Valve-in-Valve TAVR in Surgical Stentless Aortic Bioprostheses, a Challenging Scenario

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The presented manuscript constitutes a valuable systematic review addressing a complex and clinically relevant problem of valve-in-valve TAVR in stentless bioprostheses, with clear strengths including a well-structured narrative and high-quality, illustrative figures. The relatively broad dataset (54 studies, 294 procedures) is also noteworthy; however, several issues should be addressed prior to publication. In particular, the formatting of the tables, especially Table 1 (and subsequent tables), requires correction, as visible misalignment and layout inconsistencies impair data readability. 
The most important limitation relates to the temporal heterogeneity of the included studies – the timeframe starting from 2010 encompasses a period of substantial evolution in TAVI technology, including significant changes in valve design, implantation techniques, and patient selection, all of which directly impact procedural safety and outcomes; moreover, important developments in imaging (particularly CT-based planning), coronary protection strategies (e.g., BASILICA), and operator experience have occurred – in its current form, the manuscript treats these data as a homogeneous population, which may lead to oversimplified conclusions. Therefore, the inclusion of a temporal analysis (e.g., early vs contemporary era or trend-based assessment), ideally as a short dedicated subsection, would significantly enhance the manuscript. 
It is also important to acknowledge the substantial heterogeneity of the underlying evidence – the predominance of case reports and small case series, inconsistent reporting of key variables (including echocardiographic and anatomical parameters), and the limited possibility for structured comparative analysis – all of which reduce the strength of inference and require cautious interpretation of the results; in this context, a more structured presentation of findings (e.g., simple comparisons according to valve type or procedural strategy) could be considered even without a formal meta-analysis. 
Additionally, the partial use of VARC-3 definitions alongside reconstructed endpoints based on available data raises methodological concerns and would benefit from a clearer distinction between reported and derived outcomes. Furthermore, the analysis is largely limited to short-term results, with a lack of long-term follow-up data, which is clinically relevant in this setting. Finally, minor editorial corrections (including typographical errors) are recommended. 
In summary, this is a well-prepared and clinically meaningful manuscript that requires important but feasible revisions, and I recommend consideration for publ. after major revision.

Author Response

We thank all the reviewers for their precious and inspiring comments. Here are our replies.
Reviewer 1
Comment: The most important limitation relates to the temporal heterogeneity of the included studies – the timeframe starting from 2010 encompasses a period of substantial evolution in TAVI technology, including significant changes in valve design, implantation techniques, and patient selection, all of which directly impact procedural safety and outcomes; moreover, important developments in imaging (particularly CT-based planning), coronary protection strategies (e.g., BASILICA), and operator experience have occurred – in its current form, the manuscript treats these data as a homogeneous population, which may lead to oversimplified conclusions. Therefore, the inclusion of a temporal analysis (e.g., early vs contemporary era or trend-based assessment), ideally as a short dedicated subsection, would significantly enhance the manuscript. 
Response: We thank the reviewer for this important comment. In order to address this point, we performed a temporal stratification of the available data (early vs. contemporary experience, with explanation of the chosen years), and we included a dedicated analysis in the revised manuscript which is now contained in the Methods, Results and Discussion session. Given the nature of the included studies and the limited availability of granular data, this assessment was necessarily descriptive and supported by appropriate statistical testing (including Fisher’s exact test where applicable).

Comment: It is also important to acknowledge the substantial heterogeneity of the underlying evidence – the predominance of case reports and small case series, inconsistent reporting of key variables (including echocardiographic and anatomical parameters), and the limited possibility for structured comparative analysis – all of which reduce the strength of inference and require cautious interpretation of the results; in this context, a more structured presentation of findings (e.g., simple comparisons according to valve type or procedural strategy) could be considered even without a formal meta-analysis. 
Response: We thank the Reviewer for this insightful comment. While we agree that a more structured comparative presentation could further enhance interpretability, such an approach was not feasible in the present study due to the high level of missing or non-standardized data across reports, as well as the very large and methodologically diverse dataset. In addition, detailed stratified comparative analyses were beyond the primary scope of this systematic review, which aimed to provide a comprehensive qualitative synthesis of the available evidence.

Comment: the partial use of VARC-3 definitions alongside reconstructed endpoints based on available data raises methodological concerns and would benefit from a clearer distinction between reported and derived outcomes. Furthermore, the analysis is largely limited to short-term results, with a lack of long-term follow-up data, which is clinically relevant in this setting. Finally, minor editorial corrections (including typographical errors) are recommended.
Response: We thank the Reviewer for this important comment. We would like to clarify that VARC-3 criteria were applied in a strictly structured and transparent manner. Specifically, outcomes were classified as VARC-3 only when explicitly reported in the original publications. In cases where sufficient echocardiographic and procedural data were available (e.g., transvalvular gradients, presence and severity of regurgitation, and related parameters), VARC-3 outcomes were reconstructed based on predefined criteria. These derived endpoints were clearly labelled in Table 1 with a “D” (derived) to ensure full transparency and to distinguish them from directly reported outcomes. When outcome components were suggested but not explicitly or sufficiently documented, this was explicitly acknowledged and treated accordingly in the analysis, labelled with a “/” to ensure transparency. For this reason, we calculated VARC-3 device success percentages both including all derived cases and excluding cases with incomplete data, which resulted in the expected variation in estimated success rates. This approach was intended to provide both a comprehensive and conservative estimate of procedural outcomes while maintaining methodological transparency. We have clarified this approach in various sections of the revised manuscript to improve readability and clarity. Moreover, we corrected typographical errors as suggested.

Reviewer 2 Report

Comments and Suggestions for Authors

First of all, I would like to congratulate you on the work carried out in this systematic review. The topic is highly relevant and relatively underexplored, and therefore compiling the available evidence is essential to better understand current outcomes, the main procedural challenges, and future directions.

In this regard, I would like to offer several comments aimed at improving the overall quality of the manuscript.

• In the abstract, the term “Reults” appears; please revise this typo.
• I would suggest rephrasing the sentence in lines 393–394: “This confirms that ViV in stentless valves carries a coronary risk profile that may exceed…”, as it appears too categorical. These findings should be interpreted with caution and confirmed in future studies.
• Please revise the English language throughout the manuscript.
• I recommend using decimal points instead of commas and ensuring that all abbreviations in the tables are clearly defined in the legends.
• Regarding vascular access, there are nearly 70 patients for whom this information is not reported, representing approximately 25% of the cohort. This missing data should be clarified or discussed.
• The relatively low rate of permanent pacemaker implantation is noteworthy, particularly considering the advanced age of the population and in comparison with rates reported in TAVR for native aortic stenosis. Could the authors provide a possible explanation? For instance, was there a proportion of patients with a pre-existing pacemaker?
• Finally, a certain proportion of patients presented with prosthesis–patient mismatch. It would be interesting to provide comparative data on mismatch rates in valve-in-valve procedures involving stented prostheses.

 

Author Response

Reviewer 2
Comment: In the abstract, the term “Reults” appears; please revise this typo.
Response: We thank the Reviewer for highlighting this typographical error. It has been corrected in the revised version.

Comment: I would suggest rephrasing the sentence in lines 393–394: “This confirms that ViV in stentless valves carries a coronary risk profile that may exceed…”, as it appears too categorical. These findings should be interpreted with caution and confirmed in future studies.
Response: We thank the Reviewer for this helpful suggestion. The sentence has been revised to adopt a more cautious wording, avoiding overly categorical language. The revised version now better reflects the exploratory nature of the findings and acknowledges the need for confirmation in future studies.

Comment: Please revise the English language throughout the manuscript.
Response: We thank the Reviewer for this comment. The manuscript has been thoroughly revised for English language and style throughout.

Comment: I recommend using decimal points instead of commas and ensuring that all abbreviations in the tables are clearly defined in the legends.
Response: We thank the Reviewer for this helpful suggestion. Decimal points have been used throughout the manuscript, and all abbreviations in the tables have been checked and clearly defined in the legends.

Comment: Regarding vascular access, there are nearly 70 patients for whom this information is not reported, representing approximately 25% of the cohort. This missing data should be clarified or discussed.
Response: We thank the Reviewer for this important observation. The issue regarding missing data on vascular access (approximately 25% of the cohort) has been clarified in the revised manuscript. This limitation is now explicitly acknowledged in the Discussion, highlighting its potential impact on the interpretation of procedural characteristics.

Comment: The relatively low rate of permanent pacemaker implantation is noteworthy, particularly considering the advanced age of the population and in comparison with rates reported in TAVR for native aortic stenosis. Could the authors provide a possible explanation? For instance, was there a proportion of patients with a pre-existing pacemaker?
Response: We thank the Reviewer for this insightful comment. A possible explanation for the relatively low rate of permanent pacemaker implantation has been provided in the Discussion section of the revised manuscript. However, data regarding pre-existing permanent pacemaker implantation were inconsistently reported across the included studies and were therefore not available for a substantial proportion of patients, limiting any further quantitative assessment of this variable.

Comment: Finally, a certain proportion of patients presented with prosthesis–patient mismatch. It would be interesting to provide comparative data on mismatch rates in valve-in-valve procedures involving stented prostheses.
Response: We thank the Reviewer for this valuable suggestion. Prosthesis–patient mismatch has been further expanded in the revised manuscript, with comparison to rates reported in valve-in-valve procedures involving stented bioprostheses in the literature. This helps place our findings in the appropriate clinical context.

Reviewer 3 Report

Comments and Suggestions for Authors

-The authors state that JBI critical appraisal tools were applied and that "most studies fulfilled 6–8 JBI criteria, indicating overall low risk of bias." However:

• No JBI appraisal table is provided, neither in the main text nor in the supplementary material. Provide a complete JBI appraisal table as supplementary material.

-The reported VARC-3 device success rate of 63.9% (188/294) is surprisingly low and requires more explicit discussion. Key concerns I have identified:

• The authors acknowledge that hemodynamic variables (post-procedural gradients, PPM) were not uniformly available across studies. Device success under VARC-3 requires absence of PPM and acceptable gradients — if these were frequently missing, the calculated success rate may be systematically underestimated (or overestimated, depending on assumptions made).

-Coronary obstruction is the leading complication and the most clinically consequential finding of this review. Yet the analysis is superficial:

• The relationship between coronary protection use and coronary obstruction events is not analyzed. Were most obstructions in patients who did not receive coronary protection? This is clinically critical.

-The predominance of regurgitation (62.7%) as the mechanism of failure is presented as a key observation and correctly contextualized. However:

• The clinical and procedural implications of failure mode (stenosis vs. regurgitation vs. mixed) on device success or complication risk are not explored, even descriptively.

-The 30-day mortality of 7.48% (22/294) is described as "acceptable" and "consistent with the high-risk profile." However:

• No comparison is made with published 30-day mortality data from larger ViV-TAVR registries in stented bioprostheses

-In a systematic review dominated by case reports, publication bias is a critical concern: favorable cases and dramatic complications are both more likely to be reported than uneventful failures. The manuscript does not formally address this limitation.

Author Response

Reviewer 3.

Comment: The authors state that JBI critical appraisal tools were applied and that "most studies fulfilled 6–8 JBI criteria, indicating overall low risk of bias." However: No JBI appraisal table is provided, neither in the main text nor in the supplementary material. Provide a complete JBI appraisal table as supplementary material.
Response: We thank the Reviewer for this important comment. In response, we have now included the complete JBI critical appraisal tables as supplementary material. These tables provide the full study-level assessment for all included studies, in accordance with the JBI checklists applied in the manuscript.

Comment:  The reported VARC-3 device success rate of 63.9% (188/294) is surprisingly low and requires more explicit discussion. Key concerns I have identified. The authors acknowledge that hemodynamic variables (post-procedural gradients, PPM) were not uniformly available across studies. Device success under VARC-3 requires absence of PPM and acceptable gradients — if these were frequently missing, the calculated success rate may be systematically underestimated (or overestimated, depending on assumptions made).
Response: We thank the Reviewer for this important comment. As already detailed in response to another reviewer and clarified in various sections of the manuscript, VARC-3 device success was assessed using a transparent and structured approach. Specifically, outcomes were considered as VARC-3 when explicitly reported in the original studies. In cases where sufficient echocardiographic and procedural data were available (including post-procedural gradients and regurgitation severity), VARC-3 criteria were independently derived according to predefined definitions and clearly labelled as “derived (D)” in the dataset. When key components of the definition were missing or not reported, this was explicitly acknowledged and those cases were handled accordingly in the calculation. In addition, we calculated VARC-3 device success both including all derived cases and excluding cases with incomplete data, which resulted in the expected variation in estimated success rates. This approach was intended to provide both a comprehensive and conservative estimate of procedural outcomes while maintaining methodological transparency.

Comment: Coronary obstruction is the leading complication and the most clinically consequential finding of this review. Yet the analysis is superficial: The relationship between coronary protection use and coronary obstruction events is not analyzed. Were most obstructions in patients who did not receive coronary protection? This is clinically critical.
Response: We thank the Reviewer for this important comment. The relationship between coronary protection and coronary obstruction was assessed and reported in the manuscript. Specifically, coronary protection was present in 52.2% of patients who experienced coronary obstruction (12 out of 23 cases), indicating that a substantial proportion of events occurred despite the use of protection strategies. However, given the observational nature of the included studies and the selective, non-randomized use of coronary protection—likely reserved for anatomically higher-risk cases—direct comparisons or causal inferences regarding its effect on preventing coronary obstruction cannot be made. This limitation has been explicitly addressed in the revised Discussion.

Comment: The predominance of regurgitation (62.7%) as the mechanism of failure is presented as a key observation and correctly contextualized. However: The clinical and procedural implications of failure mode (stenosis vs. regurgitation vs. mixed) on device success or complication risk are not explored, even descriptively.
Response: We thank the Reviewer for this insightful comment. The clinical and procedural implications of the mode of bioprosthetic failure (stenosis vs. regurgitation vs. mixed) have been addressed in the Discussion section of the revised manuscript in a descriptive and mechanistic manner. Given the nature of the available data and the heterogeneity across studies, a formal stratified assessment was not feasible; therefore, the implications of failure mode on device success and complications were explored in a qualitative and hypothesis-generating manner.

Comment:  The 30-day mortality of 7.48% (22/294) is described as "acceptable" and "consistent with the high-risk profile." However: No comparison is made with published 30-day mortality data from larger ViV-TAVR registries in stented bioprostheses
Response: We thank the Reviewer for this comment. The Discussion has been fully expanded to include comparison with 30-day mortality rates reported in larger ViV-TAVR registries involving stented bioprostheses, providing appropriate clinical context for the observed outcomes while acknowledging inherent differences between populations.

Comment: In a systematic review dominated by case reports, publication bias is a critical concern: favorable cases and dramatic complications are both more likely to be reported than uneventful failures. The manuscript does not formally address this limitation.
Response: We thank the Reviewer for this important comment. Publication bias is an inherent limitation of systematic reviews based largely on case reports and small case series, where both favorable and adverse outcomes may be preferentially reported. This limitation has now been explicitly acknowledged in the Discussion section of the revised manuscript.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have satisfactorily answered all questions.