Sage Journals: Discover world-class research

Abstract

Background

Direct oral anticoagulants (DOACs) have been widely applied in adults for thrombosis prophylaxis. However, the effect of DOACs in pediatric patients with congenital or acquired heart diseases who need anticoagulation therapy remains unclear.

Methods

We systematically searched the databases of PubMed, Embase, and the Cochrane Library, as well as the ClinicalTrials.gov registry and the World Health Organization's International Clinical Trials Registry Platform until June 2024 to identify relevant randomized clinical trials (RCTs). If the number of included studies was less than 5, we performed a narrative review to assess the effect of DOACs in pediatric patients.

Results

Four studies were included. In the UNIVERSE study, thrombotic events occurred in 2% of the rivaroxaban group and 9% of the aspirin group, with bleeding events in 36% and 41%, respectively. The ENNOBLE-ATE study showed no thromboembolic events in the edoxaban group and 1.7% in the SOC group (rate difference: −0.07%, 95% CI: −0.22 to 0.07%). Major bleeding rates were similar (rate difference: −0.03%, 95% CI: −0.18 to 0.12%). The SAXOPHONE trial showed no thromboembolic events in either group and similar major bleeding rates (−0.8%, 95% CI: −8.1 to 3.3%). In the DIVERSITY trial, 81% of dabigatran patients achieved the primary outcome versus 59.3% in the SOC group (Odds ratio: 0.342, 95% CI: 0.081–1.229). No major bleeding occurred in either group.

Conclusion

Existing studies suggest that the use of DOACs hold promise as an effective and safe alternative for preventing and treating thromboembolism in pediatric patients with heart conditions.

Keywords

direct oral anticoagulants anticoagulation children cardiac disease review

Introduction

Pediatric heart disease encompasses a wide spectrum from congenital malformations to acquired conditions, predispose this vulnerable population to an increased risk of thromboembolism,^1,2 due to a number of mechanisms including altered hemodynamics, abnormality in vessel wall integrity, the need for surgical intervention and medical device, polycythemia and hyperviscosity, and hypercoagulable states. Notable examples include Fontan procedure/shunt-dependent single ventricle defect, Kawasaki disease with giant coronary aneurysms and intracardiac/intravascular devices.³ In order to prevent and treat thromboembolic events, anticoagulation therapy is recommended. The current Standard of care (SOC) including vitamin K antagonists (VKAs) and low-molecular-weight heparins (LMWHs) are however associated with certain limitations. The need for frequent dose monitoring due to narrow therapeutic window, possible drug and food interactions, and the lack of suitable pediatric formulation collectively impose significant burden and risk on the patients and healthcare providers. An effective, safe and easy-to-use alternative is therefore highly heralded.

Direct oral anticoagulants (DOACs) represent a newer class of anticoagulants that have transformed clinical practice since the approval of its first drug dabigatran by FDA for adult use in 2010.⁴ The paediatric population witnessed the advent of the first approved DOAC dabigatran in 2021 closely followed by rivaroxaban.⁵ The other two DOACs apixaban and edoxaban are less explored in children with relatively limited clinical data available, and therefore not yet approved for this population. DOACs offer several potential advantages compared to conventional treatments, including predictable pharmacokinetics, fewer drug interactions, and elimination of frequent monitoring requirements. However, their application in the paediatric setting, especially among patients with heart diseases, remain in the nascent stage, with limited evidence to guide clinical decision making.

This systematic review aims to synthesize existing evidence on the use of DOACs in children with cardiac conditions requiring antithrombotic treatment or thromboprophylaxis by critically analyzing data from recent clinical trials. We endeavor to provide clinicians and caregivers with the latest state of knowledge and hopefully illuminate future research directions for this particularly vulnerable population.

Methods

Inclusion and Exclusion Criteria

According to the PICOS (Population, Intervention, Comparison, Outcomes, Study design) framework, our eligibility criteria included: i) Population (P): pediatric patients diagnosed with cardiac diseases, including congenital or acquired conditions, who are at an elevated risk of thromboembolic events and necessitate anticoagulant prophylaxis; ii) Intervention (I): administration of DOACs, specifically dabigatran, rivaroxaban, apixaban, or edoxaban; iii) Comparison (C): standard of care treatments such as VKAs and LMWHs; iv) outcomes (O): the efficacy and safety outcomes related to the use of DOACs in this patient population, which include but are not limited to rates of thromboembolic events, bleeding events, and other adverse outcomes as defined by the original studies; and v) Study design (S): RCTs or observational studies that assessed the impact of DOACs in the specified pediatric population. We excluded those studies focusing on pharmacokinetics, and studies with no efficacy or safety outcomes were also excluded.

Literature Search Strategies

We systematically searched the databases of PubMed, Embase, and the Cochrane Library (CENTRAL), as well as the ClinicalTrials.gov registry and the World Health Organization's International Clinical Trials Registry Platform (ICTRP) until June 2024 to identify relevant RCTs. Three kinds of search terms were applied as follows: (i) “non-vitamin K antagonist oral anticoagulants” OR “direct oral anticoagulants” OR “novel oral anticoagulants” OR “dabigatran” OR “rivaroxaban” OR “apixaban” OR “edoxaban”; AND (ii) “pediatric” OR “children” OR “childhood”; AND (iii) “heart” OR “cardiac”. The detailed search strategies are presented in Supplemental Table 1. There were no restrictions on the languages in which the literature could be published.

Study Selection

After searching the PubMed and Embase databases, two reviewers screened the titles and abstracts of the retrieved studies. According to the predefined exclusion criteria, we initially deleted some studies if they were animal experiments, case reports, reviews, meta-analyses, comments, and conference abstracts, or other irrelevant articles. After that, we selected eligible studies during the full-text screening process. Any disagreement would be resolved by discussion with each other, or consultation with the senior author.

Data Extraction

The following baseline characteristics of included studies of this systematic review were extracted, mainly including authors and publication years, registry number of RCT, study population (sample size, age, and sex), study design, data source, DOAC type, comparators, the studied outcomes and their definitions, and treatment time.

Risk of Bias Assessment

The Cochrane's Risk of Bias tool⁶ was used to assess the bias risk of RCTs. For each of these domains, the risk of bias was categorized as ‘low’, ‘unclear’, or ‘high’.

Narrative Review

Our systematic review followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). In instances where the number of studies meeting our inclusion criteria was insufficient (less than 5), we opted for a narrative review. A narrative review allows for a qualitative analysis of the available literature, providing a descriptive and contextual understanding of the topic at hand.

Results

Study Selection Process

Figure 1 shows the flow chart of the systematic process in the study selection of this review. In total, 637 studies were identified that were searched in the databases. A total of 616 studies were excluded after the title-/abstract- screenings, and the remaining 21 studies were included in the full-text screenings. Among them, we excluded 17 studies due to the following reasons: (i) RCTs on the treatment of DOACs in pediatric patients with acute venous thromboembolism or acute lymphoblastic leukaemia/lymphoma (n = 8),^7–14 and (ii) 9 single-arm observational studies.^15–23 Finally, a total of 4 studies (3 RCTs^24–26 and 1 post hoc analysis of RCT²⁷) were included in this review.

Figure 1.

The flow chart of the systematic process in the study selection of this review.

Study Characteristics

Table 1 shows the baseline characteristics of the included studies. There were 3 pivotal RCTs enrolled pediatric patients (age of < 18 years) with cardiac diseases, namely UNIVERSE (rivaroxaban; NCT02846532), SAXOPHONEN (apixaban; NCT02981472), and ENNOBLE-ATE (edoxaban; NCT03395639). The remaining one was a post hoc analysis of the pivotal pediatric trials on dabigatran for the treatment of acute venous thromboembolism (DIVERSITY; NCT01895777) and secondary prevention for venous thromboembolism (NCT02197416). The results of the included studies are summarized in Table 2.

Table 1.

the Baseline Data of the Included Studies in This Review.

Author/Year	Study Treatment	Study Population	Age Group	Study Design	Initial Treatment	Maine Exclusion Criteria	Baseline Characteristics of the Population
McCrindle et al, 2021	rivaroxaban (n = 66) versus ASA (n = 34)	children with single-ventricle physiology who had the Fontan procedure within 4 months before enrollment	2–8 years	Prospective, multicenter, open-label, active controlled, 2-part study (UNIVERSE study)	N/A	Thrombosis, gastrointestinal disease or surgery associated with impaired absorption, active bleeding or high risk of bleeding contraindicating an antiplatelet or anticoagulant therapy	Age: DOAC(4.1 years) versus ASA(4.2 years); male sex: DOAC(55%) versus ASA(68%); mean duration between Fontan procedure and first dose of study drug: DOAC(45 days) versus ASA(37 days)
Portman et al, 2022	Edoxaban (n = 109) versus SOC (n = 58)	Kawasaki disease (22.2%), Fontan surgery(43.7%), heart failure(4.2%), Others (29.9%)	38 weeks-18 years	Prospective, multinational, randomized, open-label, blinded-endpoint phase 3 trial(ENNOBLE-ATE)	N/A	Thromboembolism, active bleeding or high bleeding risk, contraindications to LMWH or VKA, Fontan procedures with possible protein-losing enteropathy, rifampicin requirement, GFR < 30%	Age: DOAC(8.2 years) versus SOC(7.8 years); male sex: DOAC(66.1%) versus SOC(63.8%); baseline weight: DOAC(29.2 kg) versus SOC(27.4 kg);
Payne et al, 2023	Apixaban (n = 129) versus SOC (n = 63)	single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%)	29 days to 18 years	Prospective, randomized, open-label, parallel-arm, phase 2 trial(SAXOPHONE)	N/A	Thromboembolism, severe hypertension, gastrointestinal ulcer, coagulopathy, Active bleeding, intracranial vascular malformation or tumor; Pregnancy, renal or liver dysfunction, thrombocytopenia, ECMO or LVAD, antiplatelets, strong inducers/inhibitors of CYP450 3A4, chronic use of NSAIDs	Age: DOAC(8.0 years) versus SOC(7.6 years); male sex: DOAC(48.1%) versus SOC(63.5%); single ventricle: DOAC(72.9%) versus SOC(76.2%)
Albisetti et al, 2024	Dabigatran(n = 21) versus VKA(n = 22), LMWH(n = 5)	Cyanotic CHD(n = 16), Non-cyanotic CHD(n = 32)	0–17 years	International, multicenter, randomized, controlled, open-label, parallel-group, phase 2b/3, noninferiority, acute-treatment study(DIVERSITY)	≥5 days of parenteral anticoagulation(LMWH, unfractionated heparin, fondaparinux)	Conditions associated with an increased risk of bleeding, renal dysfunction, hepatic disease, infective endocarditis, heart valve prosthesis requiring anticoagulation, 0–2 years old with GA < 37 weeks, body weight < third percentile.	Age: DOAC(3.9 years) versus SOC(6.0 years); recent immobilization: DOAC(14.3%) versus SOC(3.7%); presence of other arterial/venous catheters: DOACs(19.0%) versus SOC(3.7%)

DOAC, direct oral anticoagulant; VKA, vitamin K antagonist; ASA, acetylsalicylic acid; CRNM bleeding, clinically relevant non-major bleeding; SOC, standard of care; LMWH, low-molecular-weight heparin, CHD, congenital heart disease; GFR, glomerular filtration rate; GA, gestational age; ECMO, extracorporeal membrane oxygenation; LVAD, left ventricular assist device; NSAIDs, non-steroidal anti-inflammatory drugs; N/A, not applicable.

Table 2.

The results of the included studies in this review.

Study	Efficacy Outcome	Safety Outcome
UNIVERSE (McCrindle et al)	Thrombotic events: DOACs(2%) versus ASA(9%)	Any bleeding: DOAC(36%) versus ASA(41%), P = 0.036; Major bleeding: DOAC(2%)versus ASA(0%;); Clinically relevant nonmajor bleeding: DOAC(6%) versus ASA(9%); Trivial bleeding: DOAC(33%) versus ASA(35%); Major bleeding: DOAC(2%) versus ASA(0%)
ENNOBLE-ATE (Portman et al)	Thromboembolic events: DOAC versus SOC(rate difference: −0.07%, 95% CI: −0.22 to 0.07%)	Major or CRNM bleeding events: DOAC versus SOC (rate difference:-0.03%, 95% CI:-0.18 to 0.12%); Major bleeding events: DOAC(0) versus SOC(0); All bleeding events: DOAC versus SOC(rate difference = 0.0%, 95% CI:-0.24 to 0.25%)
SAXOPHONE (Payne et al)	Thromboembolic events: DOAC(0) versus SOC(0)	Major bleeding: apixaban difference from SOC(-0.8%, 95% CI: -8.1 to 3.3%); CRNM bleeding: apixaban difference from SOC(-2.4%, 95CI:-10.5 to 1.9%); All bleeding: DOAC versus SOC(relative risk: 1.0; 95% CI: 0.7–1.5)
DIVERSITY (Albisetti et al)	Composite primary endpoint: DOAC(81.0%) versus SOC(59.3%)	Any bleeding: DOAC(14.3%) versus SOC(3.7%); Major bleeding: DOAC(0) versus SOC(0); CRNM bleeding: DOAC(0) versus SOC(0); Minor bleeding: DOAC(14.3%) versus SOC(3.7%)

DOAC, direct oral anticoagulant; ASA, acetylsalicylic acid; CRNM bleeding, clinically relevant non-major bleeding; SOC, standard of care.

Composite primary endpoint includes complete thrombus resolution, freedom from recurrent VTE, freedom from VTE-related death.

The patient population primarily consisted of children with congenital or acquired heart diseases, including conditions like single ventricle physiology, Kawasaki disease, and other heart defects. The study by McCrindle et al exclusively included children with single ventricle physiology who underwent Fontan procedure. Whereas the study by Albisetti et al included children with objectively confirmed VTE with or without CHD, but no information regarding acquired heart conditions were available, we therefore only focused on the CHD population.

In terms of intervention design, the DOACs investigated across the studies included dabigatran, apixaban, and edoxaban and the control groups received SOC which consisted of VKAs and LMWHs, with the exception of the study by McCrindle, in which the control group was treated with acetylsalicylic acid(ASA). Treatment duration and follow-up varied, with some studies observing patients for up to 12 months. The age of participants ranged from 28 days to 18 years. The mean age varied by study and treatment group, from 3.9 to 8.2 years old. Most key characteristics were fairly balanced between the interest group and control group across the studies. Supplemental Table 2 provides a comprehensive evaluation of the RCTs. Notably, all studies included in the analysis demonstrated a low risk of bias. Supplemental Table 3 presents the pharmacologic properties of the included DOACs.

Pivotal Trials on DOACs in Patients with Cardiac Diseases

The UNIVERSE trial was a clinical research study that focused on primary prevention, and thus, the trial compared the effectiveness of rivaroxaban with aspirin. On the other hand, the SAXOPHONEN trial was a phase 2 trial, meaning it was conducted to assess the safety and effectiveness of apixaban compared to the standard of care. Similarly, the ENNOBLE-ATE trial was a phase 3 trial that compared the efficacy of edoxaban with the standard of care, aiming to evaluate whether edoxaban performed better when compared to the currently accepted standard treatments. Additionally, what sets the ENNOBLE-ATE trial apart is the fact that it had an extension arm, aiming to evaluate the sustainability and long-term effects of edoxaban compared to the standard of care.

The UNIVERSE study focused exclusively on post-Pontan procedure children with single ventricle physiology. 100 participants were randomized 2:1 to receive either rivaroxaban or ASA. The study showed rivaroxaban reduced the rate of the thrombotic events to 2%, compared to 9% in the ASA group over a 12-month period. Major bleeding event was seen only in 1(2%) patient in the rivaroxaban group, but not in the ASA group. CRNM bleeding occurred less frequently in the rivaroxaban group than in the ASA group(6% vs 9%). The proportion of patients suffered from any bleeding events appeared to be comparable between both groups.

The SAXOPHONEN study included a total of 192 infants and children, 129 and 63 of which were treated with apixaban and SOC, respectively. No thromboembolic events were reported in either the apixaban or the control group. The apixaban group seemed to be associated with a significantly lower incidence of bleeding events. The reported major bleeding rates were 0.8%(95% CI: 0.0%-4.3%) in the apixaban arm, compared to 1.6%95% CI: 0.0%-8.7%) in the SOC arm. Clinically relevant non-major(CRNM) bleeding also occurred at a much lower rate in the apixaban arm(difference:-2.4, 95% CI: −10.5 to 1.9). Both groups exhibited similar rates of bleeding events, with each arm reporting a rate of 37%.

The ENNOBLE-ATE trial by Portman et al, consisting of 109 patients in the edoxaban arm and 58 patients in the SOC arm, found that during the main treatment period thromboembolic events happened in 0 patients in the edoxaban group and 1 patient (1.7%) in the SOC group. CRNM bleeding occurred in 0.9% of patients in the edoxaban group, as compared to 1.7% in the SOC group, providing annualized rates of 0.04 and 0.07%. No major bleeding was documented in both groups. During the extension period (edoxaban treatment), 1(0.7%) CRNM bleeding event and 2(2.8%) thromboembolic events were observed.

Post hoc Analysis Data on DOACs in Patients with Congenital Heart Disease

The post-hoc sub group analysis of the DIVERSITY trial on patients with CHD by Albisetti et al included 48 patients, 21 of which were treated with dabigatran and 27 with SOC. 16 patients were classified as having cyanotic CHD, where the rest were diagnosed with non-cyanotic CHD. The average age of the dabigatran group was younger than the SOC group. In terms of the effectiveness outcome, the composite primary endpoints defined by complete thrombus resolution, freedom from recurrent VTE, freedom from VTE-related death, were achieved by 81.0% and 59.3% of patients in the dabigatran and SOC group respectively. Major bleeding and CRNM bleeding did not occur in either group, minor bleeding events were seen in 14.3% of patients in the dabigatran group, compared to 3.7% of patients in the SOC group. Patients with cyanotic CHD exhibited poor response to the anticoagulation effect of both dabigatran and SOC compared to patients with non-cyanotic CHD, but dabigatran was still associated with higher rate of achieving the primary endpoint in both subgroups.

Discussion

In our systematic review, data from 3 RCTs and one post-hoc analysis of an RCT were gathered and examined to assess the effectiveness and safety of DOACs in paediatric patients with heart disease. The results indicate that DOACs are at least effective, if not more so, compared to the traditionally used antithrombotic agents including aspirin, VKAs and LMWHs in reducing the rate of thromboembolic events. Furthermore, the incidence of bleeding events appeared to be comparable between DOACs and SOC, with major and CRNM bleeding remaining low in both groups.

Several types of congenital or acquired cardiac diseases frequently occur in children. Repair of single ventricle congenital heart disease with a Fontan procedure may result in the risk of thromboembolism, which needs antithrombotic agents. Acquired cardiac disease such as Kawasaki disease with giant coronary artery aneurysms or dilated cardiomyopathy may also be at high risk of thromboembolic events. However, anticoagulation therapy remains an urgent clinical issue in these scenarios. For adult congenital heart disease with Fontan circulation, although prior observational studies and meta-analysis have demonstrated that the effectiveness and safety of DOACs are comparable to VKAs or LMWH,^28–31 the evidence level is relatively low due to the lack of RCT data. In children with heart diseases, our current systematic review included the prospective UNIVERSE (rivaroxaban), ENNOBLE-ATE (edoxaban), and SAXOPHONEN (apixaban) trials^24–26 with a total of 471 participants, suggesting that DOACs at least had similar efficacy and safety compared to VKAs or LMWH in the prevention of thromboembolism. In the SAXOPHONEN trial, the pharmacokinetics and pharmacodynamics of apixaban were also assessed, and their data were consistent with adult NOAC trials.^24,32 Further study should include more sample size to confirm our findings in the pediatric clinical practice. In addition, the dose and cost-effectiveness of NOAC in children need further examination.³³

RCTs ensure the balance of findings between the treatment groups and acquire a fair assessment of the trial treatment effect. However, the study participants enrolled in RCTs sometimes are not equal to those in real-world settings. A prior meta-analysis has indicated that both data from observational studies and NOAC trials consistently supported the use of DOACs superior to VKAs for stroke prevention in adult patients with atrial fibrillation.^32,34–38 In children, whether similar findings of DOACs in RCTs are observed in observational studies remains unclear. After searching the databases, we found that several observational single-arm studies have assessed the effectiveness and safety profiles of DOACs in pediatric patients with cardiac diseases such as Kawasaki disease with giant aneurysms,^20,23 congenital heart disease with thrombosis,^15,17,18,21 and children awaiting heart transplantation.³⁹ Most of these studies were case series with no control group, limiting the comparison between RCT and real-world evidence of DOACs in children. Nevertheless, current real-world evidence still supports systemic anticoagulation with DOACs in pediatric patients with cardiac diseases. Observational data regarding the comparison between DOACs and standard of care (VKAs or LMWH) are still extremely limited. Therefore, further multicenter real-world studies with larger sample sizes are still required to investigate the effects of DOACs compared with VKAs or LMWH in pediatric patients with a wider range of patient characteristics and a more extended follow-up period.

Safety Aspects Pertaining to the use of DOACs in Paediatric Patients

Although the occurrence of bleeding events in patients treated with DOACs, especially major and CNRM bleedings remained low or similar compared to the SOC groups, the DIVERSITY trial however reported a significantly higher rate of minor bleedings in the DOAC arm. Therefore, it is crucial to identify the underlying comorbidities, drug-drug interactions (particularly with the inducers and inhibitors of CYP3A4 and/or P-glycoprotein) that could potentially predispose the patients to a higher bleeding risk. Pediatric heart patients are often critically ill, requiring invasive procedures, therefore understanding the appropriate timing for perioperative interruption of DOACs is vital for optimal patient outcome. For low bleeding risk procedures, it is recommended to discontinue DOACs 24 h before surgery and restart on the same day if no bleeding is observed. For high bleeding risk procedures, a 48-h DOAC-free window is suggested before surgery, with a restart 24 h afterward if no bleeding occurs.⁴⁰

Age based dosing strategies are necessary to cater specifically to paediatric patients. For example, rivaroxaban dosing in the Einstein Jr phase 3 trial was adjusted based on body weight to match the pharmacokinetic profile achieved in adults. Younger children and infants, particularly neonates, often require tailored dosing due to their distinct pharmacokinetic profiles, characterized by faster clearance rates. These dosing strategies are critical in managing the balance between efficacy and safety, especially in populations like neonates where standard dosing regimens may not be applicable or safe.

The results of our systematic review underscore the potential of DOACs in pediatric patients with congenital or acquired heart conditions to enhance therapeutic outcomes. By offering a comparable or similar effectiveness without increasing the risk of bleeding, DOACs may offer additional advantages compared to traditional approaches and possibly serve as a new alternative. This could lead to simplification of the treatment protocol, reduced need for monitoring and enhanced adherence, which are particularly beneficial in this population as where treatment compliance are often challenging.

Future Directions

Current trial data on DOAC use in pediatric populations are limited, particularly for neonates, premature infants, and patients with specific conditions like caval, renal, or portal vein thrombosis, arterial thrombosis, arterial ischemic stroke, and known antiphospholipid syndrome. These groups require more data due to unique developmental hemostasis, pharmacology, and thrombosis risk factors. Future research should determine if DOACs can be safely and effectively started immediately upon VTE diagnosis without initial heparin-based treatment and establish the appropriate duration of stability in oral feeds before initiating DOACs in infants and postoperatively. Evaluating the potential role of pharmacodynamic monitoring in pediatric populations is crucial, particularly regarding thromboembolic efficacy, bleeding safety, and off-target effects impacting overall safety. Developing clear guidelines for perioperative interruption of DOACs, specifying procedure types and durations for withholding DOACs, and understanding when and how DOAC reversal agents should be used in pediatric patients are essential. Long-term safety outcomes, particularly concerning growth, neurodevelopment, and physiological processes like angiogenesis, should be studied through phase IV trials, postmarketing studies, and long-term registries. Potential long-term sequelae, such as osteoporosis or neurodevelopmental impacts, must be thoroughly investigated. Addressing these gaps will likely require shifting from traditional multicenter randomized controlled trials (RCTs) to well-designed and well-resourced cooperative cohort studies and registries. Initiatives like the ThromPeds Registry through the International Pediatric Thrombosis Network (IPTN) offer a pragmatic approach to gathering real-world data.⁴¹

Cost-Effectiveness of DOACs

DOACs are stereotypically known for its higher cost due to its status as a newer generation of anticoagulants. The economic perspective of DOACs is of great concern in actual clinical practice as the use of which could potentially harden or alleviate the burden on patients, their families and the health care system. Existing literatures^42,43 evaluating the cost-effectiveness of anticoagulants in non-valvular atrial fibrillation patients suggest DOACs are associated with higher quality-adjusted-life-year(QALY) improvement as well as lower cost as compared to warfarin. Among the DOACs, apixaban stands out as the most cost-effective option.

Limitations

We acknowledged that this systematic review was not previously registered in the PROSPERO, an international database of prospectively registered systematic reviews. In addition, there were several other limitations within this review that should be acknowledged. Firstly, the number of studies included in our study and overall sample sizes are relatively small, which may limit the generalizability of the results. Secondly, the studies included vary in their design especially their study populations and the specific types of DOACs examined, making direct comparisons challenging. Thirdly, there is also a lack of long-term data on the effectiveness and safety of DOACs in this patient population, which is crucial for chronic conditions typically seen in pediatric cardiac patients. Lastly, this study did not evaluate the cost-effectiveness of DOACs as compared to other anticoagulant agents in pediatric patients.

Conclusions

These findings suggest that DOACs have the potential to serve as an effective and safe alternative to the other agents in preventing and treating thromboembolism in paediatric patients with heart conditions, potentially improving patient outcomes and overall satisfaction. Further results from larger scale RCTs with more inclusive study designs and diverse patient subgroups are needed to confirm our findings.

Supplemental Material

sj-docx-1-cat-10.1177_10760296241271974 - Supplemental material for Systematic Review of Randomized Clinical Trials on Direct Oral Anticoagulants in Pediatric Heart Diseases

Supplemental material, sj-docx-1-cat-10.1177_10760296241271974 for Systematic Review of Randomized Clinical Trials on Direct Oral Anticoagulants in Pediatric Heart Diseases by Chaokun Guan, Linjuan Guo and Shucheng Liang in Clinical and Applied Thrombosis/Hemostasis

Footnotes

Author Contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Not required.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Shucheng Liang

Supplemental Material

Supplemental material for this article is available online.

References

Peng

. Incidence and timing of coronary thrombosis in Kawasaki disease patients with giant coronary artery aneurysm. Thromb Res. 2023;221:30-34.

Sunthankar

Moore

Byrne

, et al. Assessment of the CLOT (children's likelihood of thrombosis) real-time risk prediction model of hospital-associated venous thromboembolism in children with congenital heart disease. Am Heart J. 2024;272:37-47.

Giglia

Massicotte

Tweddell

, et al. Prevention and treatment of thrombosis in pediatric and congenital heart disease: A scientific statement from the American Heart Association. Circulation. 2013;128(24):2622-2703.

Chen

Stecker

. Direct oral anticoagulant use: A practical guide to common clinical challenges. J Am Heart Assoc. 2020;9(13):e17559.

Al-Ghafry

Sharathkumar

. Direct oral anticoagulants in pediatric venous thromboembolism: Review of approved products rivaroxaban and dabigatran. Front Pediatr. 2022;10:1005098.

Higgins

Altman

Gotzsche

, et al. The Cochrane collaboration's tool for assessing risk of bias in randomised trials. Br Med J. 2011;343:d5928.

Palumbo

Lensing

Brandao

, et al. Anticoagulation in pediatric cancer-associated venous thromboembolism: A subgroup analysis of EINSTEIN-Jr. Blood Adv. 2022;6(22):5821-5828.

Halton

Brandão

Luciani

, et al. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): A randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021;8(1):e22-e33.

Male

Lensing

AWA

Palumbo

, 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.

10.

Eghbali

Rahimi Afzal

Sheikhbeygloo

Eghbali

Taherkhanchi

Bagheri

. Dabigatran versus Warfarin for the treatment of pediatric thromboembolism: A pilot randomized trial. Pharm Sci. 2020;26(3):338-342.

11.

Young

Lensing

Monagle

Male

Kubitza

. Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation. Blood. 2019;134(Supplement_1):164.

12.

Monagle

Lensing

AWA

Thelen

, 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-e509.

13.

Brandão

Albisetti

Halton

, et al. Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children. Blood. 2020;135(7):491-504.

14.

O'Brien

Rodriguez

Lew

, et al. Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(1):e27-e37.

15.

Hardin

Michelson

McCrindle

, et al. Real-World anticoagulant use and incidence of venous thromboembolism and Major bleeding in children. Clin Ther. 2021;43(12):2074-2087.

16.

Yang

Bouma

Dimopoulos

, et al. Non-vitamin K antagonist oral anticoagulants (NOACs) for thromboembolic prevention, are they safe in congenital heart disease? Results of a worldwide study. Int J Cardiol. 2020;299:123-130.

17.

Esch

Hellinger

Friedman

VanderPluym

. Apixaban for treatment of intracardiac thrombosis in children with congenital heart disease. Interact Cardiovasc Thorac Surg. 2020;30(6):950-951.

18.

Duran

Gerber

Bilsky

Plummer

Bocks

. Use of rivaroxaban in children with congenital heart disease: A single-center case series. Pediatr Cardiol. 2024;45(6):1295–1300.

19.

Kobayashi

Cetatoiu

Esteso

, et al. Apixaban anticoagulation in children and young adults supported with the HeartMate 3 ventricular assist device. ASAIO J. 2023;69(6):e267–e269.

20.

VanderPluym

Esteso

Ankola

, et al. Real-world use of apixaban for the treatment and prevention of thrombosis in children with cardiac disease. J Thromb Haemost. 2023;21(6):1601-1609.

21.

Sagiv

Newland

Slee

Olson

Portman

. Real-world experience with edoxaban for anticoagulation in children at risk for coronary artery thrombosis. Cardiol Young. 2024;34(4):870-875.

22.

Rao

Sullivan

Takao

Badran

Patel

. Safety of continuing anticoagulation prior to cardiac catheterization in pediatric patients: A Los Angeles center experience. Pediatr Cardiol. 2023;44(5):1009-1013.

23.

Dummer

Miyata

Shimizu

, et al. DOACs in patients with giant coronary artery aneurysms after Kawasaki disease. JAMA Netw Open. 2023;6(11):e2343801.

24.

Payne

Burns

Glatz

, et al. Apixaban for prevention of thromboembolism in pediatric heart disease. J Am Coll Cardiol. 2023;82(24):2296-2309.

25.

Portman

Jacobs

Newburger

, et al. Edoxaban for thromboembolism prevention in pediatric patients with cardiac disease. J Am Coll Cardiol. 2022;80(24):2301-2310.

26.

McCrindle

Michelson

Van Bergen

, et al. Thromboprophylaxis for children post-fontan procedure: Insights from the UNIVERSE study. J Am Heart Assoc. 2021;10(22):e021765.

27.

Albisetti

Tartakovsky

Halton

, et al. Dabigatran for treatment and secondary prevention of venous thromboembolism in pediatric congenital heart disease. J Am Heart Assoc. 2024;13(4):e28957.

28.

Kawamatsu

Ishizu

Machino-Ohtsuka

, et al. Direct oral anticoagulant use and outcomes in adult patients with Fontan circulation: A multicenter retrospective cohort study. Int J Cardiol. 2021;327:74-79.

29.

Kazerouninia

Georgekutty

Kendsersky

, et al. A multisite retrospective review of direct oral anticoagulants compared to warfarin in adult fontan patients. Cardiovasc Drug Ther. 2023;37(3):519-527.

30.

Van den Eynde

Possner

Alahdab

, et al. Thromboprophylaxis in patients with fontan circulation. J Am Coll Cardiol. 2023;81(4):374-389.

31.

Yang

Veldtman

Bouma

, et al. Non-vitamin K antagonist oral anticoagulants in adults with a Fontan circulation: Are they safe. Open Heart. 2019;6(1):e985.

32.

Granger

Alexander

McMurray

JJV

, et al. Apixaban versus Warfarin in patients with atrial fibrillation. New Engl J Med. 2011;365(11):981-992.

33.

Mullen

. Apixaban for children with heart disease. J Am Coll Cardiol. 2023;82(24):2310-2311.

34.

Liu

Yang

Cheng

Zhu

. Reappraisal of non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients: A systematic review and meta-analysis. Front Cardiovasc Med. 2021;8:757188.

35.

Goto

. A patient-level meta-analysis: The End of the era of direct oral anticoagulant developmental trials in patients with atrial fibrillation? Circulation. 2022;145(4):256-258.

36.

Giugliano

Ruff

Braunwald

, et al. Edoxaban versus warfarin in patients with atrial fibrillation. New Engl J Med. 2013;369(22):2093-2104.

37.

Patel

Mahaffey

Garg

, et al. Rivaroxaban versus Warfarin in nonvalvular atrial fibrillation. New Engl J Med. 2011;365(10):883-891.

38.

Connolly

Ezekowitz

Yusuf

, et al. Dabigatran versus Warfarin in patients with atrial fibrillation. New Engl J Med. 2009;361(12):1139-1151.

39.

Benvenuto

Hartje-Dunn

, et al. Use of apixaban in children awaiting heart transplantation. Pediatr Transplant. 2024;28(1):e14632.

40.

Bhat

Young

Sharathkumar

. How I treat pediatric venous thromboembolism in the DOAC era. Blood. 2024;143(5):389-403. doi:https://doi.org/10.1182/blood.2022018966

41.

Betensky

Monagle

Male

Goldenberg

. What did we learn (and did not learn) from the pediatric direct oral anticoagulant trials, and how might we better design pediatric anticoagulant trials in the future? Res Pract Thromb Haemost. 2023;7(3):100140.

42.

Hallinen

Soini

Asseburg

, et al. Cost-Effectiveness of apixaban versus other direct oral anticoagulants and warfarin in the prevention of thromboembolic complications among Finnish patients with non-valvular atrial fibrillation. Clinicoecon Outcomes Res. 2021;13:745-755. Published 2021 Aug 13. doi:https://doi.org/10.2147/CEOR.S317078.

43.

Peng

Chan

Wong

ICK

. Cost-Effectiveness of direct oral anticoagulants in patients with nonvalvular atrial fibrillation in Hong Kong. Value Health Reg Issues. 2023;36:51-57. doi:https://doi.org/10.1016/j.vhri.2023.02.003

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB