Idarucizumab for urgent reversal of dabigatran for heart transplant: A case report

Until the recent approval of the direct acting oral anticoagulants (DOACs), vitamin K antagonists (VKA) such as warfarin were the mainstay of therapy for patients requiring long-term oral anticoagulation. It is readily reversible with phytonadione (Vitamin K), fresh frozen plasma (FFP), and four factor prothrombin complex concentrate (4PCC). DOACs have several advantages over VKA, including rapid onset of action, predictable pharmacokinetic profiles, no monitoring, and less drug–drug and drug–food interactions. Their fast onset of action limits the need for intravenous bridging with heparin or low-molecular-weight-heparin (LMWH) in the event that anticoagulation needs to be temporarily held for a procedure or planned surgery. However, for emergent surgery or life threatening bleeding, immediate reversal of anticoagulation is desirable.1 Reversal of anticoagulation in patients taking a DOAC requiring an invasive procedure should be based in part on the patient's renal function, the length of time from last DOAC administration, concomitant medications, and the risk of procedure related bleeding.2 Idarucizumab is the first targeted reversal agent available and is specific for dabigatran, a direct thrombin inhibitor (DTI). It is a humanized monoclonal antibody fragment that is FDA approved for emergency surgery/urgent procedures or for life-threatening or uncontrolled bleeding in patients taking dabigatran based on data from the REVERSE-AD study.3 We describe a real world case of a patient receiving dabigatran for stroke prevention in non-valvular atrial fibrillation (NVAF) who required unplanned orthotopic heart transplant requiring cardiopulmonary bypass (CBP). A 59-year-old female with a history of non-ischemic dilated cardiomyopathy with class III-IV heart failure (left ventricular ejection fraction 15%), an implantable cardiac defibrillator, INTERMACS 3, history of cerebrovascular accident small secundum atrial septal defect, and NVAF on amiodarone and dabigatran 150 mg orally twice daily, presented in acute heart failure for medical management. She was stabilized on two inotropes and remained hospitalized awaiting heart transplant (UNOS Status 1A). Baseline labs 24 hours (h) prior to heart transplant were international normalized ratio (INR) 1.2 (reference range 0.9-1.1), prothrombin time (PT) 15.2 (reference range 11.5-14.5 seconds), activated partial thromboplastin time (aPTT) 27.9 (reference range 23.8-36.6 seconds), creatinine 0.97 (reference range 0.50-1.20 mg/dL), and platelets 319 (reference range 150-350 K/uL). Dabigatran 150 mg was continued and was given at 8:00 am the day of notification of an available donor heart. The transplant surgery team was notified of the availability of a heart at 1:00 pm. Idarucizumab was given at 2:00 pm (2.5 grams ×2 doses fifteen minutes apart), surgery commenced at 1:30 am and she was cannulated for CPB at 2:00 am, 12 h after idarucizumab and 18 h after the last dose of dabigatran. The procedure went well without excess bleeding, requiring no blood product transfusions or concentrated clotting factor administration. Total CPB time was 98 minutes and cross clamp time was 73 minutes. Anticoagulation for CPB with unfractionated heparin (UFH) was monitored using protamine titration. Labs at 16.5 h after idarucizumab were an INR 1.6, PT 18.5, aPTT 33.7, hemoglobin (Hgb) 13.7 (reference range 13.5-18.0 g/dL), hematocrit (HCt) 39.3 (reference range 40.0-54.0%), creatinine 1.1, and platelets 142. The INR at 30 h was 1.7 and aPTT 31.9. Despite labs demonstrating post-operative coagulopathy related to CPB, the patient did not require transfusions, re-operation for bleeding, or subsequent doses of idarucizumab post procedure. The INR was 1.3 on (post operative day) POD 3. She was started on UFH for stroke prophylaxis due to NVAF on POD 2. Over the past five years, the DOACs have emerged as commonly used anticoagulants for stroke prevention in NVAF and treatment or secondary prevention of venous thromboembolism (VTE). For patients awaiting solid organ transplant, anticoagulation selection requires deliberate clinical decision making by the team to facilitate the need for urgent reversal when an organ becomes available. Prior to the availability of idarucizumab, the majority of patients awaiting heart transplant requiring oral anticoagulation were treated with warfarin. The DOACs provide predictable pharmacokinetics, lack of routine monitoring, and short half-lives that facilitate easier periprocedural management in those with planned procedures; however, the lack of a specific reversal agent limited their use in this population due to the unpredictable timing and availability of organs. Dabigatran, a direct thrombin inhibitor, is FDA approved for stroke prevention in NVAF, treatment of VTE, and for VTE prophylaxis after joint replacement surgery. It reversibly binds to the active thrombin site and prevents the conversion of soluble fibrinogen to a network of fibrin. It is administered as a prodrug, dabigatran etexilate, which is rapidly enzymatically converted to dabigatran after gastrointestinal absorption. The peak anticoagulant effect is achieved within 2-3 h. Its clearance is primarily renal dependent, and the relatively short half life of approximately 12 h can be prolonged in patients with reduced renal function.4 Idarucizumab, a humanized monoclonal antibody fragment (Fab), was developed as an antidote for dabigatran. The binding affinity of idarucizumab for dabigatran is 350 times the binding affinity of dabigatran for thrombin. As a result, idarucizumab binds to both free and thrombin bound dabigatran in the plasma to rapidly neutralize its anticoagulant effects. In the REVERSE-AD trial, rapid reduction in the plasma concentration of unbound dabigatran was observed, with dramatic decrease in anticoagulant activity based on coagulation assays after administration of 5 grams intravenous (IV) idarucizumab.3 Although REVERSE-AD included patients requiring emergent procedures, there are no published reports to date of those requiring a heart transplant.3 Heart transplant surgery is a long procedure requiring the use of CPB. It results in widespread activation of the hemostatic system therefore requiring systemic anticoagulation, and poses many challenges, including dilutional coagulopathy, consumption of coagulation factors, fibrinolysis, inflammatory reactions, and platelet and endothelial activation. Many strategies exist to mitigate bleeding, such as administration of concentrated clotting factors. These products have been used off-label to supplement transfusion protocols for bleeding after CPB in adults, however, efficacy data are limited.5 In this patient, dabigatran was chosen prior to heart transplant for stroke prevention in NVAF for ease of administration with the knowledge that idarucizumab was available should the patient develop bleeding or a donor heart become available. Although andexanet-alpha is currently being evaluated for its use to reverse factor Xa inhibitors, such as apixaban, rivaroxaban, enoxaparin, and edoxaban, for patients with life-threatening bleeding, this agent is not yet commercially available.6 Other options for reversal such as 4PCC or activated prothrombin complex concentrate such as factor eight inhibitor bypassing activity, have been studied and have uncertain efficacy when reversing anticoagulation with DOACs.7, 8 Based on these considerations, dabigatran was chosen for oral anticoagulation in this patient. Patients with an unpredictable timing of surgery or procedures requiring CPB pose a challenge for those requiring long-term oral anticoagulation, unlike elective procedures that allow time for periprocedural anticoagulation management when holding doses may be sufficient.2 In this case, idarucizumab was shown to successfully neutralize dabigatran activity and enable heart transplant on CPB without excess bleeding, blood transfusions, re-operation for bleeding, or for repeat dose of idarucizumab. Despite institutional guidelines addressing emergent use, detailed procedures regarding administration time and laboratory testing for urgent peri-operative use were not incorporated. Retrospective review by our inpatient anticoagulation management stewardship service identified a number of areas for improved guidance in this real world case, including timing of administration in relation to surgery, and appropriate lab testing. Detailed administration guidelines and education are needed at the institutional level for optimal use of idarucizumab. There were no sources of funding. The authors have no relevant conflicts of interest. Dr. Connors is a consultant for St. Jude's Thoratec and Bristol Myers Squibb, and has participated in advisory boards for Boehringer Ingelheim Scientific and Bristol Myer Squibb.