PEER REVIEW HISTORY ARTICLE DETAILS TITLE (PROVISIONAL)

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1 PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form ( and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. ARTICLE DETAILS TITLE (PROVISIONAL) AUTHORS Tunneled hemodialysis catheter and hemodialysis outcomes: a retrospective cohort study in Zagreb, Croatia Pašara, Vedran; Maksimović, Bojana; Gunjača, Mihaela; Mihovilovic, Karlo; Lončar, Andrea; Kudumija, Boris; Žabiċ, Igor; Knotek, Mladen VERSION 1 - REVIEW GRAPSA EIRINI ARETAIEIO UNIVERSITY HOSPITAL ATHENS GREECE 23-Sep-2015 The paper with the title <<Tunneled hemodialysis catheter and hemodialysis outcomes: a retrospective case-control study>> describes the Tunneled hemodialysis catheter outcomes in relation with the areriovenous fistula from a multiple hemodialysis centres in Croatia. The authors found increased use incidence of Tunneled hemodialysis catheters and a decreased relative catheter patient survival. The question which arises from this study is why are they using so often Tunneled hemodialysis catheters and why is the comparison done only with arteriovenous fistula and not also with the arteriovenous grafts when the aim of the study was to compare the catheters with vascular access in general. The authors have to clarify this point. Also language improvement is suggested. Jennifer MacRae Associate Professor Medicine Division of Nephrology and Department of Cardiac Sciences University of Calgary Calgary, Alberta, Canada 14-Oct-2015 Pasara et al performed a retrospective case control series of patients with tunnelled cuffed catheter with the intent to determine HD outcomes with respect to type of VA. The primary outcome was patient survival as a function of type of VA. 156 patients with a TDC placed during were compared to 97 patients who were dialysing with a functioning AVF. Patients were matched for similar HD vintage and HD centres. Survival was associated with a history of AVF, and previous AVF attempt, multivariate analysis showed age, male sex and TDC associated with negative survival. Introduction The authors should include the VA distribution in their geographic

2 area in order to put their results into context, this information could be added into the introduction. Methods It is unclear how the groups were determined and defined, especially in the cases where pts had used both types of access. What if the pts had an AVF for only part of the study duration which group are they analyzed in? For the pts that started on HD with a CVC and then had an AVF created but did not use it right away (presumably several months )are they an AVF or CVC group? Results Given that duration of predialysis care influences VA choice and potentially outcomes, do the authors have any data on predialysis care duration; this should be included in Table 1. Any duplicated text that is also found in Table 1 should be omitted from this paragraph. Table 1 should also include the numbers and percent of pts with a catheter as an exclusive type of VA, AVF as exclusive type of VA and those with history of mixed VA Discussion Fundamentally I think it is hard to attribute survival to type of access if pts are switching back and forth between the two groups. A more thorough discussion or acknowledgement of this needs to be considered. As the authors indicate, patient confounders may be the reason for any differences in survival ie sicker, unwell patients end up with a catheter and thus do not do as well as the healthy pts who get referred for fistula creation and end up with a functioning fistula etc. Conclusions from this data set are limited given the observational nature of the study. The authors should modify their conclusion statement to be less decisive. Parienti Caen University Hospital France 30-Oct The paper is described as a casecontrol study in the title. However, I understand this is rather a retrospective cohort study which is consistent with the statistical methods used by the authors. 2. The patients with AVF or tunnelled HD CVC are so different at baseline (i.e. stroke in the past) that any causality about outcome remains for me uncertain, even with multivatiate cox models. Probably that patients with a short expected survival were provided TDC rather than AVF. 3. The decimals are sometimes a dot, sometimes a comma. I think it should be consistantly a dot. 4. Giving 3 decimals after the dot may be overprecise given your sample size ans precision. 1 digit is enough. 5. In general, (i.e. T3 and T4), giving a Table with only percentages is disputable. The reader need to know the sample size evalauted. It is very hard to understand your Figures (KM curves) w/o the text. You should provide a title to each Figure, add the number at risk overtime.

3 VERSION 1 AUTHOR RESPONSE Response to Reviewer #1 (Eirini Grapsa) Comments C1: The paper with the title "Tunneled hemodialysis catheter and hemodialysis outcomes: a retrospective case-control study" describes the tunneled hemodialysis catheter outcomes in relation with the areriovenous fistula from a multiple hemodialysis centres in Croatia. The authors found increased use incidence of tunneled hemodialysis catheters and a decreased relative catheter patient survival. The question which arises from this study is why are they using so often tunneled hemodialysis catheters and why is the comparison done only with arteriovenous fistula and not also with the arteriovenous grafts when the aim of the study was to compare the catheters with vascular access in general. The authors have to clarify this point. A1: Catheter to fistula ratio in our study does not reflect situation in Croatia, as we did not describe prevalence of dialysis catheter use in Croatia in the present study. The rate of patients who are dialyzed through tunnelled dialysis catheter among all patients on hemodialysis in Croatia is approximately 20% (now inserted in the page 2, ln of the manuscript). University Hospital Merkur has the largest catheter placement programme in Croatia and is a referral center for tunnelled dialysis catheters to which patients from many dialysis centres are referred. Unfortunately, we could not make comparison with grafts, because they are very infrequently used in Croatia. C2: Also language improvement is suggested. A2: We reviewed and corrected language. Response to Reviewer #2 (Jennifer MacRae) Comments C1: The authors should include the VA distribution in their geographic area in order to put their results into context, this information could be added into the introduction. A1: Thank you for your suggestion. We changed the introduction section on page 2, lines C2: It is unclear how the groups were determined and defined, especially in the cases where pts had used both types of access. What if the pts had an AVF for only part of the study duration which group are they analyzed in? For the pts that started on HD with a CVC and then had an AVF created but did not use it right away (presumably several months) are they an AVF or CVC group? A2: Catheter patients were all consecutive patients who underwent tunneled hemodialysis catheter placement procedure in University Hospital Merkur. Patients who had an AVF for only part of the study duration were analyzed in AVF group. However, there were only 6 patients in whom AVF stopped working, and who were subsequently dialysed via catheters. Similarly, there were only four patients who started with hemodialysis through CVC and then had an AVF created. They were analysed in the catheter group. However, we showed that survival was not significantly different in patients who were dialyzed exclusively through AVF and those who were converted from AVF to TDC, while it was worse in patients dialysed exclusively via TDC (Table 2). C3: Given that duration of predialysis care influences VA choice and potentially outcomes, do the authors have any data on predialysis care duration; this should be included in Table 1. Any duplicated text that is also found in Table 1 should be omitted from this paragraph. Table 1 should also include the numbers and percent of pts with a catheter as an exclusive type of VA, AVF as exclusive type of VA and those with history of mixed VA. A3: Unfortunately, we are not able to provide any data on predialysis care duration. We ommited

4 duplicated text from results section. We now also included the the numbers and percent of pts with a catheter as an exclusive type of VA, AVF as exclusive type of VA and those with history of mixed VA. As the number of mixed VA patients was only ten, we included these data in the text of the Results (pg 4, ln 13-14, 20-21), in order to avoid adding additional four columns in the Table 1. However, if the reviewer would strongly prefer this data in the Table, we would provide additional Table. C4: Fundamentally I think it is hard to attribute survival to type of access if pts are switching back and forth between the two groups. A more thorough discussion or acknowledgement of this needs to be considered. A4: This is a valid comment and we agree that it would be hard to attribute survival to type of access if patient group switch was frequent. However, we showed with an additional analysis that there was a statistically significant difference in patient survival between TDC and AVF group in patients who exclusively used only one VA type and have never had a VA conversion. Please see Table 2. C5: As the authors indicate, patient confounders may be the reason for any differences in survival ie sicker, unwell patients end up with a catheter and thus do not do as well as the healthy pts who get referred for fistula creation and end up with a functioning fistula etc. Conclusions from this data set are limited given the observational nature of the study. The authors should modify their conclusion statement to be less decisive. A5: We agree with the reviewer and have edited the text to state that our conclusion is only suggested by our results and should be substantiated by a RCT. Response to Reviewer #3 (Jean-Jacques Parienti) Comments C1: The paper is described as a casecontrol study in the title. However, I understand this is rather a retrospective cohort study which is consistent with the statistical methods used by the authors. A1: Thank you for this comment- we now changed the study designation into a retrospective cohort study throughout the manuscript. C2: The patients with AVF or tunnelled HD CVC are so different at baseline (i.e. stroke in the past) that any causality about outcome remains for me uncertain, even with multivatiate cox models. Probably that patients with a short expected survival were provided TDC rather than AVF. A2: The problem of patient matching in this type of study is always present, but in general the two groups were quite well matched. The groups were primarily matched according to dialysis unit and time of VA placement. However, we also showed that patients were also well-matched with respect to gender, HD vintage and comorbidities. Among them, there was statistically significant difference between groups only in stroke prevalence, which eventually did not turn out as an independent negative risk factor for patient or access survival in a multivariate Cox regression. Physician preference with respect to vascular access type in a certain patient could not be accounted for. However, it is very unlikely that a prospective RCT would be ever performed for the TDC and AVF comparison. C3: The decimals are sometimes a dot, sometimes a comma. I think it should be consistantly a dot. A3: We corrected the text as suggested. C4: Giving 3 decimals after the dot may be overprecise given your sample size and precision. 1 digit

5 is enough. A4: We corrected the text as suggested. C5: In general, (i.e. T3 and T4), giving a Table with only percentages is disputable. The reader need to know the sample size evalauted. It is very hard to understand your Figures (KM curves) w/o the text. You should provide a title to each Figure, add the number at risk overtime. A5: We corrected the tables and figures as suggested. Figure titles are also now included. VERSION 2 REVIEW Jennifer MacRae University of Calgary Canada 18-Feb-2016 I have 2 minor suggestions for the authors 1) Given the author's high rate of catheter survival as compared to other catheter studies, the readers will want to know what types (brands) of catheters were in used during this study; the authors could add this information into the methods section 2) There is one randomized trial of catheter vs fistula (clinical trials.govclinicaltrials.gov Identifier: NCT therefore i suggest the authors change their statement on page 11, line 4-5 to " prospective RCTS, which are difficult to perform" instead of " prospective RCTSs which are unlikely to be performed for ethical reasons" VERSION 2 AUTHOR RESPONSE Reviewer s comments and author responses: 1) Given the author's high rate of catheter survival as compared to other catheter studies, the readers will want to know what types (brands) of catheters were in used during this study; the authors could add this information into the methods section We inserted required information regarding catheter type in the Patient and Methods section. 2) There is one randomized trial of catheter vs fistula (clinical trials.govclinicaltrials.gov Identifier: NCT therefore i suggest the authors change their statement on page 11, line 4-5 to " prospective RCTS, which are difficult to perform" instead of " prospective RCTSs which are unlikely to be performed for ethical reasons" We changed the sentence regarding the possibility to perform TDC vs. AVF RCT into prospective RCTS, which are difficult to perform, as requested by the reviewer.