Predictors of Mortality Following Aortic Valve Replacement in Aortic Stenosis Patients

Round 1

Reviewer 1 Report

In this paper, the authors evaluated the predictors of mortality in patients with severe aortic stenosis, undergoing surgical valve replacement. The main indicators of lethal outcome were diabetes, obesity, frequent ventricular ectopy before surgery, hemoglobin level below 12 g/dL, hematocrit level below 39%, longer cardiopulmonary bypass time and aortic cross-clamp time, additional mitral and tri-cuspid valve interventions.

The paper is objectively good written and after a careful evaluation of this manuscript these are my concerns:

 

• Line 45: standard treatment in the low-risk group of patients with severe aortic stenosis is surgical but you have to clarify both mechanical and biological prosthesis as available options.
• Line 51-52: please cite the most recent European Guidelines on valvular heart disease (https://academic.oup.com/ejcts/article/60/4/727/6358816?login=false), and add the concept that the patient can decide the treatment (surgical or transcatheter).
• Table 2-Echocardiographic parameters: if available, please add more details about echocardiographic findings if were collected, such as: peak velocity; absolute value and percentage of patients with bicuspid native valve; absolute value and percentage of patients with regurgitation and its grading.
• Table 2-Laboratory parameters: have you dosed BNP or NTproBNP? If yes, please add this important information.
• Results: provide more details about the main cause of death of the patients.

 

 

 

Author Response

Response to Reviewer 1

In this paper, the authors evaluated the predictors of mortality in patients with severe aortic stenosis, undergoing surgical valve replacement. The main indicators of lethal outcome were diabetes, obesity, frequent ventricular ectopy before surgery, hemoglobin level below 12 g/dL, hematocrit level below 39%, longer cardiopulmonary bypass time and aortic cross-clamp time, additional mitral and tri-cuspid valve interventions.

The paper is objectively good written and after a careful evaluation of this manuscript these are my concerns:

We are grateful to our reviewer for his or her very important comments to our work. We tried to correct all shortcomings according to these comments. All changes in the text are highlighted in green.

 

Line 45: standard treatment in the low-risk group of patients with severe aortic stenosis is surgical but you have to clarify both mechanical and biological prosthesis as available options.

It is really so. We have changed this sentence in the text.

Surgical aortic valve replacement (SAVR) of the affected valve represent standard treatment in the low risk group of patients (< 75 years and STS-PROM/EuroSCORE II< 4%) or in patients who are operable and unsuitable for transfemoral TAVI.

 

Line 51-52: please cite the most recent European Guidelines on valvular heart disease (https://academic.oup.com/ejcts/article/60/4/727/6358816?login=false), and add the concept that the patient can decide the treatment (surgical or transcatheter).

We have replaced the link and added the most recent actual clinical recommendations.

Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, Capodanno D, Conradi L, De Bonis M, De Paulis R, Delgado V, Freemantle N, Gilard M, Haugaa KH, Jeppsson A, Jüni P, Pierard L, Prendergast BD, Sádaba JR, Tribouilloy C, Wojakowski W; ESC/EACTS Scientific Document Group. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur J Cardiothorac Surg. 2021, 60(4): 727-800. doi: 10.1093/ejcts/ezab389. PMID: 34453161.

We have also added the following information.

Also, the choice of SAVR or TAVI depends on individual clinical, anatomical and procedural characteristics, values and expectations of the informed patient.

 

Table 2-Echocardiographic parameters: if available, please add more details about echocardiographic findings if were collected, such as: peak velocity; absolute value and percentage of patients with bicuspid native valve; absolute value and percentage of patients with regurgitation and its grading.

We additionally selected the echocardiographic parameters, mentioned by the reviewer from the database and added them to the Table 2 (peak velocity, effective orifice area, absolute value and percentage of patients with bicuspid native valve, absolute value and percentage of patients with regurgitation and its grading).

 

Table 2-Laboratory parameters: have you dosed BNP or NTproBNP? If yes, please add this important information.

We absolutely agree that BNP and proBNP indicators are very important prognostic markers, however, in our clinic these parameters are not a routine for all patients and are not included in the standard perioperative protocol for the management of all patients with aortic stenosis, this analysis is performed if indicated. Therefore, this indicator was not analyzed.

 

Results: provide more details about the main cause of death of the patients.

We have added this information to the article in the "Results" section.

The main causes of death were: acute heart failure (n=7), pneumonia (n=5), bleeding (n=4), cardiac arrhythmias (n=3), acute renal failure (n=1), complicated re-operation (n=2).

Reviewer 2 Report

Esteemed,

 

I had the pleasure and honor to review the paper: „Predictors of Lethal Outcome in Aortic Stenosis Patients after Aortic Valve Replacement“, by Vladimir Shvartz and associates. The study was aimed to identify risk factors and predictors of hospital mortality associated with aortic valve replacement surgery.

This retrospective study was well planned and conducted, with a clear end-point and a wide range of perioperative variables analyzed. Yet, I have a few concerns, which I would like to list, in order of relevance:

1. Language corrections should be done throughout the paper so that phrases like: „…the surgery was conducted retrogradely through the coronary sinus under the conditions of CPB…“ (lines 130-131), should be more understandable and readable.
2. There are no data about mechanical prostheses models and sizes used as well as no parameters depicting appropriate valve size selection (i.e. effective orifice area index). I think, (If there are such data in the database), this might add more light on postoperative hemodynamics and outcome.
3. Table 6 (independent predictors of mortality) contains „etc“ in the last row – which is (I suppose) just a typo and should be corrected.

Finally, I support the publishing of this paper after minor revisions.

Author Response

Response to Reviewer 2

I had the pleasure and honor to review the paper: „Predictors of Lethal Outcome in Aortic Stenosis Patients after Aortic Valve Replacement“, by Vladimir Shvartz and associates. The study was aimed to identify risk factors and predictors of hospital mortality associated with aortic valve replacement surgery.

This retrospective study was well planned and conducted, with a clear end-point and a wide range of perioperative variables analyzed. Yet, I have a few concerns, which I would like to list, in order of relevance:

We are grateful to our reviewer for his or her very important comments to our work. We tried to correct all shortcomings according to these comments. All changes in the text are highlighted in green.

 

Language corrections should be done throughout the paper so that phrases like: „…the surgery was conducted retrogradely through the coronary sinus under the conditions of CPB…“ (lines 130-131), should be more understandable and readable.

We corrected this part of the text in the article.

Patients underwent standard sternotomy and conventional open chest cardiopulmonary bypass (CPB), moderate hypothermia, retrograde pharmacological and hypothermic cardioplegia.

 

There are no data about mechanical prostheses models and sizes used as well as no parameters depicting appropriate valve size selection (i.e. effective orifice area index). I think, (If there are such data in the database), this might add more light on postoperative hemodynamics and outcome.

We understand the importance of the choice of the valve prosthesis model and size for each patient, the success of the operation and long-term results largely depend on the choice of the optimal size of the prosthesis. In our clinic, the surgeon focuses on the clinical characteristics of the patient, takes into account the age and body surface area, as well as echocardiographic parameters (fibrous ring of the aortic valve). The selection of each prosthesis takes place individually in order to achieve the target hemodynamic parameters. Economic aspects also influence the choice of the prosthesis model.

In our opinion, these data require separate systematization and analysis. As for the valve models, there were a lot of them during the analyzed period.

 

Table 6 (independent predictors of mortality) contains „etc“ in the last row – which is (I suppose) just a typo and should be corrected.

The typo in the table 6 was corrected, ‘etc’ was deleted.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

In this paper, authors analyzed patients with aortic stenosis who 
underwent surgical treatment in 2013-2018 with the aim of understanding of the risk factors for the development of adverse outcomes. They found that diabetes mellitus, BMI more than 29,  FVE before surgery, MV disease, hemoglobin level below 120 g/l, hematocrit level below 39%, longer CPB time and ACC time, additional mitral and tricuspid valve interventions are the main risk factors of adverse outcome. 

Some comments:

• authors did not comment about symptoms, while it is known that symptoms are very important in aortic stenosis to guide the diagnostic treatment. Please add some comments on NYHA class, for example. I would suggest to refer to "Value of ejection fraction/velocity ratio in the prognostic stratification of patients with asymptomatic aortic valve stenosis. Echocardiography. 2018 Dec;35(12):1909-1914" to explain the difficulties of stratifying asymptomatic patients with moderate to severe aortic stenosis;
• patients had low percentage of drugs, as far as less than half used beta-blockers; any esplanations of this?
• in the Discussion, line 275, authors comment on overweight as negative factors on survival. Please add this reference on support of this: "Obesity, Cardiac Remodeling, and Metabolic Profile: Validation of a New Simple Index beyond Body Mass Index. J Cardiovasc Echogr. 2018 Jan-Mar;28(1):18-25".
• among the data at the multivariate, authors found increased systolic and diastolic dimensions of the left ventricle, but they did not comment on this. I would suggest to spend some words on this result, as far as it is known that the remodelling pattern of the left ventricle is an important predictive factor of outcome, see for reference this interesting paper "New classification of geometric ventricular patterns in severe aortic stenosis: Could it be clinically useful? Echocardiography. 2018 Aug;35(8):1077-1084" where there is the  description of different cardiac geometric phenotypes that develop as a response to pressure overload in aortic valve stenosis. 

Minor point:

• in the abstract, the abbreviations are not previously explicated.
• line 215, The parameters of BMI higher than 30 U: BMI is not measured in U;

Overall, the paper is well designed. These suggestions could improve some aspects of the entire manuscript.

Author Response

Response to Reviewer 1

 

In this paper, authors analyzed patients with aortic stenosis who 
underwent surgical treatment in 2013-2018 with the aim of understanding of the risk factors for the development of adverse outcomes. They found that diabetes mellitus, BMI more than 30, FVE before surgery, hemoglobin level below 120 g/l, hematocrit level below 39%, longer CPB time and ACC time, additional mitral and tricuspid valve interventions are the main risk factors of adverse outcome.

 

We are grateful to our reviewer for his or her very important comments to our work. We tried to correct all shortcomings according to these comments. All changes in the text are highlighted in green.

 

Some comments:

• authors did not comment about symptoms, while it is known that symptoms are very important in aortic stenosis to guide the diagnostic treatment. Please add some comments on NYHA class, for example. I would suggest to refer to "Value of ejection fraction/velocity ratio in the prognostic stratification of patients with asymptomatic aortic valve stenosis. Echocardiography. 2018 Dec;35(12):1909-1914" to explain the difficulties of stratifying asymptomatic patients with moderate to severe aortic stenosis.

 

The study was retrospective and archival data from medical documentation were used for the analysis. We agree with the reviewer and understand the extreme importance of analyzing of the clinical picture of patients with aortic stenosis when choosing management tactics, however, clinical symptoms were not analyzed in the study due to the fact that this information was collected retrospectively and could be incomplete and lead to unreliable results.

We have added some comments to the discussion section about the functional class of heart failure before surgery, which can help us to assess the preoperative status of patients. This information is highlighted in green in the article.

When comparing the groups according to the severity of chronic heart failure, no statistically significant differences were obtained (p=0.849). Apparently, this was due to the fact that about 70% of patients in both groups were already in NYHA class III-IV. It is also known that surgery should be considered in asymptomatic patients and in patients with aortic stenosis at earlier stages in order to reduce the risk of surgical intervention. The use of echocardiography capabilities is an effective strategy in this cohort of patients. (Antonini-Canterin F, Di Nora C, Cervesato E, Zito C, Carerj S, Ravasel A, Cosei I, Popescu AC, Popescu BA. Value of ejection fraction/velocity ratio in the prognostic stratification of patients with asymptomatic aortic valve stenosis. Echocardiography. 2018; 35(12):1909-1914. doi: 10.1111/echo.14182.)

 

• patients had low percentage of drugs, as far as less than half used beta-blockers; any esplanations of this?

 

We suppose a small percentage of drug treatment before surgery because of the fact that patients had aortic stenosis, which already required surgical intervention, and so patients were immediately referred for surgery.

Therefore, optimal drug treatment was not prescribed in some patients. According to the recommendations of ESC 2021, drug therapy does not affect the prognosis and progression of aortic stenosis. In addition, some groups of drugs according to the recommendations are limited in use in patients with severe aortic stenosis. Since there were no significant differences in therapy between the compared groups, we did not describe the drug treatment in detail in the article.

 

• in the Discussion, line 275, authors comment on overweight as negative factors on survival. Please add this reference on support of this: "Obesity, Cardiac Remodeling, and Metabolic Profile: Validation of a New Simple Index beyond Body Mass Index. J Cardiovasc Echogr. 2018 Jan-Mar;28(1):18-25".

We have read this article, it is relevant for assessing the impact of overweight on the risk of cardiovascular complications, so we considered it appropriate to add this link to our work. (Antonini-Canterin F, Di Nora C, Poli S, Sparacino L, Cosei I, Ravasel A, Popescu AC, Popescu BA. Obesity, Cardiac Remodeling, and Metabolic Profile: Validation of a New Simple Index beyond Body Mass Index. J Cardiovasc Echogr. 2018; 28(1):18-25. doi: 10.4103/jcecho.jcecho_63_17.).

 

• among the data at the multivariate, authors found increased systolic and diastolic dimensions of the left ventricle, but they did not comment on this. I would suggest to spend some words on this result, as far as it is known that the remodelling pattern of the left ventricle is an important predictive factor of outcome, see for reference this interesting paper "New classification of geometric ventricular patterns in severe aortic stenosis: Could it be clinically useful? Echocardiography. 2018 Aug;35(8):1077-1084" where there is the description of different cardiac geometric phenotypes that develop as a response to pressure overload in aortic valve stenosis. 

Indeed, we consider your remark is correct. And we made explanations in the article about obtained indicators.

Univariate analysis yielded statistically significant independent predictors of lethal outcome: coronary heart disease, diabetes mellitus, FVE, surgical intervention on the mitral valve, more than three simultaneous interventions, etc. (Table 5). Besides, statistically significant differences were obtained for the end-diastolic dimension index (LVEDD/BSA cm/m²>2,39) and end-systolic dimension index (LVESD/BSA cm/m² >1,68): both were greater in the group of patients with a lethal outcome (OR 5,01; CI 1,07-23,4 and OR 4,81; CI 1,03-22,5), respectively. Assessing the remodeling patterns of LV is an important step for the evaluation of patients with aortic stenosis because it impacts on prognosis (Di Nora C, Cervesato E, Cosei I, Ravasel A, Popescu BA, Zito C, Carerj S, Antonini-Canterin F, Popescu AC. New classification of geometric ventricular patterns in severe aortic stenosis: Could it be clinically useful? Echocardiography. 2018; 35(8): 1077-1084. doi: 10.1111/echo.13892.).

This information has been added to the article.

 

Minor point:

 

• in the abstract, the abbreviations are not previously explicated.

We have added explications of the abbreviations used in the abstract.

 

• line 215, The parameters of BMI higher than 30 U: BMI is not measured in U;

We have corrected the article. The BMI parameter is measured in kg/m2.

 

Overall, the paper is well designed. These suggestions could improve some aspects of the entire manuscript.

Author Response File: Author Response.docx

Reviewer 2 Report

Authors have performed a prospective study including patients with aortic stentosis underwent SAVR to analyze the potential predictors of lethal outcome.

I would like to do some comments:

 

Abstract: When you use the first time an acronym must go next to the whole word in order to facilite the reading and understanding.

 

Introduction: Authors affirm that TAVR is only reccomended for patients with high and extremely high surgical risk. However, this affirmation is not correct after the publication of the last trials and last European and American guidelines. TAVR can be used as alternative in intermediate surgical risk and the first line treatment in patients higher than 75 years old with indepence of surgical risk.

 

Methods: It’s important to show a Flowchart of the patients with aortic stenosis during the time of the study. ¿How many patients underwent TAVR? ¿How many patients underwent conservative management? ¿How many patients didn’t sign the informed consent to participate in the study?

 

Results: Authors observe that the factors who predict a higher risk of mortality were Diabetes Mellitus, Overweight, FVE, Hemoglobin level,… However, the majority of these factors are already included in the scores with internal and external validation.

I have not clear the potential addition of this study to the current literature about that.

Author Response

Response to Reviewer 2

 

Authors have performed a prospective study including patients with aortic stentosis underwent SAVR to analyze the potential predictors of lethal outcome.

 

We are grateful to our reviewer for his or her very important comments to our work. We tried to correct all shortcomings according to these comments. All changes in the text are highlighted in green.

 

I would like to do some comments:

 

Abstract: When you use the first time an acronym must go next to the whole word in order to facilite the reading and understanding.

We have added explications of the abbreviations used in the abstract.

 

Introduction: Authors affirm that TAVR is only reccomended for patients with high and extremely high surgical risk. However, this affirmation is not correct after the publication of the last trials and last European and American guidelines. TAVR can be used as alternative in intermediate surgical risk and the first line treatment in patients higher than 75 years old with indepence of surgical risk.

Thank you for your comment. It is really so. We corrected the "Introduction" section when describing the choice of tactics for surgical treatment of patients based on the latest recommendations. This information is highlighted in green in the article.

Cardiopulmonary bypass (CPB) surgery and replacement of the affected valve with a mechanical prosthesis represent standard treatment in the low risk group of patients (< 75 years and STS-PROM/EuroSCORE II< 4%) or in patients who are operable and unsuitable for transfemoral TAVI. In patients with high and extremely high risk of surgical treatment (STS-PROM/EuroScore II>8%) and in older patients (>75 years) or unsuitable for surgery transcatheter valve replacement is recommended. Also the choice of SAVR or TAVI depends on individual clinical, anatomical and procedural characteristics. Patients whose life expectancy is under a year are considered inoperable [4, 6, 8, 10, 11, 13].

 

Methods: It’s important to show a Flowchart of the patients with aortic stenosis during the time of the study. ¿How many patients underwent TAVR? ¿How many patients underwent conservative management? ¿How many patients didn’t sign the informed consent to participate in the study?

This article includes an analysis of patients who underwent surgical treatment of the aortic valve. The criteria for inclusion of patients in the analysis was their aortic valve replacement with a mechanical prosthesis. Patients with a biological prosthesis or those who underwent the TAVI procedure, as well as patients receiving medical treatment were not included in this analysis. This information is given in the section "2.1. Study population" lines 67-73.

Information consent was obtained from all patients. This information is specified in the section "Informed Consent Statement" lines 359-360.

 

Results: Authors observe that the factors who predict a higher risk of mortality were Diabetes Mellitus, Overweight, FVE, Hemoglobin level,… However, the majority of these factors are already included in the scores with internal and external validation.

I have not clear the potential addition of this study to the current literature about that.

 

In the article we presented the experience of surgical treatment of patients with aortic stenosis in our department for the period 2014-2020. In addition, the peculiarity of the work is that all operations were performed according to the same technique (with retrograde cardioplegia). Of course, there are similar trials in the world literature. However, if we turn to the world literature, the problem of predicting and assessing the risk of early complications during surgical correction of aortic stenosis with a mechanical prosthesis remains relevant to this day. Data from various sources are accumulating: cohort studies, registers of cardiac surgical interventions, which could become a source of systematic reviews and meta-analyses in the future. This accumulation of data, the accumulation of experience of various practices from different countries is an important component of the development of medical science.

 

Author Response File: Author Response.docx

Reviewer 3 Report

I have read with interest the manuscript "Predictors of lethal outcome in aortic stenosis patients after aortic valve replacement".

The manuscript is well-written and the data are clearly presented. Anyhow I have significant concerns regarding the novelty of the paper (several papers have previously investigated the predictors of mortality after surgical aortic valve replacement) and the "new" take-home messages of this paper are consequently not clear. In this regard the authors should better state the potential novelty of their manuscript or which are the additional information or differences compared to previous works or multi-center international registries. 

Specifically, I have major concerns regarding the statistical analysis conducted, at first comparing just 22 patients versus 720.

Secondly, in line with the low numbers of events (in-hospital mortality), the multivariable regression model includes too many variables used as possible predictors. In this regard, following the "one in ten rule", for logistic regression, just two predictors can be fitted reliably. 

Based on this, it is difficult to make a real judgment upon the consistency of your results. 

In this regard I may suggest the authors to make a different comparison, for example the outcome and predictors of an early versus late cardiovascular mortality outcome.

Author Response

I have read with interest the manuscript "Predictors of lethal outcome in aortic stenosis patients after aortic valve replacement".

We are grateful to our reviewer for his or her very important comments to our work.

 

The manuscript is well-written and the data are clearly presented. Anyhow I have significant concerns regarding the novelty of the paper (several papers have previously investigated the predictors of mortality after surgical aortic valve replacement) and the "new" take-home messages of this paper are consequently not clear. In this regard the authors should better state the potential novelty of their manuscript or which are the additional information or differences compared to previous works or multi-center international registries.

In the article we presented the experience of surgical treatment of patients with aortic stenosis in our department for the period 2014-2020. In addition, the peculiarity of the work is that all operations were performed according to the same technique (with retrograde cardioplegia). Of course, there are similar trials in the world literature. However, if we turn to the world literature, the problem of predicting and assessing the risk of early complications during surgical correction of aortic stenosis with a mechanical prosthesis remains relevant to this day. Data from various sources are accumulating: cohort studies, registers of cardiac surgical interventions, which could become a source of systematic reviews and meta-analyses in the future. This accumulation of data, the accumulation of experience of various practices from different countries is an important component of the development of medical science.

 

Specifically, I have major concerns regarding the statistical analysis conducted, at first comparing just 22 patients versus 720.

Secondly, in line with the low numbers of events (in-hospital mortality), the multivariable regression model includes too many variables used as possible predictors. In this regard, following the "one in ten rule", for logistic regression, just two predictors can be fitted reliably.

In the statistical analysis, first we used binary indicators and one-way logistic regression model with the calculation of the odds ratio. This analysis provides an assessment of the independent influence of a particular single qualitative factor on the outcome under study. In this model, several factors turned out to be significant, indeed (Table 5). After that, in the multivariate model, we used only statistically significant factors from the one-factor model, not all available factors. Multivariate analysis evaluates the influence of several factors at the same time, taking into account their influence on each other and the displacement of less powerful factors by more powerful ones. Therefore, we have only two statistically significant factors in this model: frequent ventricular ectopy (FVE) and CPB time> 144 min.This method is always used in classical cohort studies to identify predictors of the studied outcome and event. It doesn't matter if the number of events is low or the frequency of the event is high.

 

Based on this, it is difficult to make a real judgment upon the consistency of your results. 

In this regard I may suggest the authors to make a different comparison, for example the outcome and predictors of an early versus late cardiovascular mortality outcome.

We agree and support your recommendation. We plan to analyze the long-term predictors of this cohort of patients. An important point in the long-term period will be drug therapy and maintenance of the target INR range in these patients. This article includes only initial clinical and instrumental data, factors of the surgery process.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

In this paper, authors analyzed patients with aortic stenosis who 
underwent surgical treatment in 2013-2018 with the aim of understanding of the risk factors for the development of adverse outcomes. They found that diabetes mellitus, BMI more than 29,  FVE before surgery, MV disease, hemoglobin level below 120 g/l, hematocrit level below 39%, longer CPB time and ACC time, additional mitral and tricuspid valve interventions are the main risk factors of adverse outcome. 

Authors have addressed all my previous concerns. The paper deserves space in the current form.

Reviewer 2 Report

Authors have performed the modifications that I suggested. However, I continue thinking that is important to do a Flowchart that explain the number of patients with aortic stenosis during the time of the study. It is important for the lector to know how many patients with aortic stenosis were treated in the center, how many underwent SAVR, TAVI, conservative management,...

 

Reviewer 3 Report

I have read the authors response to previous review. 

As regards the potential novelty of the manuscript I suggest to include or remark the peculiarity of this work in the Discussion, as it was not clear from a first reading.

As regards the multivariable model, I  know how it works and the method employed is correct by itself (univariate model, then multivariable model with the factors that resulted significative in the univariate one). Anyhow, although the "one-in-ten" rule is not a strict validated rule in statistics, it is important and useful for improving the truthfulness of the model. The one-in-ten rule states that one predictive variable can be studied for every ten events. In your response you mention just the two significant independent variables you got in the multivariate model, but you inserted many variables before in order to predict your outcome of just 22 patients. 

Unfortunately I remain of the idea that building a predictive model upon 22 patients/events is statistical weak.