Impact of type of dialyzable beta-blockers on subsequent risk of mortality in patients receiving dialysis: A systematic review and meta-analysis

Tzu-Hsuan Yeh; Kuan-Chieh Tu; Kuo-Chuan Hung; Min-Hsiang Chuang; Jui-Yi Chen

doi:10.1371/journal.pone.0279680

Peer Review History

Original SubmissionSeptember 1, 2022
24 Oct 2022 Decision Letter - Gianpaolo Reboldi, Editor PONE-D-22-24265Impact of type of dialyzable Beta-blockers on subsequent risk of mortality in patients receiving dialysis: A Systematic Review and Meta-AnalysisPLOS ONE Dear Dr. Chen, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. The referees found your work of potential interest, but they also noted several issues that deserve attention (see their reports below). We invite you to submit a revised version of the manuscript that addresses all issues thoroughly and unequivocally. Please note that both referees had several methodological concerns that should be dealt with with the utmost care. Please submit your revised manuscript by Dec 05 2022 11:59PM. 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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Chen et al present a systematic review and meta-analysis on mortality and cardiovascular outcomes in dialysis patients treated with high vs. low dialyzable beta blockers. 4 retrospective studies were included. The authors found no difference in mortality, MACE, or MI but a significant difference in heart failure. While the study is overall clear and analytic methods seem overall appropriate, I do have several questions/comments for the authors to consider: 1. The English needs to be improved throughout the paper prior to being suitable for publication. 2. The study compares high vs. low dialyzable beta blockers. It would be helpful to inform the reader what threshold is used to determine high vs. low dialyzability. 3. I may have missed this but how was MACE defined? I assume acute MI and heart failure were included in this (though they are also listed as separate outcomes? Were any other cardiovascular outcomes included in MACE? 4. One of the included studies included peritoneal dialysis patients. I find it questionable of whether to include these patients given the inherent differences in dialysis modalities. For instance, given the much slower/prolonged clearance with peritoneal dialysis, one would think the contribution of intradialytic hypotension from beta-blocker clearance would be much less significant in this population. 5. I am confused by the heart failure results. The abstract states that "HDBBs were associated with significant reduction of risk in HF compared with individuals with LDBBs". However, when I look at Figure 2D which is showing heart failure outcomes seems to show that the results favor LDBBs which seems contrary to the prior statement. Further, this conclusion is drawn from only two studies, one (Wu) which contributes 97% of the relative weight while the other (Weir) is questionable as per the authors as bisoprolol may have been included in the wrong HDBB/LDBB category in that study. This draws into question any conclusions that can be drawn from this analysis. Reviewer #2: The present is an interesting and timely meta-analysis Some issues should be addressed Abstract. Sentence in the results from "The risk of MACE to............]." appeared of no clear meaning and truncated Abstract. It is not clear if the present results were in hospital or at which time of follow up Methods. It is not clear if results derived from multivariable adjustement or not Methods. Meta-regression for anamnesis of CAD, of HF and of EF (if available) should be added Results. Quality of studies should be more expanded and subgroup analysis for it should be added ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0279680.r001
Revision 1
5 Dec 2022 Author Response To reviewer 1 #1. The English needs to be improved throughout the paper prior to being suitable for publication. Response: Thanks for your suggestion. Our manuscript had been edited by experts in English. #2. The study compares high vs. low dialyzable beta blockers. It would be helpful to inform the reader what threshold is used to determine high vs. low dialyzability. Response: Thank you for your comment. There was no definite cut-off value for determination of high dialyzable and low dialyzable beta blockers[1-4]. We had modified terms of high dialysable beta-blockers (HDBBs)/ low dialysable beta-blockers (LDBBs) to dialyzable beta-blockers (DBBs)/ non-dialyzable beta-blockers (NDBBs) in the modified version of manuscript. Moreover, the dialyzable thresholds of the beta-blockers were not mentioned in all included studies. According to Tieu’s study[1], only 10% of medication had reported definitive information about the threshold for drugs’ dialyzability. The classification of cardio-selective BBs and non-cardio-selective BBs in Shireman and Assimon’s studies[5, 6], it is also the categories by the dialyzability according to several studies about pharmacokinetics of beta-blockers[1, 2]. (DBBs, Cardio-selective BBs: Atenolol, metoprolol, nadolol; NDBB, Non-Cardio-selective: carvedilol, labetalol, and propranolol). Additionally, the classification of DBBs and NDBBs was based on studies of pharmacokinetics of beta-blockers[7-12] in Weir’s and Wu’s study[13, 14]. We had added the description for the detailed information in the introduction and result as following, Line 66” However, there was no definite threshold for differentiating between DBBs and NDBBs.”, Line 169” The classification of DBBs and NDBBs was based on the pharmacokinetics of beta-blockers (17-22) in two of the included studies (10, 12), while the classification of the other two studies was based on the cardio-selectivity of beta-blockers (13, 23). Previous studies have shown that cardio-selective and non-cardio-selective beta-blockers are pharmacologically equivalent to DBBs and NDBBs, respectively (11, 24).” #3. I may have missed this but how was MACE defined? I assume acute MI and heart failure were included in this (though they are also listed as separate outcomes? Were any other cardiovascular outcomes included in MACE? Response: Thank you for your comment. Several MACE definitions had been elucidated [15] including 3-point MACE, 4-point MACE and 5-point MACE. The classical 3-point MACE is composed of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death. The 4-point MACE is defined as classical 3-point MACE, with other events, like hospitalization for unstable angina or revascularization procedures. Finally, the definition of 5-point MACE is the result of 4-point MACE, and heart failure.[15] However, the MACE in the included studies were a little bit different, and it had been expressed at the response Table 1. Separately. Response Table 1. MACE definition Weir (2015) cardiovascular death, myocardial infarction, heart failure Wu (2020) acute coronary syndrome, ischemic stroke and heart failure Abbreviations: MACE, major adverse cardiovascular event We had added the description for the detailed information in the result, line 117, as following, “The definition of MACE was based on that of each included study.” And added on” There was a slight variation in the definition of overall MACE between the two studies; while it involved cardiovascular death, myocardial infarction, and heart failure in one of the studies (12), the other referred it to acute coronary syndrome, ischemic stroke, and heart failure (10).” in line 231. #4. One of the included studies included peritoneal dialysis patients. I find it questionable of whether to include these patients given the inherent differences in dialysis modalities. For instance, given the much slower/prolonged clearance with peritoneal dialysis, one would think the contribution of intradialytic hypotension from beta-blocker clearance would be much less significant in this population. Response: Thanks for your comment. Theoretically, the blood concentration of a drug would be steadier in peritoneal dialysis patient than in the hemodialysis patients due to the much slower/prolonged clearance of peritoneal dialysis. However, there are less studies discussing about the relation between drug dialyzability and peritoneal dialysis. According to Hirata’s study,[16] drug clearance for a given duration is markedly lower during CAPD than hemodialysis. Nevertheless, CAPD is a continuous procedure. Therefore, weekly clearance is not markedly different between CAPD patients and hemodialysis patients. On the other hand, we had provided sensitivity analysis which exclude the study composed of peritoneal dialysis population (S2 Table. Sensitivity analysis), and displayed no significant difference after sensitivity analysis. #5. I am confused by the heart failure results. The abstract states that "HDBBs were associated with significant reduction of risk in HF compared with individuals with LDBBs". However, when I look at Fig 2D which is showing heart failure outcomes seems to show that the results favor LDBBs which seems contrary to the prior statement. Further, this conclusion is drawn from only two studies, one (Wu) which contributes 97% of the relative weight while the other (Weir) is questionable as per the authors as bisoprolol may have been included in the wrong HDBB/LDBB category in that study. This draws into question any conclusions that can be drawn from this analysis. Response: Thanks for your comment. We had modified the Fig 2. Also, we had added on reviewer’s comments at discussion in line 370 as following,” However, this conclusion was drawn from only two studies, one (10) of which contributed to 97% of the relative weight while the finding of the other (12) was questionable because the authors classified bisoprolol into the DBB category.” To reviewer 2 #1. Abstract. Sentence in the results from "The risk of MACE to............]." appeared of no clear meaning and truncated Response: Thanks for your comment. We had revised as the following (line 30)” Analysis of four observational studies including 75,193 individuals undergoing dialysis in hospital and community settings after a follow-up from 180 days to six years showed an overall all-cause mortality rate of 11.56% (DBBs and NDBBs: 12.32% and 10.7%, respectively) without significant differences in risks of mortality between the two groups [random effect, aHR 0.91 (95% CI, 0.81–1.02), p=0.11], overall MACE [OR 1.03 (95% CI, 0.78–1.38), p=0.82], and AMI [OR 1.02 (95% CI, 0.94–1.1), p=0.66].” #2. Abstract. It is not clear if the present results were in hospital or at which time of follow up Response: Thanks for your comment. We had added on detailed description at line 30 as following” Analysis of four observational studies including 75,193 individuals undergoing dialysis in hospital and community settings after a follow-up from 180 days to six years” #3. Methods. It is not clear if results derived from multivariable adjustement or not Response: Thanks for your comment. We had revised the description in method (line 140) as” The odds ratio (OR) and 95 % confidence interval (CI) were extracted from the included studies. In addition, the hazard ratio (HR) of mortality was also analyzed. For studies that provided information on HR, the data were used for analysis.” We not only expressed the pooled result with aHR (Fig 2A) [aHR: 0.91; 95% CI, 0.81–1.02, p = 0.11], but also demonstrated a consistent result for mortality with OR (S6 appendix). #3. Methods. Meta-regression for anamnesis of CAD, of HF and of EF (if available) should be added Response: Thanks for your comment. We had added meta-regression for anamnesis of CAD and of HF. (S3 Table 3) However, there was no EF data available. We had added meta-regression in result as “The quantitative measures of CAD and HF were not associated with all-cause mortality. (CAD, Z = 1.65, p = 0.10; HF, Z = 1.28, p = 0.20, sTable 3)” (line 285) #4. Results. Quality of studies should be more expanded and subgroup analysis for it should be added Response: Thanks for your comment. We had added subgroup analysis related to the mortality rates based on scores of Newcastle-Ottawa Scale Quality Assessment for included studies (NOS score =8 versus NOS score =9). (line 266-272) We revised the manuscript as following (line 266-272), “ In respect of the impact of the quality of the included studies, analysis of the study with a NOS of eight showed a higher but non-significant increase in mortality risk in the DBB group compared to that in the NDBB group [Fig 3D, random effect, OR = 1.37 (95% CI, 0.93–2.0), p = 0.12]. In contrast, investigating the other three studies reporting a NOS score of nine demonstrated a non-significant reduction in mortality risk among those receiving DBBs compared with those taking NDBBs [Fig 3D, random effect, OR = 0.85 (95% CI, 0.71–1.02), p = 0.09].” Attachments Attachment Submitted filename: response to reviewers.docx https://doi.org/10.1371/journal.pone.0279680.r002
12 Dec 2022 Decision Letter - Gianpaolo Reboldi, Editor Impact of type of dialyzable beta-blockers on subsequent risk of mortality in patients receiving dialysis: A systematic review and meta-analysis PONE-D-22-24265R1 Dear Dr. Chen, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Gianpaolo Reboldi, MD, MSc, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: (No Response) ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: (No Response) ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: (No Response) ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors have adequately responded to all prior comments. No concerns regarding dual publication, research ethics, or publication ethics. Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: Fabrizio D'Ascenzo ******** https://doi.org/10.1371/journal.pone.0279680.r003
Formally Accepted
22 Dec 2022 Acceptance Letter - Gianpaolo Reboldi, Editor PONE-D-22-24265R1 Impact of type of dialyzable beta-blockers on subsequent risk of mortality in patients receiving dialysis: A systematic review and meta-analysis Dear Dr. Chen: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof Gianpaolo Reboldi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0279680.r004

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