Title:Relation Between E/e' ratio and NT-proBNP Levels in Elderly Patients with Symptomatic Severe Aortic Stenosis

Transcription

1 Author's response to reviews Title:Relation Between E/e' ratio and NT-proBNP Levels in Elderly Patients with Symptomatic Severe Aortic Stenosis Authors: Mihai Strachinaru Bas M. van Dalen Nicolas Van Mieghem Peter P.T. De Jaegere Tjebbe W. Galema Marielle Morissens Marcel L. Geleijnse Version:2Date:27 May 2015 Author's response to reviews: see over

2 Mihai Strachinaru, MD 20/05/2015 Erasmus MC Rotterdam Concerning: Revision Response to reviewers We thank the reviewers for their careful read and thoughtful comments on our paper. We have carefully taken their comments into consideration in preparing our revision, which has resulted in a paper that is clearer and more compelling. The following summarizes how we responded to reviewers comments: Reviewer 1 comments: 1. The results should be put into clinical perspective and the authors should comment more clearly in the discussion how the findings of their study could be possibly used in clinical practice. Do they suggest a practical approach? In fact, after having tested the correlations between two surrogates of LV filling pressure what would be the practical way of using such an information? On this first point, we agree that the clinical impact of our findings was not sufficiently highlighted. For that reson, in our discussion, on page 12, rows 10-15, the following paragraph was added: In the global population included here, the correlation between the surrogate markers of LV filling pressures remains moderate. Only about 44% of the symptomatic elderly patients with severe aortic stenosis displayed strong correlations. From a practical clinical standpoint, care should be taken in interpreting the results of the usual diastolic function parameters in the presence of the confounders defined in this study: more than mild aortic/mitral regurgitation, severe renal impairement, severe COPD, obesity and left ventricular dysfunction. 2. The authors excluded patients with significant areas of focal LV akinesia. Please define significant areas of focal LV akinesia. In the discussion section, the authors mentioned that they have excluded patients with a previous myocardial infarction involving basal septum and/or basal lateral wall. This information should also appear in the Methods section. Indeed, the definition of the significant areas of focal akinesia was missing from the Methods section, leading to ambiguity. The following definition was added on page 4 rows 4-5: (defined as an akinetic region extending to at least 3 segments, involving the basal septum and/or the basal lateral wall) 3. How many patients had coronary artery disease in this study (defined as >50% stenosis in at least one coronary artery)? Ischemic heart disease is common in elderly patients and could be an important confounding factor. As the study population included a significant

3 number of patients with CABG and as the information is most likely available in this study group I suggest the authors include it in the paper. Coronary artery disease was present in a significant proportion in our population. As suggested by the reviewer, we added the following information on this possible confounder: -on the Methods section, page 5, row 17, the following definition was added: Significant coronary artery disease was defined as >50% stenosis in at least one coronary artery.. Also, Table 1 was modified, and information about the presence of coronary artery disease was added. In the multivariate analysis the coronary artery disease did not reach significance (page 8, rows 3-11). 4. The authors excluded patients with mitral stenosis. However, patients with extensive mitral annulus calcification (a relevant entity given the age of the study group) were not excluded. This is also an important confounder as previous studies demonstrated that E/e ratio is less reliable in this setting. I suggest the authors repeat the analysis after excluding those patients who have severe mitral annulus calcification. Although we do agree that mitral annular calcification is an important problem in assessing the TDI velocities of the mitral ring. Unfortunately, this population of elderly patients with severe aortic stenosis displayed important annular calcification in practically all subjects, making it impossible to exclude it as a confounder. One of the reasons for performing this study was indeed to see if a correlation could be found in spite of some general features of this elderly group. This was already stated in our discussion, page 11, rows 9-12: Our study population has some important unique features. The patients were elderly with extensive aortic and mitral annular calcifications and a significant number of these patients had coronary artery disease and a history of previous CABG. Despite these characteristics a good correlation between the E/e ratio and NT-proBNP was found. 5. I assume all patients were in sinus rhythm. If so, please mention in the Methods section that you have excluded patients with atrial fibrillation/non-sinus rhythm. Not all patients were in sinus rhythm. The information is missing from the Methods section because the E/e ratio is usually considered reliable in atrial fibrillation. All measures were performed according to guidelines, by averaging between 5 and 10 cardiac cycles. Table 1 was modified, by adding information about AF: 47 patients (19%). 6. Patients were all symptomatic. How many of them had symptoms of angina, syncope and heart failure? How many patients were in NYHA class II, III or IV? We do agree that more precision on the symptoms of the patients would add value to our conclusions. The following sentence was added to the Results section, page 6, rows 16-19: All patients were symptomatic. 66 patients(26%) had angina and only 18(7%) syncope. 149(60%) were in class NYHA III and IV, 76 (30%) in class II and 17(7%) in NYHA class I. In 8 patients NYHA class could not be determined.. Also, Table 1 was modified and the information concerning symptoms was added. 7. How many patients have actually undergone TAVR? In how many of these was the LV pressure actually measured invasively? If such information is available what were the correlations of E/e and NT-proBNP with the invasive measurements? On the first question, we answered by changing the expression who were referred for transcatheter aortic valve replacement (TAVI). with who were treated by transcatheter aortic valve replacement (TAVI) in Methods section, page 4 row 8. This was to specify that all patients in the study underwent TAVI. In order to adequately address the next two questions, we added : Although it demonstrates a correlation between echocardiographic

4 and biological markers of elevated left ventricular filling pressures, it is possible that the cutoff value of 15 for the septal E/e is too sensitive (practically all the patients having an E/E ratio above this value, with a mean of 20±9), or that all the selected patients had chronically elevated LVEDP, as reflected by the mean value of NT probnp=217pmol/l. Unfortunately, a better cutoff point could not be determined from our data, because the LVEDP was measured in all patients during the initial phase of the intervention, before TAVI, but already on general anesthesia, which invariably leads to dramatic changes in pressures. on the Study limitation section, page 13, rows There is no Study limitation section in the manuscript. The authors should add such a section, including some of the limitations mentioned above. The cross-sectional nature of the study should also be highlighted. Some correlations had only moderate correlation coefficients in univariate analyses so the strength of the conclusions based on these analyses should be placed in the appropriate context. We do agree that a section showing the limits of the present study would benefit a lot our manuscript. To answer this comment, a Study limitation section was added on page 13. As explained in this section, although cross-sectional, the quality of the data in our study was very good, because the acquisition protocols for clinical, biological and echocardiographic data were very strict and prospectively established. Minor comments 1. In the Results section the E/e ratios are expressed in cm/s while the ratio is actually dimensionless. This should be corrected. Corrected as indicated. The cm/s were removed from page 6 rows The reference numbers appearing in text should be checked. Ref 35 is missing in the text while the Eurofilling study, cited as 36 appears as 35 in the Reference list. Apart from checking the numbers, the layout of the references should also be checked and make consistent, according to the Instructions for authors. The reference for Eurofilling study was adjusted, in order to correspond to the reference list. 3. The last paragraph before the Conclusion discusses the possible impact of study findings upon the costs of medical care in this setting. I understand the idea but it may be a bit confusing for the reader so I would suggest to rephrase this paragraph to avoid the misunderstanding that an echo study is cheaper/easier to perform/obtain than a BNP test. We agree that the phrase could have been missinterpreted, so we modified since a NT probnp assay is relatively expensive on page 12 row 20-21, presently stating, since adding a NT probnp assay to the routine evaluation is relatively expensive. Reviewer 2 comments: 1. The symptoms should be better defined in this population. The symptoms in patients with aortic stenosis can be different: dyspnea, angina, fatigue, reduced exercise capacity or can be aspecific. The authors have to report the percentage of the symptoms in this population. Consequently, it is well known that E/e ratio is correlated with dyspnea as well as NTproBNP values are better correlated with dyspnea. Therefore a sub-analysis in patients with dyspnea or aspecific symptoms could be more interesting. On the first point, we have already answered to the same request of Reviewer 1. Unfortunately, the sub-analysis demanded by the Reviewer could not be made because all patients had symptoms related to aortic stenosis in order to be referred for TAVI by the Heart

5 team. This was stressed on page 6 rows 16-17: All patients were symptomatic and further explained in the study limitation section page 13, rows 4-10: As mentioned above, the population included in this study was carefully selected by a heart team according to present guidelines on the management of valvular heart disease 38. That means first of all that they had to have clinical symptoms in association with a severe aortic stenosis in order to be considered for TAVI. An asymptomatic control group with severe aortic stenosis could have better demonstrated the role of echocardiographic data in the decision making. Such a group is difficult to constitute in an elderly population with several comorbidities. 2. A sub-group analysis in patients with aspecific symptoms could be more interesting and clinically useful. The answer to this point has already been detailed on the previous question. 3. The authors performed several correlation models in an attempt to validate the model excluding patients with potential confounders. In my opinion, maybe it would be better to make a multivariate linear regression analysis including the potential confounders and look at if the model turns out to be predictive. We do of course agree with the reviewer that a multivariable analysis would better demonstrate the role of each of the possible confounders. We added on the Methods section on page 6, row 6: Multivariable linear regression was performed in order to identify the possible confounders. Later, on the section Influence of other potential confounders on the correlations between the diastolic parameters and NT-proBNP, page 8 rows 3-11 we added : A multivariable linear regression model was constructed to assess the potential influence of the clinical, echocardiographic and biological factors on the correlation between E/e ratio and NT-proBNP. On this model, the potential confounders that were identified were: severe COPD (standardized ß=-0,088, p=0,05), obesity (standardized ß=-0,092; p=0,05), significant aortic regurgitation (standardized ß=0,096; p=0,04), significant mitral regurgitation (standardized ß=0,148; p=0,002), altered ejection fraction (standardized ß=0,314; p=0,0001) and renal dysfunction (standardized ß=0,343; p=0,0001). Diabetes (p=0,46), coronary artery disease (p=0,56), pulmonary hypertension (p=0,14), previous CABG (p=0,09) did not significantly alter the correlation between E/e and NT-proBNP. In this multivariable analysis, pulmonary hypertension was added as a possible confounder along with the other variable already analysed. It was defined in Methods section page 5 rows 18-19: Pulmonary hypertension was considered when the estimated pulmonary pressure derived from Doppler tracings of the tricuspid insufficiency was above 40mmHg. and information about the prevalence of pulmonary hypertension was added on Table The clinical implications of these results are not very clear. I believe that, maybe, if the authors clearly demonstrate in the subgroup of patients with aspecific symptoms, the E/e parameter ratio with NT-ProBNP value can help us to better categorized these patients. Otherwise, in patients with well defined symptoms we do not need more additional elements for the decision making. This is indeed an important point, and we answered by adding a few comments in the discussion section page 12 rows 10-15: In the global population included here, the correlation between the surrogate markers of LV filling pressures remains moderate. Only about 44% of the symptomatic elderly patients with severe aortic stenosis displayed strong correlations. From a practical clinical standpoint, care should be taken in interpreting the results of the usual diastolic function parameters in the presence of the confounders defined in

6 this study: more than mild aortic/mitral regurgitation, severe renal impairement, severe COPD, obesity and left ventricular dysfunction.. The second point has already been addressed on the previous comments. 5. What is the cut off value of E/e or NT-ProBNP to decide or suggest for aortic valve intervention according the data of the study? This important point has already been answered on comment 7 of Reviewer 1. Many thanks to the reviewers for the thoughtful and thorough review. Hopefully we have addressed all of your concerns. Sincerely, Dr. Mihai Strachinaru