Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies

Monagle, Paul; Lensing, Anthonie W. A.; Thelen, Kirstin; Martinelli, Ida; Male, Christoph; Santamaría, Amparo; Самочатова, Е. В.; Kumar, Riten; Holzhauer, Susanne; Saracco, Paola; Simioni, Paolo; Robertson, Jeremy; Grangl, Gernot; Halton, Jacqueline; Connor, Phillip; Young, Guy; Molinari, Angelo Claudio; Nowak‐Göttl, Ulrike; Kenet, Gili; Kapsa, Stefanie; Willmann, Stefan; Pap, Á; Becka, Michael; Twomey, T.; Beyer‐Westendorf, Jan; Prins, Martin H.; Kubitza, Dagmar; Streif, Werner; Carniero, Jorge; Logetto, Sandra; Brandão, Leonardo R.; Amédro, Pascal; Bonnet, Damien; Dietrich, Sven; Kállay, Krisztián; Revel‐Vilk, Shoshana; Tamary, Hannah; Giordano, Paola; Abbattista, Maria; Artoni, Andrea; Tormene, Daniela; Ono, Hiroshi; Loo, Maroeska Wm Te; Ommen, Heleen van; Veening, Margreet A.; Suiker, Monique H; Peters, Marjolein; Shamardina, Anastasia; Novgorod, Nizhny; Zubarovskaya, L.S.; Dasi, M. A.; Elorza, M D; Sánchez‐Luna, Manuel; Albisetti, Manuela; Grunt, Sebastian; Kavaklı, Kaan; Biss, Tina; Connor, Philip; Williams, M.; Acharya, Suchitra; Bhat, Rumi; Kearney, Susan; Patel, Kavita; Rajpukar, Madvi; Schwartz, Jeffrey H.; Vik, Terry A.; Wynn, Tung; Yee, Donald L.

doi:10.1016/s2352-3026(19)30161-9

Cited by 61 publications

(80 citation statements)

References 24 publications

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“…However, phase 2 pediatric trials of rivaroxaban and dabigatran were recently published and phase 3 trials (clinicaltrial.gov identifiers: NCT02234843 and NCT01895777, respectively) are nearing completion. 140,141 Thus, these agents may soon be available for pediatric use. Anticoagulant dosing in children is complex because of age-related hemostasis system maturation as well as pharmacokinetic differences compared to adults.…”

Section: Childhood Kidney Diseasementioning

confidence: 99%

Role of direct oral anticoagulants in patients with kidney disease

Derebail

Rheault

Kerlin

2020

Kidney International

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The anticoagulation field is experiencing a renaissance that began with regulatory approval of the direct thrombin inhibitor dabigatran, a direct oral anticoagulant (DOAC), in 2010. The DOAC medication class has rapidly evolved to include the additional approval of 4 direct factor Xa inhibitors. Commensurately, DOAC use has increased and collectively account for the majority of new anticoagulant prescriptions. Despite exclusion of patients with moderateto-severe kidney disease from most pivotal DOAC trials, DOACs are increasingly used in this setting. An advantage of DOACs is similar or improved antithrombotic efficacy with less bleeding risk when compared with traditional agents. Several post hoc analyses, retrospective studies, claims data studies, and meta-analyses suggest that these benefits extend to patients with kidney disease. However, the lack of randomized controlled trial data in specific kidney disease settings, with their unique pathophysiology, should be a call to action for the kidney community to systematically study these agents, especially because early data suggest that DOACs may pose less risk of anticoagulant-related nephropathy than do vitamin K antagonists. Most DOACs are renally cleared and are significantly protein bound in circulation; thus, the pharmacokinetics of these drugs are influenced by reduced renal function and proteinuria. DOACs are susceptible to altered metabolism by P-glycoprotein inhibitors and inducers, including drugs commonly used for the management of kidney disease comorbidities. We summarize the currently available literature on DOAC use in kidney disease and illustrate knowledge gaps that represent important opportunities for prospective investigation.

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Section: Childhood Kidney Diseasementioning

confidence: 99%

Role of direct oral anticoagulants in patients with kidney disease

Derebail

Rheault

Kerlin

2020

Kidney International

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“…40 Three phase II studies were performed to confirm or adapt the predicted body-weight-adjusted rivaroxaban regimens from the phase I study in 93 children (10 children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years). 41 Therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg were confirmed. However, children with low body weights (<20 kg, particularly <12 kg) showed low or subtherapeutic exposure.…”

Section: Clinical Pediatric Studiesmentioning

confidence: 89%

Use of Direct Oral Anticoagulants in Children and Adolescents

Albisetti

2020

Hamostaseologie

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While the need for anticoagulation in children has increased over the last decades, dose regimens of currently used anticoagulants, including low-molecular-weight heparin (LMWH) and vitamin K antagonist (VKA), are still extrapolated from adult guidelines because well-designed clinical trials were never performed in children. This approach is not optimal due to specific pediatric features of the hemostatic system and pathophysiology of thrombosis. These anticoagulants also present several disadvantages that further hamper optimal anticoagulation of pediatric patients, especially newborns and infants. The new direct oral anticoagulants (DOACs), which have the potential to overcome these disadvantages, were extensively investigated in adults and have become a valid alternative to LMWH and VKA for anticoagulation in the adult population. Several pediatric trials on all approved DOACs are currently ongoing, providing specific pediatric formulations and age- and weight-adjusted dose guidelines. First results of phase III trials indicate that DOACs are at least as efficient and safe as LMWH and VKA for the treatment and prevention of thrombotic events in children with different clinical conditions. This review article summarizes available data from terminated and ongoing controlled trials on DOACs in children and adolescents.

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“…In the EINSTEIN-Jr phase 2 single-arm study of rivaroxaban in pediatric patients previously treated with LMWH, VKAs, or fondaparinux, 15.8% of girls in the 6-to 17-year-old age group reported menorrhagia. 11 In the randomized, open-label, phase III study comparing rivaroxaban with heparin, LMWH, or VKAs, 19% of girls (ages 6-17 years) in the rivaroxaban group reported menorrhagia compared with 7.1% of girls in the control group (Table 3). 12 No uterine bleeding events meeting criteria for MB or CRNMB were reported.…”

Section: Pediatric Trialsmentioning

confidence: 99%

Evidence-Based Minireview: Abnormal uterine bleeding in users of rivaroxaban and apixaban

Jacobson-Kelly

Bannow

2020

Hematology

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Up to two-thirds of menstruating women experience abnormal uterine bleeding (AUB) when treated with oral anticoagulants. However, the true prevalence of AUB for specific agents remains uncertain, as many of these episodes, while interfering significantly with quality of life and overall health, are not captured by definitions of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) used in clinical trials. A 2017 systematic review determined that women taking rivaroxaban, but not edoxaban or apixaban, had a twofold higher risk of AUB than women taking warfarin. Since then, new data have become available from extension trials, cancer-associated venous thromboembolism trials, pediatric trials, and a few observational studies specifically examining AUB as an outcome. Reported rates of uterine CRNMB were low (around 1%) and similar for rivaroxaban and apixaban in all these studies, and no episodes of uterine bleeding meeting MB criteria were reported. Rates of AUB not meeting MB or CRNMB criteria were much higher, affecting up to 50% of women on rivaroxaban. Only 1 such study included women on apixaban, and no AUB was reported. In pediatric trials, 19% of girls experienced menorrhagia when treated with rivaroxaban. In conclusion, rates of uterine MB and CRNMB were low in all studies, but rates of other types of AUB not meeting these criteria ranged from 15.8% to 50%. We conclude that AUB is underreported due to the limitations of MB/CRNMB criteria despite its substantial impact on quality of life. We urge future investigators to include broader definitions of AUB to better capture the impact of this outcome in menstruating women treated with oral anticoagulants.

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Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies

Cited by 61 publications

References 24 publications

Role of direct oral anticoagulants in patients with kidney disease

Role of direct oral anticoagulants in patients with kidney disease

Use of Direct Oral Anticoagulants in Children and Adolescents

Evidence-Based Minireview: Abnormal uterine bleeding in users of rivaroxaban and apixaban

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