) are effective drugs for treating and preventing the formation of blood clots in patients with atrial fibrillation, mechanical heart valves and venous thromboembolism but their therapeutic effect is always counterbalanced by an increased risk of bleeding. Direct oral anticoagulants (DOACs) have brought advantages in the management of many patients, with evidence of a lower risk of intracranial bleeding in comparison to vitamin K antagonists (VKAs). However, due to the increased number of anticoagulated patients worldwide, major and life threatening OA-related bleeding is also increasing, and effective reversal strategies are needed. We reviewed the reversal strategies for both VKAs and DOACs in the light of the latest evidence and recent guidelines, taking into account non-specific methods with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) or four factor PCC, as well as specific reversal antidotes that are already approved or in approval phase. Most published studies on OA reversal have drawbacks, such as lacking a control arm or data on clinically relevant outcomes, and current guidelines’ recommendations are mainly based on panellists’ judgment. There is an urgent need for well-designed studies in this field. In the meanwhile, to improve the correct use of available resources and patients’ outcomes, we suggest a seven-element bundle for an optimal management of OA-associated major bleeding, including the implementation of fast turnaround time for laboratory tests in emergency, i.e. INR and DOAC plasma levels, and to build up a ‘bleeding team’ that includes experts of hemostasis, lab, trauma, emergency medicine, endoscopy, radiology, and surgery in every hospital.

Bleeding on oral anticoagulants: overview of reversal strategies

“…Therefore, strategies for anticoagulation neutralisation are based mainly on expert consensus [4,6]. Regardless of the strategy chosen (table 4), it is usually recommended that coagulation tests be repeated after administration of the various therapies, with the timing depending on the type of antidote administered [19], and that the efficacy of the treatment instituted be reassessed at short intervals (table 5). However, the clinician must be careful with specific antidotes.…”

Recent advances in use of fresh frozen plasma, cryoprecipitate, immunoglobulins, and clotting factors for transfusion support in patients with hematologic disease

“…Prothrombin is available in the form of a concentrate of multiple factors, referred to as prothrombin complex concentrate, and it exists in 2 forms: 3-factor PCC (3F-PCC) consisting of Factors II (prothrombin), IX, and X, as well as Protein C and S, and 4-factor PCC (4F-PCC) that also contains Factor VII [115] . Its indication is currently only for urgent reversal of the VKA warfarin in adults with acute major bleeding; however, multiple off-label uses exist including reversal of direct oral anticoagulants in major bleeding or surgery [116 , 117] , treatment of bleeding in congenital deficiencies of any of the coagulation factors found in PCC (the vitamin K-dependent factors), prophylactic usage to reduce perioperative bleeding and reduce transfusion requirements [118] , [119] , [120] , and in traumatic bleeding alongside FFP to correct coagulopathy [121] , [122] , [123] . Clinicaltrials.gov lists multiple ongoing studies investigating PCC for usage in reducing perioperative bleeding [NCT02740335, NCT04244981, NCT03341156] as well as treatment of coagulopathy and bleeding including the prehospital setting [NCT03981484, NCT04019015].…”

Preoperative cardiac assessment in liver transplant candidates

“…The need of parenteral (Low Molecular Weight Heparin, LMWH) or oral anticoagulation (vitamin K antagonists, VKA, or direct oral anticoagulants, DOACs) while on the wait list is usually planned with the cardiologist and the hepatologist. For the reversal immediately before surgery a proactive approach mandates a consultation with a cardiologist and /or with an expert in hemostasis, according to the most recent available guidelines [9,65,[66][67][68][69][70]. In case of DOACs, the need for reversal depends upon timing of the last dose before surgery, renal function and, if available, blood level of the drug to test the anticoagulant activity.…”