PONE-D-21-28723Relationship between cumulative-exposure to angiotensin-receptor blockers and risk of cancer in randomized controlled trialsPLOS ONE

Dear Dr. Ilke Sipahi,

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 respond to each of the points made below by myself and Reviewer 1.  Most importantly respond to the discrepancies in the numbers and double counting of the control group pointed out by Reviewer 1.  

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James M Wright

Academic Editor

PLOS ONE

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3. Thank you for stating the following in the Competing Interests section:

“I have read the journal's policy and the authors of this manuscript have the following competing interests:

Dr. Sipahi has received lecture honoraria from Novartis, Boehringer-Ingelheim, Sanofi, Sandoz, Bristol-Myers Squibb, Bayer, Pfizer, Ranbaxy, Servier and ARIS and served on advisory board for Novartis, Sanofi, Servier, Bristol-Myers Squibb, Pfizer, Bayer and I.E. Ulagay.”

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Additional Editor Comments:

I think you have underplayed the implications of your findings. This has profound implications for the long-term treatment of hypertension, because of the current widespread use of ARBs and the availability of safer alternatives. To emphasize the importance of your findings.

1) Have the title state your conclusions.

2) In the discussion estimate the numbers of excess cancers and lung cancers being caused by these drugs (my guess is that it is in the 10's of 1000's.

3) Discuss the safer alternatives in the discussion.

4) Include in your conclusions that this has profound implications for patients and clinicians.

5) Include in the conclusions how these critical findings can be confirmed with future research.

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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: Partly

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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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: This research article is a clinically important review article examining the relationship of cumulative exposure to ARBs and the increased risk of all new cancers as well as specific increase in lung cancer and is important review article that needs to be published.

The authors claimed to have used publicly available data from the ARB Trialist Collaboration 2011. However, Zhao et al 2016 meta-analysis of cancer risk with ARBs article, a more recent publication is missing in the reference section (see details of the reference below) and numerator and denominators reported of various studies included in this review do not match the Zhao et al 2016 article.

Zhao Y-T, Yang –Peng Li, Zhang J-Q, Wang L and Zhong Yi. Angiotensin II receptor blockers and cancer risk. A meta-analysis of randomized controlled trials. Medicine. May 2016; Volume 95 (18): 1-7.

Figure 2 data discrepancies in this review article

1. Overall cancer numbers in Zhao et al 2016 article has 3 values for CHARM studies -CHARM ALTERNATIVE 2003 – ARB + ACEI = 49/951 vs ACEI + PbO = 47/943; CHARM ADDED 2003- ARB + ACEI = 69/1198 vs ACEI = 51/1197; and CHARM OVERALL 2003 – ARB =104/3803 vs ACEI = 111/3796

However, CHARM OVERALL in this article (Sipahi et al 2021) is reported as - 192/3533 vs 186/353 (??)

2. DIRECT study – Denominators differ

Zhao et al 2016 - ARB = 47/2613 vs control 28/=2618

Sipahi et al 2021 - ARB = 47/2610 vs control 28/= 2614

3. TRANSCEND study numerator and denominators differ

Zhao et al 2016 – ARB = 236/2954 vs control = 204/2972;

Sipahi et al 2021 : ARB = 200/2806 vs 166/2826 )

4. IDNT study denominator differ

Zhao et al 2016 – ARB = 25/ 579 vs 31/569

Sipahi et al 2021. 25/577 vs 31/563

5. ONTARGET study denominators differ

Zhao et al 2016 –ARB = 630/8542 vs ACEI= 606/8576

Sipahi et al 2021 – ARB = 630/7999 vs ACEI = 606/8029

Also please note that the denominators used in Figure 5 for lung cancer meta-analysis in Sipahi et al 2021 ARB = 100/8542 and control = 101/8576 differ from the denominators used in Fig 2 in their own article and are similar to Zhao et al 2016 numbers reported above.

Zhao et al 2016 – (ARB + ACEI)= 667/ 8502 and ACEI = 606/8576

Sipahi et al 2021 used – (ARB + ACEI)= 667/ 7966 and ACEI = 606/8029

6. VALIANT study denominator differ

Zhao et al 2016 ARB = 86/4909 vs ACEI = 83/4909

Sipahi et al 2021 ARB = 86/4885 vs ACEI = 83/4879

Double counting of control groups in the meta-analysis of this article Sipahi et al

Figure 2A meta analysis of all cancer risk used ONTARGET control group twice (N = 8029) in the meta-analysis leading to over counting of including patients in the overall RR and gives more weight to the study.

Similarly in Figure 2B, VALIANT study control group was used twice (N = 4879). This double counts the same participants in the control group and does not provide an accurate estimate of relative risk of cancer.

The authors are recommended to check accuracy of their data input and avoid double counting the control groups ONTARGET and VALIANT studies to calculate RR of all cancers as well as lung cancer.

A well written review article and a clinically important topic that should be published after the above mentioned errors are corrected.

Reviewer #2: This study has led to compelling and likely impactful findings that will further fuel the controversy pertaining to the link between ARBs and cancer risk. Demonstrating an increased risk of overall cancer and lung cancer with ARBs is related to the degree of cumulative exposure may explain the contradictory findings of previous studies; however, the fact that this is a trial-level analysis that includes data for only half of the patients included in the FDA and ARB Trialists Collaboration patient-level analyses is an important limitation that cannot be overcome without full data availability from all RCTs. I am hoping the publication of the author’s study will prompt a more definitive analysis of all individual patient data by an independent group of researchers with no conflicts, or release of the full analysis already conducted by the FDA and/or ARB Trialists Collaboration.

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Reviewer #1: No

Reviewer #2: No

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Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative-exposure: Meta-regression analysis of randomized trials''

PONE-D-21-28723R1

Dear Dr. Sipahi,

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.

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Kind regards,

James M Wright

Academic Editor

PLOS ONE

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