Treatment of venous thromboembolism in pediatric patients

Abstract Venous thromboembolism (VTE) is rare in healthy children, but is an increasing problem in children with underlying medical conditions. Pediatric VTE encompasses a highly heterogenous population, with variation in age, thrombosis location, and underlying medical comorbidities. Evidence from pediatric clinical trials to guide treatment of VTE is lacking so treatment is often extrapolated from adult trials and expert consensus opinion. Aspects unique to children include developmental hemostasis and the major role of central venous access devices. There is an absence of information regarding the optimal target levels of anticoagulation for neonates and infants and lack of suitable drug formulations. Anticoagulants, primarily low-molecular-weight heparin and warfarin, are used to treat children with symptomatic VTE. These drugs have significant limitations, including the need for subcutaneous injections and frequent monitoring. Randomized clinical trials of direct oral anticoagulants in pediatric VTE are ongoing, with results anticipated soon. These trials will provide new evidence and options for therapy that have the potential to improve care. International collaborative registries offer the ability to study outcomes of rare subgroups of pediatric VTE (eg, renal vein thrombosis), and will be important to ultimately guide therapy in a more disease-specific manner.

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Treatment Patterns and Clinical Outcomes in Korean Cancer Patients With Venous Thromboembolism: A Retrospective Cohort Study

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029620979575 ◽

2021 ◽

Vol 27 ◽

pp. 107602962097957

Author(s):

Soo-Mee Bang ◽

Jin-Hyoung Kang ◽

Min Hee Hong ◽

Jin-Seok Ahn ◽

So Yeon Oh ◽

...

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Clinical Outcomes ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Events ◽

Factors Associated ◽

Vein Thrombosis ◽

Medical Chart Review ◽

Deep Vein

This study assessed epidemiologic data and clinical outcomes, including venous thromboembolism (VTE) recurrence and bleeding events, in patients with cancer-associated VTE, and assessed factors associated with clinical outcomes. Data were extracted from retrospective medical-chart review of adult patients diagnosed with cancer-associated deep vein thrombosis or pulmonary embolism who received anticoagulation treatment for ≥3 months. Patients were classified by: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and other anticoagulants. First VTE recurrence and bleeding events, and factors associated with their occurrence, were assessed during the initial 6 months of treatment. Overall, 623 patients (age: 63.7 ± 11.3 years, 49.3% male) were included (119, 132, and 372 patients in LMWH, DOACs and other anticoagulants groups, respectively). The cumulative 6-month incidence of VTE recurrence was 16.6% (total), 8.3% (LMWH), 16.7% (DOACs), and 20.7% (other); respective bleeding events were 22.5%, 11.0%, 12.3%, and 30.7%). VTE recurrence and bleeding rates differed only between LMWH and other anticoagulants (HR 2.4, 95% CI: 1.2-5.0 and 3.6, 1.9-6.8, respectively). These results highlight the importance of initial VTE treatment choice for preventing VTE recurrence and bleeding events. LMWH or DOACs for ≥3 months can be considered for effective VTE management in cancer patients.

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Management of thrombosis in children and neonates: practical use of anticoagulants in children

Hematology ◽

10.1182/asheducation-2018.1.399 ◽

2018 ◽

Vol 2018 (1) ◽

pp. 399-404 ◽

Cited By ~ 9

Author(s):

Paul Monagle ◽

Fiona Newall

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Renal Vein Thrombosis ◽

Therapeutic Agents ◽

Vein Thrombosis ◽

Cerebral Sinovenous Thrombosis ◽

Sinovenous Thrombosis ◽

American Society ◽

Evidence Based Guidelines

Abstract Venous thrombosis (VTE) in children and neonates presents numerous management challenges. Although increasing in frequency, VTE in children and neonates is still uncommon compared with adults. The epidemiology of VTE is vastly different in neonates vs children vs adolescents vs adults. In reality, pediatric thrombosis should be viewed as a multitude of rare diseases (eg, renal vein thrombosis, spontaneous thrombosis, catheter-related thrombosis, cerebral sinovenous thrombosis), all requiring different approaches to diagnosis and with different short- and long-term consequences, but linked by the use of common therapeutic agents. Further, children have fundamentally different physiology in terms of blood flow, developmental hemostasis, and, likely, endothelial function. The American Society ofHematology 2017 Guidelines for Management of Venous Thromboembolism: Treatment of Pediatric VTE provides up-to-date evidence-based guidelines related to treatment. Therefore, this article will focus on the practical use of therapeutic agents in the management of pediatric VTE, especially unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists, as the most common anticoagulants used in children. Direct oral anticoagulants (DOACs) remain in clinical trials in children and should not be used outside of formal trials for the foreseeable future.

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Direct Oral Anticoagulants in the Treatment of Venous Thromboembolism: Use in Patients with Advanced Renal Impairment, Obesity, or Other Weight-Related Special Populations

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0041-1723952 ◽

2021 ◽

Author(s):

Paul P. Dobesh ◽

Molly M. Kernan ◽

Jenni J. Lueshen

Keyword(s):

Clinical Trials ◽

Venous Thromboembolism ◽

Renal Impairment ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Safety Data ◽

Special Populations ◽

Dose Selection ◽

Phase 3 ◽

Optimal Drug

AbstractThere are currently more than 7 million patients taking a direct oral anticoagulant (DOAC), with more new prescriptions per year than warfarin. Despite impressive efficacy and safety data for the treatment of venous thromboembolism, patients with obesity or advanced renal impairment represented a small portion of the patients enrolled in the phase 3 clinical trials. Therefore, to evaluate the potential use of DOACs in these special populations, clinicians need to have an understanding of the pharmacokinetics and pharmacodynamics of these agents in these settings. Since data from randomized controlled trials are limited, data from observational trials are helpful in gaining comfort with the use of DOACs in these special populations. Selecting the appropriate dose for each agent is imperative in achieving optimal patient outcomes. We provide an extensive review of the pharmacokinetics, pharmacodynamics, phase 3 clinical trials, and observational studies on the use of DOACs in patients with advanced renal impairment, obesity, or other weight-related special populations to provide clinicians with a comprehensive understanding of the data for optimal drug and dose selection.

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Does aspirin prevent venous thromboembolism?

Hematology ◽

10.1182/hematology.2020000150 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 634-641

Author(s):

Robert Diep ◽

David Garcia

Keyword(s):

Venous Thromboembolism ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Secondary Prophylaxis ◽

Treatment Modalities ◽

Surgical Patient ◽

Vein Thrombosis ◽

Disease Therapy ◽

Deep Vein ◽

Arterial Vascular Disease

Abstract Venous thromboembolism (VTE; deep vein thrombosis and/or pulmonary embolism) is a well-established cause of morbidity and mortality in the medical and surgical patient populations. Clinical research in the prevention and treatment of VTE has been a dynamic field of study, with investigations into various treatment modalities ranging from mechanical prophylaxis to the direct oral anticoagulants. Aspirin has long been an inexpensive cornerstone of arterial vascular disease therapy, but its role in the primary or secondary prophylaxis of VTE has been debated. Risk-benefit tradeoffs between aspirin and anticoagulants have changed, in part due to advances in surgical technique and postoperative care, and in part due to the development of safe, easy-to-use oral anticoagulants. We review the proposed mechanisms in which aspirin may act on venous thrombosis, the evidence for aspirin use in the primary and secondary prophylaxis of VTE, and the risk of bleeding with aspirin as compared with anticoagulation.

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Approaches to Assessing the Quality of Observational Studies of Clinical Practice Based on the Big Data Analysis

Rational Pharmacotherapy in Cardiology ◽

10.20996/1819-6446-2021-08-01 ◽

2021 ◽

Vol 17 (4) ◽

pp. 584-593

Author(s):

S. R. Gilyarevsky

Keyword(s):

Clinical Trials ◽

Big Data ◽

Clinical Practice ◽

Observational Studies ◽

Randomized Clinical Trials ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Real Life ◽

Hierarchy Of Evidence

The article is devoted to the discussion of the problems of assessing the quality of observational studies in real clinical practice and determining their place in the hierarchy of evidence-based information. The concept of “big data” and the acceptability of using such a term to refer to large observational studies is being discussed. Data on the limitations of administrative and claims databases when performing observational studies to assess the effects of interventions are presented. The concept of confounding factors influencing the results of observational studies is discussed. Modern approaches to reducing the severity of bias in real-life clinical practice studies are presented. The criteria for assessing the quality of observational pharmacoepidemiological studies and the fundamental differences between such studies and randomized clinical trials are presented. The results of systematic reviews of real-life clinical trials to assess the effects of direct oral anticoagulants are discussed.

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The risk of bleeding minimization with direct oral anticoagulants

Atherothrombosis Journal ◽

10.21518/2307-1109-2021-11-1-106-126 ◽

2021 ◽

pp. 106-126

Author(s):

Т. N. Novikova

Keyword(s):

Atrial Fibrillation ◽

Clinical Trials ◽

Anticoagulant Therapy ◽

Randomized Clinical Trials ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Blood Analysis ◽

Systemic Embolism ◽

Risk Of Bleeding ◽

Wide Range

This review is devoted to the safety issues of anticoagulant therapy prescribed for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Direct oral anticoagulants are considered worldwide in accordance with the guidelines for the diagnosis and treatment of atrial fibrillation as the preferred anticoagulant choice for the prevention of stroke and systemic embolism. Direct oral anticoagulants in comparison with vitamin K antagonists generally have similar efficacy, but different safety profiles, primarily, this concerns the risk of large extracranial and, primarily, gastrointestinal hemorrhages. To minimize the risk of bleeding during therapy with direct oral anticoagulants, an individual approach to the choice of the drug for each individual patient is required after assessing the risk of bleeding, searching for a potential bleeding substrate, correcting existing risk factors and eliminating, if possible, the substrate. When choosing an anticoagulant therapy, special attention should be paid to the most vulnerable categories of patients, such as patients of older age groups and patients with concomitant chronic kidney disease. Among the direct oral anticoagulants registered in the Russian Federation, according to meta-analyzes of key randomized clinical trials and real clinical trials, apixaban has the most optimal benefit: risk ratio in a wide range of patients, including vulnerable populations. Dynamic observation, including regular assessment of renal function, control of clinical blood analysis, erythrocyte and platelet levels, after prescribing an individually selected anticoagulant to the patient, ensures the maximum safety of therapy. Small, so-called, annoying bleeding is not a reason for canceling the anticoagulant, but requires a careful search for the causes of bleeding and their correction.

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455Prediction of major bleeding in patients receiving DOACs for venous thromboembolism: a prospective cohort study

European Heart Journal ◽

10.1093/eurheartj/ehz747.0114 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M C Vedovati ◽

A Mancuso ◽

L Pierpaoli ◽

U Paliani ◽

S Conti ◽

...

Keyword(s):

Venous Thromboembolism ◽

Major Bleeding ◽

Prospective Cohort ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Risk Scores ◽

Bleeding Complications ◽

Risk Category ◽

Vein Thrombosis ◽

C Statistic

Abstract Background The accuracy of currently available bleeding scores in patients on treatment with direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) is undefined. Purpose In a prospective cohort of patients with VTE treated with DOACs, we evaluated the accuracy of the ATRIA, HAS-BLED, Kuijer, ORBIT, RIETE and VTE-BLEED risk scores in predicting major bleeding (according to ISTH definition). Methods The accuracy of different scores to correctly classify subjects into a defined risk category was assessed by the c-statistic. Results Overall, 1141 patients were evaluated and 1034 included in the study. The index event was pulmonary embolism in 509 patients (49.2%) and proximal deep vein thrombosis in the remaining patients (50.8%). During the 12-month study period, 26 major bleedings occurred in 25 patients (2.8% patient-year): 14 major bleedings occurred in the first 6 months of treatment and 12 from 6 to 12 months in the 654 patients remained on treatment. In the 12-month study period, the VTE-BLEED score showed the best predictive value for bleeding complications (c-statistics 0.674, 95% CI 0.593–0.755). The lowest incidence of major bleeding (0.3%) was observed in the low risk category of VTE-BLEED which includes 38% of patients. The highest incidence of major bleeding (7.1%) was observed in the high-risk category of ORBIT which includes 10.9% of patients. Conclusions The VTE-BLEED score had the best accuracy in predicting major bleeding during treatment with DOACs for VTE. Whether the VTE-BLEED score can be used for decision making on anticoagulation should be tested in a management study.

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Treatment of Acute Renal Vein Thrombosis With Direct Oral Anticoagulants

American Journal of Therapeutics ◽

10.1097/mjt.0000000000001258 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Ramsha Ahmed ◽

Fahrettin Covut ◽

Tariq Kewan ◽

Abdo Haddad ◽

Hamed Daw

Keyword(s):

Renal Vein ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Renal Vein Thrombosis ◽

Vein Thrombosis

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American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism

Blood Advances ◽

10.1182/bloodadvances.2018024786 ◽

2018 ◽

Vol 2 (22) ◽

pp. 3292-3316 ◽

Cited By ~ 62

Author(s):

Paul Monagle ◽

Carlos A. Cuello ◽

Caitlin Augustine ◽

Mariana Bonduel ◽

Leonardo R. Brandão ◽

...

Keyword(s):

Venous Thromboembolism ◽

Health Care Professionals ◽

Conflicts Of Interest ◽

Guideline Development ◽

Central Venous Access ◽

Tertiary Care ◽

Venous Access ◽

Protein C Deficiency ◽

Vein Thrombosis ◽

American Society

Abstract Background: Despite an increasing incidence of venous thromboembolism (VTE) in pediatric patients in tertiary care settings, relatively few pediatric physicians have experience with antithrombotic interventions. Objective: These guidelines of the American Society of Hematology (ASH), based on the best available evidence, are intended to support patients, clinicians, and other health care professionals in their decisions about management of pediatric VTE. Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews (up to April of 2017). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 30 recommendations, covering symptomatic and asymptomatic deep vein thrombosis, with specific focus on management of central venous access device–associated VTE. The panel also addressed renal and portal vein thrombosis, cerebral sino venous thrombosis, and homozygous protein C deficiency. Conclusions: Although the panel offered many recommendations, additional research is required. Priorities include understanding the natural history of asymptomatic thrombosis, determining subgroup boundaries that enable risk stratification of children for escalation of treatment, and appropriate study of newer anticoagulant agents in children.

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Direct Oral Anticoagulants after Ischemic Stroke: Which Patient? Which Drug? And How Early?

Hämostaseologie ◽

10.1055/a-1329-2523 ◽

2021 ◽

Vol 41 (01) ◽

pp. 031-034

Author(s):

Gian Marco De Marchis

Keyword(s):

Atrial Fibrillation ◽

Clinical Trials ◽

Ischemic Stroke ◽

Vitamin K ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Reversal Agents

AbstractDirect oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and ischemic stroke. The main advantage of DOAC over VKA is the lower rate of bleeding and mortality. This review covers challenges clinicians can encounter when treating patients with AF and ischemic stroke, including timing of DOAC start and ongoing randomized clinical trials, appropriate dosing, and available comparative evidence across DOACs. For patients without AF but with an ischemic stroke, the review outlines the role of DOACs. Finally, the risk of thrombotic events associated with specific DOAC reversal agents and DOAC pausing is reviewed.

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