Rivaroxaban for the treatment of venous thromboembolism in pediatric patients

Omri Cohen , Sarina Levy-Mendelovich & Walter Ageno

To cite this article: Omri Cohen , Sarina Levy-Mendelovich & Walter Ageno (2020): Rivaroxaban for the treatment of venous thromboembolism in pediatric patients, Expert Review of Cardiovascular Therapy, DOI: 10.1080/14779072.2020.1823218
To link to this article: https://doi.org/10.1080/14779072.2020.1823218
Accepted author version posted online: 16 Sep 2020.

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Review of Cardiovascular Therapy

DOI: 10.1080/14779072.2020.1823218
Rivaroxaban for the treatment of venous thromboembolism in pediatric patients
Omri Cohen1,2,3, Sarina Levy-Mendelovich1,2,4, Walter Ageno3
⦁ National Hemophilia Center, Institute of Thrombosis and Hemostasis and the Amalia Biron Research Institute, Sheba Medical Center, Tel-Hashomer, Israel.
⦁ Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
⦁ Department of Medicine and Surgery, University of Insubria, Varese, Italy.
⦁ Tisch cancer institue, Icahn school of medicine, Mount Sinai hospital, NY, USA. SLM and OC equally contributed to writing the manuscript.

Corresponding author:
Dr. Omri Cohen, MD
National Hemophilia Center, Institute of Thrombosis and Hemostasis and the Amalia Biron Research Institute, Sheba Medical Center, Tel-Hashomer, Israel;
Sackler School of Medicine, Tel Aviv University, Israel, and Department of Medicine and Surgery, University of Insubria, Varese, Italy.
e-mail: [email protected] ORCID ID: 0000-0002-8328-9748

 

Abstract
Introduction: Anticoagulant therapy is in use for both prevention and treatment of venous and arterial thromboembolic disorders. Delivering safe and effective anticoagulation in the pediatric population is challenging, since the available standard therapy with parenteral UFH and LMWH is troublesome for most pediatric patients, and VKAs require frequent INR monitoring due to the unpredictable pharmacokinetics and numerous food and drug interactions. Rivaroxaban, a direct FXa inhibitor, offers the convenience of oral administration and predictable pharmacokinetics across a wide range of patients. Its safety and efficacy have been previously established in various adult indications.
Areas covered: This review outlines pharmacologic and clinical aspects regarding rivaroxaban treatment in adults and children, and provides a broad appraisal of the The EINSTEIN-Jr program which evaluated the safety and efficacy of body-weight adjusted pediatric rivaroxaban regimens for the treatment of VTE in children. A review of the literature using the keywords rivaroxaban and pediatric venous thromboembolism was conducted within the National Center for Biotechnology (NCBI) and EMBASE databases.
Expert opinion: Rivaroxaban represent an appealing therapeutic alternative for VTE in children. Further research should explore additional indications for rivaroxaban in the pediatric population beyond that of VTE.

Keywords: Rivaroxaban, Anticoagulation, Venous thromboembolism, Factor Xa, Pediatric
Article highlights:
⦁ Venous thromboembolism in children is rare, and typically presents as a secondary complication, attributable to central venous catheters-associated in 65.5% of cases.
⦁ Available standard anticoagulant therapy with parenteral UFH and LMWH is troublesome for most pediatric patients, whereas vitamin K antagonists require frequent INR monitoring.
⦁ Rivaroxaban, a direct FXa inhibitor, offers the convenience of oral administration and predictable pharmacokinetics across a wide range of patients.
⦁ The EINSTEIN-Jr program evaluated the safety and efficacy of body-weight adjusted pediatric rivaroxaban regimens for the treatment of VTE in children, as well as pharmacokinetic parameters.
⦁ Rivaroxaban treatment resulted in a similarly low risk of recurrent VTE and clinically relevant bleeding, compared with standard therapy.

 

⦁ Pharmacokinetic analyses of bodyweight-adjusted rivaroxaban regimens demonstrated drug exposure levels within the adult exposure range, with no clustering for any of the pharmacokinetic parameters with efficacy, bleeding, or adverse outcomes.
⦁ Rivaroxaban may be indicated for thromboprophylaxis post-Fontan procedure, in children with nephrotic syndromes, congenital protein C, protein S and antithrombin deficiencies and for treatment of heparin-induced thrombocytopenia.

 

⦁ Introduction
Anticoagulant therapy is prescribed for both prevention as well as treatment of venous and arterial thromboembolic disorders in pediatric patients [1]. Venous thromboembolism (VTE) is a rare condition in children that is being increasingly diagnosed, usually as a secondary complication [2,3]. Risk factors include perinatal disease, medical interventions (e.g., central venous catheters), sepsis, drugs and malignancies[4-6]. Central venous catheters (CVC)-associated VTE is the commonest triggered thrombosis in children, reported in 65.5% of VTE events in children [7]. The duration of therapy in children with a triggered deep venous thrombosis (DVT) is usually between 6 weeks and 3 months, depending on the triggering factor and the resolution of thrombosis at follow-up [8].
Anticoagulants have been in use since the discovery unfractionated heparin (UFH) in 1916, whereas low molecular heparin (LMWH) was developed in 1980 adding the advantages of less frequent subcutaneous administration, lower risk of bleeding and of heparin induced thrombocytopenia (HIT), better bioavailability and longer half-life [9]. UFH and LMWH are indirect inhibitors of coagulation. Their activity is mediated by plasma cofactors, mainly antithrombin, and to a lesser extent for UFH, heparin cofactor II [10].
Since the discovery of warfarin in 1941 and until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulant agents. However, VKAs have disadvantages attributable to their unpredictable pharmacokinetics and pharmacodynamics, a narrow therapeutic index, slow onset of activity, numerous drug and food interactions, and therefore, need for routine monitoring [11]. All these, make their use in the pediatric population challenging. Therefore, there is a clear unmet need for alternative oral anticoagulants.
This review outlines pharmacologic and clinical aspects regarding rivaroxaban treatment in adults and children, and provides a broad appraisal of the The EINSTEIN-Jr program which evaluated the safety and efficacy of body-weight adjusted pediatric rivaroxaban regimens for the treatment of VTE in children. A review of the literature using the keywords rivaroxaban and pediatric venous thromboembolism was conducted within the National Center for Biotechnology (NCBI) and EMBASE databases.

⦁ The Discovery of Factor Xa inhibitors and rivaroxaban and mechanism of action
Factor Xa (FXa) has been known to have a pivotal role in hemostasis by catalyzing the production of thrombin leading to clot formation [12]. The first FXa inhibitor, antistasin, was isolated from salivary glands of the Mexican Leech Haementeria officinalis in 1987 [13]. Tick anticoagulant peptide is another naturally occurring FXa inhibitor [14]. The development of these compounds was discontinued for

 

unknown reasons [9]. Direct and indirect FXa inhibitors showed that inhibition of FXa produces its antithrombotic effect via decreasing the generation of thrombin. The residual thrombin generated seems to be sufficient to ensure normal systemic haemostasis, thus contributing to a favorable efficacy/safety ratio. On the basis of these findings, in the mid 1990’s several direct FXa inhibitor small molecules were being developed [9]. In 1998 the FXa program at Bayer Healthcare was started. Over 200,000 compounds were tested and eventually rivaroxaban was selected.
Studies demonstrated that rivaroxaban prolonged the initiation phase of thrombin generation and reduced the thrombin burst produced in the propagation phase [15].

⦁ Pharmacokinetics and pharmacodynamics of rivaroxaban
⦁ Molecular and physico-chemical properties:
Rivaroxaban—5-chloro-N-([(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- yl]methyl)thiophene-2-carboxamide is a small molecule with a molecular weight of
435.9 Da [16]. Rivaroxaban targets free and clot-bound FXa as well as FXa in the prothrombinase complex. It does not require cofactors for its anticoagulant effect [17].
As indicated by In vitro studies, the inhibition of human FXa by rivaroxaban is competitive and selective, with 10,000-fold greater selectivity than for other serine proteases [18]. It inhibited thrombin generation in a concentration-dependent manner and significantly prolonged the initiation phase of thrombin generation, reduced the rate of the propagation phase, the total amount of thrombin generated, and decreased the endogenous thrombin potential [19]. Furthermore, rivaroxaban was found to increase the permeability and degradability of the entire clot, however, it does not inhibit the activity of preexisting thrombin molecules [20].

⦁ Pharmacokinetics and pharmacodynamics in adults:
Rivaroxaban is readily absorbed, and reaches maximum plasma concentrations within 2-4 h from ingestion. Oral bioavailability for the 10 mg tablet is high (80-100 %) irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. The pharmacokinetic profile of rivaroxaban is consistent across a broad range of different patient populations studied, with modest variability in the pharmacokinetic parameters [20].
Plasma protein binding of rivaroxaban is high (approximately 92–95 % in vitro) and reversible, primarily to albumin, and therefore rivaroxaban may not be dialyzable. The volume of distribution at steady state is 50 L (0.62 L/kg), indicating a low-to-moderate affinity to peripheral tissues [20].

 

The measured plasma concentrations of rivaroxaban in clinical trials depends on the clinical setting, the population studied and the dosing regimen, ranging from a mean trough concentration of 9 μg/L in the VTE prevention after total hip replacement surgery trial to a mean maximal concentration of 270 μg/L in the VTE treatment trials. The area under the plasma concentration–time curve from time zero to 24 (AUC24) ranges between 376 μg*h/L in the trial of rivaroxaban for secondary prevention in patients with acute coronary syndromes, and 3,249 μg*h/L in the stroke prevention in patients with atrial fibrillation trial. The pharmacodynamic effect is closely correlated with its plasma concentration [20].
Rivaroxaban is eliminated by both renal excretion of the unchanged drug (approximately one 36%) and metabolic degradation (almost two thirds of the drug). Rivaroxaban is metabolized by several cytochrome P450 enzymes (CYP3A4/5, CYP2J2) and by CYP-independent mechanisms, and the resulting metabolites are eliminated both renally and via the hepatobiliary route.
It does not inhibit cytochrome P450 enzymes or known drug transporter systems, contributing to minimal drug interactions. Elimination of rivaroxaban from plasma occurs within a terminal half-life of 5–9 h in young and healthy subjects and 11–13 h in the elderly [20].
Quantitative measurement of rivaroxaban plasma levels is best achieved by anti-Factor Xa chromogenic assays [21] and anti-FXa assay kits and rivaroxaban calibrators are now commercially available for clinical use, although the situations in which to test for DOAC levels are still debated [22,23].

⦁ Pharmacokinetic and pharmacodynamic studies in children
The rivaroxaban dosing strategy in children was established based on EINSTEIN-Jr phase 1 and 2 data and through pharmacokinetic (PK) modeling, targeting drug exposure similar to the 20 mg once-daily dose for adults [24,25].
Physiological differences in the pediatric population affect pharmacokinetic parameters, such as absorption, distribution, metabolism and clearance of drugs [24]. The absorption of drugs depends on changes in intraluminal pH, which is relatively elevated in the neonatal period and gastric emptying which is also increased [26]. The distribution of drugs in young infants is altered by a relatively larger extra-cellular and total body water spaces compared with adults. Furthermore, the adipose stores have higher water-to-lipid ratio [26].
The pharmacokinetic models on which the EINSTEIN-Jr studies based the rivaroxaban pediatric dosing regimens, took these differences into account [24].
The multinational, single-dose, open-label, phase I study to describe the pharmacodynamics, pharmacokinetics and safety of a single bodyweight-adjusted rivaroxaban dose enrolled 59 children

 

aged 0.5-18 years who had completed treatment for a VTE event. Children were grouped according to age (0.5-2 years, 2-6 years, 6-12 years and 12-18 years). In all age groups, pharmacodynamic parameters (prothrombin time, activated partial thromboplastin time and anti-FXa activity) showed a predictable linear relationship versus rivaroxaban plasma concentrations, unaffected by developmental hemostasis. The results were in line with previously acquired adult data, as well as in vitro spiking experiments [24]. The phase 2 study aimed to develop pediatric rivaroxaban regimens for the treatment of VTE and enrolled 93 children and adolescents with confirmed VTE previously treated with LMWH, fondaparinux, or a VKAs. The children were treated for at least 2 months or, in children who had catheter-related venous thromboembolism, for at least 6 weeks. Rivaroxaban was given orally in a bodyweight-adjusted 20 mg-equivalent dose, based on the pharmacokinetic modelling predictions from the EINSTEIN-Jr phase 1 data, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). Therapeutic exposure to rivaroxaban with once-daily dosing was confirmed in children with a bodyweight of at least 30 kg. For children weighing between 20-30kg, a twice-daily dosing regimen was found to be ideal, whereas children weighing less then 20 kg, and in particular less than 12 kg showed lesser exposure, and therfore were dosed trice daily. None of the children had a major bleed. Four percentof the children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and a younger child with gingival bleeding). None of the children experienced symptomatic VTE recurrence [25].
Further pharmacokinetic and pharmacodynamic data is available from the phase 3 study, where bodyweight-adjusted doses of rivaroxaban were given in either tablets or newly developed granules-for- oral suspension formulation, once-daily, twice-daily, or three times a day for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. These latter regiments were based on blood sampling, the daily area under the plasma concentration-time curve, trough and maximal steady-state plasma concentrations. Of the 335 children allocated to rivaroxaban, 316 (94.3%) were evaluable for pharmacokinetic analyses. Rivaroxaban exposures were within the adult exposure range. In children aged 6-11 years, the mean trough concentration was 14.6 μg/L for the tablet formulation and 15.8 μg/L for the oral suspension. The mean maximal concentrations were 254 μg/L and 243 μg/L for the tablet formulation and for the oral suspension respectively. The area under the plasma concentration–time curve from time zero to 24 (AUC24) was 1,960 for both formulations. In children aged 12-17 years, the mean trough concentration was 21.4 μg/L for the tablet formulation and 19.7 μg/L for the oral suspension. The mean maximal concentrations were 242 μg/L and 232 μg/L for the tablet formulation

 

and for the oral suspension respectively. The area under the plasma concentration–time curve from time zero to 24 (AUC24) was 2,170 μg*h/L for the tablet formulation and 2,050 μg*h/L for the oral suspension [27]. The was no clustering for any of the pharmacokinetic parameters with efficacy, bleeding, or adverse outcomes, validating bodyweight-adjusted pediatric rivaroxaban regimens as an alternative treatment of children with VTE [27]. A comparison of pharmacokinetic parameters between adults and children is provided in table 1.

⦁ Rivaroxaban use in adults
Rivaroxaban was approved for use in adults in July 2011, however it has not been approved yet in the pediatric population [28].
Rivaroxaban indications in adults are diverse, with the most common being VTE prophylaxis and treatment, stroke and systemic emboli prevention in patients with atrial fibrillation and secondary prophylaxis in cardiovascular disease.
⦁ Thromboprophylaxis after hip and knee arthroplasty:
VTE, which includes DVT and pulmonary embolism (PE), is the third most common cause of vascular death after myocardial infarction and stroke [29]. VTE is a serious, potentially fatal complication following major orthopedic surgery. Its incidence is decreasing thanks to the use of VTE prophylaxis, as recommended by guidelines [30,31]. Rivaroxaban use for the prevention of VTE after hip and knee arthroplasty has been assessed in the RECORD studies [32-35], which consistently demonstrated its efficacy and safety when compared with enoxaparin.
⦁ Rivaroxaban for symptomatic VTE:
The feasibility of a “single drug approach” with rivaroxaban for the treatment of VTE was initially suggested by the results of two dose-finding studies [36,37], which then led to the EINSTEIN program, consisting of first three randomized trials of rivaroxaban in the settings of acute DVT, acute PE and continued treatment in patients who had received treatment for acute DVT or PE [38]. In patients with acute symptomatic DVT, rivaroxaban was non-inferior to subcutaneous enoxaparin followed by a VKA for 3, 6, or 12 months [39]. In the EINSTEIN-PE study, rivaroxaban was noninferior to standard therapy with LMWH and VKA for the initial and long-term treatment of PE with a potentially improved benefit– risk profile [40]. In the continued-treatment study, rivaroxaban had superior efficacy compared with placebo [29]. Finally, the EINSTEIN CHOICE study demonstrated that in patients with VTE who had completed 6 to 12 months of anticoagulation therapy and for whom there was an equipoise with regard to the need for continued anticoagulation, once-daily rivaroxaban at a dose of either 20 or 10 mg was

 

more effective than aspirin for the prevention of VTE recurrence, without significantly increasing the risk of bleeding [29].
⦁ Oral rivaroxaban for symptomatic VTE in patients with cancer:
Until recently, long-term daily subcutaneous LMWH has been standard treatment in patients with cancer-associated VTE [41]. In a multicenter, randomized, open-label, pilot trial in the United Kingdom, the SELECT-D trial, patients with active cancer who had PE or symptomatic lower-extremity proximal DVT were treated with either dalteparin or rivaroxaban. Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin [42]. Following this study and an analogous study with edoxaban [43], the International Society on Thrombosis and Haemostasis suggested the use of these specific direct oral anticoagulants (DOACs) for cancer patients with an acute diagnosis of VTE, a low risk of bleeding, and no drug–drug interactions with current systemic therapy [44].
⦁ Prevention of stroke and systemic embolism in patients with atrial fibrillation
Atrial fibrillation is associated with an increased risk of stroke and systemic embolism [45]. In the
double-blind Rivaroxaban Once Daily Oral Direct FXa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. The risk of major bleeding was similar between the groups, however, intracranial and fatal bleeding occurred less frequently in the rivaroxaban group [46,47].
⦁ Rivaroxaban in cardiovascular disease
The COMPASS trial was an international, multicenter, double-blind, double-dummy, randomized trial that compared the use of rivaroxaban with or without aspirin to aspirin alone in 27,395 patients with a history of stable atherosclerotic vascular disease. Patients assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes, with the expense of more major bleeding events, than those assigned to aspirin alone [48-50].

⦁ Pediatric clinical use of rivaroxaban
Rivaroxaban for the treatment and secondary prevention of DVT has been evaluated in the EINSTEIN-Jr program. A summary of the EINSTEIN-Jr program is presented in table 2. Additionally, there are case reports of its use in other clinical settings.
⦁ Rivaroxaban for pediatric VTE & the EINSTEIN-Jr program
Pediatric anticoagulation guidelines for VTE are mostly extrapolated from adults [51]. However, the suggested treatment duration of 6 weeks to 3 months for cerebral vein thrombosis, renal vein

 

thrombosis and central venous catheter-related VTE is based on expert opinion (Grade 2C recommendations) [1].
The EINSTEIN-Jr phase 3 trial compared the efficacy and safety of bodyweight-adjusted rivaroxaban regimens with those of standard anticoagulation in 500 children with acute VTE. Children allocated to rivaroxaban received a bodyweight-adjusted 20 mg equivalent-dose, targeting the therapeutic exposure range of young adults. Rivaroxaban was given either once, twice or thrice daily, according to bodyweight (Once daily for children with bodyweights of ≥30 kg, twice-daily for bodyweights of 12–<30 kg and
thrice-daily for bodyweights of, <12) and administered as immediate release filmcoated tablets or as suspension.
Rivaroxaban treatment resulted in a similarly low risk of recurrent VTE and clinically relevant bleeding, compared with standard therapy with heparins and VKAs. Rate of recurrent VTE with rivaroxaban was 1.2% compared to 3% with standard therapy. Furthermore, rivaroxaban treatment resulted in a greater reduction in thrombus mass as demonstrated on follow-up imaging studies. Children receiving rivaroxaban did not experience major bleeding events [52]. Subsequently, Young and colleagues reported the EINSTEIN-Jr phase 3 dose-exposure-response evaluation. They concluded that body-weight adjusted pediatric rivaroxaban regimens with either tablets or suspension are therapeutic alternatives for VTE in children [25].
⦁ Rivaroxaban thromboprophylaxis post-Fontan procedure – The UNIVERSE study
Single Ventricle physiology represents 10% of congenital heart disease. Fontan procedure is the final step of a 3-stage palliative procedure commonly performed in children with single ventricle physiology, however, thrombosis is a potential complication [53]. Type and duration of anticoagulant treatment are extrapolated from other clinical settings. Current guidelines recommend the use of either aspirin or UFH followed by VKAs for thromboprophylaxis in children undergoing the Fontan procedure, nonetheless, these are primarily expert opinions based on limited literature [1].
Monagle and colleagues conducted a prospective study of prophylactic anticoagulation in Fontan patients, and observed a high incidence of VTE, with the highest incidence in the first 6 month after the procedure, despite thromboprophylaxis with either aspirin or UFH/Warfarin [54].
The UNIVERSE study [53] is a prospective, open label multicenter study of rivaroxaban in children 2-8 years undergoing the Fontan procedure. Part A which aimed to assess rivaroxaban pharmacokinetics, pharmacodynamics, safety and tolerability has been completed with 12 children enrolled, while part B which aims to compare the safety and efficacy of rivaroxaban versus ASA is ongoing. All results are pending.

 
⦁ Additional potential pediatric use of rivaroxaban as suggested by case reports
⦁ Thromboprophylaxis in congenital protein C, protein S and antithrombin deficiencies
Congenital protein C (PC) deficiency is characterized by uncontrolled thrombin generation. Warfarin has been used to prevent secondary thromboembolism, however its use reduces PC levels rapidly before decreasing coagulation factors II and X, thus potentially leading to thrombosis and skin necrosis. Menon and colleagues reported a 13 year old girl who presented with extensive inferior vena cava and proximal lower extremity DVT due to May-Thurner syndrome. Following catheter thrombolysis and left iliac vein stenting anticoagulant treatment with Warfarin and concomitant UFH was initiated. Thrombophilia workup revealed PC deficiency with level <10%. Warfarin was withheld and LMWH was started as an alternative anticoagulant. The patient desired to discontinue injections and switch to an oral agent, thus rivaroxaban treatment was initiated. Therapy was tailored both by pharmacokinetics and thrombin generation, and the patient responded well with no prominent side effects [55].
Martineli and colleagues reported a 6-year-old girl with severe protein S (PS) deficiency due to a homozygous mutation and recurrent episodes of skin necrosis. She developed purpura fulminans at birth and catheter-related venous thrombosis complicated by massive pulmonary embolism at the sixth day of life. Long-term oral anticoagulant therapy with a VKAs was started with a therapeutic range of the international normalized ratio (INR) between 2.0 and 3.0. Despite treatment she experienced recurrent episodes of skin necrosis; The warfarin-related reduction in PC and severe PS deficiency induced a hypercoagulable state outweighing the anticoagulant efficacy achieved by the inhibition of the procoagulant factors II, VII, IX, and X. The patient was switched to rivaroxaban with the disappearance of skin necrosis at 1 year of follow-up [56] .
Van Bruwaene and colleagues presented a case of a 12 years old girl with severe obesity that presented with bilateral DVT, extending to the proximal inferior vena cava with extensive collateral circulation.
Despite high doses of LMWH, anti-FXa activity remained undetectable. Workup revealed antithrombindeficiency with levels as low as 26% (reference values 90-110%), and homozygosity to the Budapest III mutation. It was then decided to start VKA treatment, and bridge the period until achievement of therapeutic levels with rivaroxaban 20 mg/d, based on adult dosing. Rivaroxaban was stopped after 5 days, when the INR was in the therapeutic range, suggesting rivaroxaban may represent an alternative to heparins in these patient with AT deficiency as it exerts its effect independently of AT [57].
⦁ Treatment of heparin-induced thrombocytopenia (HIT)

 

HIT is a life-threatening immune-mediated complication of UFH and LMWH therapy, associated with increased in vivo thrombin generation and thrombotic complications. The risk for HIT correlates with the cumulative dosage of heparin exposure [58,59]. The prevalence of HIT appears lower in children compared with adults [60], however, it may complicate anticoagulant treatment in critically ill pediatric patients requiring mechanical circulatory support for respiratory or cardiac failure [61] and children undergoing the Fontan procedure [58]. HIT requires the cessation of any heparin treatment, and initiation of an alternative anticoagulant, typically a direct thrombin inhibitor or fondaparinux followed by VKAs [62].
Rivaroxaban may represent a treatment option for patients with HIT, however data is mostly supported by case reports [63,64] and a case series [65]. In a multicenter, single-arm, prospective cohort study of adult patients with suspected or confirmed HIT, platelet recovery was seen in 9/10 HIT-positive patients, while thrombosis was encountered in one patient [66]. To date, there is no data regarding rivaroxaban treatment for pediatric HIT.
⦁ Nephrotic syndromes
Patients with nephrotic syndromes are prone to venous thrombotic complications [67,68]. The exact pathophysiology of the thrombotic risk remains incompletely characterized, but may include urinary loss of antithrombin and plasminogen, in addition to an imbalance in procoagulant and anticoagulant factors [67,68]. In addition to VTE treatment, these patients may benefit from anticoagulant prophylaxis. Zhang and colleagues conducted a small randomized study comparing rivaroxaban and LMWH for the treatment of VTE in adult patients with nephrotic syndromes [67]. Effectiveness of rivaroxaban was comparable to that of standard LMWH and VKAs. Sexton and colleagues reported 2 adult patients with a nephrotic syndrome who were treated with another DOAC, apixaban, as primary prophylaxis [68]. Since the activity of rivaroxaban is independent of antithrombin activity, its use in patients with nephrotic syndrome is particularly appealing.

⦁ Expert opinion
Thrombosis in children is rare, yet the incidence of pediatric VTE has been increasing over the past decade. This is attributable in part to increased recognition, as well as the widespread use of CVCs. Other risk factors for thrombosis in children include specific chemotherapeutic agents, for example L- asparaginase in children with acute lymphoblastic leukemia, hereditary thrombophilia and congenital vascular malformations. The majority of pediatric VTE cases are triggered by transient and removable risk factors, which allow for a shorter duration of therapy.

 

Management of VTE in children is highly complex and highly individualized. The current approved therapies for children include parenteral UFH and LMWH which are troublesome for most pediatric patients due to their mode of administration. VKAs which have unpredictable pharmacokinetics and numerous food and drug interactions require frequent INR monitoring.
There is an unmet need for an oral anticoagulant with favorable safety and efficacy which does not require frequent monitoring.
Rivaroxaban, a direct FXa inhibitor, offers the convenience of oral administration and predictable pharmacokinetics across a wide range of adult and pediatric patients. It has been approved and prescribed for various indications in adults for nearly a decade, providing reliable, efficient and safe anticoagulation.
The vast data from the EINSTEIN-Jr program confirm the safety and efficacy of body-weight adjusted pediatric rivaroxaban regimens for the treatment of VTE in children, while additionally supporting its consistent pharmacokinetic profile, with comparable drug levels to adult patients.
It may provide physicians with the option to treat children with bodyweight-adjusted oral rivaroxaban regimens, administered as tablet or suspension, without the need for laboratory monitoring or dose adjustments, sparing the inconvenience associated with frequent blood sampling and subcutaneous injections.
These pediatric rivaroxaban regimens represent an appealing therapeutic alternative for VTE in children. Thus, it is our opinion that rivaroxaban should be offered to pediatric VTE patients both with and without a hereditary thrombophilia for the acute phase treatment and long-term secondary prophylaxis following its registration.
Other DOACs are currently under investigation in pediatric patients as well, including for indications that have not been studied in adults, such as CVC-related thrombosis or congenital heart disease.
Dabigatran, apixaban and edoxaban are being compared with standard of care for the treatment of acute VTE in children. Apixaban is being studied for VTE prevention in pediatric leukemia and lymphoma patients with CVCs undergoing treatment with L-asparaginase. Betrixaban is under study as thromboprophylaxis in neonates/pre-terms with umbilical catheters. Additionally, apixaban and edoxaban are being studied for various cardiac indications in children. These investigation plans also include pharmacokinetic and pharmacodynamic evaluation and may represent additional therapeutic options in the near future. We discourage the off-label use of DOACs in pediatric patients due to insufficient safety and efficacy data, however we advocate enrollment of children and adolescents into ongoing clinical trials with DOACs.

 

Additional research should explore further indications for anticoagulant treatment in pediatric patients, and these should include treatment of thrombosis at unusual sites (e.g. cerebral sinus vein thrombosis), extended thromboprophylaxis in children with congenital heart defects, and treatment of heparin- induced thrombocytopenia.
In conclusion, rivaroxaban offers the convenience of oral administration and predictable pharmacokinetics. The safety and efficacy of body-weight adjusted pediatric rivaroxaban regimens for the treatment of VTE in children has been recently established through the EINSTEIN-Jr program. Thus, rivaroxaban should be offered for the treatment of VTE in pediatric patients both with and without an inherited thrombophilia.

Funding
This paper was not funded.
Declaration of interest
W Ageno received honoraria from Boehringer Ingelheim, Bayer Pharmaceuticals, BMS-Pfizer and Daiichi- Sankyo. W Ageno also received research support from Bayer Pharmaceuticals and Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

 

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Papers of special note have been highlighted as:
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⦁ Gerotziafas GT, Elalamy I, Depasse F, et al. In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct Factor Xa inhibitor rivaroxaban. J Thromb Haemost. 2007;5:886–8
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⦁ Samama MM. Which test to measure the anticoagulant effect of rivaroxaban: the anti-Factor Xa assay. J Thromb Haemost. 2013;11:579–80
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⦁ Douxfils J, Ageno W, Samama CM, et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost. 2018;16(2):209-19
⦁ Kubitza D, Willmann S, Becka M, et al. Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study. Thromb J. 2018;16:31. Published 2018 Dec 4. doi:10.1186/s12959-018-0186-0
⦁ Monagle P, Lensing AWA, Thelen K, et al. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies. Lancet Haematol. 2019;6(10):e500-9. doi:10.1016/S2352-3026(19)30161-9 **
A key study in the EINSTEIN-Jr program evaluating weight-adjusted rivaroxaban regimens for the treatment of pediatric VTE.
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⦁ Young G, Lensing AWA, Monagle P, et al. Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation [published online ahead of print, 2020 Apr 4]. J Thromb Haemost. 2020;10.1111/jth.14813. doi:10.1111/jth.14813 * A key study in the EINSTEIN-Jr program which provides essential pharmacokinetic data.
⦁ Chhim RF, Shelton CM, Christensen ML. Recent new drug approvals, part 2: drugs undergoing active clinical studies in children. J Pediatr Pharmacol Ther. 2013;18(1):14-38. doi:10.5863/1551-6776- 18.1.14
⦁ Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017;376(13):1211-22. doi:10.1056/ NEJMoa1700518
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⦁ Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-944. doi:10.1182/bloodadvances.2019000975
⦁ Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-75. doi:10.1056/NEJMoa0800374

 

⦁ Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-9. doi:10.1016/S0140-6736(08)60880-6
⦁ Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-86. doi:10.1056/NEJMoa076016
⦁ Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676):1673-80. doi:10.1016/S0140-6736(09)60734-0
⦁ Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation.
2007;116(2):180-7. doi:10.1161/CIRCULATIONAHA.106.668020
⦁ Buller HR, Lensing AW, Prins MH, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood. 2008;112(6):2242- 7. doi:10.1182/blood-2008-05-160143
⦁ Cohen AT, Bauersachs R. Rivaroxaban and the EINSTEIN clinical trial programme. Blood Coagul Fibrinolysis. 2019;30(3):85-95. doi:10.1097/MBC.0000000000000800
⦁ EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510. doi:10.1056/NEJMoa1007903
⦁ EINSTEIN–PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97. doi:10.1056/NEJMoa1113572
⦁ Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report [published correction appears in Chest. 2016 Oct;150(4):988]. Chest.
2016;149(2):315-52. doi:10.1016/j.chest.2015.11.026
⦁ Young AM, Marshall A, Thirlwall J, et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 2018;36(20):2017-23. doi:10.1200/JCO.2018.78.8034
⦁ Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018;378(7):615-24. doi:10.1056/NEJMoa1711948

 

⦁ Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer- associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost.
2018;16(9):1891-94. doi:10.1111/jth.14219
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⦁ Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91. doi:10.1056/NEJMoa1009638
⦁ Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) [published correction appears in Circulation. 2018 Dec 18;138(25):e783]. Circulation. 2014;130(2):138-46. doi:10.1161/CIRCULATIONAHA.113.005008
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⦁ Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391(10117):219-29. doi:10.1016/S0140-6736(17)32409-1
⦁ Branch KR, Probstfield JL, Eikelboom JW, et al. Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease. Circulation. 2019;140(7):529-37. doi:10.1161/CIRCULATIONAHA.119.039609
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⦁ Male C, Lensing AWA, Palumbo JS, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3
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A key study in the EINSTEIN-Jr program evaluating weight-adjusted rivaroxaban regimens for the treatment of pediatric VTE, and the only randomized control trial evaluating the safety and efficacy of rivaroxaban in the pediatric population.
⦁ Pina LM, Dong X, Zhang L, et al. Rivaroxaban, a direct Factor Xa inhibitor, versus acetylsalicylic acid as thromboprophylaxis in children post-Fontan procedure: Rationale and design of a prospective, randomized trial (the UNIVERSE study). Am Heart J. 2019;213:97-104. doi:10.1016/j.ahj.2019.04.009

 

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Table 1: Plasma concentrations of rivaroxaban, comparison between adults and children
Population studied Pharmacokinetic parameters, geometric mean/%CV (range)
AUC
(0< 24)ss (µg*h/L) Ctrough,ss
(µg/L) Cmax,ss
(µg/L)
Adult DVT treatment Rivaroxaban 20 mg OD [20] 2,814
(1,702 – 4,773) 26
(6 – 87) 270
(180 – 419)
Children aged 6< 11 y
Tablet formulation [27] 1,960
(1,310 – 3,790) 14.6
(7.08 – 53.6) 254
(189 – 395)
Children aged 6< 11 y
Oral suspension [27] 1,960
(1,350 – 4,390) 15.8
(8.38 – 44.3) 243
(189 – 487)
Children aged 12< 17 y
Tablet formulation [27] 2,170
(1,320 – 4,490) 21.4
(8.78 – 78.5) 242
(158 – 383)
Children aged 12< 17 y
Oral suspension [27] 2,050
(1,140 – 4,540) 19.7
(7.74 – 74.9) 232
(131 – 380)

AUC24 area under the plasma concentration-time curve from time 0 to 24 h, Cmax maximum plasma concentration, Ctrough minimum plasma concentration, DVT deep vein thrombosis, OD once daily

 

Table 2: The EINSTEIN-Jr program

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
bolism
LMW
Einstein Jr phase Phase 1 [24] Phase 2 [25] Phase 3 [52]
Number of patients 59
Single arm 93
Single arm 500
335 rivaroxaban arm
165 standard anticoagulation
Age 6 months – 17 years Birth – 17 years Birth – 17 years
Indication VTE VTE VTE
Therapy Rivaroxaban Rivaroxaban Rivaroxaban,
standard anticoagulation LMWH/VKAs
Treatment duration Single dose 30 days,
7 days in children younger than 6 months 3 months,
1 month if catheter- related VTE in children
< 2 years
Main findings No significant adverse events following single- dose administration Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children.
Treatment regimens were confirmed for children with bodyweights ≥ 20 kg and predicted for bodyweights < 20 kg to be evaluated in the phase
3 trial Similarly low risk of recurrent VTE and clinically relevant bleeding, compared with standard therapy

H low molec ular weigh t hepari n, VKAs
vitami n K antago nists, VTE
Venou s throm boem

 

Table 3: Efficacy and safety outcomes in the EINSTEIN-Jr phase 3 trial

Rivaroxaban Comparator Hazard ratio
(95% CI)
Efficacy population
Number of
participants assessed 335 165
Primary efficacy outcome 4 (1%) 5 (3%) 0.4 (0.11-1.41)
Primary efficacy outcome or progression of thrombosis on repeat
imaging 5 (1%) 6 (4%) 0.41 (0.12-1.36)
Primary efficacy outcome or major
bleeding 4 (1%) 7 (4%) 0.3 (0.08-0.93)
Mortality
Cancer-related 1 (< 1%) 0
1 0
Safety population
Number of participants assessed 329 162
Major bleeding or
CRNMB 10 (3%) 3 (2%) 1.58 (0.51-6.27)
Major bleeding
Pulmonary Intracranial 0 2 (1%)
0 1
0 1
CRNMB GI
Urogenital Skin
Nasal or mouth 10 (3%) 1 (< 1%)
4 0
2 0
1 0
3 1

Adapted from Male C, Lensing AWA, Palumbo JS, et al. [52] CRNMB clinically relevant non-major bleeding, GI gastrointestinal