Acute Stroke Treatment in an Anticoagulated Patient: When Is Thrombolysis an Option?

Abstract Purpose of Review Direct oral anticoagulants (DOACs: the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran) are the mainstay of stroke prevention in patients with non-valvular atrial fibrillation (AF). Nevertheless, there is a residual stroke risk of 1–2% per year despite DOAC therapy. Intravenous thrombolysis (IVT) reduces morbidity in patients with ischemic stroke and improves functional outcome. Prior DOAC therapy is a (relative) contraindication for IVT but emerging evidence supports its use in selected patients. Recent Findings Recent observational studies highlighted that IVT in patients on prior DOAC therapy seems feasible and did not yield major safety issues. Different selection criteria and approaches have been studied including selection by DOAC plasma levels, non-specific coagulation assays, time since last intake, and prior reversal agent use. The optimal selection process is however not clear and most studies comprised few patients. Summary IVT in patients taking DOAC is a clinically challenging scenario. Several approaches have been proposed without major safety issues but current evidence is weak. A patient-oriented approach balancing potential benefits of IVT (i.e., amount of salvageable penumbra) against expected bleeding risk including appropriate monitoring of anticoagulant activity seem justified.

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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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Reversal strategies in patients treated with direct oral anticoagulants

VASA ◽

10.1024/0301-1526/a000777 ◽

2019 ◽

Vol 48 (5) ◽

pp. 389-392 ◽

Cited By ~ 2

Author(s):

Paul Gressenberger

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Invasive Procedure ◽

Bleeding Risk ◽

Study Data ◽

Current Evidence ◽

Bleeding Complications ◽

Bleeding Events ◽

Reversal Agent

Summary. Administration of direct oral anticoagulants (DOACs) for the treatment of venous thrombotic events (VTE) or non-valvular atrial fibrillation (AF) is now standard of care and has demonstrated clinical efficacy and safety in numerous clinical studies. Usually these substances have lower overall mortality and less risk of cerebral hemorrhage, but depending on the substance and study, they are more likely to cause gastrointestinal bleeding than vitamin K antagonists (VKA), the medication that used to be standard for VTE and AF. Since DOACs have very short plasma elimination half-lives compared to VKA, for most bleeding events, expert opinions suggest that withdrawal of DOACs and supportive care will likely suffice to stop a bleeding episode. Because there is a bleeding risk associated with DOACs, reversal strategies may be needed if a patient receiving DOAC therapy bleeds during surgery or an invasive procedure. So far, idarucizumab has been the only available antidote that binds specifically to dabigatran and safely and quickly reverses its anticoagulant effects. Idarucizumab has no effects on anti Xa inhibitors or other anticoagulants. To date, treatment of serious, life-threatening bleeds in patients with anti-Xa-inhibitor has involved 4 factor prothrombin complex concentrates (PCC). PCC restores normal hemostasis laboratory values in most patients with major bleeding events after anti Xa inhibitor intake. Recently, the US Food and Drug Administration (FDA) approved andexanet alfa as the first specific antidote for the anti-Xa inhibitors apixaban and rivaroxaban. So far clinical experience with this substance and data comparing it with PCC are lacking. Currently ciraparantag is under investigation as a universal reversal agent for all DOACs and low molecular weight heparin as well. Because it is so broadly applicable, ciraparantag might be a good future option for the management of most bleeding complications under anticoagulant treatment. The aim of this review is to summarize recent study data and recommendations on nonspecific and specific DOAC reversal strategies and to present the current evidence.

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Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects

European Heart Journal ◽

10.1093/eurheartj/ehab637 ◽

2021 ◽

Author(s):

Jack Ansell ◽

Sasha Bakhru ◽

Bryan E Laulicht ◽

Gregory Tracey ◽

Stephen Villano ◽

...

Keyword(s):

Steady State ◽

Anticoagulant Activity ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Hot Flashes ◽

Elderly Subjects ◽

Reversal Agent ◽

Post Dose ◽

Healthy Elderly ◽

Complete Reversal

Abstract Aims Ciraparantag is a reversal agent for anticoagulants including direct oral anticoagulants. The aim was to evaluate the efficacy and safety of ciraparantag to reverse anticoagulation induced by apixaban or rivaroxaban in healthy elderly adults. Methods and results Two randomized, placebo-controlled, dose-ranging trials conducted in healthy subjects aged 50–75 years. Subjects received apixaban (Study 1) 10 mg orally twice daily for 3.5 days or rivaroxaban (Study 2) 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120, or 180 mg) or placebo. Efficacy was based on correction of the whole blood clotting time (WBCT) at multiple timepoints over 24 h. Subjects and technicians performing WBCT testing were blinded to treatment. Complete reversal of WBCT within 1 h post-dose and sustained through 5 h (apixaban) or 6 h (rivaroxaban) was dose related and observed with apixaban in 67%, 100%, 100%, and 17% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, or placebo, respectively; and with rivaroxaban in 58%, 75%, 67%, 100%, and 13% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, 180 mg, or placebo, respectively. Adverse events related to ciraparantag were mild, transient hot flashes or flushing. Conclusions Ciraparantag provides a dose-related reversal of anticoagulation induced by steady-state dosing of apixaban or rivaroxaban. Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated.

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Recanalisation therapies for acute ischaemic stroke in patients on direct oral anticoagulants

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-325456 ◽

2021 ◽

Vol 92 (5) ◽

pp. 534-541

Author(s):

David J Seiffge ◽

Thomas Meinel ◽

Jan Christoph Purrucker ◽

Johannes Kaesmacher ◽

Urs Fischer ◽

...

Keyword(s):

Ischaemic Stroke ◽

Mechanical Thrombectomy ◽

Current Knowledge ◽

Anticoagulant Activity ◽

Therapeutic Option ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Intravenous Thrombolysis ◽

Vessel Occlusion ◽

Reversal Agents

Direct oral anticoagulants (DOACs) have emerged as primary therapeutic option for stroke prevention in patients with atrial fibrillation. However, patients may have ischaemic stroke despite DOAC therapy and there is uncertainty whether those patients can safely receive intravenous thrombolysis or mechanical thrombectomy. In this review, we summarise and discuss current knowledge about different approaches to select patient. Time since last DOAC intake—as a surrogate for anticoagulant activity—is easy to use but limited by interindividual variability of drug pharmacokinetics and long cut-offs (>48 hours). Measuring anticoagulant activity using drug-specific coagulation assays showed promising safety results. Large proportion of patients at low anticoagulant activity seem to be potentially treatable but there remains uncertainty about exact safe cut-off values and limited assay availability. The use of specific reversal agents (ie, idarucizumab or andexanet alfa) prior to thrombolysis is a new emerging option with first data reporting safety but issues including health economics need to be elucidated. Mechanical thrombectomy appears to be safe without any specific selection criteria applied. In patients on DOAC therapy with large vessel occlusion, decision for intravenous thrombolysis should not delay thrombectomy (eg, direct thrombectomy or immediate transfer to a thrombectomy-capable centre recommended). Precision medicine using a tailored approach combining clinicoradiological information (ie, penumbra and vessel status), anticoagulant activity and use of specific reversal agents only if necessary seems a reasonable choice.

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Applied Nanotechnologies in Anticoagulant Therapy: From Anticoagulants to Coagulation Test Performance of Drug Delivery Systems

Applied Nano ◽

10.3390/applnano2020009 ◽

2021 ◽

Vol 2 (2) ◽

pp. 98-117

Author(s):

Yuri B. G. Patriota ◽

Luíse L. Chaves ◽

Evren H. Gocke ◽

Patricia Severino ◽

Mônica F. R. Soares ◽

...

Keyword(s):

Drug Delivery ◽

Anticoagulant Therapy ◽

Test Performance ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Delivery Systems ◽

Reversal Agent ◽

Laboratory Assessment ◽

Administration Routes

Heparin-based delivery systems have been explored to improve their therapeutic efficacy and to reduce toxicity for different administration routes. Regardless of the applied drug delivery system (DDS), the evaluation of anticoagulant performance is instrumental for the development of a suitable DDS. The understanding of the range of anticoagulant assays, together with their key applications and limitations, is essential both within the context of scientific research and for clinical usage. This review provides an overview of the current anticoagulant therapy and discusses the advantages and limitations of currently available anticoagulant assays. We also discuss studies involving low-molecular-weight heparin (LMWH)-based nanocarriers with emphasis on their anticoagulation performance. Conventional anticoagulants have been used for decades for the treatment of many diseases. Direct oral anticoagulants have overcome some limitations of heparins and vitamin K antagonists. However, the lack of an accurate laboratory assessment, as well as the lack of a factor “xaban” (Xa) inhibitor reversal agent, remains a major problem associated with these anticoagulants. LMWHs represent anticoagulant agents with noteworthy efficacy and safety, and they have been explored to improve their outcomes with various nanocarriers through several administration routes. The main problems related to LMWHs have been surmounted, and improved efficiency may be achieved through the use of DDSs.

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Abstract TP9: Safety of Endovascular Treatment in Acute Stroke Patients Taking Oral Anticoagulants

Stroke ◽

10.1161/str.47.suppl_1.tp9 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Timo Uphaus ◽

Oliver C Singer ◽

Joachim Berkefeld ◽

Christian H Nolte ◽

Georg Bohner ◽

...

Keyword(s):

Clinical Outcome ◽

Endovascular Treatment ◽

Acute Stroke ◽

Positive Impact ◽

Therapeutic Option ◽

Oral Anticoagulants ◽

Intravenous Thrombolysis ◽

Vessel Occlusion ◽

Stroke Treatment ◽

Male Patients

Introduction: The endovascular treatment (EVT) of cerebral ischemia in the case of large vessel occlusion has been established over recent years. Randomized trials showed a positive impact on the clinical outcome of endovascular treatment in addition to thrombolysis with respect to clinical outcome and safety, so that this therapeutic option will be implemented in future guidelines. The role of EVT in patients treated with oral anticoagulants remains uncertain. Hypothesis: We assessed the hypothesis that application of EVT is safe with regard to the occurrence of intracranial bleeding and clinical outcome in patients taking anticoagulants. Methods: The ENDOSTROKE-Registry is a commercially independent, prospective observational study in 12 stroke centers in Germany and Austria launched in January 2011. An online tool served for data acquisition of pre-specified variables concerning endovascular stroke therapy. Results: Data from 815 patients (median age 70, 57% male) undergoing EVT and known anticoagulation status were analyzed. A total of 85 (median age 76, 52% male) patients (10.4%) took oral anticoagulants prior to EVT. Anticoagulation status as measured with INR was 2.0-3.0 in 24 patients (29%), <2.0 in 52 patients (63%) and above 3.0 in 7 patients (8%) of 83 patients with valid INR data prior to EVT. Patients taking anticoagulants were significantly older (median age 76 vs. 69, p < 0.001). Comparing those patients taking anticoagulants and those not, there were no differences concerning NIHSS at admission (with anticoagulants Median-NIHSS 17 vs. without Median-NIHSS 15, p = 0.492, Mann Whitney Test) and the rate of intracranial hemorrhage after intervention (with anticoagulants 11.8% vs. without 12.2%, p = 0.538). After adjustment for age and NIHSS at admission there were no significant differences between the two groups with regard to good clinical outcome, as measured with the modified ranking scale (mRS, 90d-mRS 0-2, 39.2% of patients not receiving anticoagulants; 25.9% of those receiving anticoagulants). Conclusion: The application of endovascular treatment in patients taking oral anticoagulants is safe and should be considered in acute stroke treatment as an important alternative to contraindicated intravenous thrombolysis.

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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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Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity

Molecules ◽

10.3390/molecules27010274 ◽

2022 ◽

Vol 27 (1) ◽

pp. 274

Author(s):

Konstantin V. Savateev ◽

Victor V. Fedotov ◽

Vladimir L. Rusinov ◽

Svetlana K. Kotovskaya ◽

Alexandr A. Spasov ◽

...

Keyword(s):

Bacterial Infections ◽

Anticoagulant Activity ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Antiviral Agents ◽

Multiple Organ ◽

Thrombin Time ◽

Cytokine Storm ◽

Reference Drug

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood.

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Abstract 4: Safety of Intravenous Thrombolysis Among Patients Taking Direct Oral Anticoagulants: A Systematic Review and Meta-analysis

Stroke ◽

10.1161/str.49.suppl_1.4 ◽

2018 ◽

Vol 49 (Suppl_1) ◽

Cited By ~ 1

Author(s):

Shima Shahjouei ◽

Georgios Tsivgoulis ◽

Nitin Goyal ◽

Andrei V. Alexandrov ◽

Ramin Zand

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Intravenous Thrombolysis

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Direct oral anticoagulant monitoring: what laboratory tests are available to guide us?

Hematology ◽

10.1182/hematology.2019000027 ◽

2019 ◽

Vol 2019 (1) ◽

pp. 194-197 ◽

Cited By ~ 3

Author(s):

Ravi Sarode

Keyword(s):

Clinical Decision Making ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Rapid Assessment ◽

Clinical Decision ◽

The United States ◽

Thrombin Inhibitor ◽

Thrombin Time ◽

Clinical Scenarios

Abstract Direct oral anticoagulants (DOACs) are increasingly used in the treatment and prophylaxis of thromboembolism because of several advantages over vitamin K antagonists, including no need for laboratory monitoring. However, it has become increasingly important in certain clinical scenarios to know either actual DOAC concentration (quantitative) or presence of DOAC (qualitative). These clinical conditions include patients presenting with major bleeding or requiring urgent surgery who may need a reversal or hemostatic agent, extremes of body weight, failed therapy, etc. Prothrombin time and activated partial thromboplastin time are variably affected by factor Xa inhibitors (FXaIs) and direct thrombin inhibitor (DTI), respectively, depending on reagents’ sensitivity, and hence, they cannot be relied on confidently. Thrombin time is highly sensitive to very low amounts of DTI; thus, normal value rules out a clinically significant amount. Liquid chromatography mass spectrometry accurately measures DOAC levels but is clinically impractical. Dilute thrombin time and ecarin-based assays using appropriate calibrators/controls provide an accurate DTI level. Anti-Xa assay using corresponding FXaI calibrators/controls provides accurate drug levels. However, these assays are not readily available in the United States compared with some other parts of the world. Heparin assays using anti-Xa activity often have a linear relationship with calibrated FXaI assays, especially at the lower end of on-therapy levels, and they may provide rapid assessment of drug activity for clinical decision making. Currently, there is very limited knowledge of DOAC effect on viscoelastic measurements. Although there is uniformity in expression of DOAC concentrations in nanograms per milliliter, a universal FXaI DOAC assay is urgently needed.

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