Clinical implications of the log linear association between LDL-C lowering and cardiovascular risk reduction: Greatest benefits when LDL-C >100 mg/dl

Jennifer G. Robinson; Manju Bengaluru Jayanna; C. Noel Bairey Merz; Neil J. Stone

doi:10.1371/journal.pone.0240166

Peer Review History

Original SubmissionMay 28, 2020
16 Sep 2020 Decision Letter - Katriina Aalto-Setala, Editor PONE-D-20-13528 Clinical implications of the Log Linear Association Between LDL-C Lowering and Cardiovascular Risk Reduction: Greatest Benefits When LDL-C >100 mg/dl PLOS ONE Dear Dr. Robinson, 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. We find you manuscript interesting, but the reviewers have raised some issues concerning statistics. Check them carefully and reply clearly and mark the changes. Please submit your revised manuscript by Oct 31 2020 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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Thank you for including your competig interests statement;"I have read the journal's policy and the authors of this manuscript have the following competing interests: Jennifer G Robinson MD MPH has received research grants to Institution: Acasti, Amarin, Amgen, Astra-Zeneca, Esperion, The Medicines Company, Merck, Novartis, Novo-Nordisk, Regeneron, Sanofi, Takeda and served as a consultant for The Medicines Company, Novartis, and Pfizer. Manju Bengularu Jayanna MBBS None. C Noel Bairey Merz MD has received research grants to Institution: Caladrius, Gilead, Sanofi ACT, and served as a consultant for iRhythm, Sanofi Vascular, and Abbott Diagnostics. Neil J Stone MD None." 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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). 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: Yes ****** 4. 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: 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: I’ve read with attention the paper of Robinson et al. that is potentially of interest. The background and aim of the study have been clearly defined. The methodology applied is overall correct, the results are reliable and adequately discussed. The authors should only add a couple of lines of pharmacoeconomic aspects related to their findings. Moreover, they should stress the concept that this observation could loose a bit of its strenght if considering long-term treatments beyond the trial lenght (I mean, decades) Reviewer #2: Interesting paper methods. Which is the difference betwee cv and chd death? methods: the authors spoke about weighted analysis but this should be added also in figure methods: kind of analysis is not clear. Please be more specific. Do authors performed a meta-regression? results: from figure 1, it appears that the risk for "high risk" patients is more relevant for LDL more than 70 rather thano 100. Please clarify ****** 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: No Reviewer #2: Yes:** Fabrizio D'Ascenzo [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. 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Revision 1
18 Sep 2020 Author Response Response to reviewers We thank the reviewers for their positive review of our paper, and the additional insights that they provided into our analyses. Reviewer #1: I’ve read with attention the paper of Robinson et al. that is potentially of interest. The background and aim of the study have been clearly defined. The methodology applied is overall correct, the results are reliable and adequately discussed. The authors should only add a couple of lines of pharmacoeconomic aspects related to their findings. Moreover, they should stress the concept that this observation could loose a bit of its strenght if considering long-term treatments beyond the trial lenght (I mean, decades) Response: We thank reviewer #1 for the recommending further comment on the pharmacoeconomic implications of our analysis. We agree this is an important additional perspective and took the opportunity to highlight it as such by adding this call-out paragraph and adding reference 51: PHARMACOECONOMIC IMPLICATIONS The log linear association between baseline LDL-C level and ASCVD risk reduction suggests that at any given level of ASCVD risk, additive LDL-C lowering drug therapy is likely to prove less cost-effective in those with lower LDL-C levels.35 However, analyses of the statin, PCSK9 mAb, and ezetimibe cardiovascular outcomes trials reveal subgroups of patients at very high or extremely high ASCVD risk with lower LDL-C levels for whom further LDL-C lowering may have similar cost-effectiveness as in lower risk patients with higher LDL-C levels.35 Because the time horizons for estimating cost-effectiveness are typically similar to the 2 to 5-year follow-up periods of the clinical trials, estimates of cost-effectiveness over 10 years or a lifetime are likely different. For example, initiation of PCSK9 mAb therapy at younger ages in those with higher risk factor burden and LDL-C levels may provide the greatest lifetime benefit.51 Acquisition pricing of forthcoming LDL-C lowering drugs will strongly influence the cost-effectiveness of those treatments for various patient risk groups at various baseline LDL-C levels. It should also be noted that estimates of cost-effectiveness for other cardiovascular prevention drugs should be based on the absolute risk of patient groups who have LDL-C levels close to the level that was achieved in the cardiovascular outcomes, typically 60-70 mg/dl. 51. Kaasenbrod L, Ray KK, Boekhoeldt M, Smulders YO, LaRosa JC, Kastelein JJP, van der Graaf Y, Dorresteijn JAN, Visseren FL. Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease. Heart 2018; 104:1699-1705. Reviewer #2: Interesting paper Response: Thank you methods. Which is the difference betwee cv and chd death? Response: Cardiovascular include coronary and cerebrovascular deaths, whereas CHD death includes only those of cardiac origin such as due to myocardial infarction. This clarification was added: Cardiovascular death includes deaths from CHD and stroke. methods: the authors spoke about weighted analysis but this should be added also in figure Response: Thank you for bringing this to our attention. Added to Figure legend: Line represents log linear regression line for relationship between on-treatment LDL-C level and cardiovascular event rate weighted by group size. methods: kind of analysis is not clear. Please be more specific. Do authors performed a meta-regression? Response: Thank you for the opportunity to clarify. Yes, this was a meta-regression. Revised to read: To summarize the log linear association for each of the 3 annualized ASCVD risk groups, least-squares meta-regression weighted by sample size for each subgroup results: from figure 1, it appears that the risk for "high risk" patients is more relevant for LDL more than 70 rather thano 100. Please clarify Response: Thank you for the opportunity to add this additional important insight to the Results section. Revised to read: Notably, the steepest risk reduction slopes are evident when LDL-C levels are >100 mg/dl, or in when annualized ASCVD risk is >4%. In contrast, in the high-risk groups, slope of the risk reduction is largely driven by the LDL-C level. ________________________________________ Attachments Attachment Submitted filename: Response to reviewers 09-18-20.docx https://doi.org/10.1371/journal.pone.0240166.r002
22 Sep 2020 Decision Letter - Katriina Aalto-Setala, Editor Clinical implications of the Log Linear Association Between LDL-C Lowering and Cardiovascular Risk Reduction: Greatest Benefits When LDL-C >100 mg/dl PONE-D-20-13528R1 Dear Dr. Robinson, 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, Katriina Aalto-Setala, Professor Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0240166.r003
Formally Accepted
6 Oct 2020 Acceptance Letter - Katriina Aalto-Setala, Editor PONE-D-20-13528R1 Clinical implications of the Log Linear Association Between LDL-C Lowering and Cardiovascular Risk Reduction: Greatest Benefits When LDL-C >100 mg/dl Dear Dr. Robinson: 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 Katriina Aalto-Setala Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0240166.r004

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