Extensive skin necrosis in an elderly woman on dabigatran

Dabigatran, a novel oral anticoagulant, is a direct thrombin inhibitor and is being increasingly used owing to the advantage of dosing without the need for laboratory monitoring. While extensive skin necrosis is known to be associated with oral anticoagulants such as warfarin and factor Xa inhibitors, dabigatran toxicity typically manifests with bleeding, especially in the elderly. We describe a 70-year-old woman who was prescribed dabigatran for the treatment of unprovoked deep venous thrombosis. She developed bleeding diathesis along with extensive skin necrosis and acute kidney injury shortly after commencing the drug. Haemodialysis was given in view of dabigatran toxicity and complications of kidney dysfunction which resolved promptly over a week. However, the patient succumbed to severe sepsis from secondary skin infections. It is crucial to closely monitor for signs of dabigatran toxicity, especially in the elderly patients.

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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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Therapeutic potential of apixaban at different stages of management of patients with pulmonary thromboembolism

Medical Council ◽

10.21518/2079-701x-2018-21-8-15 ◽

2019 ◽

pp. 8-15

Author(s):

O. V. Averkov ◽

V. I. Vechorko ◽

O. A. Shapsigova

Keyword(s):

Secondary Prevention ◽

Anticoagulant Therapy ◽

Therapeutic Potential ◽

Pulmonary Thromboembolism ◽

Oral Anticoagulants ◽

Factor Xa ◽

Evidence Base ◽

Thrombin Inhibitor ◽

Factor Xa Inhibitor ◽

A Priority

The article discusses the issues of anticoagulant therapy in pulmonary thromboembolism. It clearly highlights the main advantages and the preferred use of direct selective oral anticoagulants represented by the thrombin inhibitor dabigatran and the factor Xa inhibitor group including apixaban, edoxaban and rivaroxaban. This article provides a thorough introduction of apixaban with an evidence base allowing to consider it a priority anticoagulant, which may be reasonably administered to the majority of patients with pulmonary thromboembolism from the first hours of the disease to many years of secondary prevention.

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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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The Reversal of Bleeding Caused by New Oral Anticoagulants (NOACs): A Systematic Review and Meta-Analysis

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029618796339 ◽

2018 ◽

Vol 24 (9_suppl) ◽

pp. 117S-126S ◽

Cited By ~ 5

Author(s):

Sariya Udayachalerm ◽

Sasivimol Rattanasiri ◽

Teeranan Angkananard ◽

John Attia ◽

Nakarin Sansanayudh ◽

...

Keyword(s):

Case Reports ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Factor Xa ◽

New Oral Anticoagulants ◽

Thrombin Inhibitor ◽

Aggregated Data ◽

Reversal Agents ◽

Death Studies ◽

Risk Of Death

New oral anticoagulants (NOACs; ie, direct thrombin inhibitor [DTI] and factor Xa [FXa] inhibitors) were used as alternatives to warfarin. Specific antidotes (idarucizumab for dabigatran and andexanet alfa for FXa inhibitors) and hemostatic reversal agents were used for lowering bleeding, but their efficacies were still uncertain. The objectives of this study were to estimate and compare the efficacy of NOAC antidotes on bleeding reversal and death. Studies were identified from MEDLINE and Scopus databases until May 2018. Case reports/series and cohorts were selected if they assessed reversal or death rates. Data were independently extracted by 2 reviewers. Individual patient data and aggregated data of outcomes were extracted from case reports/series and cohorts. Binary regression was used to estimate outcome rates, risk ratio (RR) along with 95% confidence interval (CI). Interventions were NOACs and reversal agents (ie, DTI-specific, DTI-standard, FXa-specific, and FXa-standard). Among 220 patients of 93 case reports/series, reversal rates were 95.9%, 77.6%, and 71.5% for DTI-specific, FXa-standard, and DTI-standard. Pooled RRs for DTI-specific and FXa-standard versus DTI-standard, respectively, were 1.34 (CI: 1.13-1.60) and 1.09 (CI: 0.84-1.40). Death rate was 0.18 (CI: 0.06-0.57) times lower in DTI-specific versus DTI-standard. For pooling 10 subcohorts, pooled RRs were 1.08 (CI: 1.00-1.16), 1.29 (CI: 1.20-1.39), and 1.13 (CI: 1.01-1.25) for DTI-specific, FXa-specific, and FXa-standard versus DTI-standard. In conclusion, specific reversal agents might be useful for reversal of bleeding and lowering the risk of death than standard reversal agents. Our findings were based on case reports/series and selected cohorts, further comparative studies are thus needed.

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Type 2 Diabetes, Atrial Fibrillation, and Direct Oral Anticoagulation

Journal of Diabetes Research ◽

10.1155/2019/5158308 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Dana Prídavková ◽

Matej Samoš ◽

Tomáš Bolek ◽

Ingrid Škorňová ◽

Jana Žolková ◽

...

Keyword(s):

Atrial Fibrillation ◽

Type 2 Diabetes ◽

Clinical Course ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Current Data ◽

Thrombin Inhibitor

Type 2 diabetes (T2D) is an independent risk factor of stroke and systemic embolism in patients with atrial fibrillation (AF), and T2D patients with AF-associated stroke seem to have worse clinical outcome and higher risk of unfavorable clinical course compared to individuals without this metabolic disorder. Long-term anticoagulation is indicated in majority of T2D patients with AF to prevent adverse AF-associated embolic events. Direct oral anticoagulants (DOACs), direct oral thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban, have emerged as a preferred choice for long-term prevention of stroke in AF patients offering potent and predictable anticoagulation and a favorable pharmacology with low risk of interactions. This article reviews the current data regarding the use of DOACs in individuals with T2D and AF.

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Management consensus guidance for the use of rivaroxaban – an oral, direct factor Xa inhibitor

Thrombosis and Haemostasis ◽

10.1160/th12-03-0209 ◽

2012 ◽

Vol 108 (11) ◽

pp. 876-886 ◽

Cited By ~ 118

Author(s):

Reinhold Kreutz ◽

Juan Llau ◽

Bo Norrving ◽

Sylvia Haas ◽

Alexander Turpie

Keyword(s):

Venous Thromboembolism ◽

Large Scale ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Factor Xa ◽

Clinical Trial Data ◽

Thrombin Inhibitor ◽

Direct Factor ◽

Replacement Surgery ◽

Vein Thrombosis

SummaryA number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixaban (direct factor Xa inhibitors) and dabigatran etexilate (a direct thrombin inhibitor) have shown considerable promise in large-scale, randomised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivaroxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboembolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors’ experience with the use of rivaroxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors’ clinical experience.

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Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development

Thrombosis and Haemostasis ◽

10.1160/th09-09-0659 ◽

2010 ◽

Vol 103 (03) ◽

pp. 572-585 ◽

Cited By ~ 75

Author(s):

Mike Ufer

Keyword(s):

Oral Anticoagulants ◽

Safety Data ◽

Factor Xa ◽

Clinical Development ◽

Phase Iii ◽

Coagulation Cascade ◽

Bleeding Complications ◽

Thrombin Inhibitor ◽

Factor Xa Inhibitor ◽

Efficacy And Safety

SummaryTherapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the factor Xa inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and apixaban throughout preclinical and clinical development.

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The NOACs in special situations: the elderly, renal impairment, combination with antiplatelet agents and thrombolytics

ESC CardioMed ◽

10.1093/med/9780198784906.003.0057 ◽

2018 ◽

pp. 273-278

Author(s):

Felicita Andreotti ◽

Eliano Pio Navarese ◽

Filippo Crea

Keyword(s):

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Acute Ischaemic Stroke ◽

Oral Anticoagulants ◽

Factor Xa ◽

Antiplatelet Agents ◽

Clinical History ◽

The Elderly ◽

Arterial Disease ◽

Baseline Risk

Phase III randomised trials indicate that the non-vitamin K antagonist oral anticoagulants (NOACs) are preferable to warfarin in elderly, non-valvular atrial fibrillation patients, given a lower incidence of intracranial haemorrhage, a favourable overall efficacy and safety profile, and the lack of routine monitoring, although care is needed to dose-adjust for kidney function and to prevent gastrointestinal bleeds, depending on the NOAC. Advanced age should not exclude the use of any NOAC. Overall, NOACs perform well, relative to warfarin or aspirin, irrespective of renal function. However, all NOACs undergo variable renal clearance, and in Europe a creatinine clearance of less than 30 mL/min contraindicates dabigatran and less than 15 mL/min the factor Xa inhibitors. Trial outcomes stratified by antiplatelet therapy, after adjustment for baseline risk, show that concomitant antiplatelet use does not significantly alter the overall treatment effects of NOACs versus warfarin. Whether adding an antiplatelet to a NOAC in atrial fibrillation patients with arterial disease is beneficial requires randomized controlled testing. Current guidelines recommend that patients effectively anticoagulated with a NOAC who develop an acute ischaemic stroke should not be considered for thrombolysis unless clinical history or laboratory tests indicate low or no anticoagulation or at least two half-lives have elapsed from the last NOAC dose. Retrospective data suggest no prohibitive adverse events among selected NOAC-treated patients with acute ischaemic stroke receiving thrombolysis. Further investigation in this setting is warranted.

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Novel oral anticoagulants - key messages for the angiologist

VASA ◽

10.1024/0301-1526/a000184 ◽

2012 ◽

Vol 41 (3) ◽

pp. 177-191 ◽

Cited By ~ 7

Author(s):

Haas ◽

Spannagl ◽

M. Schellong

Keyword(s):

Clinical Evidence ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Factor Xa ◽

Novel Oral Anticoagulants ◽

Bleeding Complications ◽

Thrombin Inhibitor ◽

Clinical Scenarios ◽

Major Orthopaedic Surgery

Novel oral anticoagulants (NOACs) have become available for different clinical indications such as the prevention of venous thromboembolism (VTE) after major orthopaedic surgery, for the treatment of VTE and stroke prevention in patients with atrial fibrillation (AF). One thrombin inhibitor (dabigatran etexilate) and two factor Xa-inhibitors (rivaroxaban and apixaban) are the most advanced NOACs and therefore, up-to-date information on their evidence and use in clinical practice appears timely. In this review we give a concise overview of the pharmacology and clinical evidence derived from phase 3 clinical trials. Then the meaningfulness of laboratory testing is discussed and recommendations are given for clinical scenarios that may necessitate adjustment of their use. We conclude that NOACs are valuable alternatives to heparins or vitamin K antagonists (VKA) in the prevention and treatment of VTE and for the prevention of stroke in patients with AF. Prescribers should however be aware of special situations and patient populations where the manufacturers instructions need to be carefully followed. In particular, patients with comorbidities and co-medications may require individual decision making in order to prevent bleeding complications.

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Severe haematuria of lower urinary tract origin with low dose dabigatran use in three Indian elderly patients: unresolved issues in the safety of novel oral anticoagulants

Therapeutic Advances in Drug Safety ◽

10.1177/2042098617742344 ◽

2017 ◽

Vol 9 (1) ◽

pp. 89-91 ◽

Cited By ~ 2

Author(s):

Upinder Kaur ◽

Sankha Shubhra Chakrabarti ◽

Sukdev Manna ◽

Indrajeet Singh Gambhir

Keyword(s):

Oral Anticoagulants ◽

The Elderly ◽

The United States ◽

Novel Oral Anticoagulants ◽

Thrombin Inhibitor ◽

European Medicines Agency ◽

Oral Direct Thrombin Inhibitor ◽

United States Food ◽

States Food ◽

Lower Urinary

Dabigatran is a newer oral direct thrombin inhibitor approved by the United States Food and Drug Administration and the European Medicines Agency (EMA). The proper dosage of the drug, the potential for adverse drug reactions and the nature of bleeds with use of this drug as with other novel oral anticoagulants (NOACs), in the elderly population are still areas of uncertainty. Despite the existence of a specific antibody, idarucizumab which is an antidote to dabigatran toxicity, management of dabigatran-induced bleeds is an undefined area especially in resource constrained settings. We report severe haematuria with dabigatran in three elderly Indian patients at the lowest recommended therapeutic dose and explore these grey zones in dabigatran therapy.

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