Anticoagulation Therapy for Venous Thromboembolism in the Pediatric Population: A Systematic Review and Meta-Analysis

Introduction: Venous thromboembolism (VTE) in the pediatric population is a heterogenous disease due to the variability in age, anatomical location, and comorbidities. Anticoagulation (AC) is considered the main treatment option; however, the decision to anticoagulate necessitates consideration of benefits and risk based on multiple factors. We performed a systematic review and meta-analysis to evaluate the outcomes of AC therapy in comparison to no AC therapy in pediatric patients with VTE.

Methods: As part of the ASH/ISTH 2024 guidelines on the management of VTE, we searched the published literature in PubMed, Embase, and Cochrane, from inception till February 2024. Two reviewers independently screened the studies to assess their eligibility using Covidence. Studies were eligible if they addressed anticoagulation therapy in pediatric patients (<18 years) with VTE. We statistically pooled estimates using Review Manager (5.4). Reviewers assessed the risk of bias using Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Results: A total of 8925 studies were screened and 13 non-randomized observational studies were included. These studies assessed VTE outcomes in a total of 1,197 pediatric patients. Two studies compared AC versus no AC in pediatric patients with symptomatic DVT (n=270). All-cause mortality may have little to no difference between the two groups; absolute effect (AE) of 19 more per 1,000 (95% CI: 82 fewer to 568 more). Similarly, thrombus resolution might occur with little to no difference between the two groups; AE of 17 more per 1,000 (338 fewer to 626 more). Compared to no AC, AC may decrease thrombus recurrence, AE of 54 fewer per 1,000 (76 fewer to 18 more) and may have led to higher number of events of MB and CRNMB.

Seven studies compared AC versus no AC in patients with CSVT (n=732). Compared to no AC, AC may have led to decreased mortality; AE 97 fewer per 1,000 (105 fewer to 70 fewer), and increased thrombus resolution; AE 268 more per 1,000 (107 more to 482 more). Compared to no AC, AC might have led to little to no difference in outcomes of neurological deficit AE 17 fewer per 1,000 (106 fewer to 102 more), thrombus recurrence (0% vs 0%) or bleeding events (AE 29 more per 1000; 24 fewer to 397 more)

Three studies compared AC vs no AC in patients with RAT (n=67). More events of all-cause mortality may have occurred in patients on AC compared to no AC w(29% VS 0% respectively). Thrombus resolution may have occurred less in patients on AC compared to no AC; AE of 156 fewer per 1,000 (304 fewer to 9 more), while AC might have little to no effect in thrombus recurrence; AE of 22 more per 1,000 (304 fewer to 890 more). Additionally, AC may have more events for MB (7.3% VS 0%) but have similar events of CRNMB (0% VS 0%).

Three studies compared AC vs no AC in patients with PVT (n=128). Compared to no AC, AC may have led to more thrombus resolution; AE of 98 more per 1,000 (55 fewer to 299 more), and may have reduced thrombus progression; 2.7% vs. 0% respectively. Regarding portal hypertension, there might be no to little difference between AC vs no AC; 0% vs 0%. For bleeding, AC may have led to 1.7% bleeding risk versus 0% in patients with no AC.

The certainty of evidence for all estimates is very low due to concerns related to risk of bias and imprecision because of the small number of patients.

Conclusions: Evidence on the role of anticoagulation in children continues to be scarce, particularly evidence reporting on outcomes of pediatric subpopulations. Further research and clinical trials are essential to better understand the role of AC in these populations.

Betensky:Boston Scientific: Honoraria; Aziyo: Honoraria; Abbot: Honoraria; Zoll: Honoraria; NHLBI K23: Research Funding. Brandao:AstraZeneca: Other: Ad board meeting on andexanet alfa (Feb. and Jun. 2023/ISTH - Montreal/QC, Canada; Pfizer/Bristol Myers Squibb: Research Funding. Chan:Bayer: Honoraria, Other: clinical trials, Research Funding; C17: Research Funding; Canadian Hemophilia Society: Research Funding; CIHR: Research Funding; Novo Nordisk: Honoraria, Other: clinical trials, Research Funding; Daiichi: Other: clinical trials; Pfizer: Other: clinical trials; Sanofi: Honoraria, Other: clinical trials; Sobi: Other: clinical trials; Takeda: Honoraria, Other: clinical trials; Roche: Honoraria. Kerlin:Aurinia: Research Funding. Kucine:Protagonist Therapeutics: Consultancy; PharmaEssentia: Consultancy; AOP Health: Other: Conference Presenter. Raulji:Abbvie Inc Co: Other: current value 4000 $ and Vertex pharma - value ~2000 $. . Sartain:Alexion Discovery Partnerships: Research Funding. Takemoto:Merck: Consultancy, Honoraria; Novartis: Other: DSMB; Pfizer: Research Funding; Novo Nordisk: Research Funding. Tarango:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wilson:Octapharma: Consultancy. Zia:COR2ED GmbH: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Star Therapeutics: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Membership on an entity's Board of Directors or advisory committees.