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Table 1.  
Association of Exposure to Hydrochlorothiazide and Risk of Malignant Melanoma
Association of Exposure to Hydrochlorothiazide and Risk of Malignant Melanoma
Table 2.  
Association of Exposure to Hydrochlorothiazide and Risk of Malignant Melanoma According to Amount of Hydrochlorothiazide Use and Specified by Melanoma Subtype
Association of Exposure to Hydrochlorothiazide and Risk of Malignant Melanoma According to Amount of Hydrochlorothiazide Use and Specified by Melanoma Subtype
1.
Pottegård  A, Hallas  J, Olesen  M,  et al.  Hydrochlorothiazide use is strongly associated with risk of lip cancer.  J Intern Med. 2017;282(4):322-331. doi:10.1111/joim.12629PubMedGoogle ScholarCrossref
2.
Arnspang  S, Gaist  D, Johannesdottir Schmidt  SA, Hölmich  LR, Friis  S, Pottegård  A.  Hydrochlorothiazide use and risk of non-melanoma skin cancer: A nationwide case-control study from Denmark.  J Am Acad Dermatol. 2018;78(4):673-581.e9. doi:10.1016/j.jaad.2017.11.042Google Scholar
3.
Schmidt  M, Pedersen  L, Sørensen  HT.  The Danish Civil Registration System as a tool in epidemiology.  Eur J Epidemiol. 2014;29(8):541-549. doi:10.1007/s10654-014-9930-3PubMedGoogle ScholarCrossref
4.
Jensen  AØ, Thomsen  HF, Engebjerg  MC, Olesen  AB, Sørensen  HT, Karagas  MR.  Use of photosensitising diuretics and risk of skin cancer: a population-based case-control study.  Br J Cancer. 2008;99(9):1522-1528. doi:10.1038/sj.bjc.6604686PubMedGoogle ScholarCrossref
5.
Schmidt  SAJ, Schmidt  M, Mehnert  F, Lemeshow  S, Sørensen  HT.  Use of antihypertensive drugs and risk of skin cancer.  J Eur Acad Dermatol Venereol. 2015;29(8):1545-1554. doi:10.1111/jdv.12921PubMedGoogle ScholarCrossref
6.
Whiteman  DC, Stickley  M, Watt  P, Hughes  MC, Davis  MB, Green  AC.  Anatomic site, sun exposure, and risk of cutaneous melanoma.  J Clin Oncol. 2006;24(19):3172-3177. doi:10.1200/JCO.2006.06.1325PubMedGoogle ScholarCrossref
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    2 Comments for this article
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    Hydrochlorothiazide: overused albeit a paltry and redundant antihypertensive
    Neelesh Gupta, MD | University of South Alabama Medical Center, Mobile, AL

    Thiazide-type/like drugs plays an important role in management of Hypertension (HTN). As HTN is an incurable lifelong malady, it requires life-long therapy. Therefore, the choice of drug/drugs to treat it assumes paramount significance. The drug should not only control HTN, but it must also reduce the elevated risk of adverse cardiovascular events: the very purpose of antihypertensive therapy.


    In 1980, Multiple Risk Factor intervention Trial (MRFIT) policy advisory board changed the hypertension treatment protocol, recommending chlorthalidone (CTD) over hydrochlorothiazide (HCTZ) for initial hypertensive therapy. This was done as coronary heart disease (CHD) mortality in special intervention group using HCTZ
    was 44% higher than other clinics using CTD (importantly drug was documented at each follow-up). (1)This was the first study in the world to show disparate mortality reduction between HCTZ and CTD. Surprisingly, we still find commonly, albeit inappropriately HCTZ in combination with many drugs like ACEI/ARB/BB all over the globe, a serious mistake: in need of paradigm shift. The present study is welcome, as it shows association of malignant melanoma with HCTZ. Already HCTZ is linked with lip and nonmelanoma skin cancers.

    In lieu of HCTZ, either chorthalidone (with proven benefit with hard end points in ALLHAT ) or indapamide could be used. Indapamide is particularly recommended not only for uncomplicated primary hypertension but also for hypertension complicated with other common comorbidities like diabetes mellitus, renal impairment of any degree (including patients on long-term maintenance hemodialysis),2 target organ damage like LVH, and in very old persons etc.
    References:
    1. Multiple Risk Factor Reduction Intervention Trial Research Group Mortality after 10 ½ years for hypertensive participants in the MRFIT. Circulation. 1990;82:1616–1628. [PubMed]

    2. Acchiardo S.R., Skoutakis V.A. Clinical efficacy, safety, and pharmacokinetics of indapamide in renal impairment. Am Heart J. 1983;106(July (1 pt. 2)):237–244. [PubMed]
    CONFLICT OF INTEREST: None Reported
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    Continued use of Hydrochlorothiazide in Hypertension: a serious error
    Rajkumar Doshi, MD MPH | University of Nevada, Reno School of Medicine
    It is very heartening to read this article. Hydrochlorothiazide (HCTZ) in combination with other antihypertensives like angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers is a popular thiazide diuretic, still used all over world: a serious mistake indeed. Despite controlling hypertension (HTN), HCTZ failed to show improvement in cardiovascular (CVD) morbidity and mortality.1 Other thiazide-type/like diuretic like chlorthalidone in ALLHAT2 and indapamide in HYVET3 studies have clearly shown reduction in CVD morbidity and mortality. This recent study showing association of HCTZ with malignant melanoma, along with earlier studies showing its association with lip and nonmelanoma cancers should raise the alarm, inform the guidelines, and United States Food and Drug Association. (May be put in a black box warning).

    References:

    1. Mishra S. Diuretics in primary hypertension - Reloaded. Indian Heart J. 2016;68:720-723.
    2. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA. 2000;283:1967-75.
    3. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ and Group HS. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-98.
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    May 29, 2018

    Association of Hydrochlorothiazide Use and Risk of Malignant Melanoma

    Author Affiliations
    • 1Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark
    • 2Department of Neurology, Odense University Hospital, Odense, Denmark
    • 3Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
    • 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
    • 5Department of Plastic Surgery, Herlev Gentofte Hospital, Herlev, Denmark
    • 6Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
    • 7Department of Public Health, University of Copenhagen, Denmark
    JAMA Intern Med. Published online May 29, 2018. doi:10.1001/jamainternmed.2018.1652

    We have recently shown that hydrochlorothiazide use increases the risk of lip and nonmelanoma skin cancer, notably squamous cell carcinoma.1,2 It would have substantial implications if the carcinogenic effect of hydrochlorothiazide also extended to malignant melanoma.

    Methods

    Similarly to our recent studies of hydrochlorothiazide,1,2 we identified histologically verified melanoma cases (January 2004 to December 2015), each matched 1:10 (risk-set sampling; age, sex, and date) to cancer-free population controls. We required cases and controls to be between ages 18 and 90 years, without previous history of cancer (except nonmelanoma skin cancer), organ transplantation, HIV infection, or azathioprine use, and to have resided continuously in Denmark for 10 years.

    Using conditional logistic regression, we calculated odds ratios (ORs), with 95% CIs, for melanoma associated with cumulative hydrochlorothiazide use compared with never-use, adjusting for potential confounders (Table 1 and 2). We performed stratified analyses by localization, stage, histologic subtype, and subgroups of age, sex, and history of nonmelanoma skin cancer. To evaluate potential confounding by indication, we performed analyses for other antihypertensive drugs, including bendroflumethiazide, angiotensin-converting enzyme inhibitors, angiontensin-II receptor antagonists, and calcium-channel blockers. This study was approved by Statistics Denmark and the Danish Data Protection Agency.

    Results

    We identified 22 010 cases of melanoma. After exclusions, the final study population comprised 19 273 cases and 192 730 population controls. Cases had slightly lower comorbidity, higher educational level, and higher prevalence of previous nonmelanoma skin cancer than controls. Remaining characteristics were similar between cases and controls.

    Overall, 413 cases (2.1%) and 3406 controls (1.8%) were classified as high-users (≥50 000 mg) of hydrochlorothiazide, yielding an adjusted OR of 1.22 (95% CI, 1.09-1.36) for melanoma. No clear dose-response pattern emerged between hydrochlorothiazide use and melanoma risk (Table 1). Analyses by melanoma localization, stage, age, sex, and history of nonmelanoma skin cancer yielded results comparable to the main analysis (data not shown). When stratifying by histological subtype (Table 2), higher ORs occurred for nodular melanoma (n = 1695 cases [8.8%]; OR, 2.05; 95% CI, 1.54-2.72; P for trend = .01) and lentigo melanoma (n = 500 cases [2.6%]; OR, 1.61; 95% CI, 1.03-2.50; P for trend = .16) than for superficial spreading melanoma (n = 13 781 cases [72%]; OR, 1.11; 95% CI, 0.97-1.27; P for trend = .73).

    In secondary analyses, we observed associations close to the null for overall melanoma risk with long-term use of bendroflumethiazide (OR, 1.10; 95% CI, 1.02-1.19; P for trend = 0.47), angiotensin-converting enzyme inhibitors (OR, 1.07; 95% CI, 0.99-1.16; P for trend = .53), angiotensin-II receptor antagonists (OR, 1.18; 95% CI, 1.07-1.29; P for trend = .07), and calcium-channel blockers (OR, 1.06; 95% CI, 0.97-1.14; P for trend  = .94). These associations remained neutral in subanalyses stratified by melanoma subtype (data not shown).

    Discussion

    The main strength of our study is the use of high-quality nationwide registry data.3 The main limitations are a lack of information on risk factors such as sun exposure, skin pigmentation, and family history of melanoma. However, these characteristics are unlikely to be substantially associated with hydrochlorothiazide use, and thus unlikely to confound out estimates.

    Thiazide use and melanoma risk has been investigated in a few previous studies; however, only 2 studies,4,5 both from northern Denmark, have specifically examined hydrochlorothiazide. The first study reported an OR of 1.32 (95% CI, 1.03-1.70) for melanoma risk overall associated with 10 000 mg increments of hydrochlorothiazide.4 The corresponding OR for hydrochlorothiazide in combination with amiloride was 1.43 (95% CI, 1.09-1.88).4 The other study found no association between hydrochlorothiazide use combined with amiloride and melanoma risk (OR, 1.02; 95% CI, 0.78-1.33).5 Neither of these studies included dose-response or histology-specific analyses.

    The findings for melanoma subtype are somewhat surprising, as lentigo and superficial spreading melanoma are known to be associated with high sun exposure, whereas the etiology of nodular melanomas is less elucidated.6 It is worrying that hydrochlorothiazide use appears to be associated with an increased risk of melanoma, and the particular associations observed for lentigo melanoma and nodular melanoma warrant further research.

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    Article Information

    Corresponding Author: Anton Pottegård, MScPharm, PhD, Clinical Pharmacology and Pharmacy, University of Southern Denmark, JB Winsløwsvej 19, 2, 5000 Odense C, Denmark (apottegaard@health.sdu.dk).

    Accepted for Publication: March 10, 2018.

    Published Online: May 29, 2018. doi:10.1001/jamainternmed.2018.1652

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Pottegård A et al. JAMA Internal Medicine.

    Author Contributions: Dr Pottegård had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: Pottegård, Pedersen, Schmidt, Gaist.

    Drafting of the manuscript: Pottegård, Pedersen, Gaist.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Pottegård.

    Obtained funding: Pottegård.

    Administrative, technical, or material support: Pottegård.

    Supervision: Pedersen, Schmidt, Friis, Gaist.

    Conflict of Interest Disclosures: Dr Gaist received honoraria from AstraZeneca (Sweden) for participation as a coinvestigator in a research project outside this work. Dr Pottegård has participated in research projects, unrelated to the present study, using grants provided by LEO Pharma (manufacturer of bendroflumethiazide) to the institution where he was employed.

    Funding/Support: The work was funded by the Danish Council for Independent Research (grant No. 4004-00234B) and the Danish Cancer Society (grant No. R72-A4417).

    Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We acknowledge Morten Olesen, information technologist, and Martin Thomsen Ernst, Master of Science in Sports and Health, (both University of Southern Denmark) for valuable data management, as well as Chris B. Jakobsen (Danish Medicine Agency), who provided valuable help with identifying the hydrochlorothiazide content of combination products that are no longer marketed in Denmark. They were not compensated for their contributions.

    References
    1.
    Pottegård  A, Hallas  J, Olesen  M,  et al.  Hydrochlorothiazide use is strongly associated with risk of lip cancer.  J Intern Med. 2017;282(4):322-331. doi:10.1111/joim.12629PubMedGoogle ScholarCrossref
    2.
    Arnspang  S, Gaist  D, Johannesdottir Schmidt  SA, Hölmich  LR, Friis  S, Pottegård  A.  Hydrochlorothiazide use and risk of non-melanoma skin cancer: A nationwide case-control study from Denmark.  J Am Acad Dermatol. 2018;78(4):673-581.e9. doi:10.1016/j.jaad.2017.11.042Google Scholar
    3.
    Schmidt  M, Pedersen  L, Sørensen  HT.  The Danish Civil Registration System as a tool in epidemiology.  Eur J Epidemiol. 2014;29(8):541-549. doi:10.1007/s10654-014-9930-3PubMedGoogle ScholarCrossref
    4.
    Jensen  AØ, Thomsen  HF, Engebjerg  MC, Olesen  AB, Sørensen  HT, Karagas  MR.  Use of photosensitising diuretics and risk of skin cancer: a population-based case-control study.  Br J Cancer. 2008;99(9):1522-1528. doi:10.1038/sj.bjc.6604686PubMedGoogle ScholarCrossref
    5.
    Schmidt  SAJ, Schmidt  M, Mehnert  F, Lemeshow  S, Sørensen  HT.  Use of antihypertensive drugs and risk of skin cancer.  J Eur Acad Dermatol Venereol. 2015;29(8):1545-1554. doi:10.1111/jdv.12921PubMedGoogle ScholarCrossref
    6.
    Whiteman  DC, Stickley  M, Watt  P, Hughes  MC, Davis  MB, Green  AC.  Anatomic site, sun exposure, and risk of cutaneous melanoma.  J Clin Oncol. 2006;24(19):3172-3177. doi:10.1200/JCO.2006.06.1325PubMedGoogle ScholarCrossref
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