Specific Reversal Agent For Dabigatran Research Articles

Outcome after intracranial hemorrhage under dabigatran and reversal with idarucizumab versus under vitamin-K-antagonists - the RIC-ICH study.

Intracranial hemorrhage (ICH) is a rare but serious side effect associated with the use of oral anticoagulants, such as dabigatran. The specific reversal agent for dabigatran, idarucizumab, is available for the management of individuals with ICH. The aim of this study was to provide real-world evidence on patients with ICH and effective treatment with dabigatran and reversal with idarucizumab in clinical routine compared to those under effective treatment with vitamin-K-antagonist (VKA). Registration of Idarucizumab for Patients with IntraCranial Hemorrhage (RIC-ICH) is a non-interventional study conducted in 22 German stroke units that prospectively enrolled dabigatran patients treated with idarucizumab. Retrospective data from VKA patients served as reference population. Main objective was in-hospital mortality. Further objectives included change in bleeding volume, stroke severity, and functional status. In-hospital mortality was 26.7% in 15 dabigatran and 27.3% in 88 VKA patients (hazard ratio 1.00, 95% CI 0.29-2.60). In patients with bleeding volume > 60 ml, mortality was lower in the dabigatran group (N = 6, 33%) compared to the VKA group (N = 15, 67%; HR 0.24, 95% CI 0.04-0.96). No differences were observed in secondary endpoints between dabigatran and VKA patients. These results, based on data from routine clinical practice, suggest that in-hospital mortality after idarucizumab treatment is comparable to that in patients pretreated with VKA. Due to the low precision of estimates, the results must be interpreted with caution.

Reversal of dabigatran with IDARUCIZUMAB in Hospital Tengku Ampuan Rahimah, Klang: Case series

Dabigatran is a direct thrombin inhibitor used in non-valvular atrial fibrillation(NVAF), deep venous thrombosis(DVT)/pulmonary embolism(PE) and venous thromboembolism(VTE) prophylaxis. Idarucizumab is specific reversal agent for dabigatran which have been shown to be useful in situations such as major bleeding or emergency surgery .We are reporting the use of idarucizumab in a tertiary centre.

Idarucizumab for Reversing Anticoagulation in Patients Treated with Dabigatran: Experience in Our Center

INTRODUCTIONPatients who are receiving oral anticoagulant therapy for the prevention of stroke or thrombosis may benefit from anticoagulant reversal if they present life-threatening bleeding or if they will be undergoing urgent surgery or intervention.Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds dabigatran and its metabolites with a very high affinity, approximately 300 times more potent than the binding affinity of dabigatran to thrombin. It thus neutralizes its anticoagulant effect. It is indicated in adult patients treated with this direct oral anticoagulant when a rapid reversal of its anticoagulant effect is required, for surgical or urgent procedures and in the case of potentially fatal or uncontrolled bleeding.It is given intravenously. The recommended dose is 5 g administered in two intravenous infusions of 2.5 g every 5-10 minutes.OBJECTIVESThis is a descriptive study to determine whether darucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who are about to undergo an urgent procedure.METHODSThe two clinical cases of patients treated with idarucizumab in this year are described.CASE 1A 70-year-old woman receiving anticoagulant Dabigatran 150mg/12h for Non-valvular Atrial Fibrillation (NVAF), who comes to the emergency due to abdominal pain of several hours of evolution. In the previous 24 hours, surgical hysteroscopy had been performed, due to postmenopausal metrorrhagia, in order to rule out the endometrial process.Complementary tests showed a drop in hemoglobin levels from 14.8 mg/dL to 12.3 g/dL, prothrombin activity 8%,INR 10.58, Prothrombin time (PT) 8%, activated partial thromboplastin time (APTT) 55 seconds. Thus, it is administered 10 mgr Konakion and 1200 IU Human Prothrombin Complex. Two hours later: PT 23%, INR 3.15, PT 2.7 ratio. Renal function was normal.An abdominal/pelvic CT scan was performed, where pneumoperitoneum was observed in an important amount as well as abundant hemoperitoneum, suggesting uterine perforation.The patient was moved over specialized hospital.The last dosis of Dabigatran had been 6 hours ago. Due to the need of urgent surgery, idarazizumab was given in two intravenous boluses of 2.5 g.Hysterectomy with a double annexectomy was made.12 hours after surgery, anticoagulant treatment with low molecular weight heparin was introduced. She also presented hemorrhagic subhepatic abscess as a surgical complication (not related to dabigatran) that required percutaneous drainage, with good evolution. The patient was discharged continuing treatment with Bemiparin. 20 days later, Dabigatran 150mg/12h was reintroduced without further complications till the present date.CASE 2A 55-year-old male receiving anticoagulant Dabigatran 150mg/12h for NVAF, who came to the emergency for pain located in the right renal fossa for the previous 24h, along with dysuria and pollakiuria.On examination he had signs of severe pain; He was hemodynamically stable with fever (38ºC). Complementary tests: leukocytosis 12000x10e3/mm3, creatinine 1.5 mg/dL, and positive hematuria, Prothrombin activity 96%, APTT 37 seconds. Abdominal ultrasonography and CT scan were performed, showing complicated renal colic.It was decided to implant double J-catheter, for which we had to reverse the anticoagulant effect of Dabigatran, whose last dose had been taken in the previous 12 hours. For this, idarazizumab was given in two intravenous boluses of 2.5 g, and the intervention was carried out without incident.24 hours later, after a good clinical evolution of his renal pathology, and before no evidence of bleeding was evident, Dabigatran was restarted at its usual dose of 150mg/12h, with no new complications thus far.RESULTSThe use of idarucizumab permitted rapid and safe intervention of patients. Both had normal hemostasis during the procedure. 5 g dose of idarucizumab was sufficient and reversal was maintained for 24 hours. One patient presented hemorrhagic complication related to the surgical procedure.CONCLUSIONSIdarucizumab is integrated into protocol for the emergency management of patients on dabigatran. Idarucizumab is effective for dabigatran reversal among patients who have uncontrolled bleeding or will be undergoing urgent surgery. Idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. DisclosuresNo relevant conflicts of interest to declare.

Patterns and trends of idarucizumab use in an Italian region: a probabilistic record-linkage approach in a real-life setting

Abstract Background Idarucizumab is a specific reversal agent for dabigatran, a direct oral anticoagulant. In 2015, idarucizumab was approved in Europe to quickly restore coagulation and it is currently subject to additional safety monitoring. The drug is administered only during inpatient or emergency care: in such settings, its use is poorly captured by most real-world databases. Purpose To retrieve individual level information on idarucizumab use from an Italian record-linkage claims database in order to describe main characteristics of users. Methods Italy has a regional-based, universal coverage healthcare system. Healthcare delivered to each inhabitant of Tuscany, an Italian region, is registered in a record-linkage claims database (RLCD). This information can be traced at individual level using an encrypted identification code, except in the case of medicines administered in Inpatients or Emergency Care (IEC), where only date and ward of administration are recorded. All person-years (PYs) exposed to dabigatran from January 2015 to December 2018 were calculated from RLCD, using defined daily doses (DDDs) to estimate duration of each recorded dispensation. Idarucizumab use during the study period was identified from IEC, and incidence rate was calculated over PYs of dabigatran use. To identify subjects treated with idarucizumab, emergency admissions and hospital discharge records were probabilistically linked to dabigatran users, matching date and ward of admission as retrieved from RLCD. A further selection was made by a manual check of the diagnoses compatible with the indications of use of idarucizumab. Linked users were described in terms of indication and followed-up for 30 days to assess mortality. Results During the study period, 26,821 PYs of dabigatran use were observed, and 112 administrations of idarucizumab were recorded, corresponding to 4.2 (95% CI: 3,4–5,0) per 1,000 PYs. Overall, 103 idarucizumab administrations (92.0%) were linked to at least one patient, while 50 (44.6%) were uniquely linked to 47 patients. Most of them were men (55.3%), aged ≥80 years (68.1%). Indications were emergency surgical procedures and life-threatening bleeding in 17 (36.1%) and in 30 subjects (63.9%), respectively. Overall, 30-days mortality was 17.0% (N=8). Conclusions This analysis demonstrates the potential of the Tuscany database in retrieving patient-level information on idarucizumab use and sets the stage for post-marketing surveillance on its safety profile in a real-life setting. Funding Acknowledgement Type of funding source: None

Case Report of Endovascular Thrombectomy in Severe Acute Ischemic Stroke After Dabigatran Reversal with Idarucizumab

Non-vitamin K antagonist oral anticoagulants have provided an optimization of management of patients in the prevention of stroke in nonvalvular atrial fibrillation. The lack of an effective reversal agent has remained a challenge to these agents’ widespread utilization. Idarucizumab, a specific reversal agent for dabigatran, is approved in many countries including India. However, there is limited data for its use for Indian patients. We are reporting one of the cases of its use in India where it successfully reversed dabigatran prior to mechanical thrombectomy in acute ischemic stroke.

Reversal of the anticoagulant effect of direct thrombin inhibitor dabigatran etexilate in acute ischemic stroke and intracranial hemorrhage using idarucizumab – A case study

Reversal of the anticoagulant effect of direct thrombin inhibitor dabigatran etexilate in acute ischemic stroke and intracranial hemorrhage using idarucizumab – A case study - IJN- Print ISSN No: - 2581-8236 Online ISSN No:- 2581-916X Article DOI No:- 10.18231/j.ijn.2019.028, IP Indian Journal of Neurosciences-IP Ind

IDARUCIZUMAB, A SPECIFIC REVERSAL AGENT FOR DABIGATRAN: THE PRESENT-DAY KNOWLEDGE

Idaruzizumab (Praxbind©) is a specific reversal agent for dabigatran, which is a humanized Fab fragment of a monoclonal antibody. Immediately after administration, the drug binds to dabigatran and its metabolites, inhibiting 99% of the anti-coagulant activity of dabigatran from the very first minutes. In most cases, after the administration of two doses of idaruzizumab, 2.5 mg each, the anticoagulant effect of dabigatran is inhibited for 24 hours. The drug is safe, has no prothrombotic action on its own. The evidencebase administration of idarucizumab is supported by the open prospective cohort REVERSE-AD study. The study showed that idaruzizumab effectively inhibits the anticoagulant effect of dabigatran in patients with life-threatening bleeding, as well as in patients who required emergency invasive intervention. This study is characterized by the absence of a placebo group, which makes it possible to make only indirect evaluation of the clinical efficacy of this drug. The absence of the placebo group was due to ethical concerns that did not allow the investigators to leave patients with life-threatening conditions without a specific reversal agent for dabigatran. So far, several small series of clinical cases have been published, describing the use of idarucizumab in actual practice. In addition to official indications for the use of the drug, its use as a step to thrombolysis in patients receiving dabigatran has been described. The leading experts of cardiological communities believe that existing experience in using idaruzizumab is sufficient to recommend its use in patients with life-threatening bleeding on the top of already administered dabigatran therapy along with general measures aimed at eliminating the source of bleeding and maintaining hemodynamics.

Consensus Guides on Stroke Thrombolysis for Anticoagulated Patients from Japan: Application to Other Populations.

Development of direct oral anticoagulants and their antidotes has led to the need to reconsider the eligibility of acute stroke patients who have been taking oral anticoagulants for intravenous thrombolysis. Officially authorized Japanese guidelines on this issue were revised twice at the time of approval for clinical use of direct oral anticoagulants and idarucizumab, a specific reversal agent for dabigatran. A unique recommendation in the latest Japanese clinical guides was that thrombolysis can be recommended if the time of the last dose of direct oral anticoagulants exceeds 4 hours and if commonly available anticoagulation markers are normal or subnormal, i.e., international normalized ratio of prothrombin time <1.7 and activated partial thromboplastin time <1.5 times the baseline value (≤40 seconds only as a guide). These criteria are partly supported by the findings of domestic multicenter and single-center surveys that symptomatic or asymptomatic intracranial hemorrhage following thrombolysis was rare under the conditions of the criteria. Even for dabigatran users, stroke thrombolysis can be considered without pretreatment by idarucizumab if patients meet the above criteria. If not, direct mechanical thrombectomy can be considered without pretreatment by idarucizumab or thrombolysis, and use of idarucizumab, followed immediately by thrombolysis, can be considered only when thrombectomy cannot be quickly performed. These clinical guides are practical and to some extent economical, but they have some limitations, including lack of corroborating information from sufficient numbers of relevant cases. The guides will be further modified based on the results of future research.

How can we reverse bleeding in patients on direct oral anticoagulants?

The direct oral anticoagulants (DOACs), or non-vitamin K antagonist oral anticoagulants (NOACs), including dabigatran, which inhibits thrombin, as well as rivaroxaban, apixaban, edoxaban, and betrixaban, which inhibit coagulation factor Xa, are as-sociated with similar or lower risk of bleeding compared with warfarin. The need for reversal of their anticoagulant effect may occur in patients with life-threatening bleeding or those requiring urgent surgery. Currently, the only specific reversal agent for dabigatran, idarucizumab, is widely available, while andexanet alfa, which reverses factor Xa inhibitors, was approved in the United States in May 2018. Ciraparantag, which has been designed to reverse all DOACs and other anticoagulants, is being investigated in clinical trials. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are suggested in patients with life-threatening bleeding. Vitamin K and fresh frozen plasma should not be used to reverse DOACs. This review presents the current evidence regarding bleeding risk on DOACs and the reversal strategies to provide guidance on the management of patients treated with DOACs, who experience serious bleeding.

Reversal agents for non-vitamin K antagonist oral anticoagulants.

The non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban, and rivaroxaban, which inhibit coagulation factor Xa. Although clinical studies of NOACs were conducted without antidotes, patient outcomes with major bleeding when receiving NOACs were no worse than those in patients treated with a vitamin K antagonist. Nonetheless, in patients with life-threatening bleeding or requiring urgent surgery, the capacity for rapid NOAC reversal is likely to increase patient safety. Three NOAC reversal agents are in various stages of development: idarucizumab, a specific reversal agent for dabigatran; andexanet alfa, which reverses factor Xa inhibitors; and ciraparantag, which is purported to reverse all NOACs. Idarucizumab is licensed in many countries, andexanet is under consideration by regulatory agencies, and ciraparantag is undergoing phase III evaluation. In the absence of licensed reversal agents for the oral factor Xa inhibitors, prothrombin complex concentrates are often used in patients taking these agents who present with life-threatening bleeding. In this Review, we summarize the approved indications for the NOACs, outline how to measure their anticoagulant effects, describe the mechanism of action of the reversal strategies, assess the preclinical and clinical data supporting their use, provide guidance on potential indications for reversal, and offer a management approach for patients treated with NOACs who present with serious bleeding or require urgent surgery.

Healthcare resource utilization in patients receiving idarucizumab for reversal of dabigatran anticoagulation due to major bleeding, urgent surgery, or procedural interventions: interim results from the RE-VERSE AD™ study

Aims: Patients treated with anticoagulants may experience serious bleeding or require urgent surgery or intervention, and may benefit from rapid anticoagulant reversal. This exploratory analysis assessed healthcare resource utilization (HCRU) in patients treated with idarucizumab, a specific reversal agent for dabigatran etexilate.Materials and methods: RE-VERSE AD™ (NCT02104947), a prospective, multi-center open-label study, is evaluating idarucizumab for dabigatran reversal in patients with serious bleeding (Group A) or undergoing emergency surgery/procedures (Group B). HCRU outcome measures evaluated in the first 90 patients enrolled were use of blood products and pro-hemostatic agents, length of stay (LOS) in hospital, and LOS in intensive care unit (ICU).Results: Blood products or pro-hemostatic agents were given to 63% (32/51) of patients in Group A and 23% (9/39) of patients in Group B on the day of/day after surgery. An overnight hospital stay was reported for 82% (42/51) of patients in Group A with median LOS = 7 (range = 1–71) bed-days. For Group B, 92% (36/39) had an overnight hospital stay with a median LOS = 9 (range = 1–92) bed-days. In Group A, 17 patients were admitted to the ICU for at least 1 day with median LOS = 4 (range = 1–44) days; in Group B the number was 15 with median LOS = 2 (range = 1–92) days.Limitations: The lack of a control group and the small patient numbers limit the strength of the conclusions.Conclusions: The use of idarucizumab may simplify emergency management of dabigatran-treated patients with life-threatening bleeds and reduce perioperative complications in patients undergoing emergency surgery.

Idarucizumab, a Specific Reversal Agent for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran-Induced Anticoagulation in Japanese Healthy Male Volunteers

Background: Specific reversal agents for oral anticoagulants may be necessary to manage life-threatening bleeding or prior to emergency surgical procedures. While many reversal agents are in development, idarucizumab is approved and now available commercially in many countries. Idarucizumab is a humanized antibody fragment that specifically binds to dabigatran with high affinity and has shown immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy male Caucasian volunteers. The present study investigated the safety, tolerability and pharmacokinetics of idarucizumab (part 1) and explored the effective dose of idarucizumab to reverse the dabigatran-induced anticoagulant effect (part 2) in healthy male Japanese volunteers.Methods: This was a two-part, phase I, randomized, placebo-controlled, double-blind, single-center, rising dose study. In part 1, subjects (n = 32) were randomized to receive either placebo (n = 2/dose group) or single intravenous doses of idarucizumab, 1, 2, or 4 g as a 5-minute infusion or 8 g as a 1-hour infusion (n = 6/group). In part 2, subjects (n = 48) were treated orally for 3 days with dabigatran etexilate (DE, 220 mg bid). On day 4, subjects received a final DE dose, followed a 3-day wash out period. Subjects were again treated orally for 3 days with DE, 220 mg bid. On Day 11, subjects received a final DE dose followed 2 hours later by placebo (n = 3/group) or idarucizumab (1, 2, 4, or 5 g [2.5 g followed by 2.5 g given 15 minutes apart]) as a 5-minute intravenous infusion, n = 9/group). The number of subjects with adverse events (AEs), emergence of anti-idarucizumab antibodies (ADAs), pharmacokinetics and the impact of idarucizumab on coagulation parameters were assessed (diluted thrombin time, ecarin clotting time, activated partial thromboplastin time, and thrombin time). In addition, potential procoagulant effects were monitored as D-dimer and prothrombin fragment F1.2.Results: Idarucizumab attained a maximum concentration in plasma around the end of each infusion followed by a biphasic decline in plasma concentrations with a rapid initial phase and a longer terminal phase.. Dabigatran treatment prolonged the clotting times of all coagulation parameters. Idarucizumab infusion resulted in immediate and complete reversal of dabigatran-induced anticoagulation, reducing coagulation parameters below the upper limit of normal. The duration was dose-dependent; at 4 and 5 g of idarucizumab, complete reversal was sustained up to 72 hours, at lower doses ≤ 2 g a partial return of the anticoagulation activity of dabigatran was observed 1-2 hours after idarucizumab administration. Concentration of unbound dabigatran decreased to below the limit of quantification immediately after administration of a single dose of idarucizumab. Idarucizumab was safe and well tolerated, and no AEs were reported. There was no elevation of either D-dimer or F1.2 levels post idarucizumab as compared to levels prior to infusion in any of the dose groups. Treatment-emergent ADAs occurred in 6 of 60 patients receiving idarucizumab.Conclusion: Idarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran-associated anticoagulation in healthy male Japanese volunteers. Idarucizumab was safe and well tolerated with no procoagulant effects. Disclosuresvan Ryn:Boehringer Ingelheim: Employment. Yasaka:Sanofi: Research Funding; Nippon Boehringer Ingelheim: Other: received lecture fees (over 1 million Yen); Bristol-Myers Squibb: Other: received lecture fees (over 1 million Yen); Bayer Yakuhin: Other: received lecture fees (over 1 million Yen); Daiichi-Sankyo: Other: received lecture fees (over 1 million Yen). Harada:Boehringer Ingelheim: Employment. Taniguchi:Boehringer Ingelheim: Employment. Imazu:Boehringer Ingelheim: Employment. Norris:Boehringer Ingelheim: Employment. Gansser:Boehringer Ingelheim: Employment. Stangier:Boehringer Ingelheim: Employment.

Managing reversal of direct oral anticoagulants in emergency situations. Anticoagulation Education Task Force White Paper.

Anticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24-7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level.

Idarucizumab, a Specific Reversal Agent for Dabigatran: Mode of Action, Pharmacokinetics and Pharmacodynamics, and Safety and Efficacy in Phase 1 Subjects

The direct oral anticoagulants (DOACs) provide a number of clinical advantages over vitamin K antagonists for the treatment of thromboembolism, including improved efficacy and safety, as well as no need for regular monitoring of anticoagulant effect. However, as with all anticoagulants, bleeding complications may occur, and anticoagulant reversal may be required in specific clinical situations, such as in patients experiencing spontaneous or traumatic bleeds, or in anticoagulated patients requiring emergency surgery or other invasive procedures. Therefore, several reversal agents for the DOACs are in development. This includes the specific reversal agent idarucizumab, which has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for use in patients treated with dabigatran when urgent reversal of its anticoagulant effects is needed. Idarucizumab is a humanized monoclonal antibody fragment that binds with high affinity to free and thrombin-bound dabigatran, resulting in an almost irreversibly bound idarucizumab–dabigatran complex and thereby neutralizing dabigatran's anticoagulant activity. The reversal of the anticoagulant effects of dabigatran by idarucizumab has been demonstrated in animal bleeding models, in healthy volunteers with a range of ages and renal function, and in anticoagulated patients. In the phase 1 trials, at doses of 2 g or greater, idarucizumab resulted in immediate and complete reversal of the dabigatran anticoagulant effects and was well tolerated. In the absence of dabigatran, idarucizumab showed no effect on coagulation parameters or thrombin formation. These findings provide initial evidence that idarucizumab could provide a safe and effective means of reversing anticoagulant activity in patients treated with dabigatran in need of emergency surgery or in emergency bleeding situations.

Overview of direct oral anticoagulant therapy reversal.

Strategies for the management of bleeding complications and facilitation of an invasive procedure in patients receiving direct oral anticoagulants (DOACs) are reviewed. The DOACs provide clinical advantages versus vitamin K antagonists, including fixed dosing with no routine coagulation monitoring and evidence of a lower risk of bleeding. However, as with all anticoagulants, there is a risk of bleeding complications in patients receiving DOACs, so urgent reversal of their anticoagulant activity may be required for spontaneous or traumatic bleeding events and in patients undergoing emergency invasive procedures. Reversal strategies are dependent on the anticoagulant involved, the location and severity of the bleeding, and/or the urgency of the invasive procedure. The recently approved specific reversal agent for dabigatran, idarucizumab, together with other reversal agents in development will hopefully allow for the emergent reversal of DOACs, without increasing the underlying risk of thrombosis. However, research is required to determine the optimal use of these reversal agents, in terms of choice of agent, dosing, and concomitant management. A systematic approach to their implementation in hospitals is also required to ensure that physicians, nurses, and pharmacists receive appropriate education and have the necessary protocols and guidelines to manage these clinical situations. Reversal strategies in patients receiving a DOAC need to be tailored to the anticoagulant involved as well as the urgency and severity of the clinical situation. Reversal agents should help facilitate the urgent reversal of anticoagulation in patients with emergency bleeding or who require urgent surgery, though research and education are required to ensure the optimal use of these agents.

Efficacy of prothrombin complex concentrates for the emergency reversal of dabigatran-induced anticoagulation.

Dabigatran is effective in decreasing the risk of ischaemic stroke in patients with atrial fibrillation. However, like all anticoagulants, it is associated with a risk of bleeding. In cases of trauma or emergency surgery, emergency reversal of dabigatran-induced anticoagulation may be required. A specific reversal agent for dabigatran, idarucizumab, has been approved by the US Food and Drug Administration. Alternative reversal agents are available, such as prothrombin complex concentrates (PCCs) and activated PCCs (aPCCs). In this review we evaluate the role of PCCs and aPCCs in the reversal of dabigatran anticoagulation and consider which tests are appropriate for monitoring coagulation in this setting. Pre-clinical studies, small clinical studies and case reports indicate that PCCs and aPCCs may be able to reverse dabigatran-induced anticoagulation in a dose-dependent manner. However, dosing based on coagulation parameters can be difficult because available assays may not provide adequate sensitivity and specificity for measuring anticoagulation induced by dabigatran or the countering effects of PCCs/aPCCs. In addition, PCCs or aPCCs can potentially provoke thromboembolic complications. Despite these limitations and the fact that PCCs and aPCCs are not yet licensed for dabigatran reversal, their use appears to be warranted in patients with life-threatening haemorrhage if idarucizumab is not available.

Abstract 213: Effect of Idarucizumab on Intracranial Bleeding in Dabigatran-treated Patients: Initial Results From RE-VERSE AD

Introduction: Dabigatran is a non-vitamin K antagonist oral anticoagulant (NOAC) licensed for stroke prevention in nonvalvular atrial fibrillation. In the RE-LY trial, both doses of dabigatran (110 mg and 150 mg bid) were associated with a significantly lower annualized rate of intracranial hemorrhage (ICH) than warfarin (0.23%, 0.32% and 0.76%, respectively). Nonetheless, the mortality rate with ICH in the context of any anticoagulation remains high, probably reflecting the effects of hematoma expansion. Whether a specific reversal agent for dabigatran will improve clinical outcomes in dabigatran-treated patients with ICH is unknown. RE-VERSE AD is an ongoing, open-label, phase 3, cohort study evaluating the extent to which idarucizumab, a humanized Fab fragment directed against dabigatran, reverses the latter’s anticoagulant effects in patients with serious bleeding or in those requiring urgent interventions. This study focuses on the results in patients with ICH. Hypothesis: Compared with historical controls, idarucizumab improves clinical outcomes in dabigatran-treated patients with ICH. Methods: Patients presenting with ICH were given intravenous idarucizumab 5 g as two 2.5 g bolus infusions administered no more than 15 minutes apart. The primary endpoint was the maximum reversal of the anticoagulant effect of dabigatran, based on central laboratory determination of the dilute thrombin time or ecarin clotting time. Results: In an interim analysis at 90 patients, 18 with ICH had been enrolled in RE-VERSE AD. Updated results on the effects of idarucizumab on coagulation parameters, imaging studies, and clinical outcomes in this patient subgroup will be presented. Conclusions: Currently, there are no specific reversal agents for the NOACs. We present the first data on the clinical outcomes for idarucizumab in dabigatran-treated patients who present with ICH.

Idarucizumab: The Antidote for Reversal of Dabigatran.

Four non–vitamin K antagonist oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, are currently licensed as alternatives to heparins and vitamin K antagonists for the prevention and treatment of venous thromboembolism and for the prevention of stroke in patients with nonvalvular atrial fibrillation. Dabigatran is the only NOAC that inhibits thrombin; the others inhibit factor Xa. All of the NOACs are at least as effective as vitamin K antagonists for the prevention of stroke in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are associated with less life-threatening bleeding, in particular less intracranial hemorrhage.1,2 Nonetheless, serious bleeding can occur with NOACs. In addition, patients taking NOACs may sustain trauma and may require urgent surgery or interventions. Consequently, the availability of specific reversal agents for NOACs could improve patient management during these emergency situations. Idarucizumab is a humanized monoclonal antibody fragment that has been developed as a specific reversal agent for dabigatran. In vitro and ex vivo studies have demonstrated that idarucizumab promptly restores dabigatran-prolonged coagulation parameters to baseline values,3–5 and studies in healthy volunteers and patients with life-threatening bleeding or requiring emergency surgery or invasive procedures show that it completely reverses the anticoagulant effects of dabigatran within minutes in the majority of patients. Idarucizumab was recently licensed in the United States and Europe. This article summarizes the pharmacology and clinical data on the use of idarucizumab to reverse dabigatran. The first step in the development of idarucizumab was to immunize mice with dabigatran-derived haptens coupled to carrier proteins to produce antibodies against dabigatran.3 Monoclonal antibodies exhibiting the highest affinity for dabigatran were selected, and the antigen-binding fragment (Fab) was isolated (Figure 1). Murine protein sequences were replaced …

Abstract 16418: Reinitiation of Antithrombotic Therapy After Emergency Procedures or After an Uncontrolled or Life Threatening Bleeding Event. Initial Experience From the Re-verse Ad Trial

Background: In AF patients, oral anticoagulation is effective for stroke risk reduction, but there is uncertainty on how to manage re-initiation of anticoagulation after a bleeding complication. Ideally, therapy would be stopped immediately and reinitiated as soon as possible after the bleeding has resolved. In clinical trials comparing dabigatran to warfarin, urgent interventions were linked to higher rates of both bleeding and thromboembolic events than elective interventions. Idarucizumab immediately reverses the anticoagulant effects of dabigatran without prothrombotic effect. Due to idarucizumab’s specificity to dabigatran, other drug-drug interaction is not expected, allowing the clinician flexibility in managing antithrombotic therapy during and after the event. Methods: In the ongoing phase III RE-VERSE AD study, dabigatran-treated patients with uncontrolled bleeding (Group A) or who require emergency surgery (Group B) are given 5 g of idarucizumab IV. The primary endpoint was median maximum reversal of the anticoagulant effect of dabigatran, based on dilute thrombin time (dTT) or ecarin clotting time (ECT) within 4 h of study drug infusion. Data collection on re-initiation of antithrombotic therapy was studied as a secondary endpoint. Results: In the interim analysis of 90 patients, median maximum reversal of the anticoagulant effect of dabigatran was 100%. For antithrombotic re-initiation data, see Table. Conclusions: Idarucizumab is an immediate-acting, specific reversal agent for dabigatran. Preliminary results from RE-VERSE AD suggest that idarucizumab facilitates the periprocedural management of dabigatran-treated patients. Of note is that after an acute event, alternative antithrombotic therapy can be initiated at any time after idarucizumab application. Reintroduction of dabigatran was possible as early as 24 h after idarucizumab treatment. This is desirable to protect patients from their underlying thromboembolic risk.

What neurosurgeons need to know about dabigatran etexilate (pradax(®)/pradaxa(®)/prazaxa(®)).

Dabigatran etexaliate is a novel oral anticoagulant that directly inhibits thrombin. It offers a number of substantial medical benefits over other oral and parenteral anticoagulants but its advent raises important neurosurgical considerations. Dabigatran has important potential benefits. Unlike warfarin, it does not require routine blood tests to monitor its anticoagulative effect and there is no need for dose titration. Drug interactions are greatly simplified when compared to warfarin as dabigatran is not metabolized by cytochrome p450 isoenzymes. As a result, dabigatran has been approved in many jurisdictions for DVT prophylaxis after orthopaedic surgery and also for the prevention of embolic events associated with non-valvular atrial fibrillation. There are, however, important neurosurgical challenges associated with regular dabigatran use. Unlike current anti-coagulants, there is no specific reversal agent for dabigatran. Known reversal options include activated charcoal (within one to two hours of intake) and renal dialysis. Protamine sulfate and vitamin K are unlikely to affect the activity of dabigatran. Platelet concentrates will not inactivate dabigatran's anti-thrombin properties. Assessing the degree of anticoagulation is difficult as conventional markers of serum coagulability are typically normal in patients taking dabigatran. The potential neurosurgical challenges of dabigatran were cast in sharp relief by a recent case report from the United States that is considered in this note. In the absence of a clear reversal pathway, we propose a treatment algorithm for chronic dabigatran use based on the replacement of any deficient factors and rapid access to renal dialysis.