The effect of levocarnitine supplementation on dialysis-related hypotension: A systematic review, meta-analysis, and trial sequential analysis

Api Chewcharat; Pol Chewcharat; Weitao Liu; Jacqueline Cellini; Elizabeth A. Phipps; Jill A. Melendez Young; Sagar U. Nigwekar

doi:10.1371/journal.pone.0271307

Peer Review History

Original SubmissionMarch 10, 2022
11 May 2022 Decision Letter - Mabel Aoun, Editor PONE-D-22-07106The Effect of Levocarnitine Supplementation on Dialysis-related Hypotension: a Systematic Review, Meta-analysis, and Trial Sequential AnalysisPLOS ONE Dear Dr. Chewcharat, 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. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please provide a point-by-point response to the comments of the two reviewers. Please submit your revised manuscript by Jun 15 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. 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). 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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: In the present systematic review and meta-analysis, the authors investigated the treatment effect of L-carnitine on dialysis-related hypotension and muscle cramps in chronic hemodialysis patients. They included 8 randomized controlled trials with 224 participants, where the mean age of patients ranged from 43.8 to 66.9 years and the duration of follow-up spanned from 6 weeks to 24 weeks. They found a significantly lower odds of dialysis-related hypotension among L-carnitine supplementation group compared to placebo (pooled OR = 0.26, 95% CI [0.10-0.72], p = 0.01, I² = 76.0%), though with high heterogeneity. Further high-quality studies are needed to conclusively prove the effect of L-carnitine on muscle cramps. The paper is well written, the methodological approach is appropriate and follows PRISMA guidelines, the results are adequately commented upon, and limitations have been correctly examined. The authors have further performed a trial sequential analysis, which helped to conclude the effect of L-carnitine on dialysis-related hypotension. Moreover, subgroup analyses by dose, route and duration of treatment further revealed that oral L-carnitine supplementation at least 12 weeks with a dose above 4,200 mg/week could prevent dialysis-related hypotension. I have a few minor comments about the manuscript, which I have presented below: 1. Page 5: The authors have stated that “All relevant data are within the manuscript and its Supporting Information files.” Thus, the authors should please amend the data availability statement on Page 4 “No - some restrictions will apply.” PLOS ONE requires all data underlying the findings described fully available. 2. Page 12: Though the authors have found that the lower odds of dialysis-related hypotension among L-carnitine supplementation group compared to placebo was significant, there was high heterogeneity. The authors should please mention this here. 3. Page 13: In subgroup analysis by dose of L-carnitine supplementation, the following statement requires correction from “Three studies supplementing Lcarnitine < 4,200 mg/week (60 participants)…” to “Lcarnitine > 4,200 mg/week...” Reviewer #2: Article written in a clear, objective way and with a robust statistical analysis, performed correctly and adequately for the present study. Minor corrections: RESULTS Characteristics and quality of the studies (page 3) The total number of participants in the 8 studies is 225 (not 224). In the phrase "The trials varied in sample size from 9 to 82" patients, the correct one would be "The trials varied in sample size from 9 to 83". Effect of L-carnitine on dialysis-related hypotension (page 4) In the sentence "Eight study arms with 224 participants....", the correct would be 225 participants. In the sentence "In the subgroup analysis [...] while 5 studies supplementing L-carnitine intravenously (47 participants) failed to reveal a difference in incidence of dialysis-related hypotension between these two groups (pooled OR = 0.51, 95% CI [ 0.25-1.06], p = 0.07, I2 = 42.7%)", the correct would be "[...] while 5 studies supplementing L-carnitine intravenously (178 participants)". In the sentence "Three studies supplementing Lcarnitine > 4,200 mg/week (60 participants)....", the correct sentence would be "Three studies supplementing Lcarnitine < 4,200 mg/week (60 participants)..." Page 5 In the sentence "Five studies supplementing ≤ 4,200 mg/week (164 participants) showed a non-significant difference....", the correct one would be "Five studies supplementing ≤ 4,200 mg/week (165 participants) showed a non-significant difference...". In the sentence "Five studies with a duration of treatment at least 12 weeks (175 participants) showed a lower....", the correct sentence would be "Five studies with a duration of treatment at least 12 weeks (176 participants) showed a lower. ...." Effect of L-carnitine on muscle cramps In the sentence "Five study arms [...] to control group (pooled OR = 0.22, 95% CI [0.06-0.81], p = 0.02, I2 = 74.7%). (Table 3)", the correct percentage value would be 74.9%. In table 1, add the meanings of the abbreviations that appear (UK; NA; IV). In table 3, the values present in the "sample size" column need to be corrected: Dialysis-related hypotension: 225 and not 224 Route IV: 178 and not 177 Dose ≤ 4200mg/week: 165 and not 164 Duration ≥12 weeks: 176 not 49 Duration < 12 weeks: 45 not 176 ****** 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? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes:** Sultana Shajahan Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0271307.r001
Revision 1
14 Jun 2022 Author Response Responses to reviewer 1’s comments In the present systematic review and meta-analysis, the authors investigated the treatment effect of L-carnitine on dialysis-related hypotension and muscle cramps in chronic hemodialysis patients. They included 8 randomized controlled trials with 224 participants, where the mean age of patients ranged from 43.8 to 66.9 years and the duration of follow-up spanned from 6 weeks to 24 weeks. They found a significantly lower odds of dialysis-related hypotension among L-carnitine supplementation group compared to placebo (pooled OR = 0.26, 95% CI [0.10-0.72], p = 0.01, I² = 76.0%), though with high heterogeneity. Further high-quality studies are needed to conclusively prove the effect of L-carnitine on muscle cramps. The paper is well written, the methodological approach is appropriate and follows PRISMA guidelines, the results are adequately commented upon, and limitations have been correctly examined. The authors have further performed a trial sequential analysis, which helped to conclude the effect of L-carnitine on dialysis-related hypotension. Moreover, subgroup analyses by dose, route and duration of treatment further revealed that oral L-carnitine supplementation at least 12 weeks with a dose above 4,200 mg/week could prevent dialysis-related hypotension. Response: Thank you for your thoughtful comment. I have a few minor comments about the manuscript, which I have presented below: 1. Page 5: The authors have stated that “All relevant data are within the manuscript and its Supporting Information files.” Thus, the authors should please amend the data availability statement on Page 4 “No - some restrictions will apply.” PLOS ONE requires all data underlying the findings described fully available. Response: We amended as suggested. The extracted data file was provided in the supplementary material S3 File. 2. Page 12: Though the authors have found that the lower odds of dialysis-related hypotension among L-carnitine supplementation group compared to placebo was significant, there was high heterogeneity. The authors should please mention this here. Response: Thank you for your suggestions. We acknowledge the fact that there was high heterogeneity in our study, which led us to apply a random-effects model to analyze the data, incorporating the additional sources of variability between the studies. Despite the fact that we performed subgroup analysis on route, dose and duration of supplementation, the heterogeneity remains. As we mentioned in the discussion, the different definitions in each study for dialysis-related hypotension and muscle cramps may introduce heterogeneity. Moreover, medications such as antihypertensive medications and cardiac function were not specified in each trial which could be important confounders. However, the randomized nature of the data we are synthesizing provides a reasonable amount of confidence that the comparisons performed are not heavily affected by these factors. Nevertheless, we included this lack of information as a limitation in our discussion section. We are also aware that some RCTs had different study designs and dialysis techniques prior to 1990 were different from current practices, which led us to perform a subgroup analysis. The following statements were added in the discussion. “Second, we acknowledge the heterogeneity in our study was high even after performing subgroup analysis and utilizing a random effect model. The residual confounders such as medications, cardiac function, and different definitions in each study for dialysis-related hypotension and muscle cramps may introduce heterogeneity.” 3. Page 13: In subgroup analysis by dose of L-carnitine supplementation, the following statement requires correction from “Three studies supplementing Lcarnitine < 4,200 mg/week (60 participants)…” to “L-carnitine > 4,200 mg/week...” Response: Thank you for pointing it out. The following statements were edited in the revised manuscript. “Three studies supplementing L-carnitine > 4,200 mg/week (60 participants) demonstrated a significant lower odds of dialysis-related hypotension comparing L-carnitine group to control group (pooled OR = 0.03, 95% CI [0.001-0.58], p = 0.02, I2 = 90.0%). Five studies supplementing ≤ 4,200 mg/week (164 participants) showed a non-significant difference in dialysis-related hypotension between treatment and placebo group (pooled OR = 0.78, 95% CI [0.39-1.57], p = 0.48, I2 = 0%). (Table 3)” Response to reviewer 2’s comments Article written in a clear, objective way and with a robust statistical analysis, performed correctly and adequately for the present study. Response: Thank you for your time and effort reviewing this manuscript. RESULTS Characteristics and quality of the studies (page 3) The total number of participants in the 8 studies is 225 (not 224). In the phrase "The trials varied in sample size from 9 to 82" patients, the correct one would be "The trials varied in sample size from 9 to 83". Response: Thank you for pointing this out. After careful review of the numbers, we realized the number of participants for the study by Ahmad et al. in Table 1 was 82, not 83. Therefore, the total number of participants in the 8 studies is 224. The trials varied in sample size from 9 to 82. With this opportunity, we went back and checked all the data thoroughly, reassuring that there was no other error. Effect of L-carnitine on dialysis-related hypotension (page 4) In the sentence "Eight study arms with 224 participants....", the correct would be 225 participants. Response: Thank you for pointing this out. We confirmed that our study included 8 study arms with 224 participants. In the sentence "In the subgroup analysis [...] while 5 studies supplementing L-carnitine intravenously (47 participants) failed to reveal a difference in incidence of dialysis-related hypotension between these two groups (pooled OR = 0.51, 95% CI [ 0.25-1.06], p = 0.07, I2 = 42.7%)", the correct would be "[...] while 5 studies supplementing L-carnitine intravenously (178 participants)". Response: Thank you for pointing this out. The following sentences were edited as suggested. “... while 5 studies supplementing L-carnitine intravenously (177 participants) failed to reveal a difference in incidence of dialysis-related hypotension between these two groups (pooled OR = 0.51, 95% CI [0.25-1.06], p = 0.07, I2 = 42.7%). (Table 3)” In the sentence "Three studies supplementing Lcarnitine > 4,200 mg/week (60 participants)....", the correct sentence would be "Three studies supplementing Lcarnitine < 4,200 mg/week (60 participants)..." Response: We agreed. The following statements were edited in the revised manuscript. “Three studies supplementing L-carnitine > 4,200 mg/week (60 participants) demonstrated a significant lower odds of dialysis-related hypotension comparing L-carnitine group to control group (pooled OR = 0.03, 95% CI [0.001-0.58], p = 0.02, I2 = 90.0%). Five studies supplementing ≤ 4,200 mg/week (164 participants) showed a non-significant difference in dialysis-related hypotension between treatment and placebo group (pooled OR = 0.78, 95% CI [0.39-1.57], p = 0.48, I2 = 0%). (Table 3)” Page 5 In the sentence "Five studies supplementing ≤ 4,200 mg/week (164 participants) showed a non-significant difference....", the correct one would be "Five studies supplementing ≤ 4,200 mg/week (165 participants) showed a non-significant difference...". In the sentence "Five studies with a duration of treatment at least 12 weeks (175 participants) showed a lower....", the correct sentence would be "Five studies with a duration of treatment at least 12 weeks (176 participants) showed a lower. ...." Response: As mentioned above, "Five studies supplementing ≤ 4,200 mg/week (164 participants) showed a non-significant difference...." and "Five studies with a duration of treatment at least 12 weeks (175 participants) showed a lower...." were in fact accurate. Effect of L-carnitine on muscle cramps In the sentence "Five study arms [...] to control group (pooled OR = 0.22, 95% CI [0.06-0.81], p = 0.02, I2 = 74.7%). (Table 3)", the correct percentage value would be 74.9%. Response: Thank you for pointing this out. After a careful review of the numbers, we realized that the number in Table 3 was a typo. The I2 for muscle cramps was 74.7%. In table 1, add the meanings of the abbreviations that appear (UK; NA; IV). Response: Thank you for your comments. Abbreviations were spelled out below Table 1. In table 3, the values present in the "sample size" column need to be corrected: Dialysis-related hypotension: 225 and not 224 Route IV: 178 and not 177 Dose ≤ 4200mg/week: 165 and not 164 Duration ≥12 weeks: 176 not 49 Duration < 12 weeks: 45 not 176 Response: Thank you for pointing out. We double-checked the numbers. With this opportunity, we went back and checked all the data thoroughly, reassuring that there was no other error. Attachments Attachment Submitted filename: Responses1_AC.pdf https://doi.org/10.1371/journal.pone.0271307.r002
28 Jun 2022 Decision Letter - Mabel Aoun, Editor The Effect of Levocarnitine Supplementation on Dialysis-related Hypotension: a Systematic Review, Meta-analysis, and Trial Sequential Analysis PONE-D-22-07106R1 Dear Dr. Chewcharat, 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, Mabel Aoun, MD, MPH Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0271307.r003
Formally Accepted
6 Jul 2022 Acceptance Letter - Mabel Aoun, Editor PONE-D-22-07106R1 The Effect of Levocarnitine Supplementation on Dialysis-related Hypotension: a Systematic Review, Meta-analysis, and Trial Sequential Analysis Dear Dr. Chewcharat: 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 Dr. Mabel Aoun Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0271307.r004

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