Morales, Daniel

Pottegård, Anton

The Korean Journal of Internal Medicine

English

University of Dundee Online Publications

                                                                    University of DundeeComment on "Hydrochlorothiazide use and the risk of skin cancer in patients withhypertensive disorderPottegård, Anton; Morales, DanielPublished in:Korean Journal of Internal MedicineDOI:10.3904/kjim.2020.012Publication date:2020Licence:CC BY-NCDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Pottegård, A., & Morales, D. (2020). Comment on "Hydrochlorothiazide use and the risk of skin cancer inpatients with hypertensive disorder: a nationwide retrospective cohort study from Korea". Korean Journal ofInternal Medicine, 35(4), 1014-1015. https://doi.org/10.3904/kjim.2020.012General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 31. Jul. 2023Copyright © 2020 The Korean Association of Internal MedicineThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.pISSN 1226-3303eISSN 2005-6648http://www.kjim.orgCORRESPONDENCEComment on “Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder: a nationwide retrospective cohort study from Korea”Anton Pottegård1 and Daniel Morales2Received : January 11, 2020Accepted : March 1, 2020Correspondence to Anton Pottegård, M.D.Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, JB Winsløws Vej 19, 5000 Odense, DenmarkTel: +45-65503024E-mail: apottegaard@health.sdu.dkhttps://orcid.org/0000-0001-9314-5679We read with interest the paper by Park et al. [1] investigating the associa-tion between hydrochlorothiazide and non-melanoma and melanoma skin cancer in South Korean patients. We were, however, surprised to read that hydrochlorothiazide use was inversely associated with skin cancer risk. This contradicts previous studies [2,3], the underlying biological rationale based on hydrochlorothiazide’s known pho-tosensitizing properties, as well as con-clusions reached by medicines regula-tors [4]. We believe, however, that these contrasting findings arise due to bias in the study design. In the study, Park et al. [1] follow pa-tients from their first antihypertensive prescription which, as described, may not be a prescription for hydrochlorothi-azide in the hydrochlorothiazide exposed group. Hydrochlorothiazide is often pre-scribed in combination with other anti-hypertensives and may therefore be less likely to be prescribed first-line. In the absence of a time-varying analysis, this will induce immortal time bias in the hydrochlorothiazide user group.Patients were followed until the last day of data capture or the day of the first diagnosis of skin cancer. Exposure to hydrochlorothiazide was analyzed as having at least three hydrochlorothi-azide prescriptions filled throughout that patient’s total follow-up. However, the duration of follow-up is shorter for patients receiving a skin cancer diag-nosis (as this censor follow-up). Having filled ≥ 50,000 mg of hydrochlorothia-zide (the highest strata in the dose-re-sponse analyses) will, with a high dose of 25 mg/day, take > 5 years, or with 12.5 mg/day > 10 years. This has to be achieved within the maximum study period of 7.5 years (January 2009 to June 2017). As such, achieving such cumu-lative hydrochlorothiazide exposure levels is equivalent to requiring the near-total absence of a censoring event. Such bias will be much more pro-nounced in the dose-response analyses and corresponds quite well to the find-ing that exposure yields a very strong ‘protective’ effect against skin cancer. Whether these issues have been correctly identified, and whether they explain the findings or not, can eas-ily be tested by the authors. First, any antihypertensive drug should display similar properties, that is, if the authors performs similar cumulative analyses using their design for e.g., angioten-sin-converting enzyme inhibitors or calcium channel blockers, we would 1Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Division of Population Health and Genomic, University of Dundee, Dundee, UK2020 Mar 31 [Epub ahead of print]https://doi.org/10.3904/kjim.2020.0122 www.kjim.org https://doi.org/10.3904/kjim.2020.012The Korean Journal of Internal Medicine. 2020 Mar 31. [Epub ahead of print]expect them to identify similar protective associations. Second, hydrochlorothiazide use should be handled as a time-varying exposure. As such, each individual should contribute to the non-hydrochlorothiazide cohort from the time of the first antihypertensive prescription until the time of the first hydrochlorothiazide prescription. From the time of the first hydrochlorothiazide prescrip-tion, that person should contribute person-time to the hydrochlorothiazide user group only. If person-time is handled in this way, we would expect the protective as-sociations obtained for ‘ever use of hydrochlorothiazide’ to vanish. Nevertheless, we may not expect to see similar risks observed in a European population [2,3] replicated in an Asian population. In fact, in a recent Taiwanese study, hydrochlorothiazide showed no significant association to skin cancer [5]. This may be explained by several fac-tors, including differences in skin phenotype, use of low-er hydrochlorothiazide doses, and cultural differences in sun behavior. However, additional studies in Asian pop-ulations are necessary to confirm these findings.Conflict of interestNo potential conflict of interest relevant to this article was reported.REFERENCES1. Park E, Lee Y, Jue MS. Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disor-der: a nationwide retrospective cohort study from Korea. Korean J Intern Med 2019 Dec 18 [Epub]. https://doi.org/10.3904/kjim.2019.218.2. Pedersen SA, Gaist D, Schmidt SAJ, Holmich LR, Friis S, Pottegard A. Hydrochlorothiazide use and risk of nonmel-anoma skin cancer: a nationwide case-control study from Denmark. J Am Acad Dermatol 2018;78:673-681.e9.3. Morales DR, Pacurariu A, Slattery J, Kurz X. Association between hydrochlorothiazide exposure and different in-cident skin, lip and oral cavity cancers: A series of popula-tion-based nested case-control studies. Br J Clin Pharma-col 2020 Feb 18 [Epub]. https://doi.org/10.1111/bcp.14245.4. European Medicines Agency. PRAC recommendations on signals [Internet]. London (UK): European Medicines Agency, 2018 [cited 2020 Mar 10]. Available from: https://www.ema.europa.eu/en/documents/prac-recommenda-tion/prac-recommendations-signals-adopted-3-6-septem-ber-2018-prac-meeting_en-0.pdf.5. Pottegard A, Pedersen SA, Schmidt SAJ, et al. Use of hy-drochlorothiazide and risk of skin cancer: a nationwide Taiwanese case-control study. Br J Cancer 2019;121:973-978.

Comment on "Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder:a nationwide retrospective cohort study from Korea"

Anton Pottegård

Daniel Morales

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Comment on “Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder: a nationwide retrospective cohort study from Korea”

                                                                    University of DundeeComment on "Hydrochlorothiazide use and the risk of skin cancer in patients withhypertensive disorderPottegård, Anton; Morales, DanielPublished in:Korean Journal of Internal MedicineDOI:10.3904/kjim.2020.012Publication date:2020Document VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Pottegård, A., & Morales, D. (2020). Comment on "Hydrochlorothiazide use and the risk of skin cancer inpatients with hypertensive disorder: a nationwide retrospective cohort study from Korea". Korean Journal ofInternal Medicine. https://doi.org/10.3904/kjim.2020.012General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 01. May. 2020Copyright © 2020 The Korean Association of Internal MedicineThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.pISSN 1226-3303eISSN 2005-6648http://www.kjim.orgCORRESPONDENCEComment on “Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder: a nationwide retrospective cohort study from Korea”Anton Pottegård1 and Daniel Morales2Received : January 11, 2020Accepted : March 1, 2020Correspondence to Anton Pottegård, M.D.Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, JB Winsløws Vej 19, 5000 Odense, DenmarkTel: +45-65503024E-mail: apottegaard@health.sdu.dkhttps://orcid.org/0000-0001-9314-5679We read with interest the paper by Park et al. [1] investigating the associa-tion between hydrochlorothiazide and non-melanoma and melanoma skin cancer in South Korean patients. We were, however, surprised to read that hydrochlorothiazide use was inversely associated with skin cancer risk. This contradicts previous studies [2,3], the underlying biological rationale based on hydrochlorothiazide’s known pho-tosensitizing properties, as well as con-clusions reached by medicines regula-tors [4]. We believe, however, that these contrasting findings arise due to bias in the study design. In the study, Park et al. [1] follow pa-tients from their first antihypertensive prescription which, as described, may not be a prescription for hydrochlorothi-azide in the hydrochlorothiazide exposed group. Hydrochlorothiazide is often pre-scribed in combination with other anti-hypertensives and may therefore be less likely to be prescribed first-line. In the absence of a time-varying analysis, this will induce immortal time bias in the hydrochlorothiazide user group.Patients were followed until the last day of data capture or the day of the first diagnosis of skin cancer. Exposure to hydrochlorothiazide was analyzed as having at least three hydrochlorothi-azide prescriptions filled throughout that patient’s total follow-up. However, the duration of follow-up is shorter for patients receiving a skin cancer diag-nosis (as this censor follow-up). Having filled ≥ 50,000 mg of hydrochlorothia-zide (the highest strata in the dose-re-sponse analyses) will, with a high dose of 25 mg/day, take > 5 years, or with 12.5 mg/day > 10 years. This has to be achieved within the maximum study period of 7.5 years (January 2009 to June 2017). As such, achieving such cumu-lative hydrochlorothiazide exposure levels is equivalent to requiring the near-total absence of a censoring event. Such bias will be much more pro-nounced in the dose-response analyses and corresponds quite well to the find-ing that exposure yields a very strong ‘protective’ effect against skin cancer. Whether these issues have been correctly identified, and whether they explain the findings or not, can eas-ily be tested by the authors. First, any antihypertensive drug should display similar properties, that is, if the authors performs similar cumulative analyses using their design for e.g., angioten-sin-converting enzyme inhibitors or calcium channel blockers, we would 1Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Division of Population Health and Genomic, University of Dundee, Dundee, UK2020 Mar 31 [Epub ahead of print]https://doi.org/10.3904/kjim.2020.0122 www.kjim.org https://doi.org/10.3904/kjim.2020.012The Korean Journal of Internal Medicine. 2020 Mar 31. [Epub ahead of print]expect them to identify similar protective associations. Second, hydrochlorothiazide use should be handled as a time-varying exposure. As such, each individual should contribute to the non-hydrochlorothiazide cohort from the time of the first antihypertensive prescription until the time of the first hydrochlorothiazide prescription. From the time of the first hydrochlorothiazide prescrip-tion, that person should contribute person-time to the hydrochlorothiazide user group only. If person-time is handled in this way, we would expect the protective as-sociations obtained for ‘ever use of hydrochlorothiazide’ to vanish. Nevertheless, we may not expect to see similar risks observed in a European population [2,3] replicated in an Asian population. In fact, in a recent Taiwanese study, hydrochlorothiazide showed no significant association to skin cancer [5]. This may be explained by several fac-tors, including differences in skin phenotype, use of low-er hydrochlorothiazide doses, and cultural differences in sun behavior. However, additional studies in Asian pop-ulations are necessary to confirm these findings.Conflict of interestNo potential conflict of interest relevant to this article was reported.REFERENCES1. Park E, Lee Y, Jue MS. Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disor-der: a nationwide retrospective cohort study from Korea. Korean J Intern Med 2019 Dec 18 [Epub]. https://doi.org/10.3904/kjim.2019.218.2. Pedersen SA, Gaist D, Schmidt SAJ, Holmich LR, Friis S, Pottegard A. Hydrochlorothiazide use and risk of nonmel-anoma skin cancer: a nationwide case-control study from Denmark. J Am Acad Dermatol 2018;78:673-681.e9.3. Morales DR, Pacurariu A, Slattery J, Kurz X. Association between hydrochlorothiazide exposure and different in-cident skin, lip and oral cavity cancers: A series of popula-tion-based nested case-control studies. Br J Clin Pharma-col 2020 Feb 18 [Epub]. https://doi.org/10.1111/bcp.14245.4. European Medicines Agency. PRAC recommendations on signals [Internet]. London (UK): European Medicines Agency, 2018 [cited 2020 Mar 10]. Available from: https://www.ema.europa.eu/en/documents/prac-recommenda-tion/prac-recommendations-signals-adopted-3-6-septem-ber-2018-prac-meeting_en-0.pdf.5. Pottegard A, Pedersen SA, Schmidt SAJ, et al. Use of hy-drochlorothiazide and risk of skin cancer: a nationwide Taiwanese case-control study. Br J Cancer 2019;121:973-978.

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Comment on "Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder:a nationwide retrospective cohort study from Korea"

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