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.

Abstract and Introduction

Abstract

Controversy exists about breast cancer risk associated with long-term use of calcium channel blockers (CCBs) or angiotensin-converting enzyme inhibitors (ACEis), respectively. Our objective in this study was to separately evaluate associations between duration of CCB or ACEi use and breast cancer in hypertensive women aged ≥55 years at 3 sites in the Kaiser Permanente health-care system (1997–2012). Exposures included CCB or ACEi use of 1–12 years' duration, determined from pharmacy dispensings. Outcomes included invasive lobular or ductal carcinoma. Statistical methods included discrete-time survival analyses. The cohort included 19,674 (17.9%) CCB users and 90,078 (82.1%) ACEi users. Two percent (n = 397) of CCB users and 1.9% (n = 1,733) of ACEi users developed breast cancer. Compared with 1–<2 years of use, in adjusted analysis, there was no association between CCB use for 2–<12 years and breast cancer: All 95% confidence intervals included 1. Increasing duration of ACEi use was associated with reduced breast cancer risk: Compared with 1–<2 years of use, the adjusted hazard ratio was 0.76 (95% confidence interval: 0.63, 0.92) for 5–<6 years of use and 0.63 (95% confidence interval: 0.43, 0.93) for 9–<10 years of use. We conclude that among older women with hypertension, long-term CCB use does not increase breast cancer risk and long-term treatment with ACEis may confer protection against breast cancer.

Introduction

Controversy exists about whether antihypertensive agents are associated with breast cancer in women, particularly whether long-term use of calcium channel blockers (CCBs) is associated with increased risk and whether long-term use of angiotensin-converting enzyme inhibitors (ACEis) is associated with decreased risk.^[1–10] Most previous studies of antihypertensive agents and breast cancer have had key limitations, including the facts that duration of CCB or ACEi use was not assessed, few women with many years of use were studied, use was determined from self-reports, and/or concomitant use of antihypertensive medications was not considered.^[1–9,11]

There are important implications if alterations in breast cancer risk with long-term CCB or ACEi use are confirmed.^[12] In the United States, breast cancer is the most commonly occurring cancer in women and the second-leading cause of cancer death.^[13] Additionally, ACEis and CCBs both rank among the top classes of medications prescribed in the United States.^[14]

The primary objective of this study was to assess risk of incident invasive breast cancer in a large cohort of women with varying durations of CCB or ACEi use. Specifically, we separately evaluated associations across discrete durations of CCB or ACEi use of 1–12 years and then, as a secondary objective, we compared risks between groups. To evaluate these associations, we employed comprehensive electronic health record, administrative, medication dispensing, and tumor data from older women with hypertension enrolled in a large integrated health-care delivery system.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Characteristics of Hypertensive Women Aged ≥55 Years With at Least 1 Year of Calcium Channel Blocker or Angiotensin-Converting Enzyme Inhibitor Use at 3 Kaiser Permanente (KP) Sites (KP Colorado, KP Northwest, and KP Southern California), 1997–2012
Characteristic	Angiotensin-Converting Enzyme Inhibitors		Calcium Channel Blockers		Total
Characteristic	No. of Women	%	No. of Women	%	No. of Women	%
Total	90,078	82.1	19,674	17.9	109,752	100
Age at cohort entry, years^a	67.2 (8.9)		68.6 (9.7)		67.4 (9.0)
Race/ethnicity^b
Asian	4,911	5.5	1,420	7.2	6,331	5.8
Black	8,599	9.5	2,936	14.9	11,535	10.5
Hispanic	17,067	18.9	2,492	12.7	19,559	17.8
Other	1,870	2.1	474	2.4	2,344	2.1
White	52,485	58.2	11,285	57.4	63,770	58.1
Body mass index^a,c,d	29.9 (6.9)		29.1 (6.9)		29.7 (6.9)
Diabetes^e	32,285	35.8	4,109	20.9	36,394	33.2
Hysterectomy	12,884	14.3	2,861	14.5	15,745	14.3
Mammogram^f	66,403	73.7	13,704	69.7	80,107	73.0
Reason for censoring
Breast cancer	1,733	1.9	397	2.0	2,130	1.9
End of study	44,465	49.4	8,065	41.0	52,530	47.9
Drug switch	23,059	25.6	7,135	36.3	30,194	27.5
Disenrollment	13,199	14.7	2,117	10.8	15,316	14.0
Death	7,617	8.5	1,958	10.0	9,575	8.7
Prophylactic mastectomy	<10	0	<10	0	<10	0
Less than high school education^g	26,496	29.5	5,576	28.3	32,072	29.2
Alcohol abuse^e	477	0.5	124	0.6	601	0.5
Tobacco use^h
Current smoker	11,517	12.8	2,559	13.0	14,076	12.8
Former smoker	18,183	20.2	3,887	19.8	22,070	20.1
Never smoker	48,858	54.2	9,040	45.9	57,898	52.8
Medication use
Angiotensin receptor blockersⁱ	9,775	10.9	3,335	17.0	13,110	11.9
β-blockersⁱ	45,728	50.8	9,722	49.4	55,450	50.5
Thiazide-type diureticsⁱ	61,491	68.3	10,548	53.6	72,039	65.6
Prescription NSAIDs^e	24,788	27.5	5,446	27.7	30,234	27.5
Insulin^e	2,950	3.3	556	2.8	3,506	3.2
Metformin^e	9,533	10.6	808	4.1	10,341	9.4
Statins^e	30,369	33.7	5,317	27.0	35,686	32.6
Estrogen replacement therapy
Current use (with/without progestin)	21,364	23.7	5,454	27.7	26,818	24.4
Former use	28,310	31.4	5,394	27.4	33,704	30.7
Never use	40,404	44.9	8,826	44.9	49,230	44.9
Year of cohort entry
1997–2000	15,697	17.4	5,704	29.0	21,401	19.5
2001–2004	27,480	30.5	4,680	23.8	32,160	29.3
2005–2008	31,171	34.6	4,661	23.7	35,832	32.6
2009–2012	15,730	17.5	4,629	23.5	20,359	18.6
Length of follow-up, years^a	5.7 (3.2)		5.1 (3.4)		5.6 (3.3)
Time on study drug, years^a,j	4.1 (2.8)		3.8 (2.7)		4.1 (2.8)

Abbreviation: NSAID, nonsteroidal antiinflammatory drug.
^aValues are expressed as mean (standard deviation).
^bRace/ethnicity was unknown for 5.7% of the participants.
^cWeight (kg)/height (m)².
^dBody mass index was unknown for 7.1%.
^eWithin the year prior to cohort entry.
^fWithin the year before cohort entry and the year after cohort entry.
^gDetermined using US Census data; education was unknown for 8.4% of the participants.
^hTobacco use was unknown for 14.3% of the participants.
ⁱWithin the year prior to cohort entry and through the end of the woman's unique study time period.
^jCalculated as the total sum of days' supply of dispensed prescription medications.

Table 2. Hazard Ratios for Risk of Breast Cancer Among Hypertensive Women Aged ≥55 Years With at Least 1 Year of Use of Calcium Channel Blockers or Angiotensin-Converting Enzyme Inhibitors at 3 Kaiser Permanente Sites (Primary Analysis), 1997–2012 ^a
Duration of Use, years	Calcium Channel Blockers						Angiotensin-Converting Enzyme Inhibitors
	No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	Unadjusted		Adjusted		No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	Unadjusted		Adjusted
	No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	HR	95% CI	HR^b	95% CI	No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	HR	95% CI	HR^b	95% CI
1–<2	19,674	119	1	Referent	1	Referent	90,078	547	1	Referent	1	Referent
2–<3	13,713	93	1.12	0.86, 1.47	1.09	0.83, 1.43	65,715	345	0.86	0.76, 0.99	0.84	0.73, 0.96
3–<4	9,728	58	0.99	0.72, 1.35	0.93	0.68, 1.29	50,398	246	0.80	0.69, 0.93	0.76	0.65, 0.89
4–<5	6,789	43	1.05	0.74, 1.48	0.98	0.69, 1.41	37,895	186	0.81	0.68, 0.95	0.74	0.62, 0.88
5–<6	4,815	27	0.93	0.61, 1.41	0.84	0.55, 1.29	28,146	145	0.85	0.71, 1.02	0.76	0.63, 0.92
6–<7	3,435	22	1.06	0.67, 1.67	0.96	0.60, 1.53	20,534	89	0.71	0.57, 0.89	0.63	0.50, 0.79
7–<8	2,363	12	0.84	0.46, 1.52	0.75	0.41, 1.38	14,360	56	0.64	0.49, 0.85	0.55	0.41, 0.72
8–<9	1,649	12	1.20	0.67, 2.18	1.06	0.57, 1.95	9,374	43	0.76	0.55, 1.03	0.63	0.46, 0.86
9–<10	1,126	5	0.73	0.30, 1.80	0.65	0.26, 1.61	6,054	29	0.79	0.54, 1.15	0.63	0.43, 0.93
10–<11	754	3	0.66	0.21, 2.07	0.58	0.18, 1.84	3,844	20	0.86	0.55, 1.34	0.67	0.43, 1.06
11–<12	508	3	0.98	0.31, 3.07	0.86	0.27, 2.74	2,382	13	0.90	0.52, 1.56	0.69	0.39, 1.20

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; CCB, calcium channel blocker; CI, confidence interval; HR, hazard ratio.
^aDiscrete-time survival analysis for the association between cumulative duration of CCB or ACEi use and breast cancer risk. Crude breast cancer hazards for yearly periods were obtained using the life-table approach. A complementary log-log binary model was used to estimate duration associations.
^bAdjusted for time-varying and fixed covariates. Time-varying covariates included age, body mass index (weight (kg)/height (m)²), hysterectomy, diabetes, alcohol abuse, estrogen replacement, use of statins, mammography, and use of angiotensin receptor blockers, β-blockers, and/or diuretics. Fixed covariates included Kaiser Permanente site (Colorado, Northwest, or Southern California), race/ethnicity, education, and year of cohort entry.

Table 3. Hazard Ratios for Risk of Breast Cancer Among Hypertensive Women Aged ≥55 Years With at Least 1 Year of Use of Calcium Channel Blockers or Angiotensin-Converting Enzyme Inhibitors at 3 Kaiser Permanente Sites (Subcohort Matched on Length of Follow-up), 1997–2012 ^a
Duration of Use, years	Calcium Channel Blockers						Angiotensin-Converting Enzyme Inhibitors
	No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	Unadjusted		Adjusted		No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	Unadjusted		Adjusted
	No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	HR	95% CI	HR^b	95% CI	No. of Women Remaining at Risk	No. of Women Diagnosed With Breast Cancer	HR	95% CI	HR^b	95% CI
1–<2	17,320	96	1	Referent	1	Referent	79,304	539	1	Referent	1	Referent
2–<3	12,587	83	1.19	0.89, 1.60	1.18	0.88, 1.58	56,100	337	0.88	0.77, 1.01	0.85	0.74, 0.98
3–<4	9,254	54	1.05	0.75, 1.47	1.04	0.74, 1.46	41,525	239	0.85	0.73, 0.99	0.79	0.68, 0.92
4–<5	6,657	41	1.11	0.77, 1.60	1.10	0.76, 1.61	29,892	173	0.85	0.72, 1.01	0.76	0.64, 0.91
5–<6	4,736	27	1.03	0.67, 1.58	0.99	0.64, 1.53	21,157	124	0.86	0.71, 1.05	0.74	0.61, 0.91
6–<7	3,359	22	1.18	0.74, 1.88	1.14	0.70, 1.83	14,906	64	0.63	0.49, 0.82	0.53	0.40, 0.69
7–<8	2,293	12	0.94	0.52, 1.72	0.90	0.49, 1.66	10,415	37	0.52	0.37, 0.73	0.42	0.30, 0.59
8–<9	1,583	12	1.37	0.75, 2.50	1.28	0.69, 2.38	7,086	27	0.56	0.38, 0.82	0.44	0.29, 0.65
9–<10	1,066	5	0.85	0.34, 2.08	0.79	0.32, 1.98	4,872	15	0.45	0.27, 0.76	0.34	0.20, 0.57
10–<11	700	3	0.77	0.25, 2.44	0.72	0.22, 2.29	3,341	14	0.62	0.36, 1.05	0.45	0.26, 0.78
11–<12	459	3	1.18	0.37, 3.72	1.09	0.34, 3.49	2,222	11	0.73	0.40, 1.32	0.52	0.29, 0.96