Methods: We systematically searched PubMed, Cochrane, EMBASE, Scopus, and Web of Science for the studies that reported the event rate of infective endocarditis in both transcatheter and surgical pulmonary valve replacement between December 2012 and December 2021. Random-effects model was used in the meta-analysis.
Results: Fifteen comparison groups with 4,706 patients were included. The mean follow-up was 38.5±3.7 months. Patients with transcatheter pulmonary valve replacement had a higher risk of infective endocarditis than patients receiving surgically replaced valves (OR 2.68, 95% CI: 1.83-3.93, p<0.00001). The calculated absolute risk difference was 0.03 (95% CI: 0.01-0.05), indicating that if 1,000 patients received a surgical valve replacement, 30 cases of infective endocarditis would be prevented. A meta-regression of follow-up time on the incidence of infective endocarditis was not statistically significant (p=0.753).
Conclusion: Although transcatheter pulmonary valve replacement is a feasible alternative to surgical replacement in severe right ventricular outflow tract dysfunction, the higher incidence of infective endocarditis in transcatheter replacement remains a significant concern. Regarding this analysis, surgical treatment of right ventricular outflow tract dysfunction is still a viable option in patients with prohibitive risk.
Additionally, self-expandable TPV Venus P-valve (Venus MedTech Inc., Hangzhou, China) and Harmony (Medtronic Inc., Minneapolis, MN, USA) has been used recently in patients with large RVOT. Since transcatheter pulmonary valves have outstanding features over open heart surgery, such as short recovery time, the lack of need extracorporeal circulation, prolonged stent patency, good leaflet function, rapid life normalization, improved psychosocial outcomes, and the cheapness of the process, they appear to be a very competitive and crucial therapeutic option for pulmonary valve replacement in patients with CHD.[3,4] However, despite their advantages, infective endocarditis (IE) of the transcatheter pulmonary valves emerges as a potential threat for the long-term compared to homograft.
In this meta-analysis, we aimed to compare the incidence of IE in TPV replacement (TPVR) recipients and surgical pulmonary valve replacement (SPVR) patients to identify risk factors for IE and to evaluate the possible impact on mortality.
The EndNote and Rayyan software was used to remove any duplicates and select eligible studies from the database findings and other sources (lists of references in included studies).[5,6] Two authors independently screened titles and abstracts for eligibility of the studies using the following query terms: TPVR/implantation, SPVR/implantation, IE, and prosthetic valve endocarditis. Studies were considered eligible, if they compared TPVR with SPVR and reported IE incidence. Studies were excluded if they were published only in the form of an abstract or a conference presentation, duplicate publications and if the interest of the outcomes was not clearly declared. Any discrepancies were resolved after a discussion with the senior author. The systematic search of the literature was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) (Figure 1).[7]
Two authors independently assessed the quality of studies according to the Cochrane assessment method was used to analyze study quality. The primary outcome was the incidence rate of IE between TPVR and SPVR. The secondary outcome was overall mortality. In addition, the following study and patient-related information were extracted from the main paper and accompanying supplemental material: publication year, study design, years of inclusion, follow-up time, male sex, age, baseline CHD, type of intervention, primary and secondary endpoints.
Statistical analysis
Statistical analysis was performed using the
Review Manager (RevMan) version 5.3 software
(Nordic Cochrane Centre, The Cochrane Collaboration,
2012, Copenhagen, Denmark) to calculate the pooled
effect size with odds ratio (OR) and 95% confidence
intervals (CI) by Mantel-Haenszel method and random
effect model. The I2 statistics evaluated heterogeneity
of studies, and we considered ?25% as low, 26% to
50% as moderate, 51% to 75% as high, and >75%
as very high. A meta-regression was performed
to analyze the impact of moderator variables on
outcomes of interest, particularly the follow-up period
on the incidence of IE. A two-sided p value of <0.05
was considered statistically significant. Sensitivity
analyses were performed for the primary endpoint by
removing individual studies on the pooled effect. The
Egger and Begg tests and visual inspection of funnel
plots evaluated publication bias. The meta-regression was performed using Comprehensive Meta-analysis
software.[8]
The overall study population consisted of 4,706 patients from 15 comparison groups with a mean age of 21.6±1.2 years (95% CI: 19.2-24.0 years). The mean follow-up was 38.5±3.7 months (95% CI: 31.2-45.9). The design and characteristics of the studies included in the analysis are presented in Table 1.[9-23] The baseline characteristics of the pooled cohort are presented in Table 2. The TPVR group included higher patients with an underlying diagnosis of transposition of great arteries (TGA), ventricular septal defect (VSD), pulmonary stenosis (PS) (8% vs. 0.5%, p<0.0001), and truncus arteriosus (9.2 vs. 3.9%, p=0.0006). The surgical group, on the other hand, had higher mean percentages of younger (26.1±13.3 vs. 22.7±13.8 years, p=0.01) and underweight (56±25 vs. 52±25 kg, p=0.03) patients.
Table 1. Design and characteristics of the studies included in the analysis
Table 2. Demographic and clinical characteristics
In all patients, the diagnosis was established according to modified Duke criteria.[24] The incidence of IE was significantly higher in patients who received transcatheter pulmonary valves compared to patients receiving surgically replaced pulmonary valves (OR: 2.68, 95% CI: 1.83 to 3.93, p<0.00001). Heterogeneity within the included studies was low (I2 =5%) (Figure 2). Forest and Funnel plots of included studies are shown in supplemental Figure 1. Exclusion of the study with maximum weight did not change the analysis results (OR: 2.72, 95% CI: 1.86-3.99, p<0.00001). Among TPVR patients, the most frequently isolated pathogens in blood culture were Staphylococcus aureus ( 16.9%) and HACEK (5.6%), and Streptococcus viridians (3.9%). Blood culture was negative in 5.6%; most cases were polymicrobial (Table 3). The calculated absolute risk difference (RD) was 0.03 (95% CI: 0.01-0.05), indicating that if 1,000 patients received a surgical valve replacement, 30 cases of IE would be prevented. A meta-regression of follow-up time on the incidence of IE was not statistically significant (p=0.753), indicating the difference in follow-up times did not change the pooled risk of IE (Figure 3).
Table 3. Details of patients diagnosed with endocarditis in each study
Figure 3. Meta-regression of follow-up time on log OR of infective endocarditis.
Overall mortality was reported in eleven comparison groups. Total mortality was similar between TPVR and SPVR (OR: 0.73, 95% CI: 0.43-1.25, p=0.25) (Figure 4). Inclusion of only studies with a lower risk of bias did not alter the results with TPVR valves having similar total mortality to SPVR (OR: 0.76, 95% CI: 0.42-1.36, p=0.35). The forest plot showed a low risk of bias and low heterogeneity (I2=0%). Forest and Funnel plots and Egger's regression test results are reported in Supplemental Figures 2.
The presented study evaluated the incidence of IE, the clinical features of the included studies, the patients' characteristics, and the overall mortality in TPVR and SPVR patients. Therefore, these data provide critical information for the literature to modify the risk/benefit ratio in individual bases to lead the patients according to the complexity of the prosthesis implantation way.
Based on the data reviewed in this analysis, there was clear evidence to suggest that IE after TPVR was more common than surgical implantation of the pulmonary valve (OR: 2.68, 95% CI: 1.83-3.93, p<0.00001). This indicates that intervention methods and specific tissue characteristics may be predisposed to subsequent bacterial infection. In addition, in the light of literature, there is a considerable risk and mortality burden of endocarditis in patients with CHD, particularly those with previously operated cyanotic or conotruncal anomalies such as tetralogy of Fallot, which was also the predominant CHD in this analysis (44% vs. 43% in TPVR vs. SPVR).[27,30]
It is well known that prior history of endocarditis may transmit the risk for future endocarditis.[31] However, since most of the studies have not routinely delineated endocarditis history with a statistical confirmation, these arise the question of whether patients with a history of endocarditis have any additional risk or other adverse outcomes after TPVR versus surgical replacement.[32] Nevertheless, in this meta-analysis, infectious complications in patients with a history of IE, TPVR and SPVR did not suggest significant differences, and that could not explain why the incidence of IE was different in the two groups. Nevertheless, it is worth reinforcing practices based on potential patient-related risk factors, including dental problems and skin or mucosal breakdown, to reduce the incidence rate of this complication. Moreover, our results are in accord with recent studies indicating that younger patients were at a higher risk of endocarditis (mean age of 21.6 years (95% CI: 19.2-24.0 years), which supports particular attention in educating pediatric/adolescent patients and their families about the importance of preventive measures.
There is also a growing body of literature indicating that the risk of IE is related more to the valve tissue (i.e., bovine jugular veins versus others) rather than the mode of valve implantation. The Contegra™ conduit and Melody™ valves, composed of the same biological substrate, demonstrate a significantly increased IE risk compared to other biological pulmonary valve substrates (i.e., homografts, Sapien™valves, and Hancock™ valves).[16] This increased risk is attributed to their inherent asymmetry, altering flow dynamics. The resultant structural degeneration with high-velocity jets, coupled with thrombi on the prosthesis (non-bacterial thrombotic endocarditis), surface roughness, trauma due to the stent preparation, and implantation may serve as a nidus for the organisms to adhere prosthetic valve.[33,34] These findings further support the studies' suggestion that antiplatelet or anticoagulant therapy may reduce endocarditis risk, which merits consideration in the TPVR population.[19,35] However, there are currently no specific guideline recommendations for antiplatelet or anticoagulant therapy duration; the studies included in this meta-analysis are also limited by the lack of uniformity in the definition.
Patients with CHD regularly need reoperations for RVOT reconstruction after corrective or palliative operation in infancy or early childhood. Therefore, it was kept in mind that TPVR was preferred as an alternative for surgical treatment with much less morbidity than repeated surgery, albeit an association of IE in these patients increases. Although mortality can reach up to 24% for native valve IE and exceeds 46% for prosthetic valve endocarditis,[36] total mortality was similar between TPVR and SPVR (OR: 0.73, 95% CI: 0.43-1.25, p=0.25) in this analysis. Hence, TPVR in this group is still inspiring with procedural and long-term success rates.
We also attempted to evaluate the importance of follow-up time on the reported incidence of IE in this patient population. Although IE tended to occur earlier after TPVR than after SPVR,[9,10] the meta-regression of follow-up time on the incidence of IE, albeit positively correlated, was not statistically significant (p=0.753) in the present analysis. This indicated that the difference in follow-up times did not change the pooled risk of IE.
This present analysis, although intended to be comprehensive, still bears limitations. First, it included observational studies, and no randomized controlled trials were available for inclusion at the study time. Additionally, much of the studies tend to be descriptive to identify the outcomes on the procedure's effectiveness, but have little insight into mechanisms or potential risk factors for endocarditis or its inconsistent sequelae. Finally, moderate heterogeneity was found concerning the included studies' results, as there were changing degrees of pre-procedural gradients and patient baseline CHD characteristics although leave-one-out analysis affirmed the consistency of the results.
In conclusion, transcatheter pulmonary valve replacement is a feasible alternative to surgical pulmonary valve replacement in selected patients with severe right ventricular outflow tract dysfunction. Moreover, it was associated with similar long-term mortality incidence rates as surgical pulmonary valve replacement. However, the higher incidence of IE in transcatheter pulmonary valve replacement compared to surgical valve options remains a significant concern, despite increased experience with the technique and technology. Hence, this requires further exploration and preventive strategies. Regarding this analysis, surgical treatment of right ventricular outflow tract dysfunction is still a viable option in patients with prohibitive risk. Nevertheless, the findings reported from well-conducted randomized controlled trials with real-world evidence addressing whether the relative risk differs significantly between transcatheter pulmonary valve replacement with the Melody™ valve, the Sapien™ valve, or other devices, or surgical replacement with various conduits or prostheses and later treatment strategies are warranted.
Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Author Contributions: Analyzed, collected and review the data: E.I.C.; Contributed to the design, review of literatures and interpretation: E.I.C., B.B, and L.Ç.O.; Wrote the manuscript: E.I.C.; Contributed to supervision, last editing and the critical review: A.C.; All authors contributed to the article and approved the submitted version.
Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
Funding: The authors received no financial support for the research and/or authorship of this article.
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