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Background: The effect of the anticoagulant, dabigatran, and its antagonist, idarucizumab, on coagulation remains poorly quantified. There are few pharmacokinetic-pharmacodynamic data available to determine dabigatran dose in humans or animals undergoing cardiopulmonary bypass. Methods: Five sheep were given intravenous dabigatran 4 mg/kg. Blood samples were collected for thromboelastometric reaction time (R-time) and drug assay at 5, 15, 30, 60, 120, 240, 480 min, and 24 h. Plasma dabigatran concentrations and R-times were analyzed using an integrated pharmacokinetic-pharmacodynamic model using non-linear mixed effects. The impact of idarucizumab 15 mg/kg administered 120 min after dabigatran 4 mg/kg and its effect on R-time was observed. Results: A 2-compartment model described dabigatran pharmacokinetics with a clearance (CL 0.0453 L/min/70 kg), intercompartment clearance (Q 0.268 L/min/70 kg), central volume of distribution (V1 2.94 L/70 kg), peripheral volume of distribution (V2 9.51 L/70 kg). The effect compartment model estimates for a sigmoid EMAX model using Reaction time had an effect site concentration (Ce50 64.2 mg/L) eliciting half of the maximal effect (EMAX 180 min). The plasma-effect compartment equilibration half time (T1/2keo) was 1.04 min. Idarucizumab 15 mg/kg reduced R-time by approximately 5 min. Conclusions: Dabigatran reversibly binds to the active site on the thrombin molecule, preventing activation of coagulation factors. The pharmacologic target concentration strategy uses pharmacokinetic-pharmacodynamic information to inform dose. A loading dose of dabigatran 0.25 mg/kg followed by a maintenance infusion of dabigatran 0.0175 mg/kg/min for 30 min and a subsequent infusion dabigatran 0.0075 mg/kg/min achieves a steady state target concentration of 5 mg/L in a sheep model. [ABSTRACT FROM AUTHOR]

AIM: The 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation and the 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Background: Since the late 2000s, Europe has granted approval for various thrombotic risk‐related uses of direct oral anticoagulants (DOACs). Unlike traditional anticoagulants, DOACs do not necessitate routine coagulation monitoring. Nevertheless, clinical practice often encounters bleeding events associated with these medications, making the need for effective reversal strategies evident. Objectives: The study aims to take stock of current reversal strategies for DOACs, with a particular emphasis on the latest compounds that have been developed or are currently under development. Methods: For obtaining information regarding the ongoing reversal strategies and the compounds under development, we referred to ClinicalTrials website, PubMed, and Google Scholar. Results: In 2024, two specific antidotes to DOACs have already received approval when reversal of anticoagulation is needed owing to life‐threatening or uncontrolled bleeding: idarucizumab that reverses the effects of dabigatran, and andexanet alfa, designed to counteract activated factor X inhibitors such as apixaban and rivaroxaban. Furthermore, ciraparantag, a potential universal reversal agent, is currently in advanced stages of clinical development. Concerns remain regarding the safety of specific reversal agents, especially concerning the risk of thrombosis. Additionally, the cost of these antidotes remains high. Consequently, nonspecific strategies to counteract anticoagulant medications, including activated charcoal, hemodialysis, and concentrates of coagulation factors, still have utility. Conclusion: With the validation of specific and nonspecific antidotes, DOACs could supplant traditional oral anticoagulants. This progress represents a significant advancement in anticoagulation therapy. However, ongoing research is crucial to address remaining safety concerns of the specific reversion agents of DOACs in clinical practice. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate the characteristics, clinical outcomes, and blood product transfusion (BPT) rates of patients undergoing cardiac transplant (CT) while receiving uninterrupted anticoagulation and antiplatelet therapy. Methods: A retrospective, single‐center, and observational study of adult patients who underwent CT was performed. Patients were classified into four groups: (1) patients without anticoagulation or antiplatelet therapy (control), (2) patients on antiplatelet therapy (AP), (3) patients on vitamin K antagonists (AVKs), and (4) patients on dabigatran (dabigatran). The primary endpoints were reoperation due to bleeding and perioperative BPT rates (packed red blood cells (PRBC), fresh frozen plasma, platelets). Secondary outcomes assessed included morbidity and mortality‐related events. Results: Of the 55 patients included, 6 (11%) received no therapy (control), 8 (15%) received antiplatelet therapy, 15 (27%) were on AVKs, and 26 (47%) were on dabigatran. There were no significant differences in the need for reoperation or other secondary morbidity‐associated events. During surgery patients on dabigatran showed lower transfusion rates of PRBC (control 100%, AP 100%, AVKs 73%, dabigatran 50%, p = 0.011) and platelets (control 100%, AP 100%, AVKs 100%, dabigatran 69%, p = 0.019). The total intraoperative number of BPT was also the lowest in the dabigatran group (control 5.5 units, AP 5 units, AVKs 6 units, dabigatran 3 units; p = 0.038); receiving significantly less PRBC (control 2.5 units, AP 3 units, AVKs 2 units, dabigatran 0.5 units; p = 0.011). A Poisson multivariate analysis showed that only treatment on dabigatran reduces PRBC requirements during surgery, with an expected reduction of 64.5% (95% CI: 32.4%–81.4%). Conclusions: In patients listed for CT requiring anticoagulation due to nonvalvular atrial fibrillation, the use of dabigatran and its reversal with idarucizumab significantly reduces intraoperative BPT demand. [ABSTRACT FROM AUTHOR]

This case report examines the combined use of fibrinogen concentrate, four-factor prothrombin complex concentrate (PCC), and idarucizumab, a specific antidote for dabigatran, to reverse the anticoagulant effects of dabigatran and apixaban-induced coagulopathy. An 86-year-old patient, receiving apixaban therapy, presented to the Emergency Department after intentionally ingesting 50 tablets of dabigatran. The combination therapy contributed to the rapid normalization of coagulation parameters and stabilization of the patient's clinical status without subsequent thromboembolic complications. This case adds to the limited evidence on the effectiveness and safety of combining PCC with idarucizumab in cases of multiple anticoagulant intoxication.

Bleeding events are common in patients prescribed anticoagulants and can have devastating consequences. Several specific and nonspecific agents have been developed to reverse the effects of anticoagulant drugs or toxins. Vitamin K, as the oldest of these antidotes, specifically counteracts the effects of pharmaceuticals and rodenticides designed to deplete stores of vitamin K‐dependent factors. In cases of life‐threatening bleeding, the addition of prothrombin complex concentrates (PCCs) allows for the immediate replacement of coagulation factors. While the use of PCCs has been extended to the non‐specific reversal of the effects of newer direct oral anticoagulants, the specific agents idarucizumab, targeting dabigatran and andexanet‐α, binding factor Xa inhibitors, have recently been developed and are being preferentially recommended by most guidelines. However, despite having rapid effects on correcting coagulopathy, there is to date a lack of robust evidence establishing the clear superiority of direct oral anticoagulant‐specific reversal agents over PCCs in terms of haemostatic efficacy, safety or mortality. For andexanet‐α, a potential signal of increased thromboembolic risks, comparatively high costs and low availability might also limit its use, even though emerging evidence appears to bolster its role in intracranial haemorrhage. Protamine is the specific agent for the reversal of unfractionated heparin anticoagulation used mainly in cardiovascular surgery. It is much less effective for low molecular weight heparin fragments and is usually reserved for cases with life‐threatening bleeding. [ABSTRACT FROM AUTHOR]

Idarucizumab is an antibody fragment specific for the immediate reversal of dabigatran anticoagulation effects. The use of idarucizumab is approved for dabigatran-treated patients suffering from life-threatening or uncontrolled bleeding and those in need of urgent surgery or invasive procedures. Data from randomized controlled clinical trials and real-world experience provide reassuring evidence about the efficacy and safety of idarucizmab use in patients with acute stroke. In this narrative review, we summarize the available realworld evidence and discuss the relevance and importance of idarucizumab treatment in acute stroke patients in everyday clinical practice. In addition, we also discuss special issues like prothrombin complex concentrate application as an alternative to idarucizumab, its application before endovascular therapy, sensitivity of thrombi to lysis, and necessary laboratory examinations. [ABSTRACT FROM AUTHOR]

Given the growing number of patients receiving direct oral anticoagulant (DOAC), patients requiring rapid neutralization is also increasing in case of major bleedings or urgent surgery/procedures. Idarucizumab is commercialized as a specific antidote to dabigatran while andexanet alfa has gained the Food and Drug Administration and the European Medicines Agency approval as an oral anti-factor Xa inhibitors antidote. Other antidotes or hemostatic agents are still under preclinical or clinical development, the most advanced being ciraparantag. DOAC plasma levels measurement allows to appropriately select patient for antidote administration and may prevent unnecessary prescription of expensive molecules in some acute clinical settings. However, these tests might be inconclusive after some antidote administration, namely andexanet alfa and ciraparantag. The benefit of laboratory monitoring following DOAC reversal remains unclear. Here, we sought to provide an overview of the key studies evaluating the safety and efficacy of DOAC reversal using the most developed/commercialized specific antidotes, to discuss the potential role of the laboratory monitoring in the management of patients receiving DOAC specific antidotes and to highlight the areas that deserve further investigations in order to establish the exact role of laboratory monitoring in the appropriate management of DOAC specific antidotes. Anticoagulation monitoring and specific reversal agent targets DOAC: direct oral anticoagulant; dTT: diluted thrombin time; ECA: ecarin chromogenic assay; ECT: ecarin cloting time. [Display omitted] • Antidotes for direct oral anticoagulant (DOAC) reversal have been developed. • The role of laboratory monitoring in DOAC reversal using antidotes is unclear. • Dabigatran level prior to idarucizumab could predict reversal outcome. • Oral FXa inhibitor levels cannot be easily measured following andexanet alfa. • DOAC measurement using commercialized assays is not possible after ciraparantag. [ABSTRACT FROM AUTHOR]

Heart transplantation (HT) poses high bleeding risks, especially for patients on anticoagulation. This study evaluates the use of idarucizumab for dabigatran (DBG) reversal compared to vitamin K antagonist (VKA) strategies in HT. A retrospective analysis of HT patients from January 2018 to December 2022, excluding those requiring ECMO immediately before or after surgery, was conducted. Outcomes included transfusion needs, re-surgery due to bleeding, ICU stay lengths, and 30-day survival. A cost analysis compared the direct expenses of each strategy. Among 34 patients, 20 were on DBG and 14 on VKAs or not anticoagulated. Idarucizumab significantly reduced the number of patients requiring transfusion (p = 0.034) and ICU stay lengths (p = 0.014), with no significant impact on re-surgery rates (p = 0.259) or survival (p = 0.955). Despite higher initial costs, overall expenses for idarucizumab were comparable to VKA reversal due to reduced transfusion needs and shorter ICU stays. Idarucizumab offers a viable and potentially cost-neutral anticoagulation reversal option for HT patients on DBG, presenting an alternative to VKA strategies. However, due to the retrospective nature of the study and the small sample size, further prospective studies are needed to confirm these findings.

Use of anticoagulants is increasing with the aging of societies. The safe first-line drug is likely to be a direct oral anticoagulant (DOAC), but outcomes of treatment of traumatic brain injury (TBI) with anticoagulants are uncertain. Therefore, we examined the clinical effect of idarucizumab as reversal therapy in elderly patients with TBI who were treated with dabigatran. A retrospective multi-center observational study was performed in patients ?65 years of age who developed acute traumatic subdural hematoma during treatment with dabigatran and underwent reversal therapy with idarucizumab. The items examined included patient background, neurological and imaging findings at arrival, course after admission, complications, and outcomes. A total of 23 patients were enrolled in the study. The patients had a mean age of 78.9 years. Cause of TBI was fall in 60.9% of the subjects. Mean Glasgow Coma Scale score at arrival was 8.7; anisocoria was present in 31.8% of cases. Exacerbation of consciousness was found in 30.4%, but only in 13.3% of subjects treated with idarucizumab before consciousness and imaging findings worsened. Dabigatran was discontinued in 81.8% of cases after hematoma development, with a mean withdrawal period of 12.1 days. The favorable outcome rate was 21.7%, and mortality was 39.1%. In multi-variate analysis, timing of idarucizumab administration was associated with a favorable outcome. There were ischemic complications in 3 cases (13.1%), and all three events occurred ?7 days after administration of idarucizumab. These findings suggest that in cases that develop hematoma during treatment with dabigatran, it is important to administer idarucizumab early and restart dabigatran after conditions stabilize.

Abstract Introduction Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. Methods This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). Results The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. Conclusions The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. Trial Registration This study is registered with ClinicalTrials.gov (NCT02946931). Graphical Abstract

Idarucizumab is an antibody fragment specific for the immediate reversal of dabigatran anticoagulation effects. The use of idarucizumab is approved for dabigatran-treated patients suffering from life-threatening or uncontrolled bleeding and those in need of urgent surgery or invasive procedures. Data from randomized controlled clinical trials and real-world experience provide reassuring evidence about the efficacy and safety of idarucizmab use in patients with acute stroke. In this narrative review, we summarize the available real-world evidence and discuss the relevance and importance of idarucizumab treatment in acute stroke patients in everyday clinical practice. In addition, we also discuss special issues like prothrombin complex concentrate application as an alternative to idarucizumab, its application before endovascular therapy, sensitivity of thrombi to lysis, and necessary laboratory examinations.

Les anticorps thérapeutiques font désormais partie intégrante de l'arsenal médical dans le traitement de nombreuses affections, y compris en hémostase. Ce sont tous des anticorps monoclonaux humanisés – au suffixe "zumab" – permettant de restaurer partiellement l'hémostase (emicizumab, concizumab), ou ayant une action d'antidote (idarucizumab) pour antagoniser l'effet de certains anticoagulants (dabigatran) ou des antiagrégants plaquettaires (bentracimab encore à l'étude) ; d'autres ont été ou pourront être utilisés pour leur propre pouvoir antiagrégant (abciximab arrêté en septembre 2019 ou le futur antiagrégant antiGPVI, glencozimab). Le caplacizumab est quant à lui un nanobody indiqué dans la phase aiguë du purpura thrombotique thrombocytopénique acquis. Therapeutic antibodies are now an integral part of the therapeutic arsenal in the treatment of many conditions, including haemostasis. They are all humanized monoclonal antibodies (suffix : zumab) that can partially restore hemostasis (emicizumab, concizumab), or used as an antidote (idarucizumab) to antagonize the effect of certain anticoagulant (dabigatran) or platelet antiagregants (bentra-cimab, still under study). Others therapeutic antibodies have been or may be used for their own antiagregant properties (abciximab, discontinued in September 2019, or the future anti-GPVI antiagregant glencozimab, still under study). As for caplacizumab, it is a nanobody indicated in the acute phase of acquired throm-botic thrombocytopenic purpura. [ABSTRACT FROM AUTHOR]

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed. [ABSTRACT FROM AUTHOR]

Introduction: Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. Methods: This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). Results: The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. Conclusions: The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. Trial Registration: This study is registered with ClinicalTrials.gov (NCT02946931). Plain Language Summary: Atrial fibrillation is an irregular heart rhythm (arrhythmia), and the type of atrial fibrillation not caused by a heart valve problem is known as "non-valvular atrial fibrillation" or NVAF. People with NVAF have an increased risk of ischemic stroke, in which a blood clot (thrombus) blocks an artery in the brain. Drugs that inhibit blood clots, known as anticoagulants, are prescribed to people with NVAF to prevent ischemic stroke. Historically, warfarin has been one of the most prescribed anticoagulant drugs. However, a novel anticoagulant drug, known as dabigatran, has clinical advantages over warfarin and is approved in many countries for people with NVAF. People who take anticoagulants may experience life-threatening bleeding or need urgent surgery, and thus rapid and effective reversal of the anticoagulant effects is critical. The drug idarucizumab specifically binds to dabigatran to reverse its anticoagulant effects in people with uncontrolled bleeding or who require an urgent procedure. Idarucizumab was approved for use in Japan in September 2016. In Japan, drug companies are obligated to collect data after a new drug is launched as an approval condition, which is done through a postmarketing surveillance study. Here, we report the final results of a postmarketing surveillance study conducted between September 2016 and November 2020 to evaluate the safety and effectiveness of idarucizumab in Japanese patients receiving dabigatran. The results of our study show that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients, and support the continued use of idarucizumab in Japan in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction. Our study analysed the safety and effectiveness of idarucizumab in enabling intravenous thrombolysis (IVT) in dabigatran-treated patients with acute ischaemic stroke (AIS). Clinical rationale for the study. New oral anticoagulants (NOAC), including dabigatran, are the first-choice treatment option for preventing ischaemic stroke in patients with non-valvular atrial fibrillation (AF). However, a significant percentage of AF patients develops AIS despite NOAC treatment. According to current guidelines, treatment with IVT is contraindicated in patients who have received NOAC within the last 48 hours. Idarucizumab is a fragment of a monoclonal antibody that reverses the anticoagulation effect of dabigatran. The latest research shows that it can enable safe and successful IVT in patients with recent dabigatran intake, but more data is needed to confirm the safety and effectiveness of such treatment. Material and methods. Our study included dabigatran-treated patients who received idarucizumab to allow AIS treatment with IVT in the University Hospital in Kraków (Poland) from December 2018 to June 2023. We gathered data on their past medical history, stroke severity, course of treatment and outcomes as defined by modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS) scores at discharge. A good functional outcome was defined as mRS 0-2 points at discharge. Results. This observational study included 19 patients (13 male and six female) with a median age of 74 (IQR = 13) years. In all patients (100%), the reason for dabigatran treatment was AF. A good functional outcome after treatment (mRS 0-2) was achieved in 68.4% of patients, but mRS was already = 3 points before stroke onset in three (15.8%) patients. Haemorrhagic transformation of stroke occurred in three (15.8%) patients, including symptomatic intracranial haemorrhage in two (10.5%). The mortality rate was 5.3%. Conclusions and clinical implications. Our study results are in line with previous research on this topic, showing that IVT after idarucizumab can be successfully administered and is reasonably safe in dabigatran-treated patients with AIS. [ABSTRACT FROM AUTHOR]

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En los últimos años, con la introducción de anticoagulantes directos orales la terapia anticoagulante ha vuelto a dar un salto. Tiene como ventajas no requerir un monitoreo estricto como la Warfarina, una menor cantidad de interacciones y una farmacocinética predecible, pero con limitaciones ante enfermedades renales y válvulas protésicas. Los anticoagulantes son empleados en patologías como la fibrilación atrial, infarto agudo de miocardio, tromboembolismos, válvulas protésicas, neoplasias y trombofilias; es indispensable para los profesionales de salud conocer sus características. En especial durante la preparación prequirúrgica, tanto en procedimientos urgentes como en electivos. En los últimos años, las innovaciones en la anticoagulación han cambiado las recomendaciones y guías constantemente; el traslape de anticoagulantes como la Warfarina con heparinas se reservan para ciertos casos, según el juico clínico y manejo interdisciplinario de otras especialidades médicas. Considerando los antecedentes, comorbilidades y el riesgo quirúrgico del procedimiento, con el objetivo de tener un balance entre los riesgos de tromboembolismo y sangrado. Los nuevos anticoagulantes directos orales no requieren traslape anticoagulante, facilitando más las preparaciones quirúrgicas. En procedimientos agudos, el objetivo es revertir la anticoagulación. Al mismo tiempo, los antídotos de anticoagulantes han avanzado, con Idarucizumab y Andexanet, para la reversión de los anticoagulantes directos orales. El Ciraparantag aún no ha sido aprobado, con posibilidad de ser un antídoto universal para todos los fármacos anticoagulantes. Con estos avances, ciertas prácticas se han vuelto la segunda opción de tratamiento, como el uso de plasma fresco congelado, por los riesgos y desventajas en comparación con los nuevos manejos.

Background Intravenous thrombolysis (IVT) is an effective stroke therapy that remains underused. Currently, the use of IVT in patients with recent direct oral anticoagulant (DOAC) intake is not recommended. In this study we aim to investigate the safety and efficacy of IVT in patients with acute ischemic stroke and recent DOAC use. Methods and Results A systematic review and meta‐analysis of proportions evaluating IVT with recent DOAC use was conducted. Outcomes included symptomatic intracranial hemorrhage, any intracranial hemorrhage, serious systemic bleeding, and 90‐day functional independence (modified Rankin scale score 0–2). Additionally, rates were compared between patients receiving IVT using DOAC and non‐DOAC by a random effect meta‐analysis to calculate pooled odds ratios (OR) for each outcome. Finally, sensitivity analysis for idarucizumab, National Institutes of Health Stroke Scale, and timing of DOAC administration was completed. Fourteen studies with 247 079 patients were included (3610 in DOAC and 243 469 in non‐DOAC). The rates of IVT complications in the DOAC group were 3% (95% CI, 3–4) symptomatic intracranial hemorrhage, 12% (95% CI, 7–19) any ICH, and 0.7% (95%CI, 0–1) serious systemic bleeding, and 90‐day functional independence was achieved in 57% (95% CI, 43–70). The rates of symptomatic intracranial hemorrhage (3.4 versus 3.5%; OR, 0.95 [95% CI, 0.67–1.36]), any intracranial hemorrhage (17.7 versus 17.3%; OR, 1.23 [95% CI, 0.61–2.48]), serious systemic bleeding (0.7 versus 0.6%; OR, 1.27 [95% CI, 0.79–2.02]), and 90‐day modified Rankin scale score 0–2 (46.4 versus 56.8%; OR, 1.21 [95% CI, 0.400–3.67]) did not differ between DOAC and non‐DOAC groups. There was no difference in symptomatic intracranial hemorrhage rate based on idarucizumab administration. Conclusions Patients with acute ischemic stroke treated with IVT in recent DOAC versus non‐DOAC use have similar rates of hemorrhagic complications and functional independence. Further prospective randomized trials are warranted.

The number of patients with indications for direct oral anticoagulants (DOACs) to prevent thrombotic events is steadily growing. However, in 1,1-2,2% of cases, ischemic strokes occur within DOAC therapy. In this case, DOAC use is a limitation for systemic thrombolysis, except for available reversal of anticoagulation. In order to immediately inactivate the anticoagulant effect of dabigatran etexilate (DE), reversal agent idarucizumab is used.Aim. To evaluate the effectiveness and safety of idarucizumab in clinical practice.Material and methods. The study included 9 patients taking DE who developed urgent conditions that required emergency reversal of anticoagulation with idarucizumab.Results. Normalization of thrombin time (TT) was achieved in 7 (77,8%) patients immediately after idarucizumab administration. In two patients, 10 minutes after the administration of a specific DE reversal agent, TT decreased, but did not reach reference values (case 1: TT decreased from 181 to 23,3 seconds; case 2: TT decreased from 181 to 18,3 seconds); 30 minutes after the idarucizumab administration, TT normalization was achieved.Conclusion. Nobody developed clinically significant arterial and/or venous thrombotic events during the entire period of hospitalization. Rapid reversal of anticoagulation with idarucizumab allows immediate systemic thrombolytic therapy or surgery in patients taking DE without the increase of bleeding or thrombosis risk and the need for control coagulation analysis.

Background: 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). Methods: 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. Result: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Idarucizumab has been approved to reverse the anticoagulant effect of dabigatran. However, there is little knowledge of the effectiveness and safety of idarucizumab in daily practice. This systematic review and meta-analysis aims to evaluate the use, effectiveness and outcomes of idarucizumab. A systematic literature search was performed up to September 8th 2022. Original studies including patients prescribed idarucizumab, evaluating prescription indications, prescription appropriateness, haemostatic efficacy and/or the occurrence of adverse events were eligible. Case-reports and studies performed in patients ≤18 years or in healthy volunteers were excluded. Study selection and data extraction were performed by two independent reviewers. Pooled estimates were calculated using the random-effects model, after Freeman-Tukey double-arcsine transformation. Thirty studies comprising 3602 patients were included. Idarucizumab was prescribed for bleeding (63.1 %, 95%CI 57.0 %–69.0 %), invasive procedures (30.5 %, 95%CI: 24.1 %–37.2 %), to enable thrombolysis (range: 2.0 %–27.3 %), dabigatran intoxication without bleeding (range: 3.6 %–7.0 %) or unspecified reasons (range: 0.4 %–18.8 %). Overall, 2.8 % (95%CI 0.5 %–6.2 %) of prescription indications were reported to be inappropriate upon post-hoc evaluation. Hemostatic effectiveness was achieved in 77.7 % (95%CI 66.7 %–87.2 %) and peri-procedural haemostasis was normal in 98.5 % (95%CI 86.6 %–100 %) of patients. The pooled incidences of all-cause mortality and thromboembolic events at any follow-up duration were 13.6 % (95%CI 9.6 %–17.9 %) and 2.0 % (95%CI 0.8 %–3.4 %), respectively. Idarucizumab was mainly prescribed in the setting of bleeding. The reported hemostatic effectiveness was good, especially perioperatively, and the incidence of thromboembolic events was low. Patients with dabigatran-associated bleeding or requiring an urgent procedure nonetheless face a high mortality risk. • Idarucizumab is mainly prescribed in the context of bleeding. • The hemostatic efficacy of idarucizumab is good, especially peri-operatively. • The incidence of thromboembolic events after idarucizumab administration is low. • Patients prescribed idarucizumab still face a high mortality risk. • Re -initiation of anticoagulant therapy needs to be monitored. [ABSTRACT FROM AUTHOR]

BackgroundIntracranial 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).MethodsRegistration 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.ResultIn-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.ConclusionThese 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.

Over the past 20 years, there has been a shift from vitamin K antagonists to direct oral anticoagulants (DOACs), which include the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding than vitamin K antagonists, bleeding still occurs with DOACs, particularly in the elderly and in those with comorbidities. Reversal of the anticoagulant effects of the DOACs may be needed in patients with serious bleeding and in those requiring urgent surgery or intervention. Reversal can be effected with specific agents, such as idarucizumab for dabigatran and andexanet alfa for apixaban, edoxaban, and rivaroxaban, or with non-specific agents, such as prothrombin complex concentrates, activated prothrombin complex concentrate, and recombinant activated factor VII. This paper (i) provides an update on when and how to reverse the DOACs, (ii) describes new reversal agents under development, and (iii) provides a strategic framework for the reversal of the factor XI inhibitors currently under investigation in phase three clinical trials. [ABSTRACT FROM AUTHOR]

Background and Objectives: The effectiveness and safety of idarucizumab for the reversal of the effects of dabigatran have been proven. However, there remains a paucity of literature comprehensively investigating outcomes in real-world patients. This is especially true when comparing patients who were eligible for inclusion in the RE-VERSE AD trial with patients who were ineligible. As the prescription of dabigatran has become increasingly popular, the generalizability of the results to real-world populations has come into question due to the broad variability of real-world patients receiving dabigatran. Our study aimed to identify all patients who were prescribed idarucizumab and examined how effectiveness and safety varied among those patients who were eligible and ineligible for the trial. Materials and Methods: This retrospective cohort study analyzed the largest medical database in Taiwan. We enrolled all patients who were prescribed and received idarucizumab from when it became available in Taiwan up until May 2021. A Total of 32 patients were included and analyzed, and they were further divided into subgroups based on their eligibility for inclusion in the RE-VERSE AD trial. Multiple outcomes were evaluated, including successful hemostasis rate, complete reversal efficacy of idarucizumab, 90-day thromboembolic events, intra-hospital mortality, and adverse event rate. Results: In our study, we found that 34.4% of real-world cases of idarucizumab use were ineligible for the RE-VERSE AD trials. The eligible group had higher successful hemostasis rates (95.2% vs. 80%) and anticoagulant effect reversal rates compared to the ineligible group (73.3% vs. 0%). The mortality rates were 9.5%, compared to 27.3% in the ineligible group. Few adverse effects (n = 3) and 90-day thromboembolic events (n = 1) were observed in either group. Among the ineligible cases, all acute ischemic stroke patients (n = 5) received definite, timely treatments without complications. Conclusions: Our study demonstrated the real-world effectiveness and safety of idarucizumab infusion for trial-eligible patients and all acute ischemic stroke patients. However, although it seems to be effective and safe, idarucizumab appears to be less effective in other trial-ineligible patients. Despite this result, our study provides further evidence for extending the applicability of idarucizumab in real-world scenarios. Our study suggests that idarucizumab can be a safe and effective option for reversing the anticoagulant effect of dabigatran, particularly for eligible patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: Our objective is to describe currently available reversal agents for direct oral anticoagulants (DOACs), their target population, the available clinical practice recommendations and future directions. Recent Findings: Specific (idarucizumab for dabigatran and andexanet alfa for direct factor Xa inhibitors) and non-specific (prothrombin complex concentrates) reversal agents are effective in neutralizing the anticoagulant effect of DOACs. New investigational antidotes such as ciraparantag and VMX-C001 offer an alternative to andexanet alfa in reversing the anticoagulant activity of direct oral factor Xa inhibitors, but more clinical data are needed before they could be licensed for use. Summary: Specific reversal agents are recommended for use in clinical situations within their licensed indications (i.e.: reversal of DOACs in patients with severe uncontrolled or life-threatening bleeding or in need of emergency surgery or other invasive procedures), while non-specific reversal agents may be used when specific antidotes are not available or indicated. [ABSTRACT FROM AUTHOR]

Background: Reversal of dabigatran anticoagulation activity using idarucizumab is indicated for individuals suffering from life-threatening or non-controlled bleeding and those in need of urgent operation or invasive intervention. Through idarucizumab application patients with acute ischemic stroke (AIS) may regain eligibility for intravenous thrombolysis (IVT) and patients with intracranial hemorrhage (ICH) may show less hematoma growth, thereby improving functional outcome in both groups. However, evidence is limited, and international guidelines contain heterogenous recommendations substantiating the need for the review of evidence and standard operating procedures (SOPs). Materials and methods: For our review, we searched PubMed for all published articles using idarucizumab and ischemic stroke/hemorrhagic stroke as keywords. Illustrating two clinical cases, we discuss the current literature and national guidelines. Results: Our search retrieved 47 articles of which 8 case studies or series made public after 2020/2021, 28 reviews, 1 leading opinion article, 1 editorial and 10 guidelines. Summarizing the available evidence, idarucizumab application in stroke patients taking dabigatran results in decreased mortality rate and improved functional outcomes. Based on two clinical cases from our departments, we provide SOPs on how to deal with eligible patients in a time-efficient way, thereby reducing door-to-needle times in AIS and preventing early deterioration in ICH patients. Conclusion: Reversal of dabigatran with idarucizumab in stroke patients appears easy to manage, safe and beneficial. The SOPs aim to reassure stroke physicians to include dabigatran reversal into their daily clinical routine when dealing with patients presenting with ischemic or hemorrhagic stroke under dabigatran therapy. Key points: Application of idarucizumab is indicated in dabigatran-treated patients suffering from life-threatening/uncontrolled bleeding and those in need of urgent surgery or invasive procedures. Sufficient high-quality data from randomized trials allowing creation of definitive and uniform guidelines for clinical use of idarucizumab in acute stroke patients are lacking. Reversal of dabigatran with idarucizumab in stroke patients appears easy to manage, safe and beneficial. The SOPs aim to reassure stroke physicians to include dabigatran reversal into their daily clinical routine when dealing with patients presenting with acute stroke under dabigatran therapy. [ABSTRACT FROM AUTHOR]

The indications of direct oral anticoagulants (DOACs) have expanded over the past 15 years. DOACs are effective and safe oral anticoagulants associated with lower bleeding risks and mortality than vitamin K antagonists. However, DOAC users are prone to a considerable bleeding risk, which can occur at critical sites or lead to severe life-threatening conditions. Recent statistics indicated that major bleeding occurs in up to 6.62 DOAC users per 100 treatment years. With the increased use of DOACs in clinical practice, DOAC-associated major bleeding is expected to be encountered more frequently in the emergency department. The current international guidelines recommend specific reversal agents for the management of DOAC users with severe bleeding to reverse the anticoagulant effect and restore normal hemostasis. An individualized assessment was incorporated in specific clinical situations to guide the decision pathway of major bleeding management. However, specific reversal agents are unavailable or have limited availability in many countries, which is expected to negatively impact the clinical outcomes of DOAC-associated major bleeding. Limited real-world evidence is available from these countries regarding the clinical outcomes of patients with DOAC-associated major bleeding. This narrative review provided an updated assessment of the evidence-based approaches for the management of major bleeding in DOAC users. We also explored the clinical outcomes of patients with major bleeding from clinical settings where specific reversal agents are unavailable. [ABSTRACT FROM AUTHOR]

Summary: In this case report, we present a rare case of life‐threatening gastrointestinal haemorrhage associated with deranged coagulation due to supratherapeutic levels of dabigatran. Dabigatran is a potent, synthetic, reversible non‐peptide thrombin inhibitor which is increasingly used for stroke prevention in patients with non‐valvular atrial fibrillation. It is generally accepted that dabigatran dosing does not require titration or the monitoring of plasma levels due to its predictable pharmacokinetics and pharmacodynamics. However, this case report challenges this viewpoint while identifying an important knowledge gap in relation to the effect of altered gastrointestinal motility on the absorption of direct oral anticoagulants. Furthermore, it demonstrates the successful use of high‐dose idarucizumab in a critical care setting. Idarucizumab is a monoclonal antibody fragment that binds specifically to dabigatran and its metabolites, thereby reversing the anticoagulant effect. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eleni Arnaoutoglou reports a relationship with Bayer, CLS Behring, Astra Zeneca, and Werfen that includes consulting or advisory and speaking and lecture fees. The other author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Competing Interests: Declaration of competing interest The authors declare the following financial interests and/or personal relationships that may be considered potential competing interests: Marc Maegele reports relationships with Astra Zeneca and Bayer that include consulting or advisory and speaking and lecture fees. Maria Ntalouka declares no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

There has been a landmark shift in the last several decades in the management and prevention of thromboembolic events. From the discovery of parenteral and oral agents requiring frequent monitoring as early as 1914, to the development of direct oral anticoagulants (DOACs) that do not require monitoring or dose adjustment in the late 20th century, great advances have been achieved. Despite the advent of these newer agents, bleeding continues to be a key complication, affecting 2 to 4% of DOAC-treated patients per year. Bleeding is associated with substantial morbidity and mortality. Although specific reversal agents for DOACs have lagged the release of these agents, idarucizumab and andexanet alfa are now available as antagonists. However, the efficacy of these reversal agents is uncertain, and complications, including thrombosis, have not been adequately explored. As such, guidelines continue to advise the use of nonspecific prohemostatic agents for patients requiring reversal of the anticoagulant effect of these drugs. As the indications for DOACs and the overall prevalence of their use expand, there is an unmet need for further studies to determine the efficacy of specific compared with nonspecific pro-hemostatic reversal agents. In this review, we will discuss the evidence behind specific and nonspecific reversal agents for both parenteral and oral anticoagulants. [ABSTRACT FROM AUTHOR]

Background and Objectives: Thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) is used to treat acute ischemic stroke. Dabigatran is a reversible thrombin inhibitor approved for stroke prevention in patients with nonvalvular atrial fibrillation. In such cases, thrombolytic therapy can be administered to certain patients after idarucizumab treatment. We evaluated the effectiveness of idarucizumab in dabigatran-treated patients receiving rt-PA. Materials and Methods: We included the data of nine idarucizumab-treated patients from the Riga East University Hospital Stroke Registry from 2018 to 2022 in our retrospective medical records analysis. We used the National Institutes of Health Stroke Scale (LV-NIHSS) score and modified Rankin scale (mRS) on admission and discharge to evaluate neurological deficit and functional outcomes. Results: We analyzed the data of nine patients (seven males and two females) with a mean age of 75.67 ± 8.59 years. The median door-to-needle time for all patients, including those who received idarucizumab before rt-PA, was 51 min (IQR = 43–133); the median LV-NIHSS score was 9 (IQR = 6.0–16.0) on admission and 4 (IQR = 2.5–4.0) at discharge; and the intrahospital mortality rate was 11.1% due to intracranial hemorrhage as a complication of rt-PA. Conclusions: Our study shows that idarucizumab as an antidote of dabigatran appears to be effective and safe in patients with acute ischemic stroke. Furthermore, the administration of idarucizumab slightly prolongs the door-to-needle time; however, the majority of cases showed clinical improvement after receiving therapy. Further randomized controlled trials should be performed to evaluate the safety and effectiveness of idarucizumab for acute ischemic stroke treatment. [ABSTRACT FROM AUTHOR]

This article reports the first experience of the N.V. Sklifosovsky Research Institute for Emergency Medicine in reperfusion therapy for ischemic stroke in a patient taking oral anticoagulant.

Dabigatran is a direct thrombin inhibitor used to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. For patients who present with an acute stroke despite dabigatran therapy, clinical data on the use of intravenous tissue plasminogen activator (IV-tPA) is limited. There is an anticipated increased risk of symptomatic intracranial hemorrhage (sICH) when using IV-tPA in patients on dabigatran therapy. In 2015, the humanized monoclonal antibody fragment idarucizumab was approved for rapid (minutes) reversal of anticoagulant effects of dabigatran. Dabigatran reversal with idarucizumab before administration of IV-tPA might reduce the risk of sICH. We report a case of a 69-year-old stroke patient on dabigatran for paroxysmal atrial fibrillation who presented with an initial National Institutes of Health Stroke Scale (NIHSS) of 12. There was no early evidence of ischemic stroke or hemorrhage on head computed tomography, and coagulation studies implied therapeutic dabigatran levels. After controlling blood pressure, dabigatran was reversed with idarucizumab, and IV-tPA was administrated beginning 197 minutes after he was last seen at his baseline. Subsequent brain magnetic resonance imaging showed 2 punctate infarcts in the left temporal lobe and occipital lobe with no evidence of hemorrhage. The patient was discharged with an NIHSS of 1. Telephone follow-up 2 months later indicated that he was at his prestroke baseline, except for a complaint of worsened short-term memory. Idarucizumab reversal of dabigatran may reduce the risk of sICH and should be considered for acute stroke patients arriving in the IV-tPA time window.

Background and objectives: Oral anticoagulants prevent thromboembolic events but expose patients to a significant risk of bleeding due to the treatment itself, after trauma, or during surgery. Any physician working in the emergency department or involved in the perioperative care of a patient should be aware of the best reversal approach according to the type of drug and the patient’s clinical condition. This paper presents a concise review and proposes clinical protocols for the reversal of oral anticoagulants in emergency settings, such as bleeding or surgery. Contents: The authors searched for relevant studies in PubMed, LILACS, and the Cochrane Library database and identified 82 articles published up to September 2020 to generate a review and algorithms as clinical protocols for practical use. Hemodynamic status and the implementation of general supportive measures should be the first approach under emergency conditions. The drug type, dose, time of last intake, and laboratory evaluations of anticoagulant activity and renal function provide an estimation of drug clearance and should be taken into consideration. The reversal agents for vitamin K antagonists are 4-factor prothrombin complex concentrate and vitamin K, followed by fresh frozen plasma as a second-line treatment. Direct oral anticoagulants have specific reversal agents, such as andexanet alfa and idarucizumab, but are not widely available. Another possibility in this situation, but with less evidence, is prothrombin complex concentrates. Conclusion: The present algorithms propose a tool to help healthcare providers in the best decision making for patients under emergency conditions.

Idarucizumab, a dabigatran-specific reversal agent, was launched in Japan in 2016. The J-Dabigatran Surveillance 2 study was designed to assess the characteristics and outcomes of dabigatran-treated patients after the launch of idarucizumab. Patient characteristics and outcomes, including thromboembolic and bleeding events, of dabigatran-naïve patients with non-valvular atrial fibrillation (NVAF) who received dabigatran etexilate [110 mg or 150 mg twice-daily (b.i.d.)] for the prevention of ischemic stroke and systemic embolism were investigated and presented descriptively. Absolute standardized differences (ASD) in baseline characteristics compared with the first J-Dabigatran Surveillance (J-Dabi1; 2011–2013) study were included. In total, 5660 patients were enrolled and 5436 were analyzed in this study; 3516 and 1898 received 110 mg b.i.d. and 150 mg b.i.d. dabigatran, respectively; 22 received other doses. The overall duration of follow-up (mean ± standard deviation) was 287 ± 179 days. Baseline characteristics, including stroke/bleeding-risk scores, were typical of this patient population. Overall, paroxysmal, persistent, permanent, and symptomatic atrial fibrillation were observed for 53.2%, 27.1%, 13.7%, and 53.9% of patients, respectively (J-Dabi1 ASD: 0.2, 0.0, 0.3, and 0.2, respectively). Catheter ablation was selected in 27.9% of patients (J-Dabi1 ASD: 0.6). Rates of clinical outcomes were low in the study (mostly <2%/year). The incidence rate of major bleeding was 1.1%/year (n = 46) and stroke/transient ischemic attack/systemic embolism was 1.7%/year (n = 71). Twelve (0.2%) patients received idarucizumab, commonly for serious bleeding events, and most recovered. Dabigatran continues to be safe and well tolerated in patients with NVAF for stroke and systemic embolism prevention and continues to be prescribed appropriately. Treatment outcomes have not changed since the availability of idarucizumab. Since the J-Dabi1 study, treatment guidelines for anticoagulation use in NVAF have been updated based on emerging clinical evidence, accounting for differences in patient characteristics, and making dabigatran a preference for distinct patient populations. [Display omitted] • In Japan, dabigatran is used to prevent ischemic stroke in patients with atrial fibrillation • The J-Dabigatran Surveillance 2 study assessed current dabigatran clinical practice • Trends in treatment outcomes have not changed since the availability of idarucizumab • Dabigatran continues to be prescribed appropriately, is safe, and is well tolerated [ABSTRACT FROM AUTHOR]

Purpose: This case report describes a patient with dabigatran accumulation due to acute kidney injury on chronic kidney disease, requiring multiple administration of idarucizumab along with renal replacement therapy because of rebound effect causing numerous episodes of bleeding. Summary: An 86-year-old man on dabigatran etexilate 110 mg twice daily for stroke prevention with atrial fibrillation was admitted to the hospital for bowel obstruction and severe acute kidney injury on chronic kidney disease. The patient had an abnormal coagulation profile and no history of bleeding. Initial laboratory values revealed a hemoglobin concentration of 10.7 g/dL, a platelet count of 115 × 103 platelets/μL, an activated partial thromboplastin time of 150.4 seconds, an international normalized ratio of 10.28, a thrombin time greater than 100 seconds and a serum creatinine of 5.54 mg/dL (490 μmol/L). An initial dose of idarucizumab was administered 1 hour prior to surgery to prevent bleeding. Significant bleeding and hemodynamic instability occurred following surgery. Three additional doses of idarucizumab, 2 sessions of intermittent hemodialysis, continuous venovenous hemofiltration and blood products were required to achieve normalization of coagulation parameters and hemodynamic stability due to rebound coagulopathy after each dose of idarucizumab. Conclusion: Acute kidney injury on chronic kidney disease and third-space redistribution could have led to important dabigatran accumulation and favored rebound coagulopathy. Multiple therapeutic approaches may be required in the management of complex dabigatran intoxication. [ABSTRACT FROM AUTHOR]

Recently, the atrial fibrillation treatment guidelines have been updated to now recommend Non-vitamin K antagonist oral anticoagulants (NOACs) as the preferred alternative to warfarin for systemic embolism and stroke prevention in patients with non-valvular atrial fibrillation. NOACs have major pharmacologic advantages over warfarin, although the most common complications are gastrointestinal bleeding and NOAC-induced nephropathy within 6 weeks after starting therapy, as several recent case-reports stated. We are reporting for the first time a chronic delayed adverse reaction (regularly reported to Authorities) observed in an 82-year-old woman 27 months after starting dabigatran (110 mg twice a day), characterized by concomitant gastrointestinal bleeding and nephropathy. Idarucizumab administration immediately improved both bleeding and renal parameters. Moreover, we are going to highlight the importance of the compliance, the adherence to the therapeutic plan and the supervision of the Hospital Pharmacy on drug prescriptions. In fact in our case, dabigatran was firstly prescribed by the neurologist and delivered by the hospital pharmacy, but the patient continued the treatment for 27 months, prescribed by general practitioner without any laboratory control. This lack of supervision certainly contributed to the onset of the adverse reaction reported. [ABSTRACT FROM AUTHOR]

Introducción. El sangrado en contexto de anticoagulación es uno de los riesgos que tienen ciertos pacientes durante determinados tratamientos, y es potencialmente mortal. Es importante conocer la farmacocinética de estas moléculas para predecir cuál será su comportamiento. Además se requiere juicio clínico en todos los casos de sangrado para determinar el manejo de acuerdo a la severidad. El objetivo de esta revisión es presentar un enfoque del paciente anticoagulado con sangrado en el servicio de urgencias. Temas tratados. Farmacocinética y farmacodinámica, generalidades, sangrado mayor y no mayor, opciones de reversión y tratamiento. Conclusión. En presencia de anticoagulantes orales directos (DOACS) se debe evaluar la gravedad del sangrado y el grado de anticoagulación, pues las estrategias de manejo se orientan dependiendo de si se trata de un sangrado mayor o menor. Cómo citar. Zuluaga-Gómez M, Zuluaga-Arbeláez N, Berrouet-Mejía MC, Estrada-Atehortua AF. Reversión de anticoagulantes orales directos: una perspectiva desde Urgencias. MedUNAB. 2020;23(3): 483-490. doi: https://doi.org/10.29375/01237047.3841 Introduction. Bleeding in the context of anticoagulation is one of the risks faced by some patients during certain treatments, and is potentially deadly. It is important to be aware of the pharmacokinetics of these molecules in order to predict their behavior. Clinical judgment is also required in all cases of bleeding, because management will depend on its severity. The purpose of this review is to present an approach to an anticoagulated patient with bleeding in the emergency ward. Topics Discussed. Pharmacokinetics and pharmacodynamics, generalities, major and non-major bleeding, reversal options and treatment. Conclusion. If direct oral anticoagulants (DOACS) are present, it is necessary to assess the severity of bleeding and the degree of anticoagulation, because the management treatment depends on whether bleeding is major or minor. Cómo citar. Zuluaga-Gómez M, Zuluaga-Arbeláez N, Berrouet-Mejía MC, Estrada-Atehortua AF. Reversión de anticoagulantes orales directos: una perspectiva desde Urgencias. MedUNAB. 2020;23(3): 483-490. doi: https://doi.org/10.29375/01237047.3841 Introdução. O sangramento no contexto da anticoagulação é um dos riscos que alguns pacientes apresentam durante certos tratamentos e é potencialmente fatal. É importante conhecer a farmacocinética dessas moléculas para prever qual será o seu comportamento. Além disso, o julgamento clínico é necessário em todos os casos de sangramento para determinar o manejo de acordo com a gravidade. O objetivo desta revisão é apresentar uma abordagem do paciente anticoagulado com sangramento no departamento de emergência. Tópicos abordados. Farmacocinética e farmacodinâmica, visão geral, sangramento maior e não maior, opções de reversão e tratamento. Conclusão. Na presença de anticoagulantes orais diretos (DOACS), a gravidade do sangramento e o grau de anticoagulação devem ser avaliados, uma vez que são orientadas as estratégias de manejo de acordo com o sangramento, se for maior ou menor. Cómo citar. Zuluaga-Gómez M, Zuluaga-Arbeláez N, Berrouet-Mejía MC, Estrada-Atehortua AF. Reversión de anticoagulantes orales directos: una perspectiva desde Urgencias. MedUNAB. 2020;23(3): 483-490. doi: https://doi.org/10.29375/01237047.3841

Aim. Description of risk factors, pathogenesis and treatment strategies of gastrointestinal bleeding (GIB) in the course of antithrombotic therapy in patients with coronary heart disease (CHD).Key points. Risk factors of GIB during antithrombotic therapy in CHD patients include: GIB, gastric and/or duodenal ulcer in the history, reflux esophagitis, presence of H. pylori, inflammatory bowel disease, diverticula, haemorrhoids, angiodysplasia, gastrointestinal neoplasia, age above 65 years, concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs), glomerular filtration rate

Plain Language Summary Patients with an abnormal heart rhythm (nonvalvular atrial fibrillation [NVAF]) have a higher risk of blood clots and stroke (which is when the blood supply to part of the brain is blocked). To reduce these risks, patients can take anticoagulants that slow or prevent the formation of blood clots. However, if the patient needs major emergency surgery or has a severe injury, the anticoagulants can increase their risk of bleeding, which can sometimes be life-threatening. There are drugs (e.g., idarucizumab) that can be used to reverse the effects of anticoagulants in this type of emergency. What we don’t know is how many NVAF patients in Japan who are on anticoagulants have emergency surgeries or major bleeding after an injury, and therefore may require a reversal drug. The authors looked at Japanese health insurance claim data from 62,888 adult patients with NVAF who started taking an anticoagulant. They found that, annually, approximately 0.5% of the patients had emergency surgery or a major bleed associated with a fracture or injury. In very elderly patients (aged at least 75 years), the annual percentage was approximately 0.6%, which was almost double the annual percentage in patients aged less than 65 years. The authors concluded that, even though the number of people requiring a reversal agent are quite small, it is important to have an effective reversal agent for patients on anticoagulants, particularly older patients.

Abstract Background In the initial absence of specific reversal agents for factor Xa inhibitors (FXa‐Is), prothrombin complex concentrate (PCC) as a hemostatic agent has been recommended by guidelines. Since 2017, idarucizumab has been registered for dabigatran reversal. Still, data on the clinical outcome of direct oral anticoagulant (DOAC)‐related emergencies (major bleeding or urgent interventions) is scarce. In addition, it is unknown to what extent PCC restores thrombin generation in FXa‐I–related emergencies. Our aim was to describe management and clinical outcomes of DOAC‐related emergencies and to assess the laboratory effect of PCC in patients with FXa‐I emergencies. Methods In this prospective cohort study in 5 Dutch hospitals, patients presenting with DOAC‐related emergencies were eligible. The primary outcome was effective hemostasis according to the ISTH definition. Safety outcomes were 30‐day mortality and thromboembolic rate. In patients treated with PCC, additional blood samples were taken to assess the effect on thrombin generation. Results We included 101 patients with major bleeding (FXa‐I, 76; dabigatran, 25) and 21 patients requiring an urgent intervention (FXa‐I, 16; dabigatran, 5). Of patients with major bleeding, 67% were treated with PCC or idarucizumab. Effective hemostasis, 30‐day mortality, and thromboembolism rate were 67%, 22%, and 1%, respectively. In a subset of bleeding patients on FXa‐I managed with PCC, thrombin generation increased, with 96% immediately after PCC administration. In patients requiring an urgent intervention, effective hemostasis, 30‐day mortality, and thromboembolic rate were 95%, 14%, and 5%. Conclusions Effective hemostasis was achieved in the majority of patients presenting with DOAC‐related emergencies;, thromboembolic complications were rare, and mortality was quite high.