Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial

Halton, Jacqueline; Brandão, Leonardo R.; Luciani, Matteo; Bomgaars, Lisa; Chalmers, Elizabeth; Mitchell, Lesley; Nurmeev, Ildar; Sharathkumar, Anjali; Svirin, Pavel; Gorbatikov, Kirill; Tartakovsky, Igor; Simetzberger, Monika; Huang, Fenglei; Sun, Zhichao; Kreuzer, Jörg; Gropper, Savion; Reilly, Paul; Brueckmann, Martina; Albisetti, Manuela; Сафина, А. И.; Zapletal, Ondřej; Kuhn, Tomáš; Votava, Tomáš; Felgenhauer, Judy; Amid, Ali; Saracco, Paola; Kiss, Csongor; Halimeh, Susan; Reschke, Madlen; Wulff, Beate; David, Michèle; Novák, Zbyněk; Trunina, I.I.; Frisk, Tony; Glosli, Heidi; Groll, Andreas H.; Lvova, O.; Şaşmaz, İlgen; Sosothikul, Darintr; Žilinskaitė, Virginija; Cockrell, Erin; Digtyar, Valeriy; Hadacová, I; Palmu, Sauli; Pawar, Anjali; Bizzacchi, Joyce Maria Annichino; Çalışkan, Ümran; Çelkan, Tiraje; Dmytriiev, Dmytro; Druzgal, Colleen; Elena, Graciela; Kattamis, Antonis; Kavakli, Ramazan; Male, Christoph; Özdemir, Nihal; Damme, An Van; Зверева, Т. Н.; Aarli, Å.; Aguilera, Rogelio a Paredes; Aytaç, Selin; Carneiro, Jorge David Aivazoglou; Chistolini, Antonio; Mazzucconi, Maria Gabriela; Corrales-Medina, Fernando F.; Couturaud, Francis; Croteau, Stacey E; Trenor, Cameron C.; Damgaard, Michael; Dixon, Natalia; Galustyan, A.N.; Hak, Jiří; Hoffmann, Marianne; Küpesiz, Alphan; Labarque, Veerle; Geet, Christel Van; Lin, Ming-Chih; Fu, Yun‐Ching; Loggetto, Sandra Regina; Mondelaers, Veerle; Odri-Komazec, Irena; Revel‐Vilk, Shoshana; Sevilla, Julián; Silva, Luciano Fuzzato; Saraiva, José Kerr; Montes-Tapia, Fernando; Woods-Swafford, Wendy

doi:10.1016/s2352-3026(20)30368-9

Cited by 99 publications

(96 citation statements)

References 26 publications

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“…Dabigatran use in paediatric patients with VTE demonstrated non-inferiority to standard treatment. 121 Rivaroxaban use in paediatric patients (Einstein-Jr clinical trial, NCT02234843) is completed and awaiting approval for use in cerebral venous thrombosis 122 and catheter-related VTE. 123 Summary of the use of rivaroxaban in the paediatric population is also available elsewhere.…”

Section: Future Perspectivesmentioning

confidence: 99%

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

Adcock²,

et al. 2021

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In 2018, the International Council for Standardization in Hematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alpha. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author’s personal experience/expert opinion and (3) good laboratory practice.

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Section: Future Perspectivesmentioning

confidence: 99%

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

Adcock²,

et al. 2021

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“…13,[28][29][30] In the paediatric anticoagulant field, few phase 3 trials have successfully completed planned enrolment; recent exceptions include the investigatorled NIH-sponsored Kids-DOTT trial, 31 EINSTEIN-Junior, 18 and DIVERSITY. 20 A few additional industry-sponsored phase 3 studies of direct oral anticoagulants are ongoing, but few have been powered to demonstrate non-inferior or superior safety and efficacy relative to the standard of care. 32 The paediatric direct oral anticoagulant trials, including this study, are the outcome of collaboration between pharmaceutical companies and academic experts in the fields of paediatric thrombosis and paediatric cardiac care.…”

Section: Discussionmentioning

confidence: 99%

“…19 In addition, the phase 3 randomised controlled trial of dabigatran for a conventional course of venous thromboembolism treatment was recently published. 20 Edoxaban is an oral, direct, specific inhibitor of activated factor X. Its pharmacokinetic properties include rapid peak plasma concentration, low cytochrome P450 metabolism, limited protein binding, and linear pharmacokinetics.…”

mentioning

confidence: 99%

ENNOBLE-ATE trial: an open-label, randomised, multi-centre, observational study of edoxaban for children with cardiac diseases at risk of thromboembolism

et al. 2021

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Children with cardiac diseases suffer from significant morbidity and mortality secondary to thromboembolic complications. Anticoagulant agents currently used for thromboprophylaxis have many limitations, including subcutaneous administration (low molecular weight heparins) and requirement for frequent monitoring via venipuncture (vitamin K antagonists). Edoxaban is an oral direct factor Xa inhibitor without need of monitoring. In the treatment of venous thromboembolism in adults, edoxaban has shown to be effective and safe. This manuscript summarises the rationale and design of a phase 3, open-label, randomised controlled trial to evaluate and compare the safety and efficacy of edoxaban against standard of care (namely, vitamin K antagonist and low molecular weight heparin) in children with cardiac diseases. A goal of 150 children with cardiac diseases at risk of thromboembolic complications who need primary or secondary anticoagulant prophylaxis will be recruited. Eligible children between 6 months and <18 years of age will be randomised in a ratio of 2 to 1 for edoxaban versus standard of care. Randomisation will be stratified based on underlying cardiac disease and concomitant use of aspirin for patients other than Kawasaki disease. The primary outcome will be safety, comprised of major and clinically relevant non-major bleeding in first 3 months of treatment. Bleeding beyond 3 months, symptomatic and asymptomatic thromboembolic events, and pharmacokinetic and pharmacodynamic parameters will be evaluated as secondary outcomes. Randomised controlled anticoagulation trials are challenging in children. This study will evaluate a potentially valuable alternative of oral anticoagulant prophylactic use in children with cardiac diseases.

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“…First, the DIVERSITY study is a randomized, controlled, open-label, parallel-group, phase 2b/3 noninferiority trial comparing dabigatran and SOC for acute VTE. 20 Two-hundred and sixty-seven children younger than 18 years with a diagnosis of VTE, treated initially with 5 to 21 days of parenteral therapy, and expected to required anticoagulation for at least 3 months were eligible for randomization. Patients were then further stratified by age group (12 to <18 years; 2 to <12 years; birth to <2 years).…”

Section: Dabigatranmentioning

confidence: 99%

“…The DIVERSITY study showed dabigatran was noninferior to SOC and might be a suitable alternative anticoagulant for the management of VTE in children. 20 Second, an open-label, single-arm, phase 3 study by Brandão et al enrolled 203 patients with a goal to assess the safety of dabigatran for long-term secondary prevention of VTE. 21 Patients who previously had been treated for VTE with SOC or patients from the dabigatran arm in the DIVERSITY study treated for 3 months or longer and who had unresolved clinical risk factors for VTE were treated for up to 12 additional months or until resolution of clinical risk factors.…”

Section: Dabigatranmentioning

confidence: 99%

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature

Branstetter

Kiskaddon

King

et al. 2021

Semin Thromb Hemost

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Venous thromboembolism (VTE) in children can lead to significant morbidity and mortality. Traditionally, treatment for thrombotic events in pediatric patients has been limited mainly to unfractionated heparin, low-molecular-weight heparin (LMWH), or vitamin K antagonists. Since the first non–vitamin K antagonist oral anticoagulant (NOAC) was approved for adult use, these agents have gained popularity for a variety of indications. This is largely due to their ease of administration, favorable pharmacokinetic and pharmacodynamic profile, decreased food interactions, and decreased need for therapeutic drug monitoring. Treating and preventing VTE with traditional anticoagulants in pediatric patients presents many challenges. This systematic review evaluated the current literature regarding pediatric NOAC trials. Additionally, based on an up-to-date query of clinicaltrials.gov, we detail current ongoing and as-yet unpublished clinical trials, study outcomes, and projected completion dates. Published pediatric NOAC trials have included 1,007 total children to date and have ranged from phase 1 to 4, with “indications” including both thromboembolism prophylaxis and VTE treatment. Three recent phase 3 trials, specifically involving rivaroxaban and dabigatran, have shown the agents to be at least as effective as traditional anticoagulants for acute and/or extended VTE treatment, with low frequency of recurrent thrombosis and clinically significant bleeding rates. Additionally, specially developed and tested pediatric formulations have allowed for accurate and reliable dosing, oral administration, stable pharmacokinetics and pharmacodynamics, and fewer drug or food interactions. Ongoing trials, anticipated for completion in the next few years, will reveal important information with regard to thromboembolism prophylaxis in special pediatric subpopulations and settings.

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Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial

Cited by 99 publications

References 26 publications

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

ENNOBLE-ATE trial: an open-label, randomised, multi-centre, observational study of edoxaban for children with cardiac diseases at risk of thromboembolism

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature

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