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.

Lessons learnt from local real-life experience with idarucizumab for the reversal of dabigatran.

BACKGROUND: Idarucizumab is a specific antidote for the direct thrombin inhibitor oral anticoagulant dabigatran etexilate. It has been used with increasing frequency in Australia since it was granted Therapeutic Goods Administration approval in October 2016. AIMS: To assess idarucizumab usage, effect on coagulation parameters and clinical outcomes in patients who received idarucizumab in Western Sydney Local Health District (WSLHD). METHODS: A retrospective audit was conducted of all patients who received idarucizumab in WSLHD between September 2015 and December 2017. RESULTS: Of the 23 patients who received idarucizumab, 17 (74%) had bleeding, and 6 (26%) required urgent surgery/procedure. Thrombin time (TT) or activated partial thromboplastin time (APTT, when TT not available) remained prolonged at 24 h post-idarucizumab infusion in 10 of 20 (50%) patients. Renal impairment at admission was associated with prolonged TT/APTT at 24 h (P = 0.02). Of the six (26%) patients who died during hospital admission, five had raised TT/APTT at 24 h (P = 0.05). Two deaths were due to continued bleeding despite idarucizumab. Only 17% of patients received prohaemostatic treatments, and none received plasma derivatives. Despite assay availability, dabigatran drug level was only measured in eight patients. CONCLUSION: Idarucizumab helped achieve haemostasis in 15 bleeding patients and allowed 6 patients to undergo urgent surgery. Half the patients had prolonged TT/APTT at 24 h post-idarucizumab, which was more likely to occur in patients with impaired renal function.

Evidence for Idarucizumab (Praxbind) in the Reversal Of the Direct Thrombin Inhibitor Dabigatran: Review Following the RE-VERSE AD Full Cohort Analysis.

Idarucizumab is the first reversal agent approved for the direct thrombin inhibitor dabigatran. The authors summarize the findings from the clinical trial series and describe case reports, post-marketing data, and ongoing studies.

Idarucizumab for Reversal of Dabigatran-Associated Anticoagulation.

OBJECTIVE: To review clinical data on idarucizumab for the reversal of dabigatran-associated anticoagulation. DATA SOURCES: Articles for this review were identified via PubMed using the MeSH term dabigatran combined with the keyword idarucizumab Additional online searches via PubMed and Google Scholar were conducted for both prescribing and cost information. STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials published between 1946 and May 2016 were included for review. Bibliographies of selected articles were also manually reviewed for relevant publications that focused on reversal strategies for dabigatran-associated anticoagulation. DATA SYNTHESIS: The safety and tolerability of idarucizumab has been evaluated in 3 phase I clinical trials. The use of idarucizumab for reversing dabigatran-associated anticoagulation is also being evaluated in the phase III RE-VERSE AD study. Interim results of the RE-VERSE AD study have been published. CONCLUSIONS: Idarucizumab rapidly neutralizes the anticoagulant effect of dabigatran in healthy volunteers, in patients with life-threatening bleeding, and in patients requiring urgent surgery that cannot be delayed. These observations are largely based on laboratory assessments rather than clinical outcomes. Idarucizumab is well tolerated, and it does not appear to induce procoagulant or immunogenic adverse effects.

Carbon-13 and carbon-14 labeled dabigatran etexilate and tritium labeled dabigatran.

Dabigatran etexilate or pradaxa, a novel oral anticoagulant, is a reversible, competitive, direct thrombin inhibitor. It is used to prevent strokes in patients with atrial fibrillation and the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or a knee. Pradaxa is the only novel oral anticoagulant available with both proven superiority to warfarin and a specific reversal agent for use in rare emergency situations. The detailed description of the synthesis of carbon-13 and carbon-14 labeled dabigatran etexilate, and tritium labeled dabigatran is described. The synthesis of carbon-13 dabigatran etexilate was accomplished in eight steps and in 6% overall yield starting from aniline-13 C6 . Ethyl bromoacetate-1-14 C was the reagent of choice in the synthesis of carbon-14 labeled dabigatran etexilate in six steps and 17% overall yield. Tritium labeled dabigatran was prepared using either direct tritium incorporation under Crabtree's catalytic conditions or tritium-dehalogenation of a diiodo-precursor of dabigatran.

Hemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose.

Dabigatran is an oral direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with nonvalvular atrial fibrillation. Since its approval in the United States in 2010, dabigatran-associated hemorrhages have garnered much attention because bleeding rates were higher than initially expected. Additionally, reversing anticoagulation remains challenging. Traditional modes of reversing warfarin-associated coagulopathies are ineffective in reversing anticoagulation from dabigatran. Although hemodialysis is proposed as a method to accelerate dabigatran elimination, evidence supporting its clinical utility remains unproved. We report the case of an 80-year-old man who presented with worsening hemoptysis in the setting of unintentional ingestion of excess dabigatran. Despite transfusion of 2 units of fresh frozen plasma, he continued to bleed, although his international normalized ratio improved from 8.8 to 7.2. He underwent hemodialysis, and serum dabigatran concentration decreased from 1,100 to 18 ng/mL over 4 hours, with an initial extraction ratio of 0.97 and blood clearance of 291 mL/min. Although his serum dabigatran concentration rebounded to 100 ng/mL 20 minutes after the cessation of dialysis, his bleeding stopped and he improved clinically. Hemorrhage in the setting of dabigatran anticoagulation remains a therapeutic predicament. Hemodialysis may play an adjunct role in accelerating the elimination of dabigatran in bleeding patients.

Extensive spontaneous cervical epidural hematoma due to oral anticoagulant (dabigatran) successfully treated with reversal agent idarucizumab alone.

Background: Dabigatran is an anticoagulant (novel oral anticoagulant) that is a direct thrombin inhibitor and only recently has a reversal agent, idarucizumab, been made available (2015). Case Description: An 86-year-old male taking dabigatran for atrial fibrillation, acutely presented with the spontaneous onset of neck pain and quadriparesis. When the MRI demonstrated a C2-T2 spinal epidural hematoma, the patient was given the reversal agent idarucizumab. Due to his attendant major comorbidities, he was managed nonoperatively. Over the next 7 days, the patient's neurological deficits resolved, and within 2 weeks, he had regained normal neurological function. Conclusion: In this case, a C2-T2 epidural cervical hematoma attributed to dabigatran that was responsible for an acute, spontaneous quadriparesis was successfully treated with the reversal agent idarucizumab without surgical intervention being warranted.

Reversal of the Anticoagulation Effects of Dabigatran Etexilate by Idarucizumab in Three Patients Needing Urgent Surgical Intervention and One Case of Intravenous Thrombolysis in Ischaemic Stroke.

OBJECTIVE: To describe the benefits of reversal of the anticoagulation effects of dabigatran etexilate in patients requiring urgent surgery or thrombolysis for ischaemic stroke. MATERIALS AND METHODS: Four patients, treated with dabigatran etexilate and presenting with cholecystitis, tibial fracture, lower limb ischaemia and ischaemic stroke, respectively. RESULTS: Administration of idarucizumab normalized bleeding parameters and provided safe conditions for surgery and, in one case, successful thrombolysis of an ischaemic stroke. CONCLUSION: The introduction of an effective reversal agent for dabigatran etexilate allows physicians perform surgery under conditions of normal coagulation and permits thrombolysis in patients with ischaemic stroke despite being treated with dabigatran etexilate. LEARNING POINTS: Novel oral anticoagulants (NOACs) are a safe alternative to warfarin to prevent ischaemic stroke.Ability to reverse the anticoagulant effects of NOACs could increase adherence to anticoagulation therapy, thereby decreasing the risk of ischaemic stroke.Reversal of the anticoagulant effect of dabigatran etexilate can improve the outcome in patients needing urgent surgery, intervention and thrombolysis.

Thrombin time and anti-IIa dabigatran's activity: hypothesis of thrombin time's predictive value.

Dabigatran etexilate (Pradaxa®) is a new oral anticoagulant, competitive inhibitor, selective, fast, direct and reversible of thrombin. Dabigatran has an impact on a large panel of used coagulation tests. There is no relationship between thrombin time's lengthening and anti-IIa activity. This study defines thrombin time's predictive value, when its time is normal. The result of negative value is 97,6%. 255 patients were studied between January 2013 and July 2014. Thrombin time and anti-IIa activity were dosed for each patient. This study can be an assistant for therapeutic decision for laboratories without specialized test.

Dabigatran etexilate: An alternative to warfarin for patients with nonvalvular atrial fibrillation.

PURPOSE: To critically appraise the evidence on dabigatran etexilate, Pradaxa, as an alternative to warfarin for stroke prevention among patients with nonvalvular atrial fibrillation. This information can assist nurse practitioners in making informed treatment decisions. DATA SOURCES: A review of the literature was conducted using CINAHL and PubMed databases. Reports published on cardiovascular organizational web sites were also searched, along with reference lists of relevant published articles and reports. CONCLUSIONS: Significant evidence from the PETRO and RE-LY trials and postmarketing analyses of dabigatran etexilate indicate that this direct thrombin inhibitor is as efficacious as warfarin in ischemic stroke prevention. In fact, the studies found that patients taking dabigatran etexilate had fewer incidences of ischemic stroke and intracranial hemorrhage than those taking warfarin. Risk for major gastrointestinal bleeding appears to be higher than that for warfarin. IMPLICATIONS FOR PRACTICE: Patients taking dabigatran etexilate do not require blood work to assess international normalized ratio (INR) levels. Because this drug is excreted primarily by the kidneys, reassessment of renal function is critical during treatment, especially with concomitant use of diuretics, fluctuating renal function, or hypovolemia. As with warfarin, nurse practitioners should educate patients about when to seek immediate care for the development of anticoagulant-associated bleeding.

Structure-guided residence time optimization of a dabigatran reversal agent.

Novel oral anticoagulants are effective and safe alternatives to vitamin-K antagonists for anticoagulation therapy. However, anticoagulation therapy in general is associated with an elevated risk of bleeding. Idarucizumab is a reversal agent for the direct thrombin inhibitor, dabigatran etexilate (Pradaxa®) and is currently in Phase 3 studies. Here, we report data on the antibody fragment aDabi-Fab2, a putative backup molecule for idarucizumab. Although aDabi-Fab2 completely reversed effects of dabigatran in a rat model in vivo, we observed significantly reduced duration of action compared to idarucizumab. Rational protein engineering, based on the X-ray structure of aDabi-Fab2, led to the identification of mutant Y103W. The mutant had optimized shape complementarity to dabigatran while maintaining an energetically favored hydrogen bond. It displayed increased affinity for dabigatran, mainly driven by a slower off-rate. Interestingly, the increased residence time translated into longer duration of action in vivo. It was thus possible to further enhance the efficacy of aDabi-Fab2 based on rational design, giving it the potential to serve as a back-up candidate for idarucizumab.

Dabigatran Use in the Real World: A Multihospital System Experience.

Dabigatran etexilate, an oral direct thrombin inhibitor, was approved by the Food and Drug Administration to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation based on the outcomes of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) study. Although this study provides robust data on the efficacy and safety of dabigatran, there may be differences in the drug use and outcomes in routine clinical practice following drug approval. In this retrospective chart review study, we describe the use of dabigatran in 160 patients in 4 adult hospitals (1 academic and 3 community), including appropriate prescribing for indication, starting dose, concomitant anticoagulant and antiplatelet use, and clinical outcomes such as bleeding, myocardial infarction, and stroke. The study revealed appropriate indication of nonvalvular atrial fibrillation in 145 (91%) of the 160 patients. The dose of dabigatran was appropriate in 90% of the patients, with the most common cause of inappropriate dosing due to perceived bleeding risk. Over a follow-up period of 6 months, bleeding complications were noted in 6 patients still taking dabigatran, 5 of which were gastrointestinal bleeding. Our study underscores the importance of prescriber education regarding the appropriate indication, dosage, and safety of dabigatran with active participation of pharmacists in this process.