A pilot safety, feasibility and efficacy study of an oral anticoagulant, apixaban, in secondary prophylaxis of a primary venous thromboembolism in children and adolescents

Venous thromboembolism (VTE) is a major complication in hospitalised children and adolescents secondary to its association with increased morbidity and mortality.1, 2 Historically, the standard of care for secondary VTE prophylaxis in children and adolescents with primary VTE is the use of either warfarin or low molecular weight heparin (LMWH).2, 3 Each of these approaches has significant limitations in the paediatric population including the need for frequent laboratory testing, erratic oral absorption or frequent subcutaneous injections leading to decreased compliance and treatment failure.4 Direct oral anticoagulants (DOACs), direct factor Xa inhibitors, such as apixaban, are approved in adults with established efficacy and safety. In the randomised, double blind AMPLIFY trial, apixaban was found to be noninferior to conventional therapy in rates of secondary symptomatic VTE or death related to secondary VTE.5 However, there is a paucity of information related to safety, feasibility and efficacy of apixaban as secondary VTE prophylaxis in children and adolescents with a history of a primary VTE.6 We conducted a phase II pilot open label study of apixaban as secondary VTE prophylaxis in children and adolescents. The study was reviewed and approved by the institutional review board. Written consent was obtained from patients and/or legal guardians, and assent was obtained in age appropriate patients. The study was registered on clinicaltrials.gov (NCT04041843). Children and adolescents through age 21.99 years, in compliance with the adolescent definition in our hospital, weighing >40 kg diagnosed with a primary VTE were eligible for study entry. Treatment began within 72 h of diagnosis of a primary VTE and transition from other anticoagulants was permitted. Consented patients received apixaban 10 mg twice daily orally for 7 days followed by 5 mg twice daily until day 90, based on the AMPLIFY trial in adults (NCT04041843). Participants had a chest computed tomography angiogram and Doppler ultrasound of affected areas on day 1, between days 8 and 15, day 30 (if not resolved), and day 90. Anti-Xa level was obtained prior to dose administration on days 8 and 30, and 4 h after dose administration on days 1, 15 and 90. If indicated, a thrombophilia workup was performed including, but not limited to, Factor V Leiden, Protein C and S, antithrombin III, and prothrombin gene mutation to rule out a primary or hereditary thrombotic disorder. Any Grade III–V haemorrhage probably or definitely related to apixaban therapy was considered a dose-limiting toxicity. Stopping criterion was not reached so there was no dose modification made to the protocol (Table S1). In total, 26 patients were enrolled with a median age of 16 years (12–21 years) and 61.5% were females (16 females and 10 males). In all, 14 patients had isolated new onset deep venous thrombosis (DVT), eight patients had isolated pulmonary emboli (PE) and 4 patients had both DVT and PE upon study entry (Table 1). Evaluable thrombi (Table S2) on imaging at day 30 revealed 40.9% showed complete response (CR), 40.9% showed a partial response (PR), 9.1% showed stable disease and 9.1% showed progressive disease (Figure 1). For the two patients with an increase in clot burden, one patient was taken off study for noncompliance. The remaining patient suffered from autoimmune encephalitis unrelated to study drug and was taken off study. At the completion of 3 months of therapy, 63.6% (14 of 22) had a CR and 36.4% (8 of 22) had a PR with no patients having stable disease (Figure 1). Importantly, there were no patients who experienced a new VTE, which equates to 100% successful VTE secondary prophylaxis. Some patients did not have a second timepoint due to study removal (2), COVID-19 (2), contrast allergy (1) and lost to follow-up (1). The average anti-Xa level was 1.02 iu/mL 4 h after apixaban treatment while the average trough level was 0.78 iu/mL. There were no episodes of bleeding, classified as Grade I–IV haemorrhage (CTCAE 4.0), or other adverse events and no patients required dose modifications. Our preliminary results demonstrate that apixaban administered in children and adolescents with a primary VTE for secondary prophylaxis is feasible, safe and effective. Apixaban is an oral therapy that does not require daily injections or frequent laboratory monitoring, potentially leading to improved compliance of children and adolescents with their therapy. It is important to note that this study was initiated prior to the suggestion that DOACs should not be used in patients with anti-phospholipid antibody (APLA) syndrome. This is based on publications of APLA patients who received DOACs and developed new thrombi on therapy.7 Four patients were diagnosed with APLA on our study—two had decrease in their thrombus and one had complete resolution at the end of 3 months of therapy with no untoward event in the study period with the final patient taken off study once diagnosed. One limitation of our study is the use of repeat imaging as a secondary outcome rather than symptomatic or recurrent VTE especially when considering cost, radiation exposure, variation on imaging interpretation and burden on families. The KIDS-DOTT study suggests 6 weeks of therapy may be sufficient if a thrombus is nonocclusive in some paediatric patients with VTE.8 This provides guidance regarding timing of follow-up imaging and characterisation of occlusion in future studies. National trials are currently underway to further investigate the use of apixaban in specific populations of children, adolescent and young adults. The SAXOPHONE study is a multi-national trial prospective, randomised trial of using apixaban in children with congenital and acquired cardiac disease.9 The Children's Oncology Group PREVAPIX-ALL trial is a randomised trial exploring the use of apixaban to prevent VTE in patients with B- and T-cell acute lymphoblastic leukaemia and lymphoma who receive asparaginase during induction chemotherapy and have the presence of a central venous line.10 Results of these studies will help to determine the optimal use of apixaban in specific paediatric populations. There are no published randomised studies to date comparing DOACs, to oral warfarin or LMWH prophylaxis in paediatric patients with primary VTEs. A meta-analysis looking to compare apixaban, dabigatran, edoxaban and rivaroxaban found that apixaban had the most favourable safety profile.11 There is an ongoing randomised phase IV clinical trial looking at the use of apixaban compared to standard of care in paediatric patients less than 18 years of age (NCT02464969). In summary, our study demonstrates that apixaban administered for secondary VTE prophylaxis was feasible, safe and effective in children and adolescents weighing more than 40 kg in the prevention of recurrent VTEs. In addition, stable anti-Xa levels were demonstrated. Larger studies are warranted to validate these findings and apply these principles to neonates and younger children. Ashley Pinchinat, Oya Levendoglu-Tugal, Yara Perez, Liana Klejmont and Mitchell S. Cairo wrote and revised the research protocol. Emily Thatcher, Neida Otero, Arvind Budhram, Harshini Mahanti and Erin Morris provided excellent research and patient support throughout the trial. Adele Brudnicki, Deborah Friedman and Simon Li provided expertise in their respective fields during protocol creation. Ashley Pinchinat, Oya Levendoglu-Tugal, Yara Perez, Erin Morris and Mitchell S. Cairo wrote and revised the paper. The authors would like to thank Ginny Davenport, RN for her assistance in the submission of this manuscript and the patients and families who participated in this study. This study was supported in part by the Paediatric Cancer Research Foundation (PCRF). Mitchell S. Cairo has served as a consultant for Jazz Pharmaceuticals, Omeros Pharmaceuticals, Servier Pharmaceuticals, NEKTAR and Novartis Pharmaceuticals; Speakers Bureau for Jazz Pharmaceuticals, Servier Pharmaceuticals, Amgen, Inc., Sanofi and Sobi; Advisory Board for Astra Zeneca; and research funding from Celularity, Merck, Miltenyi Biotec, Servier, Omeros and Jazz. All other authors declare no conflict of interest. Requests for secondary use of the dataset can be made by emailing Dr. Mitchell S. Cairo at [email protected]. Table S1. Table S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.