Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-α and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.

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Andexanet alfa for reversal of factor Xa inhibitors: a critical review of the evidence

Future Cardiology ◽

10.2217/fca-2019-0038 ◽

2019 ◽

Vol 15 (6) ◽

pp. 395-404

Author(s):

Jameel Abdulrehman ◽

John W Eikelboom ◽

Deborah M Siegal

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Factor Xa Inhibitors ◽

Activity Levels ◽

Reversal Agents ◽

Life Threatening ◽

Andexanet Alfa ◽

Anticoagulated Patients

Direct oral anticoagulants are associated with lower rates of bleeding than vitamin K antagonists, but life-threatening bleeding still occurs. Andexanet alfa is a catalytically inactive recombinant modified human factor Xa molecule that reverses the anticoagulant effect of direct and indirect acting factor Xa inhibitors. In the ANNEXA-4 study, treatment with andexanet was associated with a 92% reduction in median anti-Xa activity levels and excellent or good hemostasis in 82% of patients presenting with serious bleeding while receiving apixaban or rivaroxaban. In this review, we discuss the burden of bleeding in anticoagulated patients and the need for reversal agents, review the mechanism of action of andexanet and critically evaluate the evidence for its efficacy and safety.

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Difficult Intraoperative Heparinization Following Andexanet Alfa Administration

Clinical Practice and Cases in Emergency Medicine ◽

10.5811/cpcem.2019.9.43650 ◽

2019 ◽

Vol 3 (4) ◽

pp. 390-394 ◽

Cited By ~ 2

Author(s):

C. James Watson ◽

Sara Zettervall ◽

Matthew Hall ◽

Michael Ganetsky

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Hemodynamic Instability ◽

The United States ◽

Major Hemorrhage ◽

Reversal Agents ◽

Abdominal Aortic ◽

United States Food ◽

Andexanet Alfa

Direct oral anticoagulants are now commonplace, and reversal agents are recently becoming available. Andexanet alfa (AnXa), approved by the United States Food and Drug Administration in 2018, is a novel decoy molecule that reverses factor Xa inhibitors in patients with major hemorrhage. We present a case of a 70-year-old man taking rivaroxaban with hemodynamic instability from a ruptured abdominal aortic aneurysm. He received AnXa prior to endovascular surgery, and intraoperatively he could not be heparinized for graft placement. Consideration should be given to the risks and benefits of AnXa administration in patients who require anticoagulation after hemorrhage has been controlled.

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Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0040-1716750 ◽

2020 ◽

Author(s):

Amin Polzin ◽

Lisa Dannenberg ◽

Manuela Thienel ◽

Martin Orban ◽

Georg Wolff ◽

...

Keyword(s):

Platelet Activation ◽

Arterial Thrombosis ◽

Thrombus Formation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Cascade ◽

Platelet Activity ◽

Vein Thrombosis

AbstractNonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

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Direct oral anticoagulants (DOAC) – Management of emergency situations

Hämostaseologie ◽

10.5482/hamo-16-11-0043 ◽

2017 ◽

Vol 37 (04) ◽

pp. 257-266 ◽

Cited By ~ 3

Author(s):

Edelgard Lindhoff-Last

Keyword(s):

Vitamin K ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Real Life ◽

Bleeding Complications ◽

Severe Bleeding ◽

Emergency Operations ◽

Reversal Agents ◽

Life Threatening

SummaryThe worldwide increase in the aging population and the associated increase in the prevalence of atrial fibrillation and venous thromboembolism as well as the widespread use of direct oral anticoagulants (DOAC) have resulted in an increase of the need for the management of bleeding complications and emergency operations in frail, elderly patients, in clinical practice. When severe bleeding occurs, general assessment should include evaluation of the bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on anti-platelet drugs and nonsteroidal anti-inflammatory drugs (NSAID). The last intake of the DOAC and its residual concentration are also relevant. The site of bleeding should be immediately localized, anticoagulation should be interrupted, and local measures to stop bleeding should be taken. In life-threatening bleeding or emergency operations immediate reversal of the antithrombotic effect may be indicated. If relevant residual DOAC-concentrations are expected and surgery cannot be postponed, prothrombin complex concentrate (PCC) and/or a specific antidote should be given. While idarucizumab, the specific antidote for dabigatran, has been recently approved for clinical use, the recombinant factor X protein andexanet alfa, an antidote for the reversal of inhibitors of coagulation factor Xa, and ciraparantag, a universal antidote, are not available. Future cohort studies are necessary to assess the efficacy and safety of specific and unspecific reversal agents in “real-life” conditions. This was the rationale for introducing the RADOA-registry (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists), a prospective non-interventional registry, which will evaluate the effects of specific and unspecific reversal agents in patients with life-threatening bleeding or emergency operations either treated with DOACs or vitamin K antagonists.

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DOACs- balance between thrombosis and bleeding - A Review

Archives of Public Health ◽

10.3889/aph.2020.5192 ◽

2020 ◽

Vol 12 (2) ◽

pp. 32-36

Author(s):

Emilija Lazarova Trajkovska

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Event ◽

Common Side Effect ◽

Clotting Factors ◽

Bleeding Events ◽

Real World Data ◽

Reversal Agents ◽

Life Threatening

Bleeding is a common side effect of anticoagulant use. However, the majority of bleeding events are not life-threatening and can be managed conservatively. The first step in managing any significant bleeding event is to temporarily stop using the anticoagulant. The aim of this review was to determine the appropriate management strategy for an acutely bleeding patient on DOACs. Direct oral anticoagulants (DOACs) are now widely used in treatment of venous thromboembolism (VTE) and are recommended first-line over vitamin K antagonists (VKAs) in non-cancer associated VTE. Until recently, supportive measures and infusion of clotting factors were the only available options for reversal of DOACs. Within the last 4 years, approval of specific antidotes has led to hopes for improved outcomes in DOAC-related acute bleeding, however limitations remain including cost, availability and "real-world" data. In severe and life-threatening bleeding events, use of non-specific (e.g. PCC) or specific (e.g. idarucizumab, andexanet alpha) reversal agents are recommended. However, further data is needed to compare outcomes between these two management strategies and identify the cost-effectiveness of these various strategies.

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A Review on the Use of Reversal Agents of Direct Oral Anticogulant Drugs in Case of Gastrointestinal Bleeding

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200624193938 ◽

2020 ◽

Vol 15 ◽

Author(s):

Veronica Ojetti ◽

Angela Saviano ◽

Mattia Brigida ◽

Luisa Saviano ◽

Alessio Migneco ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Medical Emergency ◽

Management Approach ◽

Emergency Setting ◽

Reversal Agents ◽

Life Threatening ◽

Andexanet Alfa

Background : Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant’s intake. Anticoagulants are commonly used for the prevention and the treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, betrixaban) showed a better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. Methods: We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. AIM: This review summarizes the current evidences about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with an active major bleeding or who need urgent surgery to offer physicians indications for a better management approach in order to increase patient’s safety. Conclusion: Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

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The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data

Stroke Research and Treatment ◽

10.1155/2017/6516401 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Kyle M. Ware ◽

Douglas L. Feinstein ◽

Israel Rubinstein ◽

Prudhvi Battula ◽

Jose Otero ◽

...

Keyword(s):

Vitamin K ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Hemoglobin Concentration ◽

Thrombin Inhibitor ◽

Free Hemoglobin ◽

Intracranial Hemorrhages ◽

The Brain

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists.

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Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

Advances in Hematology ◽

10.1155/2015/920361 ◽

2015 ◽

Vol 2015 ◽

pp. 1-19 ◽

Cited By ~ 5

Author(s):

Ali Zalpour ◽

Thein Hlaing Oo

Keyword(s):

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factors ◽

Current Evidence ◽

Thrombin Inhibitor ◽

Prevention And Treatment ◽

Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

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Abstract MP38: Intracerebral Hemorrhage Across the United States: Incidence and Mortality Trends From 1990 to 2017

Stroke ◽

10.1161/str.52.suppl_1.mp38 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Augustin DeLago ◽

Harpreet Singh ◽

Arashdeep Rupal ◽

Chinmay Jani ◽

Arshi Parvez ◽

...

Keyword(s):

United States ◽

Intracerebral Hemorrhage ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

The United States ◽

Mortality Trends ◽

Reversal Agents ◽

Incidence And Mortality ◽

The Us

Background: Intracerebral Hemorrhage (ICH) accounts for 10% of strokes annually in the United States (US). Up-to-date trends in disease burden and regional variation remain unknown; especially after a dramatic increase in the use of direct oral anticoagulants (DOACs) since 2010. Our study reports updated incidence, mortality and mortality to incidence ratio (MIR) data related to ICH across the US. Methods: This observational study utilized the Global Burden of Disease database to determine age-standardized incidence (ASIR), death (ASDR) and MIR rates for ICH overall and for each state in the US from 1990-2017. All analyses were stratified by sex. Trends were analyzed using Joinpoint regression analysis, with presentation of estimated annual percentage changes (EAPCs) in ASIRs, ASDRs and MIRs over the observation period. Results: We observed an overall decrease in ASIRs, ASDRs and MIRs in both genders from 1990-2017, apart from female ASIRs and ASDRs in West Virginia and Kentucky. In 2017, the mean ASIR per 100,000 population for men was 25.67 and 19.17 for women. The 2017 mean ASDRs per 100,000 population for men and women were 13.96 and 11.35, respectively. The District of Columbia had the greatest decreases in ASIR EAPCs for males at -41.25% and females at -40.58%, and the greatest decreases in ASDR EAPCs for both males and females at -55.38% and -48.51%, respectively. The overall MIR during the study period decreased in males by -12.12% and females by -7.43%. However, MIR increased in males from 2014-2017 (EAPC +2.2% [95% CI +0.9%-+3.5%]) and in females from 2011-2017 (EAPC +1.0% [CI +0.7%-+1.4%]). Conclusion: This report reveals overall decreasing trends in incidence, mortality and MIR from 1990-2017. Notably, no significant change in mortality was found in the last 6 years of the study period, and MIR worsened in males from 2014-2017 and in females from 2011-2017, suggesting decreased ICH related survival lately. The substitution of vitamin K antagonists with DOACs is one possible explanation for a downtrend in incidence despite an aging population and increased use of anticoagulants. Limited access to reversal agents for DOACs is a potential reason for increase in MIR, however concrete deductions cannot be made owing to the observational nature of the study.

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