Keywords
pediatric medicine - thrombosis - heparins - vitamin K antagonists - direct oral anticoagulants
Schlüsselwörter
Kinderheilkunde - Thrombose - Heparin - Vitamin-K-Antagonisten - direkte orale Antikoagulanzien
Introduction
There is a strong and increasing need for new anticoagulants in pediatric medicine.
For this, there are two reasons. The first reason is the progress in pediatric intensive
care. In children, thrombotic events occurred almost exclusively as complications
of underlying diseases and/or their treatment.[1] Most of the affected pediatric patients had at least one severe underlying disease,
such as congenital heart defects or cancer among other. Raffini et al showed a 70%
increase in thrombotic events in children in U.S. hospitals for the years 2001–2007.[1] As thrombotic event become more common in pediatric clinical care, the need for
anticoagulation suitable for children is also growing. The second reason is that the
current standard of care (SoC) anticoagulant drugs mostly used in children, including
unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and vitamin K antagonists
(VKAs), have several disadvantages.
Standard of Care in Pediatric Anticoagulation
Standard of Care in Pediatric Anticoagulation
The SoC in pediatric anticoagulation consists mainly of three types of drugs: UFH,
LMWH, and VKAs like phenprocoumon and warfarin. Currently available recommendations
on the use of these anticoagulants include the ones by Monagle et al for the American
College of Chest physician,[2] Monagle et al for the American Society of Hematology,[3] and Chalmers et al for the British Society for Haematology.[4]
Heparins in Children
Both types of heparins, UFH and LMWH, need to be administered parenterally. Frequent
injections cause stress and anxiety, especially in small children, making subsequent
administration increasingly difficult.[5] Heparins exert only an indirect anticoagulant effect by enhancing the action of
endogenous antithrombin. However, antithrombin levels are often too low in neonates
and critically ill children.[6]
Unfractionated Heparin in Children
Since the pharmacokinetic (PK) and pharmacodynamic (PD) properties of UFH in children
are strongly influenced by their age and health status, UFH effects show a high variability
and therefore require intensive monitoring via intravenous access, which is very inconvenient
for children.[7] This monitoring is based on the interpretation of two assays: activated partial
thromboplastin time (aPTT) and heparin assay (anti-Xa). However, due to the high variability
of their values, the interpretation of these assays is limited, especially in severely
ill children.[8] Target therapeutic levels are extrapolated from the values of adult patients, because
there are no reference values for children.[9]
Moreover, heparin-induced thrombocytopenia (HIT) may occur. In 2012, a systematic
review found an HIT incidence of 2.3 to 3.7% in children receiving UFH treatment.[10] Nevertheless, UFH has a short half-life, and with protamine sulfate, an antidote
is available[11]; therefore, it still has its place in short-term prophylaxis (procedures, intensive
care, and surgery) and in the treatment of acutely ill children at risk of bleeding.[12]
Low-Molecular-Weight Heparin in Children
The PD and PK properties of LMWH show less variance than those of UFH. It has a longer
half-life. Though the incidence of HIT with LMWH is probably lower than with UFH,
the exact numbers are unknown.[13] LMWH requires twice-daily subcutaneous administration and often monitoring of anti-Xa
levels via intravenous access, with the same monitoring challenges as UFH. Because
of risk of liver dysfunction and bone deterioration in children undergoing long-term
LMWH therapy, it is suggested to carefully monitor bone density and liver function
after 3 months of use.[13] LMWHs have more stable, though age-dependent, PK/PD properties; require less frequent
monitoring; have longer half-lives than UFH; and are therefore well-suited for longer-term
use and the outpatient setting in children.[12]
Vitamin K Antagonists in Children
VKAs like Sintrom, Marcumar, and warfarin have only a narrow therapeutic range.[14] In 2012, a pediatric retrospective study with 4,883 patients identified independent
risk factors such as Asian race, drug interactions, mitral value replacement, and
length of hospital stay for readmission of patients to hospitals within 30 days due
to warfarin-associated bleeding.[14] VKAs take about 3 days to build their anticoagulant effect, which is often too slow
in the context of intensive care.[15]
Long-term use of VKAs requires international normalized ratio (INR) monitoring and
therefore frequent visits to a healthcare provider, which is inconvenient and time
consuming. Infants and many small children have difficulties to swallow pills. Though
VKAs have the advantage of oral administration, they are available only as pills,
not as liquids. VKAs show interactions with vitamin K–containing foods. This causes
problems, especially for infants, because breast milk contains little vitamin K and
also because breast milk substitutes and parenteral nutrition for infants are usually
fortified with vitamin K.[16]
[17]
Eight Criteria for New Anticoagulants in Pediatric Care
Eight Criteria for New Anticoagulants in Pediatric Care
The increasing need for new anticoagulants in pediatric care may be specified as a
need for anticoagulant drugs, which meet the following eight criteria, compared with
current anticoagulation:
-
Exert their effect directly, not via antithrombin.
-
Have a faster onset than VKAs.
-
Have more predictable PKs and PDs.
-
No or minimal need for laboratory monitoring.
-
Administer orally, preferably in liquid form.
-
Have fewer interactions with drugs and foods.
-
Have a comparable or higher effectiveness and safety.
-
Are approved for use in children by regulatory authorities such as the European Medicines
Agency (EMA) and the U.S. Food and Drug Administration (FDA).
Pediatric Investigation Plans for Direct Oral Anticoagulants
Pediatric Investigation Plans for Direct Oral Anticoagulants
Direct oral anticoagulants (DOACs) such as dabigatran (Pradaxa), rivaroxaban (Xarelto),
apixaban (Eliquis), and edoxaban (Lixiana) have been shown in numerous studies to
meet the first seven of the above eight criteria for the treatment of thrombosis,
but so far only in adult patients.[13]
[14]
To address this, “pediatric investigation plans” (PIPs) for dabigatran, rivaroxaban,
apixaban, and edoxaban have been developed and published by the EMA and pharmaceutical
companies.[18]
These PIPs describe in detail how age-appropriate pediatric formulations are to developed,
to ensure reliable and accurate administration of the medicine to children of different
ages, and what kind of studies have to be done for this.[12]
The necessary phase I to III studies have already been completed for dabigatran and
rivaroxaban and only the phase IV postmarketing studies are missing, while the PIPs
for edoxaban and apixaban are still ongoing. Therefore, this clinical review will
focus on dabigatran and rivaroxaban.
Aim of this Review
To evaluate the extent to which DOACs will be able to meet the growing need for new
anticoagulation agents in pediatric care, we will describe the latest results of the
current pediatric studies on rivaroxaban and dabigatran.
Characteristics of DOACs in Adults
The DOACs can be divided into two main classes: direct oral thrombin inhibitors and
direct oral factor Xa inhibitors. Dabigatran belongs to the first class, and all other
DOACs belong to the second class.
All DOACs are small molecules, which were artificially designed to specifically and
reversibly inhibit certain coagulation factors in the coagulation pathway and are
orally administered. Anticoagulant effects do not rely on endogenous cofactors; hence,
they are called “direct” anticoagulants.[12]
Pharmacological Characteristics of DOACs in Adults
The pro-drug dabigatran etexilate differs from dabigatran by an ethyl group at the
carboxylic acid and a hexyloxycarbonyl side chain at the amidine. In the gastrointestinal
tract, dabigatran etexilate is converted into the active metabolite, dabigatran.[19] In a study on 40 male adults, dabigatran etexilate onset was fast, the peak plasma
concentration was reached within 2 hours of administration, and half-life was at 8
to 10 hours.[20] As Albisetti[21] pointed out, studies have shown that renal function has the most important, clinically
relevant impact on dabigatran exposure.[22]
[23]
In a study on 108 healthy adults, peak plasma levels of rivaroxaban after a single
escalating oral dose were observed at 0.5 to 0.6 hours by the liquid and at 1.5 to
3.0 hours for the tablet formulation, with a half-life of 3.24 to 4.15 hours for the
liquid solution and 7 to 10 hours for the tablets.[24]
Drug–Drug Interaction of DOACs
The currently available data on drug–drug interaction (DDI) of DOACs come from studies
in adults only.
Interaction of Dabigatran in Adults
Because of the increased risk of bleeding, dabigatran should not be coadministered
with any other anticoagulant/antiplatelet drugs, such as aspirin and diclofenac.[25] Clopidogrel increases the absorption rate of dabigatran; therefore, it should also
not be coadministered.[26]
According to a review on drug interaction with DOACs by Di Minno et al,[27] both rivaroxaban and dabigatran interact with drugs that are inducers or inhibitors
of cytochrome P450 isoenzyme (CYP3A4) or of P-glycoprotein (P-gp). Therefore, in dabigatran
users, there are at least eight drugs to be avoided: carbamazepine, cyclosporine,
dronedarone, ketoconazole, verapamil, phenytoin, rifampicin, and St. John's worth.
Drugs to be used with caution in dabigatran users are quinidine, quinine, and verapamil.
Proton-pump inhibitors impair the effect of dabigatran.[27]
Interactions of Rivaroxaban in Adults
In contrast to dabigatran, rivaroxaban can in principle be coadministered with aspirin[28] and clopidogrel,[29] although the later does prolong the mean bleeding time of patients treated with
rivaroxaban.[30] Any other anticoagulant drug should not be coadministered with rivaroxaban because
of the increased bleeding risk.[26]
[31] Simultaneous treatment of rivaroxaban with strong inhibitors of both CYP3A4 and
P-gp should also be avoided, because they affect the rivaroxaban–plasma concentrations.[32]
There are at least 11 drugs that should be avoided in rivaroxaban users: amiodarone,
chloramphenicol, clarithromycin, cyclosporine, dronedarone, itraconazole, ketoconazole,
quinidine, quinine, ritonavir, and verapamil. The following five drugs should be used
with caution in rivaroxaban users: carbamazepine, hypericum, perforatum, phenytoin,
and rifampicin. The following six drugs impair the effect of rivaroxaban: carbamazepine,
hypericum, perforatum, phenobarbital, phenytoin, and rifampicin.[27]
DOACs–Food Interaction
The little knowledge of DOACs–food interaction (DFI) that we already have is based
on the modulation of P-gp activity, which can either enhance or inhibit the effectiveness
of DOACs and comes from three sources: (1) pharmacological studies in adults, (2)
animal studies, (3) in vitro studies. According to these, the following 13 foods inhibit
effects of DOACs: ginkgo biloba, berberine, black pepper, grape fruit, apigenin, rutin,
capsaicin, lemon, soybean extract, notoginsenoside R1, curcumin, green tea, fisetin,
and honokiol. The following eight foods are considered inducers of effects of DOACs:
St. John's wort, quercetin, Scutellaria, soy milk and miso, sucralose, licorice root, genipin, and mango.[27]
Results of Current Pediatric Trials on DOACs
Results of Current Pediatric Trials on DOACs
We searched pediatric studies on DOACs on clinicaltrials.gov[33] and current literature on the findings of pivotal studies for DOACs in children.
We found that 30 pediatric DOACs studies have been registered so far; 18 of these
studies have been completed, and 13 of these had their results published. We could
not find any published pivotal studies on apixaban and edoxaban.
For the evaluation of the efficacy and safety of pediatric DOACs and thus for the
implementation of the PIPs[34] of the EMA mentioned at the beginning, there were three large, multinational, and
thus multicenter studies: the DIVERSITY trial for dabigatran[35] and the EINSTEIN and the UNIVERSE trials for rivaroxaban.[34]
[36] In addition, there was also a single-arm phase III study assessing dabigatran for
extended secondary venous thromboembolism (VTE) prevention.[37]
In further DOACs studies they identified, Branstetter et al counted 16 neonates, 152
non-neonatal infants (>30 days to <2 years), 351 children, and 488 adolescents.[38]
In the following summary of the results of the three trials, we will describe only
the pivotal phase III trials, that is, the trials that ultimately led to the approval
of both dabigatran and rivaroxaban for the treatment of children. In all three trials,
there were two types of endpoints: primary endpoints on the efficacy of the two DOACs
compared with standard therapy and secondary endpoints related to adverse effects
and the need for therapy adjustments.[35]
[36]
[39]
The DIVERSITY and EINSTEIN trials were in children with acute VTE, and the UNIVERSE
trial was in children post Fontan procedure.
DIVERSITY Trial
The randomized, controlled, open-label, multicenter, phase IIb/III DIVERSITY trial
represented the execution of a PIP jointly developed by the EMA and the FDA and was
conducted in 65 centers in 26 countries.[35]
In the phase III study, after enrolment, eligibility screening was performed during
initial parenteral anticoagulation. Subsequently, children were randomized in a 1:2
ratio (standard treatment vs. dabigatran) to receive either standard treatment or
dabigatran. The SoC was defined as treatment with LMWHs, UFH, VKAs, or fondaparinux,
at the discretion of the investigators and standard clinical practice. The patients
were assigned to three age groups: birth to 2 years, 3 to 12 years, and 13 to 18 years.
The doses in the dabigatran group were extrapolated from the usual doses of adult
patients based on the weight and age of the children. Extrapolations were based on
Hayton's nomogram, in which estimated renal function is derived from age and weight
to achieve similar exposure to dabigatran-treated adults.[40] Ninety patients were in the SoC control group and 177 patients were in the dabigatran
group.
The study results in all three primary endpoints: (1) complete thrombus resolution,
(2) freedom from recurrent VTE, and (3) freedom from VTE-related death—were at least
equal in the dabigatran group comparing to SoC.[35]
As shown in [Table 1], almost all relative numbers of adverse events were lower in the dabigatran group,
except for the relative and absolute numbers of adverse events leading to treatment
discontinuation.
Table 1
Summary of adverse events in the DIVERSITY trial, according to Halton et al[35]
|
Standard-of-care group, n = 90
|
Dabigatran group,a
n = 176
|
|
Mild
|
Moderate
|
Severe
|
Mild
|
Moderate
|
Severe
|
|
Children with any adverse event
|
31 (34%)
|
21 (23%)
|
8 (9%)
|
89 (51%)
|
33 (19%)
|
13 (7%)
|
|
Children with serious adverse eventsa
|
0
|
10 (11%)
|
8 (9%)
|
3 (2%)
|
8 (5%)
|
11 (6%)
|
|
Leading to death
|
0
|
0
|
2 (2%)
|
0
|
0
|
0
|
|
Life-threatening
|
0
|
1 (1%)
|
1 (1%)
|
0
|
0
|
2 (1%)
|
|
Requiring hospitalization
|
0
|
4 (4%)
|
7 (8%)
|
2 (1%)
|
5 (3%)
|
10 (6%)
|
|
Prolonged hospitalization
|
0
|
1 (1%)
|
0
|
0
|
2 (1%)
|
3 (2%)
|
|
Other
|
0
|
5 (6%)
|
1 (1%)
|
2 (1%)
|
1 (1%)
|
3 (2%)
|
|
Children with adverse events of special interests
|
0
|
0
|
1 (1%)
|
1 (1%)
|
0
|
1 (1%)
|
|
Children with adverse events leading to treatment discontinuation
|
0
|
1 (1%)
|
2 (2%)
|
5 (3%)
|
3 (2%)
|
5 (3%)
|
The DIVERSITY trial was thus able to prove that dabigatran is at least equal to the
SoC in terms of efficacy and safety.
EINSTEIN Trial
The EINSTEIN-Jr phase III study compared the efficacy and safety of body weight–adjusted
rivaroxaban treatment regimens with those of standard anticoagulation in 500 children
with acute VTE. Children in the rivaroxaban group received a body weight–adjusted
20 mg equivalent dose, which corresponds to the therapeutic exposure range of young
adults. Rivaroxaban was administered once daily in children weighing more than 30 kg,
twice daily in children weighing 12 to 30 kg, and three times daily in children weighing
less than 12 kg. Young children were given a specially developed liquid formulation,
while older children were given film-coated tablets.[41]
[Table 2] summarizes the efficacy and safety outcomes of the EINSTEIN-Jr phase III trial.
Table 2
Efficacy and safety outcomes of the EINSTEIN-Jr phase 3 trial, according to Cohen
et al[41]
|
Rivaroxaban
|
Comparator
|
Hazard ratio (95% CI)
|
|
Efficacy population
|
|
Number of patients assessed
|
335
|
165
|
|
|
Primary efficacy outcome
|
4 (1%)
|
5 (3%)
|
0.4 (0.11–1.41)
|
|
Primary efficacy outcome or progression of thrombosis 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%)
1
|
0
0
|
|
|
Safety population
|
|
Number of patients assessed
|
329
|
162
|
|
|
Major bleeding or CRNMB
|
10 (3%)
|
3 (2%)
|
1.58 (0.51–6.27)
|
|
Major bleeding
|
0
|
2 (1%)
|
|
|
Pulmonary
|
0
|
1
|
|
Intracranial
|
0
|
1
|
|
CRNMB
|
10 (3%)
|
1 (<1%)
|
|
|
GI
|
4
|
0
|
|
Urogenital
|
2
|
0
|
|
Skin
|
1
|
0
|
|
Nasal or mouth
|
3
|
1
|
Abbreviations: Cl, confidence interval; CRNMB, clinically relevant non-major bleeding.
The successful implementation of the DIVERSITY phase III study led to the approval
of dabigatran for use in children by the EMA in November 2020 and by the FDA in June
2021. Dabigatran is therefore the first and only approved oral direct thrombin inhibitor
for children in the European Union and the United States.[38]
[42]
[43]
[Table 3] summarizes the DIVERSITY and EINSTEIN phase III trials, according to Branstetter
et al.[38]
Table 3
Summary of the DIVERSITY and EINSTEIN phase III trials, according to Branstetter et
al[38]
|
Identifier
|
Indication
|
Intervention
|
Comparator
|
Age
|
Efficacy (n, %)
|
Safety (n, %)
|
|
Diversity phase 3 trial
|
VTE treatment
|
Dabigatran etexilate
|
SOC (LMWH, VKA, or fondaparinux)
|
Birth to < 18 y
|
Composite efficacy score[a]: 81 (46%) vs. 38 (42%); p = 0.001[b]; complete thrombus resolution: 81 (46%) vs. 38 (42%); recurrent VTE: 7 (4%) vs.
7 (8%), VTE-related mortality: 0 (0%) vs. 1 (1%)
|
MBEs[c]: 4 of 176 (2%) vs. 2 of 90 (2%), p = 0.95
|
|
EINSTEIN-Jr phase 3 trial
|
VTE treatment
|
Rivaroxaban
|
SOC (heparin, LMWH), fondaparinux or VKA
|
Birth to 17 y
|
Symptomatic recurrent VTE: 4 of 335 (1.2%) vs. 5 of 165 (3.0%), HR: 0.40 (95% CI:
0.11–1.41); mortality 1 (<1%) vs. 0 (0%)
|
MBEs: 0 (0%) vs. 2 (1%); MBEs or CRNMBEs[d]: 10 (3§) vs. 3 (2%), HR 1.58 (95% CI, 0.51–6.27)
|
Abbreviations: Cl, confidence interval; CRNMBEs, clinically relevant non-major bleeding
events, HR, hazard ratio; LMWH, low-molecular-weight heparin; MBEs, major bleeding
events, SOC; standard of care; VKA, vitamin K antagonist; VTE, venous thromboembolism.
a Composite efficacy score: combined endpoint of complete thrombus resolution, freedom
from recurrent VTE, and freedom from VTE-related mortality.
b
p-Value relates to a test for noninferiority.
c MBEs: fatal bleeding, clinically overt bleeding (decrease in hemoglobin of at least
20 g/L in a 24-hour period), bleeding that is retroperitoneal, pulmonary, intracranial,
or otherwise involves the central nervous system.
d Overt bleeding not meeting the criteria for major bleeding, but associated with medical
intervention, or unscheduled contact (visit or telephone call) with a physician, or
(temporary) cessation of study treatment, or discomfort for the child such as pain
or impairment of activities of daily life.
The rivaroxaban phase III trials were also successful and led to EMA approval for
VTE treatment in children, while FDA approval is still pending. Rivaroxaban was approved
by the EMA in January 2021.[44] In the United States, rivaroxaban was submitted for approval in children in June
2021.
UNIVERSE Trial
The UNIVERSE trial was a randomized, multicenter, two-part, open-label trial of rivaroxaban
for thromboprophylaxis in children following a Fontan procedure. The aim of the study
was to investigate the dosing regimen, safety, and efficacy. The first, single-arm
part of the UNIVERSE study assessed the PKs/PDs and safety of rivaroxaban in 12 participants.[41]
In the second part of the UNIVERSE trial, participants were randomized in a 2:1 ratio
(rivaroxaban vs. SoC) (open-label). A total of 112 participants were enrolled in the
study at 35 sites in 10 countries.
[Table 3] summarizes the bleeding events in the UNIVERSE phase III trial.
Therefore, the safety profile compared with the SoC was similar and, in the efficacy
results, a trend toward less thrombotic events could be demonstrated in the rivaroxaban
group ([Table 4]).[36]
Table 4
Summary of bleeding events in the UNIVERSE trial, according to McCrindle et al[36]
|
Bleeding events
|
Rivaroxaban
|
ASA
|
|
Part A (N = 12)
|
Part B (N = 64)
|
Part B (N = 34)
|
|
Participant with ≥1 on-treatment bleeding events
|
4 (33%)
|
23 (36%)
|
14 (41%)
|
|
Major bleeding
|
0
|
1 (2%)
|
0
|
|
Clinically relevant non-major bleeding
|
1 (8%)
|
4 (6%)
|
3 (9%)
|
|
Gastrointestinal
|
0
|
2 (3%)
|
1 (3%)
|
|
Lower gastrointestinal
|
0
|
2 (3%)
|
1 (3%)
|
|
Gingival
|
0
|
1 (2%)
|
0
|
|
Hematoma
|
0
|
0
|
1 (3%)
|
|
Skin
|
1 (8%)
|
1 (2%)
|
1 (3%)
|
|
Subconjunctival
|
0
|
0
|
1 (3%)
|
|
Trivial bleeding
|
3 (25%)
|
21 (33%)
|
12 (35%)
|
|
Epistaxis
|
0
|
7 (11%)
|
3 (9%)
|
|
Gastrointestinal
|
0
|
1 (2%)
|
1 (3%)
|
|
Lower gastrointestinal
|
0
|
0
|
1 (3%)
|
|
Upper gastrointestinal
|
0
|
1 (2%)
|
1 (3%)
|
|
Gingival
|
1 (8%)
|
3 (5%)
|
1 (3%)
|
|
Hematoma
|
2 (17%)
|
7 (11%)
|
2 (6%)
|
|
Skin
|
0
|
14 (22%)
|
8 (24%)
|
|
Vascular access site
|
0
|
2 (3%)
|
0
|
Notes: Percentages were calculated with the number of participants in each group as
denominator. Incidence is based on the number of subjects, not the number of events.
A participant may appear in different sites/categories. Safety analysis set: all participants
in part A who received at least 1 dose of study drug and all participants in part
B who were randomized and received at least 1 dose of study drug. The primary safety
outcome is major bleed that meets the International Society on Thrombosis and Haemostasis
definition: overt bleeding and associated with a decrease in hemoglobin of ≥2 g/dL;
leading to a transfusion of the equivalent of ≥2 units of packed red blood cells or
whole blood in adults; occurring in a critical site: intracranial, intraspinal, intraocular,
pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal;
or contributing to death. ASA indicates acetylsalicylic acid.[36]
The UNIVERSE study (thromboprophylaxis for children post–Fontan procedure) has been
submitted for approval in the United States. As this study was not part of the PIP
agreed with the EMA, it has not yet been submitted in the European Union.[45]
The dosing regimens for dabigatran and rivaroxaban in children and neonates are so
complex that their detailed presentation is beyond the scope of this review. We recommend
that you refer to the EMA- and FDA-approved package inserts for dosing information.
Ongoing Pediatric DOACs Studies
Ongoing Pediatric DOACs Studies
According to Branstetter et al,[38] there are currently nine ongoing phases I to IV pediatric DOACs studies, for rivaroxaban
(one phase III study), apixaban (five studies, phases I–IV), and edoxaban (three studies,
one phase I and two phase III studies). Therefore, it is at least possible that similarly
meaningful pivotal studies will be published in the future for apixaban and edoxaban
as for rivaroxaban and dabigatran.
Discussion
If we assess the described results from the pivotal studies on dabigatran and rivaroxaban
against the eight criteria for new anticoagulants in pediatrics described at the beginning,
it becomes clear that both dabigatran and rivaroxaban meet these eight criteria. Both
rivaroxaban and dabigatran:
-
Exert their effect directly, not via antithrombin.
-
Have a faster onset than VKAs.
-
Have more predictable PKs and PDs.
-
Require only minimal need for laboratory monitoring.
-
Are administered orally, and, for rivaroxaban, even in liquid form.
-
Have fewer interactions with drugs and foods, although data on DDI in children are
still missing and the DDI are more common than initially expected.
-
Have shown to probably have at least the same effectiveness and safety as the SoC,
although all of these studies lack in power to provide a high level of evidence.
-
Were therefore approved for use in children by regulatory authorities such as the
EMA and the FDA.
Although the number of severe bleeding events in the pivotal studies was small, the
lack of established reversal agents for pediatric patients in the case of a major
bleeding event or accidental/intentional overdose remains a major disadvantage of
DOACs in pediatric anticoagulation.[46] Promising candidates for this are currently the reversal agent idarucizumab/Praxbind
and Ondexxya/andexanet alfa—currently, there are just anecdotal reports of its use
in children; therefore, it can only be used off-label for the time being.[47] For rivaroxaban, the antidote Ondexxya (andexanet alfa) was granted EMA-approval
for use in adults in 2019.[48]
Though the three phase III trials we described here evaluated adverse events, we still
lack knowledge of possible pediatric DDI and DFI. From the discussion of the advantages
of DOACs over conventional anticoagulation in children, we already know that the responses
of the child and adult metabolism to anticoagulants are not always the same.[6] Although DDI and DFI studies are routinely conducted in drug development, due to
ethical, logistical, and methodological challenges, they are ever conducted only in
healthy adult volunteers, never in multimorbid and severely morbid pediatric patients.
Because pediatric DDI and DFI assessments are therefore lacking, adult DDI and DFI
data are extrapolated to pediatric patients.[49]
A systematic literature search on DDI reported in pediatrics but not in adults from
1945 to 2011 by Salem et al found 145 corresponding reports on 20 victim drugs and
25 interacting drugs. This study showed that children younger than 2 years were particularly
affected by pediatric DDI.[50]
None of the phase I to IV studies discussed in this review specifically looked for
pediatric DOACs-DDI, so we still know far too little about this and therefore need
to be particularly cautious in children younger than 2 years.
Events involving pediatric DOACs-DDI can and should be reported to the Bundesinstitut
für Arzneimittel und Medizinprodukte (BfArM) in Germany,[51] to EudraVigilance in the European Union,[52] and to the FDA's Adverse Event Reporting System (FAERS) in the United States.[53]
In their 2016 review of pediatric DOACs, von Vajna et al[46] concluded that it was too early to make recommendations. After reviewing these three
latest trials, it is now possible to recommend dabigatran etexilate and rivaroxaban
for the treatment of pediatric thrombosis—with the two caveats, there might be a lack
of reversal agents and the possible occurrence of DDI and DFI. These will probably
be avoided by taking the DDI and DFI into account, which we already know from adult
patients, animal experiments, and in vitro studies.
Finally, we would like to emphasize that, in our experience, the decision between
SoC and DOACs in the prevention and treatment of VTE in children still requires careful
clinical case-by-case evaluation, as the treatment situation in phase III trials differs
in some respects from everyday clinical practice.
