https://orcid.org/0000-0002-3970-8984
TO THE EDITOR:
The American Society of Hematology (ASH) guidelines on treatment of pediatric venous thromboembolism (VTE) published in 2018,1 were landmark pediatric guidelines for a number of reasons. Primarily they were the first guidelines that were explicit in the evidence to decision framework to attempt to quantify the role of extrapolation from adult data vs the contribution of direct pediatric data. Second, novel methods were developed to enhance the GRADE approach in the absence of direct published evidence.2 In addition, there were a number of other key innovations throughout the ASH 2018 VTE guideline series,3 and a formal standardized publication template which improved transparency and completeness of guideline reporting.4 Finally the involvement of parent representatives as full and equal members of the guideline panel was a critical step forward.
In the last 4 years there has been a 10-fold increase in the number of children involved in VTE treatment trials, primarily owing to multiple industry sponsored trials of direct oral anticoagulants (DOACS), which were many years in the making (Tables 1 and 2). The publications from these studies include data on various thrombosis locations, underlying conditions, and use of anticoagulant agents including novel pediatric formulations and dosing regimens.5-20 In addition, randomized trials of primary antithrombotic prophylaxis using DOACS have been published21-23 or recently reported at major conferences, with publications expected shortly, giving further insights into the use of DOACS in children. Finally, investigator led randomized trials have addressed critical questions of duration of anticoagulation.24 In addition, further nonrandomized data in children have also recently been published which contributes to our body of evidence, as have significant changes to adult practice which may influence currently extrapolated data.25-29
Number of children that contributed to the recommendations in the ASH 2018 guidelines (total number of reported children by study type in the literature up to 2018)
| Neonate to 18 y . | LMWH . | VKA . |
|---|---|---|
| DVT/PE RCT data | N=36 | N=40 |
| DVT/PE observational data | N=940 (recurrent DVT/major bleeding) | N=107 (recurrent DVT) N=590 (major bleeding) |
| CVC-associated VTE: from RCT | N=20 | N=29 |
| CVC associated: RA thrombosis | 28 observational studies N=30 | |
| CVST RCT data | Nil | Nil |
| CVST observational data | Children/neonates: 17 studies N=752 Neonates only: 6 studies N=127 | |
| Neonate to 18 y . | LMWH . | VKA . |
|---|---|---|
| DVT/PE RCT data | N=36 | N=40 |
| DVT/PE observational data | N=940 (recurrent DVT/major bleeding) | N=107 (recurrent DVT) N=590 (major bleeding) |
| CVC-associated VTE: from RCT | N=20 | N=29 |
| CVC associated: RA thrombosis | 28 observational studies N=30 | |
| CVST RCT data | Nil | Nil |
| CVST observational data | Children/neonates: 17 studies N=752 Neonates only: 6 studies N=127 | |
CSVT, cerebral sinovenous thrombosis; DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PE, pulmonary embolus; RA, right atrium; RCT, randomized controlled trials; VKA, vitamin K antagonists.
Recent trials of DOACS in children
| Study . | Design . | Indications . | Population . | Interventions . | Status . |
|---|---|---|---|---|---|
| VTE treatment | |||||
| EINSTEIN Jr | Phase 3, noninferiority, open label, RCT | Acute VTE treatment and secondary prevention | Children ≤17 y with acute VTE N=500 | Rivaroxaban (n=335) vs SoC (n=165) Treatment period: 3 mo (1 mo for children <2 y with CVC-associated VTE) | Published |
| DIVERSITY | Phase 2b/3 noninferiority, open label, RCT | Acute VTE treatment and secondary prevention | Children <18 y with acute VTE N=267 | Dabigatran (n=177) vs SoC (n=90) Treatment period: 3 mo followed by 1-mo observation period | Published |
| NCT02197416 | Phase 3, single arm, open-label | Extended secondary prevention | Children <18 y with VTE s/p SoC for ≥3 mo, or completed the DIVERSITY study with persistent VTE risk factor(s) N=203 | Dabigatran (n=203) Treatment period: ≤12 mo with an additional 28 d of observation | Published |
| Hokusai VTE PEDIATRICS | Phase 3, noninferiority, open-label, RCT | Acute VTE treatment and secondary prevention | Children <18 y with acute VTE N=290 | Edoxaban vs SoC Treatment period: 3 mo, followed by extension period of 9 mo using edoxaban (1-y postenrollment) | Not published |
| NCT02464969 CANINES | Phase 4, open-label, RCT | Acute VTE treatment | Children <18 y with acute VTE N=250 (target) | Apixaban vs SoC Treatment period: 3 mo (12 wk) | Ongoing |
| Thromboprophylaxis | |||||
| UNIVERSE | Phase 3 open-label, active controlled, 2-part study | TE prevention after Fontan procedure | Children of 2 to 8 y with single ventricle physiology status after the Fontan procedure N=112 | Part A: rivaroxaban (n=12) Part B: rivaroxaban (n=66) vs ASA (n=34) | Published |
| ENNOBLE-ATE | Phase 3, open-label, RCT | TE prevention various cardiac diseases | Children <18 y with cardiac disease at risk for TE complications N=168 | Edoxaban (n=110) vs SoC (n=58) Treatment period: 3 mo, followed by extension period of 9 mo using edoxaban (1-y postenrollment) | Preprint |
| SAXOPHONE | Phase 2, open-label, RCT | TE prevention various cardiac diseases | Children 29 days to <18 y with heart disease at risk for TE complications N=192 | Apixaban (n=129) vs SoC (n=63) Treatment period: ≤12 mo | Completed; not published |
| PREVAPIX-ALL | Phase 3, superiority, open-label, RCT | Primary VTE prevention | Children ≥1 to <18 y with ALL or B or T cell LL N=512 | Apixaban (n=256) vs no systemic anticoagulation (n=256) Treatment period: from randomization through day 28 of induction | Completed; not published |
| Study . | Design . | Indications . | Population . | Interventions . | Status . |
|---|---|---|---|---|---|
| VTE treatment | |||||
| EINSTEIN Jr | Phase 3, noninferiority, open label, RCT | Acute VTE treatment and secondary prevention | Children ≤17 y with acute VTE N=500 | Rivaroxaban (n=335) vs SoC (n=165) Treatment period: 3 mo (1 mo for children <2 y with CVC-associated VTE) | Published |
| DIVERSITY | Phase 2b/3 noninferiority, open label, RCT | Acute VTE treatment and secondary prevention | Children <18 y with acute VTE N=267 | Dabigatran (n=177) vs SoC (n=90) Treatment period: 3 mo followed by 1-mo observation period | Published |
| NCT02197416 | Phase 3, single arm, open-label | Extended secondary prevention | Children <18 y with VTE s/p SoC for ≥3 mo, or completed the DIVERSITY study with persistent VTE risk factor(s) N=203 | Dabigatran (n=203) Treatment period: ≤12 mo with an additional 28 d of observation | Published |
| Hokusai VTE PEDIATRICS | Phase 3, noninferiority, open-label, RCT | Acute VTE treatment and secondary prevention | Children <18 y with acute VTE N=290 | Edoxaban vs SoC Treatment period: 3 mo, followed by extension period of 9 mo using edoxaban (1-y postenrollment) | Not published |
| NCT02464969 CANINES | Phase 4, open-label, RCT | Acute VTE treatment | Children <18 y with acute VTE N=250 (target) | Apixaban vs SoC Treatment period: 3 mo (12 wk) | Ongoing |
| Thromboprophylaxis | |||||
| UNIVERSE | Phase 3 open-label, active controlled, 2-part study | TE prevention after Fontan procedure | Children of 2 to 8 y with single ventricle physiology status after the Fontan procedure N=112 | Part A: rivaroxaban (n=12) Part B: rivaroxaban (n=66) vs ASA (n=34) | Published |
| ENNOBLE-ATE | Phase 3, open-label, RCT | TE prevention various cardiac diseases | Children <18 y with cardiac disease at risk for TE complications N=168 | Edoxaban (n=110) vs SoC (n=58) Treatment period: 3 mo, followed by extension period of 9 mo using edoxaban (1-y postenrollment) | Preprint |
| SAXOPHONE | Phase 2, open-label, RCT | TE prevention various cardiac diseases | Children 29 days to <18 y with heart disease at risk for TE complications N=192 | Apixaban (n=129) vs SoC (n=63) Treatment period: ≤12 mo | Completed; not published |
| PREVAPIX-ALL | Phase 3, superiority, open-label, RCT | Primary VTE prevention | Children ≥1 to <18 y with ALL or B or T cell LL N=512 | Apixaban (n=256) vs no systemic anticoagulation (n=256) Treatment period: from randomization through day 28 of induction | Completed; not published |
SoC, standard of care; TE, venous thromboembolism.
Most of the recommendations from 2018 remain valid and appropriate, that is the decision as to whether to anticoagulate or not. However, the new pediatric data influence not only the evidence to decision framework for almost all recommendations, but also several recommendations about which antithrombotic agents should be used in children. Hence the ASH Committee on Quality decided to update these guidelines. The process of updating the guidelines will take place through 2023 with the new guidelines hopefully completed and published by early 2024. Until that time, it is our opinion that the 2018 guidelines continue to be the optimal source of guidance with regard to when to anticoagulate VTE in children. However, clinicians will need to assess the current literature carefully in deciding which anticoagulants are the most appropriate in any given situation. The updated guidelines will provide information on the optimal use of DOACS in children and the specific thrombosis locations for which direct pediatric data can be applied.
Contribution: All authors drafted the manuscript, revised all versions, and agreed on the final format for submission.
Conflict-of-interest disclosure: P.M. reports membership of steering committees for EINSTEIN-Jr (Rivaroxaban) and SAXOPHONE (Apixaban) studies, and unpaid advisory board participation for Takeda, Bayer, and Janssen. C.M. reports fees to the institution for study participation from Bayer, Bristol Myers Squibb, and Pfizer; personal honoraria (consultancy, speaker, and chair) from Anthos, Bayer, Chiesi, Janssen, and Norgine; and membership in Pediatric Antithrombotic Trials Leadership and Steering (Pedi-ATLAS) Group (no payments), for the past 3 years. L.R. reports participation in advisory boards for Boeringer Ingelheim, Genentech, and Jannsen.
Correspondence: Paul Monagle, Department of Pediatrics, University of Melbourne, 50 Flemington Rd, Parkville, VIC 3165, Australia; e-mail: paul.monagle@rch.org.au.
References
Author notes
Data are available on request from the corresponding author, Paul Monagle (paul.monagle@rch.org.au).
