Idarucizumab (PRAXBIND®) as a sole reversal agent in an unstable hemorrhagic shock patient on an unknown anticoagulant with elevated protime/international normalized ratio (PT/INR).

Dabigatran is a direct oral anticoagulant thrombin inhibitor approved for stroke prophylaxis in patients with non-valvular atrial fibrillation and prophylaxis or treatment of venous thromboembolism. Since approval, there has been increasing concern regarding bleeding risk, predominantly in the elderly population and those with renal disease. We present a case of an 85-year-old female with an unknown medication history, shortness of breath and severe anemia due to an upper gastrointestinal bleed. Laboratory abnormalities were significant for INR 6.43 and serum creatinine 2.21 mg/dL. While in the emergency department the patient decompensated requiring intubation, aggressive crystalloid resuscitation, blood products and initiation of vasopressors. The inability to distinguish between warfarin- and dabigatran-induced coagulopathies paired with the lack of medical information complicated selection of the appropriate anticoagulation reversal agent. In an attempt to prevent a prothrombotic state, prothrombin complex concentrates (PCC) were held and reversal was accomplished with idarucizumab alone, although warfarin-induced coagulopathy remained a possibility. 30 min after administration, repeat PT/INR was 16.1 s and 1.55, respectively. It was later confirmed that the patient was on sole dabigatran therapy. This case highlights the potential for dabigatran to cause extreme elevation in PT/INR in patients with acute renal failure, which may mimic warfarin-induced coagulopathy. Further, it demonstrates significant, rapid correction of abnormal coagulation assays following administration of idarucizumab in a patient with severe INR elevation and suspected dabigatran use.

Stroke reperfusion therapy following dabigatran reversal with idarucizumab in a national cohort.

OBJECTIVE: To assess the frequency and utilization trends of dabigatran reversal with idarucizumab and compare associated complications, outcomes, and door-to-needle times to those of patients not exposed to idarucizumab in a nationwide cohort of thrombolyzed patients over a 24-month period. METHODS: This is an observational cohort study of all New Zealand patients with stroke treated with stroke reperfusion entered into a mandatory online national registry. Each hospital records data including patient demographics, treatment delays, complications, 7-day outcomes, and idarucizumab use. RESULTS: Between 1 January 2017 and 31 December 2018, 1,336 patients received thrombolysis. Fifty-one patients received idarucizumab prior to thrombolysis (median [interquartile range] age 73 [57-83] years): 8 (1.3%) in 2017 and 43 (6%) in 2018 (p < 0.001). Over the same 24-month period, 386 patients had stroke clot retrieval, of whom 8 (2.1%) were first treated with idarucizumab. Idarucizumab-treated patients had slower door-to-needle times (83 [54-110] minutes vs 61 [43-85] minutes, p = 0.0006). Symptomatic intracerebral hemorrhage occurred in 2 (3.9%) of the idarucizumab-treated patients and 49 (3.8%) of the other thrombolyzed patients (p = 0.97). None of the idarucizumab-treated patients had significant thrombotic complications. At 7 days, 3 (5.9%) idarucizumab-treated and 101 (7.9%) of the other thrombolyzed patients had died (p = 0.61). CONCLUSION: Idarucizumab was used in 6% of all thrombolyzed patients in a national cohort during 2018, up from 1.3% in 2017. Idarucizumab appeared to be safe with similar clinical outcomes to routinely managed patients, despite a 22-minute door-to-needle time delay. Idarucizumab can facilitate thrombolysis in patients with stroke taking dabigatran. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that idarucizumab use is associated with similar early post-thrombolysis outcomes compared with patients not exposed to this drug.

Global Use of Idarucizumab in Clinical Practice: Outcomes of the RE-VECTO Surveillance Program.

Idarucizumab was approved for the reversal of dabigatran in 2015. We investigated whether postapproval usage patterns of idarucizumab in a real-world setting reflect those observed in the pivotal trials. No safety or efficacy data were collected in this medical record-based observational study. RE-VECTO, a global postapproval, international, surveillance program, involved hospital pharmacies in countries where idarucizumab was licensed and dispensed (August 2016-June 2018). Characteristics of sites prescribing idarucizumab and of eligible patients (≥ 18 years old and receiving idarucizumab regardless of prior oral anticoagulant use), as well as idarucizumab utilization data, were collected and analyzed descriptively. Sixty-one sites enrolled 359 patients. Most pharmacies (85.2%) were centralized, and the median idarucizumab units stocked per hospital was 2.0 (interquartile range, 1.0-3.0). Almost three-quarters of patients were elderly (74.9% aged > 70 years), and only four (1.1%) had received idarucizumab before. Nearly all patients were treated with dabigatran (97.5%). There was a low frequency of unapproved dabigatran dosage regimens (3.3%). Life-threatening or uncontrolled bleeding was the most frequent indication for idarucizumab (57.7%), followed by emergency surgery/urgent procedure (35.9%). Of the life-threatening bleeding events, the most frequent were gastrointestinal tract (44.4%) and intracranial (38.6%). Most patients (95.0%) were given the full dose of two vials (2 × 2.5 g) of idarucizumab initially, and very few (1.7%) received a second dose. Of those patients requiring emergency or scheduled/planned surgery/procedures, 25.5% underwent gastrointestinal and/or abdominal surgery/procedures. Real-world usage patterns of idarucizumab provide valuable insights into emergency reversal strategies. Off-label use was minimal.

Idarucizumab for Reversal of Dabigatran in Early/Emergency Surgeries: A Case Series.

BACKGROUND: Idarucizumab is a humanized, monoclonal antibody fragment used specifically to reverse the anticoagulant effects of dabigatran. CASE REPORTS: We discuss 4 cases of patients who were treated with idarucizumab to reverse dabigatran before early/emergency surgery. Two of the patients had subdural hematomas, 1 had a splenic laceration, and 1 had Fournier gangrene. All patients received 5 g of idarucizumab before surgery. Intraoperative blood loss in all patients was normal, no adverse events were reported, and the patients recovered normally. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The case reports presented provide detailed, practical, real-world experience beyond that reported in other case reports and the Reversal Effects of Idarucizumab on Active Dabigatran study. This can help guide clinicians on how idarucizumab can reverse the anticoagulant effect of dabigatran in emergency situations, including patients with subdural hematoma. Our experience suggests that idarucizumab may be a safe and effective antidote to the effects of dabigatran in real-life bleeding situations involving early or emergency surgeries.

Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa® in clinical routine (MR REPAIR).

OBJECTIVES: To evaluate daily life management and functional outcome of Idarucizumab administration in case of emergency situations in patients with Dabigatran treatment. DESIGN: Multicenter observational registry study. SETTING: All hospitals with full neurological departments (n = 6) in Munich, Germany INCLUDED PATIENTS: All patients treated with Idarucizumab from 01/2016 to 03/2019. ANALYZED DATA: Indication and application of Idarucizumab, demographics and clinical parameters, and further interventions and treatments; clinical outcome was assessed with the modified Rankin scale (mRS) at 3 months after Idarucizumab administration RESULTS: Idarucizumab was administered to 32 patients for severe bleeding complications and ischemic strokes, more precisely for the following specific indications: intracranial bleeding (17 patients, 53%), ischemic stroke (8 patients, 25%), gastrointestinal bleeding (3 patients, 9%), femoral fracture, aortic dissection, and abdominal trauma and ileus (1 patient each, 3%). Additional coagulation management was performed in 7 patients (22%). Nine patients (28%) underwent emergency surgery. Seven patients (22%) received Idarucizumab before intravenous thrombolysis due to ischemic stroke and 4 of these 7 patients (13%) received mechanical thrombectomy in addition. Indication was mainly based on the history of Dabigatran intake and was irrespective of laboratory testing. At follow-up, 25% of the investigated patients had a mRS 0-2, while 25% had an unfavorable outcome (mRS 4-5). Mortality was 31%. CONCLUSION: In our study, we have shown that the administration of Idarucizumab is a rare intervention and restricted to patients with severe bleeding complications or ischemic stroke. The clinical outcome of patients who received Idarucizumab in emergency situations was poor.

Reversal of dabigatran requiring hemodialysis, fresh frozen plasma, and 2 doses of idarucizumab in a patient with acute kidney injury.

PURPOSE: A case report of dabigatran-associated coagulopathy that lasted for about 1 week after drug discontinuation despite use of several treatment measures is presented. SUMMARY: Life-threatening hemorrhage can occur in patients receiving dabigatran, a direct-acting oral anticoagulant. Idarucizumab is a newly approved dabigatran antidote that neutralizes the drug's anticoagulant activity. An 80-year-old Caucasian man with a medical history of hypertension, coronary artery disease, congestive heart failure, gout, and atrial fibrillation was hospitalized with acute kidney injury (AKI) caused by bilateral hydronephrosis secondary to distal urethral stricture. The patient had prolonged coagulation parameters and major bleeding. Initial laboratory values revealed anemia, with a hemoglobin concentration of 8.9 g/dL; a serum creatinine concentration of 3.9 mg/dL; a prothrombin time of 15 seconds; an International Normalized Ratio of 1.1; and a platelet count of 142,000 platelets/mm3. Three hemodialysis sessions and administration of fresh frozen plasma (FFP), packed red blood cells, and 2 doses of idarucizumab were required in order to achieve hemostasis 8 days after dabigatran was discontinued. CONCLUSION: A patient with AKI who had been taking dabigatran and developed major bleeding needed 2 doses of idarucizumab in addition to FFP and 3 sessions of hemodialysis in order for hemostasis to be restored. This case suggests that idarucizumab might not produce hemostasis in a timely manner in patients with poor renal function.

Reversal agents for direct oral anticoagulants: considerations for hospital physicians and intensivists.

Direct oral anticoagulants (DOACs) include dabigatran etexilate, a direct thrombin inhibitor, and specific inhibitors of activated coagulation factor X (FXa; e.g. apixaban, betrixaban, edoxaban, rivaroxaban). DOACs are associated with lower rates of major and fatal bleeding events compared with warfarin. Clinicians may need to achieve rapid reversal of anticoagulation effects of the DOACs in an emergency setting. Idarucizumab and andexanet alfa, which reverse the anticoagulant effects of dabigatran and FXa inhibitors, respectively, are DOAC reversal agents available in the US. Other reversal agents (e.g. ciraparantag for heparins, DOACs) are in development. Alternative nonspecific agents (e.g. fresh frozen plasma, prothrombin complex concentrate) are available. Nonspecific prohemostatic agents can counteract the anticoagulant action of DOACs in emergency situations, when specific reversal agents are unavailable. However, specific reversal agents are efficacious and safe and should be preferred when available. In this review, we discuss practical issues in the initiation of DOAC therapy, situations where reversal may be needed, coagulation assays, reversal agents, and post-reversal complications in the context of published evidence and guidelines.

Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution.

BACKGROUND: Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to idarucizumab. METHODS: Twenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer's solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters. RESULTS: Mean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups. CONCLUSION: This study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of idarucizumab to dabigatran.

Performance of idarucizumab as antidote of dabigatran in daily clinical practice.

AIMS: Because practice-based data on the usage of idarucizumab for urgent dabigatran reversal is unavailable, we evaluated the appropriateness of idarucizumab usage, its haemostatic effectiveness and clinical outcomes. METHODS AND RESULTS: An observational cohort study was performed including consecutive patients who were treated with idarucizumab between 2016 and 2018. Appropriate usage was assessed with predefined criteria. Post-reversal effectiveness was evaluated according to International Society on Thrombosis and Haemostasis (ISTH) recommendations. Patients were followed for 90 days for occurrence of thromboembolism, (re-)bleeding and death. Idarucizumab was used in 88 patients, of whom 53 (60%) presented with severe bleeding (20 gastrointestinal and 18 intracranial) and 35 (40%) requiring urgent surgical intervention. Use of idarucizumab was judged inappropriate in 25 patients (28%). Effective haemostasis was achieved in 32 of 48 (67%) bleeding patients in whom assessment was possible. Seven of 16 patients with major bleeding who did not achieve effective haemostasis (five intracranial) died, compared with two of 32 patients with effective haemostasis (relative risk 7.0, 95% confidence interval 1.6-30). Four patients (4.2%) developed thromboembolism [2 (2.1%) within 30 days] and four patients (4.2%) re-bleeding, all within 10 days. Seventeen patients (19%) died; 10 (11%) within 5 days. CONCLUSION: In this practice-based cohort, idarucizumab use was considered inappropriate in 28% of patients. Effective haemostasis was achieved in two-third of bleeding patients and was associated with lower mortality risk. Clinical outcomes were similar to those observed in the RE-VERSE AD trial, comprising re-bleeds and thromboembolism, and a high-mortality rate.

Treatment With Intravenous Alteplase for Acute Ischemic Stroke After Reversal of Dabigatran With Idarucizumab: A Case Study.

Treatment options for anticoagulated patients presenting with ischemic stroke are limited. Off-label use of idarucizumab to rapidly reverse the anticoagulant effect of dabigatran may ensure eligibility for thrombolytic therapy with alteplase. This case describes a 77-year-old white male who presented to the hospital 89 minutes after sudden onset of right-sided hemiparesis, dysarthria, and facial palsy. Significant history included atrial fibrillation and previous right-sided cortical stroke. Medication reconciliation revealed he was taking dabigatran 150 mg twice a day, with the last dose being 179 minutes before presentation. Neuroimaging revealed no new infarct or hemorrhage, and 60 minutes after arrival, a decision was made to give idarucizumab to reverse the anticoagulant effect of dabigatran. In the absence of any contraindication, he was then treated with intravenous alteplase and idarucizumab. No adverse outcomes were noted, and at discharge, his new stroke symptoms were completely resolved.

Intravenous Thrombolysis After Idarucizumab Application in Acute Stroke Patients-A Potentially Increased Sensitivity of Thrombi to Lysis?

BACKGROUND: Rapid inactivation of dabigatran by its specific inhibitor idarucizamab allows intravenous thrombolysis (IVT) in patients suffering ischemic stroke while being treated with dabigatran. Only limited data of this approach is available and numerous questions regarding efficacy/safety remain to be answered. Herein, we present the findings from the Slovenian national cohort study. METHODS: Retrospective analysis of all stroke patients treated with idarucizumab and IVT (n = 11) in the period from July 2016 to February 2018 from Slovenian region were analyzed. RESULTS: The indication for dabigatran treatment in all 11 cases was nonvalvular atrial fibrillation. Importantly, 6 out of 11 cases were classified as severe ischemic strokes (National Institutes of Health Stroke Scale; NIHSS ≥ 10) with a median NIHSS 13. At admission, prolonged activated partial thromboplastin time was present in 9 patients indicating therapeutic anticoagulation activity. The average door-to-needle time was 156 minutes. After 3 months, 9 patients had a modified Rankin Score of less than or equal to 2 and 7 patients had mRS less than 1 whereas, 2 patients died due to symptomatic intracranial hemorrhage (sICH); 1 due to spontaneous sICH, and the other due to a large ischemic stroke with hemorrhagic transformation. No thrombotic complications were observed. CONCLUSIONS: Our data show that IVT after idarucizumab administration is a safe and effective method of treatment in ischemic stroke patients on dabigatran. We recorded a higher proportion of patients with favorable outcome as well as with sICH compared to the randomized controlled studies which could suggest a higher sensitivity of thrombi to IVT in dabigatran treated patients.

Intravenous Thrombolysis in Acute Ischemic Stroke After Idarucizumab Reversal of Dabigatran Effect: Analysis of the Cases From Taiwan.

BACKGROUND: Asians with atrial fibrillation carry a higher risk of ischemic stroke than non-Asians even under treatment of nonvitamin K antagonist oral anticoagulants. The purpose of the study was to observe the feasibility of intravenous thrombolytic therapy after administering a reversal agent, idarucizumab, in dabigatran-treated patients with acute ischemic stroke in Taiwan. METHODS: Dabigatran-treated patients with acute ischemic stroke who received intravenous recombinant tissue plasminogen activator (rt-PA) after idarucizumab reversal were enrolled in the retrospective nationwide study. The clinical data, treatment course, and outcomes were recorded. Stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) score. Any intracerebral hemorrhage (ICH) after rt-PA was detected by neuroimaging studies. RESULTS: Ten dabigatran-treated patients (6 men, mean age 71.10 ± 7.96 years) with acute ischemic stroke were included. Before stroke, the mean CHA2DS2-VASc score was 4.50 ± 1.57 and 8 patients (80%) received dabigatran 110 mg twice daily. All patients were treated with 5 g idarucizumab, following which the activated partial thromboplastin time normalized. Intravenous rt-PA (mean dose .78 mg/kg) was initiated a mean time of 11.11 minutes after idarucizumab infusion. The NIHSS score improved significantly after thrombolysis (16.0 ± 6.67 at admission to 9.38 ± 4.75 at discharge, P = .016). ICH developed in 3 patients (30%). Two of them were asymptomatic and 1 patient suffered from symptomatic ICH leading to mortality. CONCLUSION: Our data reconfirmed the feasibility of intravenous rt-PA for Asian stroke patients after reversal of dabigatran effect with idarucizumab.

Reversal of dabigatran by intraosseous or intravenous idarucizumab in a porcine polytrauma model.

BACKGROUND: Idarucizumab is licensed to reverse dabigatran in life-threatening haemorrhage. Establishment of venous access can be challenging, and the intraosseous (IO) route is a potentially life-saving alternative. In this study, we compared the efficacy and safety of IO or intravenous (i.v.) idarucizumab for dabigatran reversal in a porcine polytrauma model. METHODS: Male pigs (n=21) received oral dabigatran etexilate (30 mg kg-1 bid) for 3 days. On the 4th day, animals received dabigatran infusion and were randomised 1:1:1 to receive IO saline (control), i.v. idarucizumab (60 mg kg-1), or IO idarucizumab (60 mg kg-1), or animals were included in a sham group (n=7). Study treatment was administered after polytrauma and the animals were monitored for 240 min, or until death. Coagulation status was monitored by thromboelastometry, thromboelastography, and thrombin measurements. RESULTS: Total blood loss was lowest in sham animals [521 (52) ml, P<0.01 vs all other groups], and comparable in the two idarucizumab groups [IO: 1085 (102) ml vs i.v.: 1142 (125) ml], and highest in the control group [4065 (557) ml, P<0.001 vs all other groups]. Survival to 240 min was 100% in the sham group and both idarucizumab groups, and 14% in the control group. IO and i.v. idarucizumab promptly normalised global coagulation assays and thrombin generation. Thromboelastography showed a strong correlation between dabigatran concentrations and R-time (R2=0.90 and 0.89) in idarucizumab-treated animals. CONCLUSIONS: Intravenous and intraosseous idarucizumab were comparable for reversing dabigatran in a porcine trauma model. Dabigatran reversal could be monitored using fully automated thromboelastography.

Real-World Experience with Idarucizumab to Reverse Anticoagulant Effect in Dabigatran-Treated Patients: Report of 11 Cases from Taiwan.

BACKGROUND: This study aims to observe the effectiveness and safety of idarucizumab in dabigatran-treated patients with severe bleeding or requiring surgery in Taiwan. METHODS AND RESULTS: In Taiwan, 11 dabigatran-treated patients developed severe bleeding, fracture that needed surgery, and acute ischemic stroke requiring thrombolysis. These patients were treated with idarucizumab and obtained adequate hemostasis. Our experiences reconfirmed the efficacy and safety of idarucizumab in Asian patients. CONCLUSIONS: Idarucizumab improves safety in dabigatran-treated patients. Continued education about the availability and appropriate use of idarucizumab is necessary in Asia.