Abstract
Background:
Postoperative thrombosis remains a significant cause of mortality and morbidity, especially in patients with single-ventricle physiology (SVP). The standard management plan for SVP consists of a three-stage surgical palliation, with widely varying thromboprophylaxis strategies. While routine thromboprophylaxis is standard after stages I and III, its role for stage II palliation remains controversial. This study aims to evaluate the impact of routine thromboprophylaxis in patients undergoing stage II palliation, with particular attention to cases involving pulmonary artery (PA) reconstruction, where the risk-to-benefit ratio of therapy may differ from routine stage II procedures.
Methods and Results:
Analyses were conducted across 15 studies published between 1981 and 2021 (n = 1682), assessing the impact of routine thromboprophylaxis on thromboembolic events, mortality, and major adverse events (MAEs). A significant potential benefit of thromboprophylaxis use was observed only in the subgroup of patients undergoing PA reconstruction (14% in the thromboprophylaxis group versus 6% in the no-thromboprophylaxis group; P = 0.01). The prevalence of thromboembolic events in the overall population was 5% (95% confidence interval [CI]: 3%–8%) without a significant difference between the two groups (P = 0.88). The pooled odds ratio (OR) showed a nonsignificant effect of thromboprophylaxis in reducing thrombotic events (OR = 0.35, 95% CI: 0.02–7.81). No significant differences were observed in thromboembolic events, MAEs, and mortality rates between the groups receiving thromboprophylaxis or no thromboprophylaxis (P = 0.88, 0.29, 0.45, respectively).
Conclusions:
This study supports the use of routine thromboprophylaxis following second-stage palliation of SVP, particularly in patients undergoing PA reconstruction. However, the evidence is limited by observational study designs, heterogeneity among studies, and the lack of recent high-quality data. Further well-designed studies are warranted to confirm these findings and to identify the optimal antithrombotic agent.
Keywords: Bidirectional cavopulmonary shunt, pulmonary artery reconstruction, second-stage palliation, single ventricle, thrombosis
INTRODUCTION
Congenital heart disease (CHD) constitutes one of the major groups of severe congenital anomalies, diagnosed in up to 0.9% of live births.[1,2,3] Postoperative thrombosis continues to be a significant cause of mortality and morbidity, particularly in neonates and infants undergoing complex cardiac surgical reconstruction.[1,4] Among these, patients with single-ventricle physiology are at the highest risk for thrombotic complications due to their unique anatomical and physiological circumstances and the staged nature of their surgical palliation.[5,6,7] Single-ventricle palliation involves a three-stage surgical process. Stage I palliation, typically the Norwood procedure, involves creating a shunt between the systemic and pulmonary circulations, such as a Blalock–Taussig–Thomas shunt. Stage II is the hemi-Fontan or bidirectional Glenn (BDG) procedure, which directly connects the superior vena cava to the pulmonary artery (PA). Finally, stage III, known as Fontan completion, connects all systemic venous blood directly to the PAs, bypassing the heart. While routine thromboprophylaxis is standard after the Norwood and Fontan operations, its role in stage II palliation remains controversial, given the infrequent use of prosthetic materials. However, even without the use of the prosthetic material, the patient remains at risk for thromboembolic events during this period.[8,9] Reported rates of thrombotic events following second-stage surgery vary widely from 0% to 28%, depending on patient characteristics, surgical technique, and surveillance method.[5,10,11,12] Thrombotic events at this stage are associated with increased mortality, prolonged hospital stay, and a lower likelihood of Fontan completion.[10] PA reconstruction performed in some patients to address preexisting hypoplasia or stenosis may further increase thrombotic risk by disrupting endothelial integrity and altering flow patterns within the pulmonary circulation.[13,14]
Despite these theoretical concerns, no established guidelines exist for thromboprophylaxis following stage II palliation, especially for patients undergoing concomitant PA reconstruction. Given the limited availability of large-scale studies, we conducted a comprehensive review of follow-up outcomes in patients undergoing stage II palliation over the past 45 years. Both comparative and single-arm analyses were performed, with subgroup analysis based on the presence of PA reconstruction. This study aims to evaluate the impact of routine thromboprophylaxis in patients undergoing stage II palliation, with particular attention to cases involving PA reconstruction, where the risk-to-benefit ratio of therapy may differ from routine stage II procedures.
METHODS
Protocol registration and search strategy
This systematic review and meta-analysis were conducted under the title “Routine Use of Thromboprophylaxis Following Stage II Palliative Cardiac Surgery: A Meta-Analysis.” The protocol has been registered in PROSPERO with registration number CRD420251083013. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive literature search was conducted across electronic databases, including PubMed/MEDLINE, ScienceDirect, and the Cochrane Library. The search terms included (“second stage palliation” OR “superior cavopulmonary shunt” OR “bidirectional Glenn” OR “hemi-Fontan”) AND (thromboprophylaxis OR antithrombotic OR antiplatelet OR anticoagulation OR aspirin OR heparin OR warfarin). We also manually searched the reference lists of relevant articles.
Eligibility criteria and study searches
Inclusion criteria were categorized according to the population, interventions, outcome, and study design strategy. The population included patients who underwent second-stage palliative cardiac surgery (e.g., bidirectional cavopulmonary shunt (BCPS), BDG, or hemi-Fontan) and only those for whom routine thromboprophylaxis was explicitly documented as an intervention. Studies were eligible if they reported outcomes on thrombus, major adverse events (MAEs), or mortality following surgery. Finally, for the study design, we included both double-arm comparative studies (thromboprophylaxis vs. no thromboprophylaxis postsurgery) and single-arm observational studies. Comparative studies were analysed using odds ratios (ORs), while single-arm studies were analyzed based on pooled prevalence. Studies were excluded if they involved patients with other conditions that contributed to thromboembolic risk, were not published in English, were not available in full text, or were duplicate reports. Study selection was conducted using Rayyan software, independently screened by two reviewers. Any disagreements were resolved through consensus discussion.
Data extraction and management
For each included study, two authors independently extracted the following data: Author, year of publication, number of patients, age at surgery, type of surgical procedure, diagnosis, thromboprophylaxis strategy, occurrence of thromboembolism, MAEs, mortality, and bleeding rate. For duplicate data, only the most recent publication was included. A tabulated format was used to summarize study and patient characteristics.
Postoperative thrombosis was defined as any clinically significant thrombotic event following surgery, confirmed by imaging (intravascular or intracardiac thrombus) and/or requiring therapy (anticoagulation, surgical re-intervention, catheterization). We included intravascular thrombosis (venous, arterial, or intracardiac), cardioembolic strokes, or pulmonary embolism.
Risk of bias assessment
The quality of observational studies (both cohort and case–control designs) was evaluated using the Newcastle–Ottawa Scale (NOS). This scale assesses study quality across three domains: Selection, comparability, and outcome. Two reviewers independently assessed the risk of bias, and disagreements were resolved by discussion.
Data synthesis and statistical analysis
A meta-analysis was conducted using RStudio, utilizing both common and random-effects models. For double-arm studies, outcomes were synthesized using ORs with 95% confidence intervals (CIs). For single-arm studies, pooled prevalence was calculated for thromboembolic events, MAEs, and mortality. Additional subgroup comparisons focused on patients with PA reconstruction versus those without. Forest plots were used to visualize pooled estimates, and P values were used to determine statistical significance. Heterogeneity was assessed using Cochran’s Q-test and the I2 statistic. Publication bias was explored using funnel plots and Egger’s test when more than 10 studies were available.
Certainty and confidence in the results
Although the grading of recommendations assessment, development and evaluation (GRADE) was not applied in this analysis, we interpreted the results in consideration of potential limitations in study design, imprecision, inconsistency, and publication bias.
RESULTS
Study selection
A total of 2734 studies were identified from electronic databases (PubMed/MEDLINE, ScienceDirect, and the Cochrane Library). After removing 331 duplicates, 2526 articles remained for screening. Based on titles and abstracts, 1015 studies were excluded. A full-text review of 907 articles identified 15 studies for inclusion in the final analysis. The screening and selection process of the articles is illustrated in the PRISMA flow chart [Figure 1].
Figure 1.
PRISMA flowchart of the included studies
Study characteristics
The included studies consisted of both single-arm and double-arm designs, with sample sizes ranging from 4 to 423 patients. A total of 1682 patients were included across 15 eligible studies, six of which included over 100 patients. These studies included patients who underwent any type of second-stage palliation, including BCPS or BDG, a hemi-Fontan, or a Kawashima procedure. Patients typically underwent these procedures at 9.52 months. All studies evaluated thrombus occurrence, MAEs, or mortality following these procedures. Ten of 15 studies evaluated the effect of thromboprophylaxis, with 5 including subgroups undergoing PA reconstruction. Characteristics of the included studies are presented in Table 1.
Table 1.
Characteristics and outcomes of the included studies
| Author, year | Characteristics | PA reconstruction | Thrombo-prophylaxis use | Thromboembolic events | Bleeding events, n (%) | ||||
|---|---|---|---|---|---|---|---|---|---|
|
|
|
||||||||
| Total, n | Age (months), mean (SD) | Cardiac conditions | Procedure | Events, n (%) | Type | ||||
| Behrend et al., 2024[15] | 423 | 6.3 (2.0) | TA (88) SV (120) DILV (78) PAIVS (29) cc-TGA (27) Unbalanced AVSD (34) |
BCPS | No | No | 8 | Systemic | - |
| Day et al., 2006[16] | 177 | 17.3 (2.2) | DILV (23) TA (36) LV hypoplasia (33) RV hypoplasia (9) Multiple anomalies (61) DORV (12) Other (3) |
BCPS | No | No | 5 | Systemic | - |
| Jacobs et al., 2002[17] | 72 | NR | HLHS (33) SV (8) TA (7) DORV (7) TC (5) PA (4) Heterotaxy (3) MACD (3) Truncus arteriosus (1) Ebstein anomaly (1) |
Hemi-Fontan (62) BCPS (10) |
No | No | 0 | Systemic | - |
| Kopf et al., 1990[18] | 91 | NR | TA (27) SV (22) TOF (14) D transposition (5) Ebstein’s anomaly (4) Others (20) |
BCPS | No | No | 0 | Shunt | - |
| Pennington et al., 1981[19] | 50 | NR | TA (25) Others (25) |
BCPS | No | No | 5 | Shunt | - |
| Chun et al., 2004[20] | 71 | NR | NR | Hemi-Fontan | No | Yes | 4 | Stroke | - |
| Manlhiot et al., 2012[11] | 139 | NR | NR | BCPS | No | Yes | 35 | Systemic | - |
| Zampi et al., 2013[21] | 244 | 5.8 (1.67) | HLHS (13) DORV (1) DILV (1) Others (7) |
BCPS or hemi-Fontan | No | Yes | 3 | Shunt | - |
| Tzanetos et al., 2012[22] | 4 | 5.07 (0.87) | HLHS (2) DORV (1) DILV (1) |
BCPS | No | Yes | 1 | IVC | - |
| Truong et al., 2017[23] | 10 | NR | NR | BCPS (8) Kawashima (2) |
n=No | Yes | 0 | Shunt | - |
| Honjo et al., 2010[12] | 61 | 10 (14) | HLHS (5) DORV (6) DILV (1) Others (12) |
BCPS | Yes, with an autologous pericardial patch | Yes | 1 | PA | - |
| Hansen et al., 2011[24] | 119 | 16.9 (32.9) | HLHS | hemi-Fontan (113) BCPS (6) |
Yes, with an allograft patch | Yes | 10 | PA | - |
| Ando et al., 2014[25] | 40 | 16.3 (13.34) | TA (9) PAIVS (5) Ebstein’s anomaly (3) DORV (2) Unbalanced AVSD (2) ccTGA (1) PAVSD (2) Others (16) |
BCPS | Yes, with an autologous pericardial patch | Yes | 0 | Systemic | 1 (8) |
| Galantowicz and Yates, 2016[26] | 129 | 5.6 (1.4) | HLHS | BCPS | Yes, NR | Yes | 7 | PA | 3 (5.4) |
| Ono et al., 2022[10] | 52 | NR | NR | BCPS | Yes, NR | Yes | 3 | Systemic | - |
TA: Tricuspid atresia, SV: Single ventricle, DILV: Double inlet left ventricle, PAIVS: Pulmonary atresia–intact ventricular septum, cc-TGA: Congenitally corrected transposition of the great arteries, AVSD: Atrioventricular septal defect, DORV: Double outlet right ventricle, HLHS: Hypoplastic left heart syndrome, TC: Transposition complex, MACD: Malaligned atrioventricular canal defect, TOF: Tetralogy of fallot, PAVSD: Pulmonary atresia–ventricular septal defect, BCPS: Bidirectional cavopulmonary shunt, NR: Not reported, SD: Standard deviation, PA: Pulmonary artery, LV: Left ventricular, RV: Right ventricular
Of the 15 included studies, 10 specifically analyzed the use of routine thromboprophylaxis [Table 2]. Among these studies, aspirin was the most commonly used antithrombotic agent, although in some studies it was combined with other therapies. Only four studies reported using aspirin as the sole antithrombotic therapy. Five studies involved heparin as the initial antithrombotic agent. Several studies also include other thromboprophylaxis agents, including warfarin (4 studies), enoxaparin (2 studies), and low-molecular-weight heparin (2 studies).
Table 2.
Thromboprophylaxis regimen
| Author, year | Population receiving TPx | TPx |
||
|---|---|---|---|---|
| Type | Dose | Duration | ||
| Chun et al., 2004[20] | 71 | ASA (NR) Warfarin (NR) |
NR | NR |
| Honjo et al., 2010[12] | 24 | UFH LMWH (20) ASA (4) |
UFH: NR LMWH: 1 mg/kg/12 h; titrated to reach an anti-Xa level of 0.5–1.0 u/mL ASA: NR |
Initial UFH for 24 h, followed by LMWH or ASA |
| Hansen et al., 2011[24] | 119 | UFH ASA |
Heparin: 100 IU/kg/day ASA: 3 mg/kg/days |
Initial heparin followed by ASA continued until Fontan |
| Manlhiot et al., 2012[11] | 64 | ASA (9) ASA + enoxaparin (5) Enoxaparin (48) Warfarin + enoxaparin (2) |
Aspirin: 5 mg/kg/days Enoxaparin: 1.5 mg/kg/days for age <2 months or 1 mg/kg/days for noninfants; titrated to reach an anti-Xa level of 0.5–1.0 u/mL Warfarin: Loading dose of 0.1 mg/kg with target INR of 2.0–3.0 |
Continued until Fontan |
| Zampi et al., 2013[21] | 244 | ASA | NR | NR |
| Ando et al., 2014[25] | 40 | UFH ASA Warfarin |
Heparin: 200–400 IU/kg/days; ACT target of 130–150 s ASA: 1 mg/kg/days Warfarin: Titrated with a target INR of 1.5 |
Initial heparin followed by ASA and/or warfarin |
| Galantowicz and Yates, 2016[26] | 55 | Heparin Enoxaparin ASA |
NR | Initial heparin for 24 h, followed by Enoxaparin for 6 weeks Then ASA until Fontan |
| Tzanetos et al., 2012[22] | 4 | ASA (3) LMWH (1) |
NR | NR |
| Truong et al., 2017[23] | 10 | ASA | 3–5 mg/kg/days | Continued until Fontan |
| Ono et al., 2022[10] | 52 | UFH ASA Warfarin |
UFH: 5000 IU/days; PTT target of 60 s ASA: NR Warfarin: NR |
Initial UFH for 4–5 days followed by ASA or warfarin |
TPx: Thromboprophylaxis, ASA: Aspirin, UFH: Unfractionated heparin, LMWH: Low-molecular-weight heparin, NR: Not reported, PTT: Partial thromboplastin time
Methodological quality of studies
The quality of the included studies was assessed using the NOS. Most studies were of low risk of bias, with clearly defined study populations and adequate outcome assessments. Common limitations included a lack of blinding and incomplete adjustment for confounding variables. The average NOS score was 7 (range: 5–9), indicating an overall acceptable methodological quality for observational studies [Table 3]. Risk bias across studies was assessed using funnel plots and Egger’s test [Supplementary Figure 1 (477.1KB, tif) ].
Table 3.
Quality of included studies based on Newcastle-Ottawa Scale Criteria
| Author | Study Design | Selection Quality | Comparability | Outcome Measure and Analysis | Score | Quality |
|---|---|---|---|---|---|---|
| Ando., 2014[25] | Cohort | * * * * | - | * * * | 7/9 | Good |
| Chun., 2004[20] | Cohort | * * * * | - | ** | 6/9 | Moderate |
| Day ., 2006[16] | Cohort | * * * * | - | * * * | 7/9 | Good |
| Galantowicz., 2016[26] | Cohort | * * * * | - | ** | 6/9 | Moderate |
| Hansen ., 2011[24] | Cohort | * * * * | - | * * * | 7/9 | Good |
| Honjo., 2010[12] | Cohort | * * * * | ** | * * * | 9/9 | Good |
| Jacobs., 2002[17] | Cohort | * * * | - | ** | 5/9 | Moderate |
| Kopf., 1990[18] | Cohort | * * * * | - | * * * | 7/9 | Good |
| Manlhiot., 2012[11] | Cohort | * * * * | ** | * * * | 9/9 | Good |
| Ono., 2022[10] | Cohort | * * * * | ** | * * * | 9/9 | Good |
| Pennington., 1981[19] | Cohort | * * * | - | ** | 5/9 | Moderate |
| Truong., 2017[23] | Cohort | * * * * | - | ** | 6/9 | Moderate |
| Tzanetos., 2016[22] | Cohort | * * * * | - | ** | 6/9 | Moderate |
| Zampi., 2013[21] | Cohort | * * * * | - | * * * | 7/9 | Good |
No score: *Each represents one score
Thromboembolic event in population with and without thromboprophylaxis
Thromboprophylaxis shows no significant antithromboembolic effect in the overall population. However, a significant effect was observed among patients undergoing PA reconstruction. In the analysis of 15 single-arm studies involving 1672 patients, both groups showed an identical pooled thromboembolic incidence of 5%. There was no significant difference found between the two groups (P = 0.88), with moderate heterogeneity (I2 = 56.8%), indicating that thromboprophylaxis did not significantly reduce the risk of thromboembolism in the overall population undergoing the Glenn procedure [Figure 2a]. In three comparative studies (n = 319), the pooled OR showed the superiority of thromboprophylaxis in reducing thromboembolic events compared to no thromboprophylaxis after surgery, although the effect was statistically nonsignificant and demonstrated moderate heterogeneity (OR = 0.35, 95% CI: 0.02–7.81, I2 = 52.1%) [Figure 2b]. This suggests that while thromboprophylaxis may reduce the incidence of thrombus, further studies are needed to clarify its true impact.
Figure 2.
Pooled estimates for thromboembolic incidents in single-arm studies (a), double-arm studies (b), and the pulmonary artery reconstruction population (c)
Among patients undergoing PA reconstruction, thromboprophylaxis shows significant anti-thromboembolic benefit. Five studies, including 495 patients, assessed thrombus formation 1 year after PA reconstruction [Figure 2c]. The pooled incidence at 1 year was 14% (95% CI: 9%–23%) in patients without thromboprophylaxis and 6% (95% CI: 4%–10%) in those with thromboprophylaxis. Subgroup analysis showed a statistically significant difference (P = 0.01), suggesting a potential reduction in thrombus formation with thromboprophylaxis prescription. Heterogeneity was low (I2 = 18.5%) in the nonthromboprophylaxis group and absent in the thromboprophylaxis group, suggesting a high degree of consistency in the observed effects across studies.
Major adverse events in population with and without thromboprophylaxis
Eleven single-arm studies, involving 1312 patients, were included to assess MAEs in this population. The pooled proportion of MAEs was 8% (95% CI: 7%–11%) in patients without thromboprophylaxis and 7% (95% CI: 4%–12%) in those with thromboprophylaxis [Figure 3a]. There was no significant difference between groups (P = 0.29). This indicates that thromboprophylaxis may not be associated with reduced MAEs following second-stage palliation.
Figure 3.
Pooled estimates for major adverse events (a) and mortality incidence (b) following second-stage palliation in single-ventricle physiology, comparing patients with and without thromboprophylaxis
Mortality in population with and without thromboprophylaxis
Ten studies, with 1186 patients, were analyzed to evaluate the mortality population. The pooled mortality rate was 11% (95% CI: 3%–30%) in patients without thromboprophylaxis and 7% (95% CI: 4%–12%) in those receiving thromboprophylaxis. There was no significant difference between the two groups (P = 0.45), and high heterogeneity was observed (I2 = 89%) [Figure 3b]. These findings suggest that thromboprophylaxis therapy does not significantly influence mortality outcomes following second-stage palliation.
DISCUSSION
Thrombosis is a well-recognized, life-threatening complication in children with CHD, with the single-ventricle population considered to be at higher risk.[5,6,7] The highest risk period occurs during the initial palliation, with a previous study reporting thrombotic complication rates of 40% and 28% following the initial and second-stage palliation, respectively.[11] Although thrombotic events following second-stage palliation are reported to be relatively rare, the potential impact on pulmonary vasculature has led to recommendations for routine thromboprophylaxis to enhance the likelihood of a successful subsequent Fontan completion.[27] Several pathophysiological factors contribute to this prothrombotic state, including altered flow dynamics secondary to nonpulsatile flow, reduced cardiac output, hypercoagulability, and endothelial dysfunction.[8,9] The studies included in this analysis showed a thromboembolic event rate of 0% to 25%, with a pooled rate of 5% (95% CI 0.03–0.08). These rates are within the range observed in Fontan patients, which ranged from 3% to 24%.[28,29,30] Our meta-analysis demonstrated a nonsignificant trend toward reduced thromboembolic events in patients receiving thromboprophylaxis. This lack of significant results is probably attributable to the small sample sizes and heterogeneity in surveillance protocols for diagnosing thromboembolic events among the included studies. As the first meta-analysis to address this question, our findings underscore the need for larger, multicenter studies with standardized protocols.
Given the negative impact of thrombotic complications on subsequent Fontan completion, routine thromboprophylaxis following second-stage palliation has been encouraged, although protocols vary across institutions. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for Antithrombotic Therapy and the Prevention of Thrombosis (9th edition) are among the most commonly referenced pediatric antithrombotic guidelines. These guidelines state that it is advisable to reduce the risk of thrombosis to increase the likelihood of a fully patent Fontan circuit. Currently, no single antithrombotic agent has been proven superior in this population; hence, recommendations are based on extrapolation from other major vascular procedures. These guidelines recommend postoperative unfractionated heparin (grade 2C) for children undergoing BCPS.[27] In parallel, the American Heart Association guidelines of Prevention and Treatment of Thrombosis in Pediatric and CHD recommend a low dose of aspirin (1–5 mg/kg) as antithrombotic therapy in patients undergoing shunt-creation procedures, such as Glenn and Fontan procedures.[6] This aligns with the treatment approaches observed in our studies, which mostly utilized aspirin, either as monotherapy or in combination with other antithrombotic agents.
The benefit of thromboprophylaxis may not be uniformly applicable to all patients. Our findings highlight the importance of identifying high-risk subgroups to inform more individualized strategies, rather than applying a general approach. PA reconstruction is considered a high-risk factor in this population, associated with increased endothelial injury risk due to the manipulation of fragile vascular structures, although direct observations in this specific subgroup are still lacking. Published articles report that PA reconstruction is performed in a substantial proportion of patients, ranging from 8% to over 50%, depending on institutional practice.[31,32,33] Our study found a significant subgroup difference in patients undergoing PA reconstruction, with lower thromboembolic event rates among those receiving thromboprophylaxis. Moreover, the low heterogeneity within each group indicates consistent findings across involved studies and reinforces the reliability of these findings. Since there is a lack of literature specifically addressing the use of thromboprophylaxis in patients undergoing second-stage palliation surgery with PA reconstruction, we referred to the study by Li et al.,[34] which evaluates 10 patients with unilateral absence of the PA who underwent PA reconstruction using direct anastomosis, an autologous pericardial patch, or synthetic materials. All patients were prescribed aspirin for 6 months postoperatively, and no hospital deaths were reported. However, it is important to note that our analysis included only studies that explicitly stated they did not use synthetic patch material. The use of synthetic materials would have necessitated routine thromboprophylaxis prescription, thereby introducing bias and limiting our ability to evaluate its true efficacy in this subgroup.
It is equally important to recognize the potential risk of bleeding complications with the long-term use of thromboprophylaxis. However, among the included studies, only two specifically reported the incidence of postoperative bleeding following second-stage palliation in patients receiving routine thromboprophylaxis. This limited data restricts the ability to assess further the balance of benefits and harms of thromboprophylaxis in this population. Ando et al. and Galantowicz and Yates reported low event rates of 1 in 40 (2.5%) and 3 in 55 (5.5%), respectively.[25,26] Galantowicz and Yates[26] noted a nonsignificant higher risk of bleeding complications, defined as new intracranial or systemic bleeding requiring transfusion, that occurred within 6 weeks of routine thromboprophylaxis. All were successfully managed with temporary anticoagulation cessation, without the need for surgical intervention. Similarly, Manlhiot et al.,[11] reported a low risk of serious bleeding complications across all three palliative stages with thromboprophylaxis, supporting the routine use of a thromboprophylaxis agent from the initial palliation through the post-Fontan period. In a broader context, Ho et al.[35] suggested the early initiation of thromboprophylaxis following cardiac surgery in patients who have no active bleeding, emphasizing its benefit for thrombotic risks unless proven otherwise from more robust trials.
Several limitations should be acknowledged. First, the number of eligible studies was limited, with many utilizing single-arm designs without control groups, which introduces potential bias. Second, several important sources of heterogeneity must be highlighted as key limitations of this analysis. Patient selection varies widely, with differing underlying cardiac conditions and risk profiles that may affect thrombotic outcomes. The thromboprophylaxis protocols also showed considerable variation, from aspirin monotherapy to combination therapies with different dosing and durations, preventing a clear assessment of which protocols were associated with better outcomes. Furthermore, this meta-analysis includes studies spanning 36 years, during which advances in surgical techniques and perioperative care must have occurred. Improvements such as advances in cardiopulmonary bypass strategies, enhanced imaging modalities, and better critical care monitoring likely influence thrombotic and bleeding risks and the efficacy of thromboprophylaxis protocols. Discrepancies in follow-up duration, along with variability in the definitions and reporting of outcomes, also further compromise comparability. Due to the methodological limitations, we did not use the GRADE approach to assess the certainty of the evidence. Despite these limitations, we believe this meta-analysis provides valid insights into the effectiveness of thromboprophylaxis in managing thrombotic risk in patients undergoing second-stage palliation with PA reconstruction.
CONCLUSIONS
This meta-analysis suggests that thromboprophylaxis may provide a potential benefit in reducing thromboembolic events among stage II palliation patients undergoing PA reconstruction. However, due to the variability of the evidence and significant heterogeneity within the included studies, the decision to use thromboprophylaxis should be based on each patient’s individual conditions. In addition, robust observational studies are needed to clarify the impact of routine thromboprophylaxis use following second-stage palliation with PA reconstruction and other high-risk patients, and to identify the most effective and safe thromboprophylaxis protocols for this setting.
Conflicts of interest
There are no conflicts of interest.
Funnel plots and Egger’s test were conducted to assess publication bias, (a) double-arm thromboembolic events, (b and c) thromboembolic events, (d and e) major adverse events, (f and g) mortality, (h and i) thromboembolic events in pulmonary artery reconstruction
Funding Statement
Nil.
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Supplementary Materials
Funnel plots and Egger’s test were conducted to assess publication bias, (a) double-arm thromboembolic events, (b and c) thromboembolic events, (d and e) major adverse events, (f and g) mortality, (h and i) thromboembolic events in pulmonary artery reconstruction