Oral anticoagulant reversal agent use in paediatric patients: a survey

Andexanet alfa versus prothrombin complex concentrates/blood products as apixaban/rivaroxaban reversal agents: a survey among pediatric hematologists

Rodriguez V, Stanek J, Kerlin BA, Dunn AL. Clin Appl Thromb Hemost. 2022;28:10760296221078842.

The direct oral anticoagulants (DOACs) apixaban and rivaroxaban, also known as direct oral factor Xa inhibitors (DXIs), are used for stroke prevention in adult patients with non-valvular heart disease, and treatment and prevention of venous thromboembolism (VTE)¹. Given the increased risk of bleeding, however, reversal agents are sometimes necessary to counter the effects of DXIs. Administration of a reversal agent is advised only if bleeding is life-threatening or involves a critical organ and cannot be controlled despite maximum supportive measures².

In 2018, and 2019 andexanet alfa became the first agent to be approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), respectively, for the reversal of life-threatening or uncontrolled bleeding in patients receiving apixaban or rivaroxaban³. Prior to 2018, several pro-haemostatic agents such as prothrombin complex concentrate (PCC) were used for the management of factor Xa inhibition-related bleeding.

Andexanet, PCC, apixaban and, until recently, rivaroxaban have been used off-label for treatment and prevention of childhood VTE. Data on the safety and efficacy of rivaroxaban in paediatric patients published in 2020⁴ supported its use for childhood VTE management and led to its recent FDA approval for this indication⁵. In a recent pilot study, apixaban was also found to be safe and well tolerated in children and adolescents⁶. A clinical trial for the use of apixaban in children is currently in progress⁷.

Rodriguez and colleagues have noted that, in their experience, the use of DOACs for paediatric patients is increasing⁸. To better understand prescribing practices, they designed a brief survey of 10 questions, which they distributed to paediatric haematology members of the Hemostasis and Thrombosis Research Society, who specialise in thrombosis and regularly prescribe anticoagulants in their practices.

Why was the survey needed?

There is a lack of evidence-based literature regarding the use of andexanet alfa or PCC therapy for DXI reversal in children, although these agents are currently used in children⁸. There is also a lack of dosing recommendations for children. Rodriguez and colleagues conducted their survey to gain an understanding of the current prescribing practices of paediatric providers regarding apixaban and rivaroxaban, and their preferred reversal agent, depending on the severity of bleeding.

With the increasing use of DXIs, there will be an increasing need for reversal of these agents in the context of anticoagulant-related bleeding

What did the survey find?

Key findings of the survey are shown in Figure 1.

Figure 1. Key findings of paediatric haematologists survey. DOAC, direct acting anticoagulant; DXI, direct oral factor Xa inhibitor; LMWH, low molecular weight heparin; OAR, oral anticoagulant reversal; PCC, prothrombin complex concentrates. *Combines survey answers: PCC at 25 units/kg dose, PCC at 50 units/kg, PCC then andaxanet alfa if ongoing bleeding; †Combines survey answers: andaxanet alfa per FDA dosing, 1) in all ages, 2) in adolescents, 3) in >50 kg, and andaxanet alfa then PCC if ongoing bleeding.

• Choosing the right anticoagulant agent takes into account multiple factors, including the age of the patient, route of administration, bleeding risk, organ function and compliance. When asked about clinical scenarios in which experts would prescribe apixaban or rivaroxaban, 89% of responders said that prophylaxis and treatment of VTE were the most common reasons for using DXI therapy. Interestingly, 41% of doctors prescribed apixaban or rivaroxaban regardless of the patient's age, while 15% said they only used DXI in patients who weighed more than 50 kg
• In terms of drug of choice for anticoagulation reversal of apixaban or rivaroxaban, the survey showed a divided opinion among paediatric haematologists regarding the preferred DXI reversal strategy, with 44% choosing andexanet alfa and 52% PCC therapy
• Formulary availability was indicated as the primary reason for choosing a particular reversal agent, followed by the lack of data to recommend one reversal agent over the other
• Twenty-two percent of respondents were concerned about thrombotic risk with reversal, and 15% reported the cost of medication as another reason to choose a specific agent
• The volume of patients with thrombosis (less or more than 10 per month) or the number of years in practice (less or more than 10 years) did not significantly influence the reversal agent choice

What were the limitations of this study?

The response rate to the survey was quite low (17% of those who received it, n = 27) and, as a result, the sample size might not be a true representation of the paediatric haematologists who regularly prescribe DXI therapy and reversal agents.

What was learned from this survey?

Paediatric haematologists who completed the survey use both rivaroxaban and apixaban for management of childhood VTE. The respondents did not have a clear preference for a reversal agent and were equally divided between PCC therapy or andexanet alfa. However, no paediatric guidance has been formulated to address the management of the rare but serious complications of DXI-related bleeding and there is no conclusive evidence to support a preference for one reversal agent over the other.

It is expected that DXI use will continue to become more common in paediatric patients but there is an unmet need for evidence-based guidance on the use of reversal agents to manage DXI-related bleeding in these patients

References

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3. Demchuk AM, Yue P, Zotova E, Nakamya J, Xu L, Milling TJ, Jr., et al. Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy. Stroke. 2021;52(6):2096-2105.
4. Male C, Lensing AWA, Palumbo JS, Kumar R, Nurmeev I, Hege K, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2020;7(1):e18-e27.
5. U.S. Food & Drug Administration, 2021. FDA approves drug to treat, help prevent types of blood clots in certain pediatric populations [press release]. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-help-prevent-types-blood-clots-certain-pediatric-populations. Accessed 21 June 2022.
6. Pinchinat A, Otero N, Mahanti H, Morris E, Brudnicki A, Friedman D, et al. A Pilot Study of an Oral Anticoagulant, Apixaban, in Secondary Prophylaxis of Venous Thromboembolism (VTE) in Children and Adolescents. Blood. 2019;134(Supplement_1):2443.
7. Payne RM, Burns KM, Glatz AC, Li D, Li X, Monagle P, et al. A multi-national trial of a direct oral anticoagulant in children with cardiac disease: Design and rationale of the Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE) study. Am Heart J. 2019;217:52-63.
8. Rodriguez V, Stanek J, Kerlin BA, Dunn AL. Andexanet Alfa Versus Prothrombin Complex Concentrates/Blood Products as Apixaban/Rivaroxaban Reversal Agents: A Survey Among Pediatric Hematologists. Clin Appl Thromb Hemost. 2022;28:10760296221078842.