What is the recommended duration of anticoagulant therapy for pediatric patients with venous thromboembolism (VTE)?

Background

Venous thromboembolism (VTE) is an under-recognized problem in pediatric patients.¹ The annual incidence of VTE in the pediatric patient population is low overall, estimated at 0.07 to 0.14 per 10,000 children; however, the risk of VTE is dramatically increased among hospitalized children.^1,2 The incidence of VTE among hospitalized children has risen since the early 1990s, from an estimated 5.3 events per 10,000 hospital admissions to a current estimate of up to 58 events per 10,000 admissions.³ This may be due in part to a better understanding of the disease and increased survival rates among patients with chronic illnesses, as well as more frequent use of catheters and other interventional techniques associated with VTE risk.² Pediatric VTE, like VTE in adults, can lead to significant morbidity and mortality.³ Potential consequences of VTE in children include organ dysfunction, infection, postthrombotic syndrome, loss of venous access, pain, and increased length/cost of hospital stay. Risk of VTE recurrence is estimated at 10% to 15%.² Approximately 2.2% of pediatric VTEs are ultimately fatal.³

The age distribution of pediatric VTE is bimodal, with peaks occurring in the neonatal and adolescent patient populations.³ Although idiopathic or unprovoked VTE accounts for an estimated 30% to 50% of adult VTEs, idiopathic VTE is rare in children.⁴ Approximately 95% of pediatric VTEs are precipitated by at least 1 identifiable risk factor.⁵ One of the most common precipitating factors in pediatric patients is the presence of a central venous access device (CVAD).^1,6 Over 50% of pediatric VTEs and over 90% of neonatal VTEs are associated with CVADs.¹ Other risk factors for pediatric VTE include congenital heart disease, trauma, surgery, immobilization, local or systemic infection, malignancy, and prematurity.⁶ In adolescent patients, adult risk factors such as oral contraceptive use and obesity may also be present.^2,3

Goals of treatment in pediatric VTE are to prevent further propagation of the acute thrombosis, prevent embolization, and prevent the occurrence of secondary/recurrent VTE.⁷ Warfarin, low-molecular-weight heparins, and unfractionated heparin are the mainstays of therapy for pediatric VTE, although few clinical trials have been conducted in pediatric patient populations.^1,6,7 Recently, 2 direct oral anticoagulants (rivaroxaban and dabigatran) have also gained approval for use in pediatrics.^8,9 However, while pharmacologic treatment options are expanding, there are still several issues in this area of practice that require further clarification. One such issue is the appropriate duration of anticoagulant therapy after a VTE event. It is important to clarify the optimal duration of anticoagulation in pediatric patients, as anticoagulant therapy itself is associated with certain risks and costs.⁷ The duration of anticoagulation in pediatric patients must provide an appropriate balance between the population-specific risks of recurrent VTE and the population-specific risks of bleeding, while also considering impacts on cost of care and quality of life.

Guideline recommendations on duration of anticoagulation in pediatrics

In 2012, the American College of Chest Physicians (ACCP) published a comprehensive guideline related to the treatment and prevention of VTE.⁵ While portions of this guideline have been updated in recent years, the pediatric and neonatal recommendations have not yet been revised. The American Society of Hematology (ASH) published an additional updated guideline on pediatric VTE in 2018.¹⁰ Recommendations from these guidelines pertaining to treatment duration are summarized in the Table.^5,10 However, the recommendations for treatment duration in pediatric VTE have largely been extrapolated from data in adult VTE populations, due to the lack of well-designed clinical trials available in the pediatric population.^1,6 In its review of evidence for the 2018 guideline, ASH found only one small observational study in the pediatric population that specifically examined the efficacy associated with different therapeutic anticoagulation durations.^10,11 In this study of 149 patients aged less than 19 years, VTE recurred in 23% of patients who received more than 6 months of anticoagulation, 15% of patients who received 3 to 6 months of anticoagulation, and 21% of patients who received less than 3 months of anticoagulation (p-value not significant).¹¹ Most of the patients in this trial (93%) had at least 1 underlying condition that may have precipitated VTE.

New evidence on length of therapy in pediatric VTE

As mentioned above, current guideline recommendations for anticoagulant therapy duration in pediatric VTE primarily rely on evidence from adult studies.^1,5,6,10 However, pediatric VTE differs from adult VTE in important ways.⁶ Pediatric patients have a different hemostatic physiology than adults, and differ from adults in terms of common underlying medical conditions, common anatomic VTE locations, profile of provoked versus unprovoked VTE, and rates of VTE-associated morbidity and mortality.^1,6,7,12 Therefore, data specific to the pediatric population are needed to further inform treatment recommendations.

Since the publication of the guidelines mentioned above, an additional study has sought to clarify the most appropriate duration of anticoagulant therapy in pediatric patient populations. The Kids-DOTT trial was an international, open-label, blinded end point randomized controlled trial that enrolled patients aged less than 21 years (median age, 8.3 years; range, 0.04 to 20.9 years).¹³ In order to be eligible for the trial, patients had to have an acute VTE (diagnosed within the past 30 days) and an identifiable provoking factor. The most common VTE-provoking factor was the presence of a central venous catheter (52.5%), followed by infection (34%) and trauma or surgery within the past 30 days (19.9%). Importantly, patients with previous VTE were excluded from the trial, as were those with active malignancy, clinically significant deficiencies in natural anticoagulant factors, or pulmonary embolism without deep vein thrombosis.

Patients were randomized to receive 6 weeks of anticoagulant therapy or 3 months of anticoagulant therapy.¹³ The choice of anticoagulant was left to the discretion of the treating physician, but dosing for the selected anticoagulant was guided by the 2012 ACCP recommendations. Most patients were anticoagulated with low-molecular-weight heparin (84% during the acute treatment period and 86% during the subacute treatment period). Patients were followed for 2 years. The primary efficacy endpoint was symptomatic recurrence of VTE within 1 year, and the primary safety endpoint was clinically relevant bleeding events (major or clinically relevant nonmajor bleeding) within 1 year after VTE diagnosis. Clinically relevant bleeding events included any event that met one of the following criteria: fatal bleeding; clinically overt bleeding associated with a decrease in hemoglobin level of at least 2 g/dL in a 24-hour period; clinically overt bleeding requiring administration of a blood product; retroperitoneal, pulmonary, or central nervous system bleeding; bleeding requiring medical or surgical intervention; or bleeding for which the patient sought medical attention. Noninferiority of 6 weeks of treatment versus 3 months of treatment was determined based on 3 scenarios of risk-benefit trade-off. For the 3 scenarios, noninferiority boundaries were absolute risk differences in VTE recurrence and clinically relevant bleeding, respectively, of 1% and -12%; 0% and -4%; and -5% and 4%.

A total of 297 patients were included in the per-protocol primary endpoint analysis.¹³ At 1 year, VTE recurrence rates were 0.65% in the 6-week group and 1.4% in the 3-month group (estimated 1-year risk of recurrent VTE, 0.66% versus 0.7%, respectively; absolute risk difference, -0.04; 95% confidence interval [CI], -3.81% to 3.56%). Rates of clinically relevant bleeding were 0.65% in the 6-week group and 0.7% in the 3-month group (estimated 1-year risk of clinically relevant bleeding, 0.65% versus 0.7%, respectively; absolute risk difference, -0.05; 95% CI, -3.78% to 3.54%). Authors concluded that 6 weeks of anticoagulant therapy was noninferior to 3 months of anticoagulant therapy; noninferiority was confirmed in both the per protocol analysis population and the full population of randomized patients.

Significant limitations of this trial include the small number of patients with cancer or pulmonary embolism and the predominant use of low-molecular-weight heparins for treatment.¹³ Use of direct oral anticoagulants has increased in clinical practice, especially with the recent pediatric approvals of 2 such drugs; it is unclear whether the results of this trial would also be applicable to patients receiving such therapies. However, this is the first randomized controlled trial to compare different treatment durations in a pediatric patient population, and the results of this trial can be used to inform the use of shorter treatment durations in patients who meet the inclusion criteria of the trial.

Conclusion

Data on the duration of anticoagulant therapy for pediatric VTE are extremely limited; however, the recent publication of the Kids-DOTT trial provides valuable insight into this clinical question. The Kids-DOTT trial demonstrated that, in a population of pediatric patients with provoked DVTs being treated predominantly with low-molecular-weight heparin, a 6-week course of anticoagulant therapy was noninferior to a 3-month course of anticoagulant therapy. It is important to note, however, that several important populations (patients receiving direct oral anticoagulants, patients with cancer, patients with pulmonary embolism, and patients with unprovoked/idiopathic VTEs) were underrepresented or missing from this trial; therefore, the results of this trial cannot be appropriately extrapolated to these patient populations.

References

1. George C, Rahman M, Monagle P. Challenges and opportunities in the pharmacological treatment of acute venous thromboembolism in children. Paediatr Drugs. 2020;22(4):385-397. doi:10.1007/s40272-020-00403-5
2. Lassandro G, Palmieri VV, Palladino V, Amoruso A, Faienza MF, Giordano P. Venous thromboembolism in children: from diagnosis to management. Int J Environ Res Public Health. 2020;17(14). doi:10.3390/ijerph17144993
3. Witmer C, Raffini L. Treatment of venous thromboembolism in pediatric patients. Blood. 2020;135(5):335-343. doi:10.1182/blood.2019001847
4. Mahajerin A, Croteau SE. Epidemiology and risk assessment of pediatric venous thromboembolism. Front Pediatr. 2017;5:68. doi:10.3389/fped.2017.00068
5. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S. doi:10.1378/chest.11-2308
6. Bosch A, Albisetti M. Management of venous thromboembolism in children: current recommendations and therapeutic options. Ther Clin Risk Manag. 2020;16:673-679. doi:10.2147/tcrm.S218622
7. Tarango C, Schulman S, Betensky M, Goldenberg NA. Duration of anticoagulant therapy in pediatric venous thromboembolism: Current approaches and updates from randomized controlled trials. Expert Rev Hematol. 2018;11(1):37-44. doi:10.1080/17474086.2018.1407241
8. FDA approves first oral blood thinning medication for children. U.S. Food and Drug Administration. Published June 21, 2021. Accessed February 21, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-blood-thinning-medication-children
9. FDA approves two new indications for Xarelto® (rivaroxaban) to help prevent and treat blood clots in pediatric patients. Johnson and Johnson. Published December 20, 2021. Accessed February 21, 2022. https://www.jnj.com/fda-approves-two-new-indications-for-xarelto-rivaroxaban-to-help-prevent-and-treat-blood-clots-in-pediatric-patients
10. Monagle P, Cuello CA, Augustine C, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Adv. 2018;2(22):3292-3316. doi:10.1182/bloodadvances.2018024786
11. Estepp JH, Smeltzer M, Reiss UM. The impact of quality and duration of enoxaparin therapy on recurrent venous thrombosis in children. Pediatr Blood Cancer. 2012;59(1):105-109. doi:10.1002/pbc.23396
12. Spentzouris G, Scriven RJ, Lee TK, Labropoulos N. Pediatric venous thromboembolism in relation to adults. J Vasc Surg. 2012;55(6):1785-1793. doi:10.1016/j.jvs.2011.07.047
13. Goldenberg NA, Kittelson JM, Abshire TC, et al. Effect of anticoagulant therapy for 6 weeks vs 3 months on recurrence and bleeding events in patients younger than 21 years of age with provoked venous thromboembolism: the Kids-DOTT randomized clinical trial. JAMA. 2022;327(2):129-137. doi:10.1001/jama.2021.23182

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

March 2022

The information presented is current as of February 17, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.