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- Page navigation anchor for RE: Responses to Association between antihypertensive medications and risk of skin cancer in people older than 65 years: a population-based studyRE: Responses to Association between antihypertensive medications and risk of skin cancer in people older than 65 years: a population-based study
We thank Dr. Dawes and Dr. Parmar for their thoughtful responses to our study.1 We agree that when interpreting and applying our findings to clinical practice, they must be considered in each individual patient’s clinical context. Thiazides are effective, inexpensive antihypertensive medications that lower cardiovascular risk;2 for most patients the benefits will outweigh the potential risk of skin cancer.
Understanding absolute risk difference would be helpful. However, we cannot estimate the survival function, cumulative incidence function or absolute risk in our study design with cumulative exposure as a time-varying covariate. As Dr. Dawes mentions, hazard ratios do not directly translate to and should not be interpreted as relative risks. The hazard ratio is larger in magnitude and in the same direction of effect as the corresponding relative risk, with the exact relationship between the measures changing over the course of study follow-up.3
Baseline absolute risk for skin cancer varies across patients and therefore the absolute risk difference associated with thiazide exposure is likely variable as well. Our study did not include data on important skin cancer risk factors such as skin pigmentation or sun exposure or sun damage, such as the presence of premalignant lesions (e.g., actinic keratosis). It is likely that any effect of thiazides on photosensitivity and consequent increase in absolute skin cancer risk is accentuated in people with fair skin a...
Show MoreCompeting Interests: None declared.References
- Drucker AM, Hollestein L, Na Y, et al. Association between antihypertensive medications and risk of skin cancer in people older than 65 years: a population-based study. CMAJ 2021;193:E508-E16
- Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97
- Sutradhar R, Austin PC. Relative rates not relative risks: addressing a widespread misinterpretation of hazard ratios. Annals of epidemiology. 2018;28:54-7.
- Pedersen SA, Gaist D, Schmidt SAJ, Holmich LR, Friis S, Pottegard A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. Journal of the American Academy of Dermatology. 2018;78:673-81 e9.
- Pottegard A, Pedersen SA, Schmidt SAJ, et al. Use of hydrochlorothiazide and risk of skin cancer: a nationwide Taiwanese case-control study. Br J Cancer. 2019;121:973-8
- Page navigation anchor for RE: Association between thiazide diuretics and skin cancer: still nebulousRE: Association between thiazide diuretics and skin cancer: still nebulous
I read with interest the article by Drucker et al1, that concludes, ‘higher cumulative exposure to thiazides was associated with increased risk of skin cancer.’ No doubt, an important study, and efforts should be made in identifying modifiable risk factors to prevent these. However, Tables S7, in the supplementary appendix of the manuscript shows that the hazard ratios for all 3-types of skin cancers was similar or higher with angiotensin receptor blockers when compared to thiazides, yet the association between thiazides is highlighted in the manuscript. This association between thiazide diuretics and skin cancer had been raised in some2, 3 and refuted4-6 in other studies, and the current study does not resolve this issue conclusively. In fact, both hypertension and all antihypertensive agents are associated with increased risk of cancer, and two meta-analysis of observational studies failed to show evidence of association with the use of thiazide diuretics but showed an association between calcium channel blockers and beta-blockers5, 6. Furthermore, though diuretics were first-line agents in the treatment of hypertension but no longer hold this status of first-line therapy for uncomplicated hypertension for at least over 2 decades7, and any of the classes of antihypertensive agents, except beta-blockers may be used as first line therapy7. The use of thiazides for treatment of hypertension has been declining8-10 and defined daily dose of thiazide diuretics is decreasing11...
Show MoreCompeting Interests: None declared.References
- 1. Drucker AM, Hollestein L, Na Y, et al. Association between antihypertensive medications and risk of skin cancer in people older than 65 years: a population-based study. CMAJ. Apr 12 2021;193(15):E508-E516.
- 2. Pedersen SA, Gaist D, Schmidt SAJ, Holmich LR, Friis S, Pottegard A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol. Apr 2017;78(4):673-681 e679.
- 3. Pottegard A, Hallas J, Olesen M, et al. Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med. Oct;282(4):322-331.
- 4. Pottegard A, Pedersen SA, Schmidt SAJ, et al. Use of hydrochlorothiazide and risk of skin cancer: a nationwide Taiwanese case-control study. Br J Cancer. Nov 2019;121(11):973-978.
- 5. Tang H, Fu S, Zhai S, Song Y, Asgari MM, Han J. Use of antihypertensive drugs and risk of keratinocyte carcinoma: A meta-analysis of observational studies. Pharmacoepidemiol Drug Saf. Mar;27(3):279-288.
- Page navigation anchor for RE: Antihypertensives and skin cancerRE: Antihypertensives and skin cancer
This is a great paper that raises questions about antihypertensive medications and side effects. The adjusted melanoma HR of thiazides is quite high at 1.34 ( CI 1.01–1.78)
The baseline risk can be found from many papers including https://dceg2.cancer.gov/melanomarisktool_prvw/fears_all.html
“The melanoma incidence rate for men 40 to 44 years old is 23.50/100,000”Giving thiazides increases the risk by 34% (very rough translation of HR and apologies to all biomedical statisticians) so going from 23.5 to 31.49/ 100,000 – basically an extra 8 people.
That means if you gave 100,000 HCTZ then 8 (plus or minus the CI) more would get melanoma – an approximate NNH of 12,500 per year. If the patient had a greater risk of melanoma based on skin color, family history, etc, maybe 10 times – the approximate NNH is now 1,250. For some individuals that may cross the decision threshold to take, or not to take a thiazide.
I would appreciate someone checking my back of the envelope numbers but if they are correct this paper indicates we should be considering melanoma risk in our review of drug options for patients with hypertension.Competing Interests: None declared.References
- Aaron M. Drucker, Loes Hollestein, Yingbo Na, et al. Association between antihypertensive medications and risk of skin cancer in people older than 65 years: a population-based study. CMAJ 2021;193:E508-E516.