Dabigatran-associated Bleeding Research Articles

Reversal of direct oral anticoagulants: Highlights from the Anticoagulation Forum guideline.

The 2019 guideline from the Anticoagulation Forum provides clear instructions on how to use 2 agents for reversing the effects of direct oral anticoagulants (DOACs): idarucizumab for dabigatran-associated bleeding and andexanet alfa for bleeding associated with rivaroxaban and apixaban. The guideline also discusses off-label use of andexanet alfa for bleeding associated with edoxaban and betrixaban and the use of hemostatic agents such as activated prothrombin complex concentrate and 4-factor prothrombin complex concentrate. Lastly, it offers approaches for building and managing stewardship programs at the health system level.

What is the Role of Reversal Agents in the Management of Emergency Department Patients with Dabigatran-Associated Hemorrhage?

BackgroundIn 2010, the U.S. Food and Drug Administration (FDA) approved dabigatran as the first non-warfarin oral anticoagulant for use in the United States. At the time of FDA approval, there was no antidote or effective treatment for dabigatran-induced hemorrhage. In 2015, the FDA approved idarucizumab for the treatment of dabigatran-induced hemorrhage. The purpose of this clinical practice statement is to evaluate the role of select reversal agents in the management of patients with dabigatran-associated bleeding. MethodsA PubMed literature review was completed to identify studies that investigated the role of reversal agents in the management of emergency department patients with dabigatran-associated hemorrhage. Articles included were those published in the English language between January 2010 and January 2017, enrolled human subjects, and limited to the following types: randomized controlled trials, prospective trials, meta-analyses, and retrospective cohort studies. Review articles, case series, and case reports were not included in this review. All selected articles then underwent a structured review by the authors. ResultsSix hundred fifty-two articles were identified in the search. After use of predetermined inclusion and exclusion criteria, six articles were selected for structured review. ConclusionThe clinical efficacy of activated prothrombin complex concentrates, idarucizumab, and recombinant factor VIIa remains unclear until further research is performed. Activated prothrombin complex concentrates, idarucizumab, and recombinant factor VIIa may be considered in patients with serious bleeding from dabigatran, after careful consideration of possible benefits and risks.

Reversal of Anticoagulation: Therapeutic Advances and Clinical Guidelines

Background: Anticoagulants are life-saving medications that prevent and treat thromboembolic disease and are of particular importance in the elderly population for prevention of stroke in atrial fibrillation. The advent of direct oral anticoagulants and reversal agents has yielded more options for patients, although complicating clinical decision-making. Areas of Uncertainty: The decision to anticoagulate in atrial fibrillation depends on the risks of stroke versus bleeding. The accompanying HAS-BLED score for predicting bleeding allows an estimation of net clinical benefit. Despite these tools, uncertainty remains. Notably, anticoagulation has traditionally been avoided in patients with recurrent falls. Yet, decision analytic modeling has shown that patients on warfarin would need hundreds of falls annually to warrant discontinuation. At the same time, direct oral anticoagulants, while theoretically simpler to dose than warfarin, should be dose-reduced or avoided in cases of renal impairment, extreme age or weight, or concomitant use of strong P-glycoprotein and/or CYP3A4 inducers/inhibitors. Therapeutic Advances: Prothrombin complex concentrates consist of endogenous coagulation factors and anticoagulants. One 4-factor prothrombin complex concentrates (factors II, VII, IX, X, proteins C, and S), when administered with intravenous vitamin K, effectively reversed warfarin in cases of life-threatening bleeding or need for urgent surgery/procedure in 2 phase IIIb trials, although it may be associated with thrombogenesis. Idarucizumab, a humanized monoclonal antibody, reversed dabigatran-associated bleeding in 11.4 hours in a late-stage trial and had no effect on thrombin in pharmacodynamic studies. Andexanet alfa, a recombinant molecule derived from factor X, is a class-specific reversal agent for factor Xa inhibitors. In trials of healthy individuals (ANNEXA-A, ANNEXA-R), andexanet alfa reversed apixaban and rivaroxaban, although increased levels of d-Dimer and prothrombin fragments 1 and 2, suggesting potential thrombogenesis; the later stage ANNEXA-4 trial is ongoing. Finally, ciraparantag, a small water-soluble molecule, reversed edoxaban and enoxaparin in phase 1/2 trials (by whole blood clotting time), and holds promise as a potential universal reversal agent.

Reversal of dabigatran-associated major bleeding with activated prothrombin concentrate: A prospective cohort study

The reversal of dabigatran-associated major bleeding can now be achieved with the antidote idarucizumab. We evaluated activated prothrombin complex concentrate (aPCC) as an alternative for this purpose.Patients treated with dabigatran and suffering a major bleed were treated as per existing hospital protocol with aPCC. They were subsequently recruited for a 30-day follow-up. Effectiveness was evaluated by the treating physician, using an Assessment Guide. Safety outcomes were arterial or venous thromboembolism or death. A comparison was also made with historic cases with dabigatran-associated major bleeds treated with supportive care, by matching 1:2 for type of bleed, age and sex.We aimed at 32 evaluable cases but the study was prematurely discontinued after 14 cases due to the availability of the approved antidote. The effectiveness of aPCC was assessed as Good in 9 (64%), moderate in 5 (36%) and poor in none. There were no thromboembolic events and one death. In the secondary adjudication of effectiveness, using the same criteria and by the same adjudicators as previously done for the historic cases, the outcome was graded for the current cases versus the historic cases as Good, Moderate, or Poor in 10 (71%) versus 16 (57%), 3 (21%) versus 4 (14%), and 1 (7%) versus 8 (29%), respectively.Although supportive care is sufficient to manage many patients with dabigatran-associated bleeding, aPCC might provide an additional benefit to control life-threatening bleeding in selected cases and does not appear to cause an excess of thromboembolic events.

Idarucizumab for Reversal of Dabigatran-Associated Bleeding: Misnomer or Miracle?

BackgroundThe development of novel oral anticoagulants (NOACs) has revolutionized oral anticoagulation. Rapid incorporation of NOACs into general practice has heightened the demand for directed reversal agents. Idarucizumab is a targeted reversal agent that is approved for the urgent reversal of the anticoagulant effects of dabigatran. While it is a welcome addition to reversal strategies of dabigatran, a number of clinical questions exist regarding its place in therapy. ObjectiveWe describe controversies regarding the use of idarucizumab therapy in patients with dabigatran-associated bleeding. DiscussionAlthough existing clinical studies show a rapid reversal of coagulation assays, these studies did not describe a corresponding improvement in mortality or rapid cessation of hemorrhage. It is questionable how heavily clinicians can rely upon the use of the surrogate endpoints in clinical studies, such as ecarin clotting time and dilute thrombin time. Another issue is whether patients exhibiting re-elevation of coagulation assays would benefit from an additional dose of idarucizumab, because this has not been studied. It is currently unclear if blood products must be given in addition to idarucizumab can be used as monotherapy. ConclusionsThe initial data suggest a definite role for idarucizumab in treatment of bleeding associated with dabigatran. As more clinical practice experience is gained with the agent and the remaining data on its use are released, clinicians can better guide the clinical use of idarucizumab. At present, there is currently not enough evidence for idarucizumab to be used as monotherapy.

Hémorragie survenant chez un patient traité par un anticoagulant oral direct

Direct oral anticoagulants (DOAC) are recommended for stroke prevention in atrial fibrillation and for the treatment of venous thromboembolism. However, they are associated with hemorrhagic complications. Management of DOAC-induced bleeding remains challenging. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. Therapeutic options also include antidotes: idarucizumab, antidote for dabigatran, has been approved for use whereas andexanet alpha, antidote for anti-Xa agents, and aripazine, antidote for all DOAC, are under development. Other options include hemodialysis for the treatment of dabigatran-associated bleeding and administration of oral charcoal if recent DOAC ingestion. DOAC plasma concentration measurement is necessary to guide DOAC reversal. We propose an update on DOAC-associated bleeding, integrating the availability of dabigatran antidote and the critical place of DOAC concentration measurements.

Hemodialysis for the treatment of dabigatran‐associated bleeding: a case report and systematic review

Dabigatran, a direct thrombin inhibitor, is effective for the treatment of venous thromboembolism and the prevention of stroke and systemic embolism resulting from atrial fibrillation. The most effective way of reversing the anticoagulant effect of dabigatran in patients who have bleeding complications is unknown. To document the clinical outcomes of patients undergoing renal replacement therapy (RRT) for dabigatran-associated bleeding. We searched MEDLINE and EMBASE up to May 2015. Articles were selected if the patients presented with dabigatran-associated bleeding, underwent RRT for dabigatran removal, and reported an effect on bleeding. The search yielded 22 studies representing 35 unique patient cases. The median patient age was 74.1years (range, 56-94years). Thirteen patients (37.1%) were female, and 32 (91.4%) patients received dabigatran for atrial fibrillation. Twenty-three patients (65.7%) underwent intermittent hemodialysis, 10 patients (28.6%) underwent continuous RRT (CRRT), and two patients underwent both intermittent hemodialysis and CRRT. Following RRT, there were significant reductions in dabigatran concentrations (P=0.001). Rebound of the dabigatran concentration was reported in 12 (57.1%) patients following cessation of RRT. Hemostasis was reportedly achieved in 24 patients (70.6%), and 10 patients (29.4%) died because of bleeding. In patients with dabigatran-associated bleeding, RRT appears to be effective in reducing dabigatran concentrations, and in case reports this has been associated with a reduction in the duration and/or severity of bleeding. However, a rebound in concentrations may be seen following withdrawal of RRT, suggesting that a prolonged course of RRT may be more effective.

Abstract T MP113: Mortality after Gastrointestinal Hemorrhage in Patients taking Dabigatran and Warfarin

Background: Clinical trial data suggest greater likelihood of gastrointestinal (GI) bleeding for patients taking dabigatran 150 mg compared to warfarin, and similar likelihood for patients taking dabigatran 75 mg. Dabigatran-associated GI bleeding is concerning because no antidote exists to reverse the effects of dabigatran, possibly increasing the likelihood of death. Objective: Examine mortality after GI bleeding for patients taking warfarin, dabigatran 150mg, or dabigatran 75mg. Method: We used Medicare inpatient, carrier, and pharmacy claims for beneficiaries age 65 or older with new atrial fibrillation from 11/2010 through 12/2011 who received dabigatran 150mg, dabigatran 75mg, or warfarin. GI bleeds were identified by the primary diagnosis on inpatient claims, and death dates were determined from the CMS enrollment file. Patient demographics, comorbid conditions, and prior health service use were determined from claims incurred during the 12 months prior to the GI bleed. Each patient taking dabigatran 150 mg or 75 mg was matched to a single patient taking warfarin based on patient characteristics at the time of the bleed using an optimal propensity matching algorithm. Results: Of 2,889 GI bleeding events, 2326 (81%), 465 (16%), and 98 (3%) occurred in patients taking warfarin, dabigatran 150 mg, and dabigatran 75 mg, respectively. Compared to patients taking warfarin, patients on dabigatran 150mg were less likely to have renal disease, heart failure, or previous GI bleed, and had fewer previous inpatient days of care. In contrast, patients on dabigatran 75 mg were older and more likely to have renal disease, heart failure, or previous GI bleed compared to patients taking warfarin. The unadjusted 30-day mortality rate was 5.3%, 6.5%, and 8.1% for patients taking warfarin, dabigatran 150 mg, and dabigatran 75 mg and did not differ significantly by anticoagulant type. In the propensity-matched samples, mortality was similar for patients taking dabigatran 150 mg compared to warfarin (6.6% vs. 5.5%; p=0.49), and dabigatran 75 mg compared to warfarin (8.2% vs. 5.1%; p=0.39). Conclusions: Death after GI bleeding does not differ for patients taking dabigatran or warfarin, despite the lack of antidote for dabigatran.

Venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit.

Dabigatran is a direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with non-valvular atrial fibrillation. The procedure to manage dabigatran-associated haemorrhages is not well formalized. Conventional haemodialysis has been evaluated with good results. Patients with dabigatran-associated bleeding may be unstable and convective techniques like venovenous haemodiafiltration (HDF) can be interesting. We report the case of a 74-year-old, critically ill patient with haemorrhagic shock and dabigatran overexposure due to acute kidney injury. He underwent HDF and dabigatran blood concentrations decreased from 325.3 ng/mL to 160.5 ng/mL. We report here key pharmacokinetics parameters (half-life, extraction coefficient, clearance).

Risk of dabigatran-associated bleeding in patients with AF

Risk of dabigatran-associated bleeding in patients with AF

C0247: Management of Dabigatran-Associated Severe Bleeding: The Experience of a Central Hospital

C0247: Management of Dabigatran-Associated Severe Bleeding: The Experience of a Central Hospital

Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban

Dabigatran, apixaban, and rivaroxaban have been approved for primary and secondary stroke prevention in patients with atrial fibrillation. However, questions have arisen about how to manage emergency situations, such as when thrombolysis would be required for acute ischemic stroke or for the managing intracranial or gastrointestinal bleedings. We summarize the current literature and provide recommendations for the management of these situations. Peak plasma levels of the direct oral anticoagulants (DOACs) apixaban, dabigatran, or rivaroxaban are observed about 2-4h after intake. Elimination of dabigatran is mainly dependent on renal function. Consequently, if renal function is impaired, there is a risk of drug accumulation that is highest for dabigatran followed by rivaroxaban and then apixaban and thus dosing recommendations are different. To date, no bedside tests are available that reliably assess the anticoagulatory effect of DOACs, nor are specific antidotes available. We recommend performing the following tests if DOAC intake is unknown: dabigatran-associated bleeding risk is minimized or can be neglected if thrombin time, Hemoclot test, or Ecarin clotting time is normal. Apixaban and rivaroxaban effects can be ruled out if findings from the anti-factor Xa activity test are normal. High plasma levels of DOAC are also mostly excluded if PTT and PTZ are normal four or more hours after DOAC intake. However, normal values of global coagulation tests are not sufficient if thrombolysis is indicated for treating acute stroke. The decision for or against thrombolysis is an individual decision; in these cases, thrombolysis use is off-label. In case of bleeding, prothrombin complex concentrates seems to be the most plausible treatment. For severe gastrointestinal bleeding with life-threatening blood loss, the bleeding source needs to be identified and treated by invasive measures. Use of procoagulant drugs (antifibrinolytics) might also be considered. However, there is very limited clinical experience with these products in conjunction with DOAC.

Abstract 484: Real World Experience with the Use of Dabigatran

Background The RE-LY trial in 2009 ushered in a new era in anticoagulation options for stroke prevention in atrial fibrillation.We sought to determine the safety, efficacy, and tolerability of dabigatran in a community setting. Methods We retrospectively reviewed demographics, bleeding rates, stroke rates, and reasons for discontinuation in patients on dabigatran for non-valvular atrial fibrillation. Results Of the 263 patients, mean age was 73.8 years (32 to 96) and 41.06% were female. The 150 mg BID dose was used in 93.54% of patients and 75 mg BID in 6.46%. Major bleeding was noted in 4 (1.52%), minor bleeding in 25 (9.5%), and rate of discontinuation was 22.3%. Patients who experienced major bleeding were more likely to be older, male, have higher HAS-BLED scores, and a history of gastrointestinal bleeds. All these patients were managed conservatively with no mortality.Of note, three of the four patients with major bleeds were on amiodarone in addition to dabigatran 150 mg BID.Two presented with transient ischemic attacks and had elevated PTTs suggesting compliance with dabigatran. Four patients who were admitted to the hospital with pneumonia, atrial fibrillation, and COPD exacerbation had elevated troponins without accompanying symptoms of acute coronary syndrome. In patients maintained on the 75 mg BID dose, minor bleeding was noted in two, who were also on dronedarone. No strokes or intracranial bleeds were noted in patients on either dose of dabigatran Conclusions This retrospective analysis demonstrates safety and efficacy of dabigatran as an oral anticoagulant in patients with non-valvular atrial fibrillation over a two-year follow-up while describing the factors associated with increased bleeding risk.It is the first study to describe experience with use of 75 mg of dabigatran. Drug interactions are a common and avoidable reason for dabigatran-associated bleeding and were noted with both amiodarone and dronedarone in our study. There was no increased incidence of myocardial infarction noted. In our study population, dabigatran is safe, effective, and convenient when there is careful patient selection with consideration of renal function and possible drug-drug interactions

Treatment of Dabigatran-Associated Bleeding

Dabigatran etexilate is a competitive, direct thrombin inhibitor that works in the coagulation cascade to ultimately prevent thrombus formation. It is recommended by the 2012 American College of Chest Physicians evidence-based clinical practice guidelines as first-line therapy over vitamin k antagonists for long-term antithrombotic therapy in patients with paroxysmal or persistent nonrheumatic atrial fibrillation who are at intermediate to high risk of stroke and systemic embolism (grade 2B). However, serious postmarketing events involving life-threatening bleeding are emerging with no antidote for reversal of the anticoagulant effect being available for use. Potential reversal agents are being used in clinical practice with questionable efficacy and safety profiles. We report a case involving an 84-year-old male with acute kidney injury who developed life-threatening gastrointestinal and surgical site bleeding secondary to dabigatran accumulation. Use of the Naranjo probability scale indicated a probable cause between the bleeding event and dabigatran use. After discontinuation of drug therapy, fresh frozen plasma, recombinant coagulation factor VIIa, and cryoprecipitate were administered as potential reversal agents with negligible benefit. However, this patient appeared to slowly benefit with administration of continuous venovenous hemodialysis. Based upon our experience with this patient and literature review, the most effective treatment algorithm for dabigatran-associated bleeding may be to utilize hemodialysis initially.

Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model

One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation. This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran-associated bleeding diathesis. Anesthetized rabbits were treated with 0.4 mg kg(-1) dabigatran followed by PCC doses of 20, 35 or 50 IU kg(-1) or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined. From an initial mean of 29 mL, blood loss progressively declined by 5.44 mL with a 95% confidence interval (CI) of 2.21-8.67 mL per 10 IU kg(-1) increment in PCC dose (P = 0.002). At a PCC dose of 50 IU kg(-1) blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7 min (P < 0.001). The rate of hemostasis was nearly trebled with each 10 IU kg(-1) increment in PCC dose (rate ratio, 2.89; CI, 1.64-5.09). In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted.