Efficacy and Safety of Apixaban for Pediatric Patients Requiring Anticoagulation for Treatment of Venous Thromboembolism

Background: In children, the incidence of VTE was initially reported to be very low at 0.07-0.14 per 10,000 children; however, contemporary data revealed a higher incidence for hospitalized children: ≥ 106 per 10,000 admissions (Andrew M et al. Blood 1994;83:1251-7, van Ommen CH et al. J Pediatr 2001;139:676-81, O'Brien SH et al. Pediatrics 2022;149:e2021054649). Pediatric evidence-based VTE treatment guidelines recommend unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or vitamin K antagonists (VKAs) as standard of care (SOC), acknowledging the gap surrounding the use of direct oral anticoagulants, such as apixaban, in children (Monagle P et al. Chest 2012;141[suppl 2]:e737S-e801S, Monagle P et al. Blood Adv 2018;2:3292-3316). The safety and efficacy profile of apixaban in adults with VTE has been established (Agnelli G et al. N Engl J Med 2013;368:699-708 and 2013;369:799-808). This study assessed the efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of apixaban in pediatric patients (pts) requiring anticoagulation for the treatment of VTE.

Methods: In this 12-week, open-label, active-controlled descriptive study (NCT02464969), pediatric pts (aged < 18 years) with image-confirmed VTE were randomized 2:1 to receive apixaban dosed according to a fixed-dose, body weight tiered (mg/kg) regimen by age group (birth to 27 days, 28 days to < 2 years, 2 to < 12 years, 12 to < 18 years), or SOC prescribed per local practice (VKA, LMWH, and UFH). The primary efficacy endpoint was image-confirmed and adjudicated recurrent VTE defined as contiguous progression or non-contiguous new thrombus (new), including deep vein thrombosis (DVT), pulmonary embolism (PE), other thrombosis, paradoxical embolism, and VTE-related mortality. The primary safety endpoint was adjudicated major bleeding and clinically-relevant non-major bleeding (CRNMB). Secondary endpoints included new or recurrent symptomatic/asymptomatic DVT, PE, VTE other than DVT or PE, stroke, index event status, minor bleeding events, and apixaban PK/PD (plasma concentration and anti-Factor Xa activity [AXA] of apixaban). Pts who discontinued anticoagulation completed end-of-treatment and safety visits. The study was not powered and used descriptive statistics.

Results: Overall, 229 pts were randomized (full analysis set: apixaban n = 155, SOC n = 74). In total, 26 pts (11.4%) discontinued treatment (apixaban n = 17, SOC n = 9) and 4 (1.7%) were not treated (apixaban n = 3, SOC n = 1). The majority of pts were female (55.9%) and White (76.4%); median (range) age was 14.2 (0.04-18.0) years. Baseline demographics were comparable between treatment arms. Primary efficacy endpoint: in the apixaban group, 4 (2.6%, 95% CI 0.8-6.7) pts had ≥ 1 symptomatic or asymptomatic recurrent VTE event compared with 2 (2.7%, 95% CI 0.2-9.9) pts in the SOC group; no pts had VTE-related death. Primary safety endpoint: no pts in either treatment group had major bleeding events. In the apixaban group, 2 (1.3%, 95% CI 0.1-5.0) pts had CRNMB compared with 1 (1.4%, 95% CI 0.0-8.1) in the SOC group. The overall safety profile of apixaban was similar to SOC based on the incidence of treatment-emergent adverse events (AEs) and serious AEs. No clinically meaningful treatment differences in hematology and clinical chemistry laboratory parameters were observed. Day 14 pre-dose and corresponding post-dose median apixaban concentrations were similar across age groups at the administered doses. AXA was linearly correlated to apixaban concentrations across all age groups and body-weight tiers.

Conclusions: In this active-controlled descriptive study in children from birth to < 18 years of age with acute VTE, treatment with apixaban resulted in a low risk of VTE recurrence and comparable risk of major and CRNMB events compared to SOC therapy. No new safety signals were observed in apixaban-treated pts. The safety profile was generally consistent with that reported in adult VTE studies. PK/PD findings demonstrated linear correlation and were consistent across age and body-weight tiers.

Study support: This study was sponsored by Pfizer and Bristol Myers Squibb.

Acknowledgments: We thank the Study B0661037 investigators and patients for their participation. Editorial and medical writing support were provided by Caudex, a division of IPG Health Medical Communications, New York, NY, USA, and were funded by Pfizer and Bristol Myers Squibb.

Driscoll:Pfizer: Current Employment, Current equity holder in publicly-traded company. O'Brien:Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; iECURE: Other: Ad hoc DSMB member. Newburger:Pfizer: Other: Chair, Independent Events Adjudication Committee, Research Funding; Bristol Myers Squibb: Other: Chair, Independent Events Adjudication Committee for trial of apixaban. Co-Chair, Data Safety Monitoring Committee for trial of mavacamten. Mitchell:Bristol Myers Squibb: Research Funding. Holzhauer:Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria; Böhringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Current equity holder in publicly-traded company, Honoraria. Ahuja:BioMarin: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; XaTek: Membership on an entity's Board of Directors or advisory committees, Research Funding; Case Western Reserve University: Patents & Royalties: Patent for US 11,408,844 issued; US FDA: Honoraria, Other: Member of the Blood Products Advisory Committee; Governor's Office, State of Ohio: Other: Membership on Rare Disease Advisory Council for the State of Ohio; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rubio:Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding. Gaitonde:Pfizer: Current Employment, Current equity holder in publicly-traded company. Robertson:Pfizer Research and Development UK: Current Employment. Polinsky:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Masiukiewicz:Pfizer: Current Employment, Current equity holder in publicly-traded company. Brandao:Pfizer/Bristol Myers Squibb: Research Funding; AstraZeneca: Other: Ad board meeting on andexanet alfa (Feb. and Jun. 2023/ISTH - Montreal/QC, Canada.