Risk of Breast Cancer With Long-term Use of Calcium Channel Blockers or Angiotensin-Converting Enzyme Inhibitors Among Older Women

Marsha A. Raebel; Chan Zeng; T. Craig Cheetham; David H. Smith; Heather Spencer Feigelson; Nikki M. Carroll; Kristin Goddard; Heather M. Tavel; Denise M. Boudreau; Susan Shetterly; Stanley Xu

Disclosures

Am J Epidemiol. 2017;185(4):264-273. 

In This Article

Results

The cohort included 19,674 (17.9%) women taking CCBs and 90,078 (82.1%) women taking ACEis for mean durations of 3.8 (standard deviation, 2.7) years and 4.1 (standard deviation, 2.8) years, respectively. Women taking CCBs were older (CCBs, mean age = 68.6 years; ACEis, mean age = 67.2 years), had a lower mean body mass index (CCBs, 29.1; ACEis, 29.9), included a lower proportion of Hispanics (CCBs, 12.7%; ACEis, 18.9%), more frequently used angiotensin-receptor blockers (CCBs, 17.0%; ACEis, 10.9%), less frequently used thiazide-type diuretics (CCBs, 53.6%; ACEis, 68.3%) or metformin (CCBs, 4.1%; ACEis, 10.6%), and had a lower prevalence of diabetes (CCBs, 20.9%; ACEis, 35.8%) ( Table 1 ). More women were censored from the CCB cohort due to switching to an ACEi (36.3%) than from the ACEi cohort due to switching to a CCB (25.6%). Two percent (n = 397) of CCB users and 1.9% (n = 1,733) of ACEi users were diagnosed with incident invasive breast cancer.

Hazard ratios and 95% confidence intervals for durations of CCB use of up to 12 years are shown in Table 2 . Compared with using CCBs for 1–<2 years, in adjusted analysis there was no association between increasing durations of CCB use and breast cancer risk. The results of the analysis restricted to women with ≥2 hypertension diagnoses prior to the first CCB dispensing (n = 10,791) were similar (see Web Table 1, available at http://aje.oxfordjournals.org/).

Hazard ratios and 95% confidence intervals for ACEi use durations of up to 12 years are also shown in Table 2 . Increasing durations of ACEi use were associated with reduced breast cancer risk: Compared with 1–<2 years of use, the adjusted hazard ratio was 0.84 (95% confidence interval (CI): 0.73, 0.96) for 2–<3 years of use, 0.76 (95% CI: 0.63, 0.92) for 5–<6 years, 0.63 (95% CI: 0.43, 0.93) for 9–<10 years, and 0.69 (95% CI: 0.39, 1.20) for 11–<12 years. The analysis restricted to women with more than 2 hypertension diagnoses prior to the first ACEi dispensing (n = 46,930) produced similar findings (Web Table 2).

The results of the secondary analysis of CCB use, in which overlapping dispensings and stockpiled medications were not included in duration of use, did not differ from the results of the primary analysis. Compared with using CCBs for 1–<2 years, the adjusted hazard ratio for all durations of use up to 12 years revealed no increased breast cancer risk. Compared with using ACEis for 1–<2 years, the adjusted hazard ratios for all durations of ACEi use up to 12 years had point estimates consistent with decreased breast cancer risk.

The subcohort matched on length of follow-up included 17,320 (17.9%) women taking CCBs and 79,304 (82.1%) women taking ACEis. In this subset of women, 358 (2.1%) CCB users and 1,594 (2.0%) ACEi users developed breast cancer. In this subcohort, longer durations of CCB use were not associated with increased breast cancer risk ( Table 3 ). Breast cancer risk among ACEi users again decreased with longer durations of use.

In primary analysis, the hazard profile of CCB users did not show an increasing or decreasing trend (P = 0.06). The hazard profile of ACEi users suggested a decreasing duration association over time (P < 0.001) (Figure 2A). The P value from the test of difference in trend of the duration association between CCBs and ACEis was not significant (P = 0.81). In the matched subcohort, the P value from the trend test of the duration association between CCB use and ACEi use was significant (P = 0.02) (Figure 2B). In the analysis restricted to women with ≥2 hypertension diagnoses prior to cohort entry, the hazard profiles of CCB users (P = 0.55) and ACEi users (P < 0.001) were similar to those of the primary analyses. The P value from the trend test of the duration association between CCB use and ACEi use was significant (P = 0.02) (Figure 2C), similar to the situation with the matched subcohort.

Figure 2.

Hazard rates for risk of breast cancer according to long-term use of a calcium channel blocker (CCB) or angiotensin-converting enzyme inhibitor (ACEi) among women in a cohort selected from 3 Kaiser Permanente sites, 1997–2012. A) All women (n = 109,752; CCB test for trend: P = 0.06; ACEi test for trend: P < 0.001; test for difference in linear trend of duration association between CCBs and ACEis: P = 0.81); B) women in the subcohort matched on length of follow-up time (n = 96,624; CCB trend test: P = 0.41; ACEi trend test: P < 0.001; test for difference in linear trend of duration association: P = 0.02); C) women with at least 2 diagnoses of hypertension prior to CCB or ACEi prescription (n = 57,721; CCB trend test: P = 0.55; ACEi trend test: P < 0.001; test for difference in linear trend of duration association: P = 0.02 (limited to >1–9 years' duration of use because there were no breast cancer outcomes in this CCB subgroup after year 9)). Bars, 95% confidence intervals.

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