Dabigatran Reversal With Idarucizumab in Patients Requiring Urgent Surgery

A Subanalysis of the RE-VERSE AD Study

Jerrold H. Levy, MD; Joanne van Ryn, PhD; Frank W. Sellke, MD; Paul A. Reilly, PhD; Amelie Elsaesser, PhD; Stephan Glund, PhD; Jörg Kreuzer, MD; Jeffrey I. Weitz, MD; Charles V. Pollack Jr., MD, MA

Disclosures

Annals of Surgery. 2021;274(3):e204-e211. 

In This Article

Discussion

The important findings of this surgical and procedural patient analysis of the REVERSE-AD study is that idarucizumab showed a rapid and complete reversal of dabigatran activity that was maintained in nearly all patients for 24 hours in more than 95% of patients based on the dTT, with normal to acceptable hemostasis, and minimal requirements for allogeneic blood transfusions or factor concentrates. Although DOAC-related major bleeding is a major concern in surgical patients, in idarucizumab treated patients, hemostasis was manageable, an important finding especially in patients at high risk for postoperative bleeding including aortic dissections, transplantation, and other procedures requiring cardiopulmonary bypass. Hemostasis was also manageable in other patients at high risk for bleeding including patients undergoing neurosurgical procedures or surgery for fractures. Of note is that with idarucizumab administration, heparin anticoagulation can be used at any time, an important consideration in cardiovascular surgical patients requiring cardiopulmonary bypass.

The practical design of our study was developed as a real-world evaluation and did not require waiting for initial coagulation testing before idarucizumab administration. As a result, some patients had normal clotting times at entry. Nonetheless, our study population included critically ill patients with acute renal failure requiring dialysis catheter insertion, patients with acute abdomen and sepsis, and patients with multiple comorbidities requiring emergency orthopedic procedures. The consistency of acute anticoagulation reversal is particularly important in elderly patients following falls and bone fractures because surgery is often delayed if they are taking anticoagulants that cannot be readily reversed. Studies have shown that delay of these procedures result in poorer outcomes in patients.[12,13] Although idarucizumab enables rapid surgery in patients taking dabigatran, it remains unknown whether andexanet will provide the same benefit for those taking oral factor Xa inhibitors.

Overall, the use of additional allogeneic transfusions was low for an elderly population undergoing emergency surgery and procedures. Fresh frozen plasma was transfused in approximately 10% to 25% of patients (except those with gynecological-urinary surgery, who required no transfusions), consistent with effective surgical hemostasis.[14] This is further supported by the relatively low rate of platelet transfusion, because dilutional thrombocytopenia is common following major hemorrhage and resuscitation in surgical patients. Red blood cells were transfused in patients because critically ill patients presenting for emergency surgery often have anemia and require obligatory red blood cell transfusion to maintain hemoglobin levels of 7 to 10 g/dL. Only 5 patients undergoing surgery received prothrombin complex concentrate or recombinant factor VIIa, therapies often used for refractory bleeding and in patients with major hemorrhage following cardiac surgery.[15,16] This finding is consistent with recent reports of normal hemostasis after dabigatran reversal in patients undergoing emergency cardiac surgery and cardiac transplantation.[17–19] Therefore, dabigatran reversal with idarucizumab enables rapid surgery or procedures with good hemostasis.

The 30- and 90-day mortality rates were 12.4% and 18.3%, respectively, results consistent with critically ill and elderly patients with multiple comorbidities that include sepsis, acute abdomen, dialysis catheter placement for acute renal failure, or emergency cardiovascular surgery.[20,21] As a result, mortality was related to the severity of the initial presentation or other associated multiple organ failure.

Thrombotic events occurred in 10 of 202 (5%) patients within 30 days; of these 10 patients, only 5 had restarted anticoagulant therapy by 30 days. The frequency of thrombotic complications at 30-days with idarucizumab is consistent with the 7.8% 30-day rate of thrombotic events reported in patients requiring warfarin reversal after major surgical procedures.[22,23]

In some cases a re-elevation of dabigatran is seen after 24 hours, the most likely explanation for the re-elevation in dabigatran levels is redistribution of unbound dabigatran from the extravascular to the intravascular compartment.[6] However, in the majority of cases, the emergency has been addressed at this point and often parenteral anticoagulation was considered at this time point post-procedure. However, if dabigatran levels persist and another emergency procedure or rebleeding occurs, then the possibility to give a second dose of idarucizumab is given, as included in the label.[24]

In summary, in patients requiring urgent surgery or procedural interventions, idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in more than 95% of patients based on the normalization of dTT, and in 90% of patients based on aPTT. The time from administration of idarucizumab to surgery ranged from 1.2 to 1.9 hours and was consistent across groups. Intraoperative hemostasis was judged as normal in 91% or more patients across all surgery/procedure types, and there was a low rate of postreversal thrombotic events. Therefore, idarucizumab facilitates management of patients requiring urgent procedures by providing specific and rapid reversal and provides an important paradigm for clinical management.

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