-->PONE-D-25-58381-->-->Incidence and Risk Factors of Calcium Channel Blocker–Related Edema in Hypertensive Patients: A Multicenter Retrospective Cohort Study-->-->PLOS ONE

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Additional Editor Comments:

1. Please correct the definition of hypertension to the more accepted 140/90 mmHg realizing that this is an arbitrary number from guidelines.

2. An important statistic that is missing is the number os people who stopped the drug due to the edema.

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Reviewers' comments:

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1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Please see my Comments on the PDF manuscript. I think it's worth publishing, consistent with the mission of PLoS One. I think you need someone else to comment on whether the statistical approach is appropriate (or not). I do suggest reporting adjusted ORs (after defining what adjustment was done, or what "AOR" means), rather than arbitrarily saying one AOR is "significant" but another is not.

I think the main value of the manuscript is to remind readers that edema is frequent and can occur early during CCB treatment, especially with dihydropyridines. It would be even more interesting to know the following, and if this MS is not accepted, perhaps the authors would undertake a prospective study in the same environment to answer these questions:

1. How early can edema occur from CCBs - if one checks before drug initiation (Day 0) could edema be present by Day 1 or Day 2, or only by Day 7 (1 week)?

2. Does edema relate in any way to antihypertensive effect? For example, if there is no change in BP, can edema still occur (assuming patient is taking the drug)???

This raises the question of how authors ascertained whether patients were taking the prescribed drugs, and also of how they measured BP. I have commented about the latter on the MS, but didn't think about adherance until writing this comment.

Also, I have always figured that if I had diabetic or other peripheral neuropathy, edema would be BAD - more chance of failing to notice a cut or abrasion, more "tissue fluid" in which bacteria or fungi could breed, etc. If the authors know anything about this, or could review the issue as part of discussion, I think that could be very interesting and useful to readers - and a real advance in discussion of the issue.

I recommend acceptance, but asking the authors to address these and any other comments. The English is fine, but I recommended consistent active voice over passive voice. That is a trivial issue of style, about which PLoS One may or may not have its own views.

The authors are welcome to my comments on the PDF, and my name and qualifications.

Thomas L. Perry MD, FRCPC (general internal medicine)

Editor, Therapeutics Letter, www.ti.ubc.ca

Clinical Professor

Dept. of Anaesthesiology, Pharmacology & Therapeutics, University of BC, Canada

Reviewer #2: This is an automated report for PONE-D-25-58381. This report was solicited by the PLOS One editorial team and provided by ScreenIT.

ScreenIT is an independent group of scientists developing automated tools that analyze academic papers. A set of automated tools screened your submitted manuscript and provided the report below. Each tool was created by your academic colleagues with the goal of helping authors. The tools look for factors that are important for transparency, rigor and reproducibility, and we hope that the report might help you to improve reporting in your manuscript. Within the report you will find links to more information about the items that the tools check. These links include helpful papers, websites, or videos that explain why the item is important. While our screening tools aim to improve and maintain quality standards they may, on occasion, miss nuances specific to your study type or flag something incorrectly. Each tool has limitations that are described on the ScreenIT website. The tools screen the main file for the paper; they are not able to screen supplements stored in separate files. Please note that the Academic Editor had access to these comments while making a decision on your manuscript. The Academic Editor may ask that issues flagged in this report be addressed. If you would like to provide feedback on the ScreenIT tool, please email the team at ScreenIt@bih-charite.de. If you have questions or concerns about the review process, please contact the PLOS One office at plosone@plos.org.

Reviewer #3: 1. The study presents the results of original research.

Yes, results were specifically obtained following a protocol that was submitted to, and agreed by, a local ethical committee.

2. Results reported have not been published elsewhere.

No, as far as I can ascertain… Another publication is unlikely due to the delay.

3. Experiments, statistics, and other analyses are performed to a high technical standard and are described in sufficient detail.

Almost: The sample size is justified and has been reached, but its justification lacks some details. Indeed, there is an appropriate power (80%), but we do not know what is the hypothesis behind. Is this the precision of the confidence interval for the estimate of the incidence of edema? Or is this the possibility to identify risk factors, i.e. to contrast the incidence or edema between two groups presenting or not the risk factor?

4. Conclusions are presented in an appropriate fashion and are supported by the data.

In general yes, but I would suggest to the authors some changes.

4.1. Definition of hypertension

Such a definition is arbitrary. The risk of cardiovascular events rises continuously for all levels of blood pressure1, and the lowest level could be adopted as well as more conservative ones. The issue behind such choice is obviously the association of a definite hypertension with an indication for pharmacological treatment. As a consequence, the lowest level of the definition will be associated with the largest volume of prescription. Guidelines have progressively moved towards lower levels along decades, from 160 mmHg initially re. systolic blood pressure to 130 mmHg as adopted by the authors. It is well established that guidelines are produced by experts who are full of conflicts of interest with pharmaceutical industry. The lower levels of hypertension definition along time is a likely explanation for the increase of the prevalence of hypertension mentioned by the authors.

Another possibility would be to chose as a definition of hypertension the level of blood pressure that is associated with a certainty that pharmacological treatment is beneficial. Guidelines acknowledge that there is weaker evidence for a benefit in mild hypertension, i.e. between 140 and 160 mmHg of systolic blood pressure. We established that there is no evidence for a favourable risk to benefit ratio in mild hypertension2. As a consequence, it is highly likely that the studied population is overtreated, confronted to side effects of pharmacological treatment without any solid hope for a benefit. This fact must be acknowledged in the introduction and in the discussion.

4.2. Methods of an observational retrospective study.

The strengths of the study are notable. The design is defined around the main objective of estimating the incidence of edema. They use medical files of known quality from two big hospitals with appropriate medical staff, and a supervision of the data extraction. The sampling procedure seems appropriate. Some aspects of the results suggest that there is a strong reality behind them: the relationship between dosage and the rate of edema; the increase of this rate along time of exposure.

The specific limitations of the experimental design must be better acknowledged by the authors.

First, there is no control group to compare the incidence of edema, which could be attributable to the exposure to CCBs or to other factors as well. The authors could have merely chosen to complete their study in comparing edema incidence with hypertensive people never treated by CCBs. The higher rate of edema they observe could be related to the fact that they attribute to CCBs edema that would have occurred under placebo. Placebo control in randomized trial is the best way to attribute causally an event to the treatment exposure, which is not possible here. In a meta-analysis of RCTs on edema with CCBs, authors found that 29% of edema observed on CCBs were also observed on placebo3.

Second, retrospective analyses are exposed to specific biases that must be discussed.

4.3. The coherence of these results with the existing literature is convincing, e.g. the standing position as a risk factor of edema, or the protective effect of ACE inhibitors against edema occurrence, well illustrated elsewhere4.

4.4. The conclusion that physicians should avoid unnecessary interventions is a truism, and has nothing specific to this population, or this treatment. CCBs are among the best BP lowering drugs to reduce the risk of stroke5. So the risk of oedema has to be balanced against the benefit from this drugs relative of stroke. And the majority of patients are likely to have mild hypertension without any solid hope for benefit.

5. The article is presented in an intelligible fashion and is written in standard English.

Yes, at least for a French reader !!!

6. The research meets all applicable standards for the ethics of experimentation and research integrity.

Yes, with informed consent collected for retrospective use of data collected within medical files.

7. The article adheres to appropriate reporting guidelines and community standards for data availability.

Yes. Data are said to be fully available without restriction.

1. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335(8692): 765-74.

2. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev 2012; 2012(8): Cd006742.

3. Makani H, Bangalore S, Romero J, et al. Peripheral edema associated with calcium channel blockers: incidence and withdrawal rate--a meta-analysis of randomized trials. J Hypertens 2011; 29(7): 1270-80.

4. Liang L, Kung JY, Mitchelmore B, Cave A, Banh HL. Comparative peripheral edema for dihydropyridines calcium channel blockers treatment: A systematic review and network meta-analysis. J Clin Hypertens (Greenwich) 2022; 24(5): 536-54.

5. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003; 362(9395): 1527-35.

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Reviewer #1: Yes: Thomas L. Perry MD, FRCPC

Reviewer #2: No

Reviewer #3: Yes: François GUEYFFIER

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Attachments

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Submitted filename: TL Perry comments Nov. 15, 2025 - PONE-D-25-58381_reviewer.pdf

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Submitted filename: report_10.1101+2025.10.30.25339181.pdf

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Submitted filename: PLOS One Review F Gueyffier V2.docx

Incidence and Risk Factors of Calcium Channel Blocker–Related Edema in Hypertensive Patients: A Multicenter Retrospective Cohort Study

PONE-D-25-58381R1

Dear Dr. Solela,

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