Association between antihypertensive medications and risk of skin cancer in people older than 65 years: a population-based study

Abstract

Background: The risk of skin cancer associated with antihypertensive medication use is unclear, although thiazides have been implicated in regulatory safety warnings. We aimed to assess whether use of thiazides and other antihypertensives is associated with increased rates of keratinocyte carcinoma and melanoma.

Methods: We conducted a population-based inception cohort study using linked administrative health data from Ontario, 1998-2017. We matched adults aged ≥ 66 years with a first prescription for an antihypertensive medication (thiazides, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, β-blockers) by age and sex to 2 unexposed adults who were prescribed a non-antihypertensive medication within 30 days of the index date. We evaluated each antihypertensive class in a separate cohort study. Our primary exposure was the cumulative dose within each class, standardized according to the World Health Organization's Defined Daily Dose. Outcomes were time to first keratinocyte carcinoma, advanced keratinocyte carcinoma and melanoma.

Results: The inception cohorts included a total of 302 634 adults prescribed an antihypertensive medication and 605 268 unexposed adults. Increasing thiazide exposure was associated with an increased rate of incident keratinocyte carcinoma (adjusted hazard ratios [HRs] per 1 Defined Annual Dose unit 1.08, 95% confidence interval [CI] 1.03-1.14), advanced keratinocyte carcinoma (adjusted HR 1.07, 95% CI 0.93-1.23) and melanoma (adjusted HR 1.34, 95% CI 1.01-1.78). We found no consistent evidence of association between other antihypertensive classes and keratinocyte carcinoma or melanoma.

Interpretation: Higher cumulative exposure to thiazides was associated with increased rates of incident skin cancer in people aged 66 years and older. Consideration of other antihypertensive treatments in patients at high risk of skin cancer may be warranted.

Figure 1:

Patient flow diagram. Note: OHIP = Ontario Health Insurance Plan. *Baseline characteristics of new users of antihypertensive medications excluded because they could not be matched are presented in Appendix 1, Table S1 (available at www.cmaj.ca/lookup/doi/10.1503/cmaj.201971/tab-related-content).

Figure 2:

Rate of keratinocyte carcinoma associated with increasing cumulative dose of (A) thiazide diuretics (adjusted hazard ratio [HR] per unit increase 1.08, 95% confidence interval [CI] 1.03–1.14), (B) calcium channel blockers (adjusted HR 1.03, 95% CI 0.95–1.13), (C) β-blockers (adjusted HR 0.98, 95% CI 0.93–1.04), (D) angiotensin II receptor blockers (adjusted HR 1.09, 95% CI 0.91–1.29) and (E) angiotensin-converting enzyme inhibitors (adjusted HR 1.08, 95% CI 0.95–1.06) in Ontario. Note: y-axes are on a log₁₀ scale. Blue lines represent the adjusted HR and orange lines represent the 95% CI with 0–0.5 Defined Annual Dose units as the reference. Models are adjusted for age, sex, rurality, income according to postal code (quintile), number of physician visits, Charlson–Deyo comorbidity index, history of hypertension, year of index date, immunosuppressive medication use (time-varying), phototoxic medication use (time-varying), cumulative dosage or duration of other antihypertensive classes (time-varying) and ever use of each antihypertensive class (time-varying).

Figure 3:

Rate of advanced keratinocyte carcinoma associated with increasing cumulative dose of (A) thiazide diuretics (adjusted hazard ratio [HR] per unit increase 1.07, 95% confidence interval [CI] 0.93–1.23), (B) calcium channel blockers (adjusted HR 1.08, 95% CI 0.86–1.36), (C) β-blockers (adjusted HR 0.95, 95% CI 0.82–1.10), (D) angiotensin II receptor blockers (adjusted HR 1.49, 95% CI 0.93–2.39) and (E) angiotensin-converting enzyme inhibitors (adjusted HR 0.91, 95% CI 0.79–1.06) in Ontario. Note: y-axes are on a log₁₀ scale. Blue lines represent the adjusted HR and orange lines represent the 95% CI with 0–0.5 Defined Annual Dose units as the reference. Models are adjusted for age, sex, rurality, income according to postal code (quintile), number of physician visits, Charlson–Deyo comorbidity index, history of hypertension, year of index date, immunosuppressive medication use (time-varying), phototoxic medication use (time-varying), cumulative dosage or duration of other antihypertensive classes (time-varying) and ever use of each antihypertensive class (time-varying).

Figure 4:

Rate of melanoma associated with increasing cumulative dose of (A) thiazide diuretics (adjusted hazard ratio [HR] per unit increase 1.34, 95% confidence interval [CI] 1.01–1.78), (B) calcium channel blockers (adjusted HR 0.86, 95% CI 0.55–1.36), (C) β-blockers (adjusted HR 0.76, 95% CI 0.55–1.04), (D) angiotensin II receptor blockers (adjusted HR 1.73, 95% CI 0.63–4.74) and (E) angiotensin-converting enzyme inhibitors (adjusted HR 0.98, 95% CI 0.73–1.32) in Ontario. Note: y-axes are on a log₁₀ scale. Blue lines represent the adjusted HR and orange lines represent the 95% CI with 0–0.5 Defined Annual Dose units as the reference. Models are adjusted for age, sex, rurality, income according to postal code (quintile), number of physician visits, Charlson–Deyo comorbidity index, history of hypertension, year of index date, immunosuppressive medication use (time-varying), phototoxic medication use (time-varying), cumulative dosage or duration of other antihypertensive classes (time-varying) and ever use of each antihypertensive class (time-varying).