The Long-term Use of Calcium Channel

Blockers and the Risk of Breast Cancer.

NOYCIA 2015

Sara Soldera1, Nathaniel Bouganim1, Jamil Asselah1,

Hui Yin2, Ralph Maroun1 and Laurent Azoulay2

Department of Oncology, McGill University Health Center1 and Centre for Clinical Epidemiology,

Lady Davis Institute, Jewish General Hospital2,, Montreal, QC

Background

• Calcium channel blockers (CCB) are

widely used in the treatment of various

cardiovascular conditions.

• Their safety remains controversial, with

studies associating their use with several

adverse events, including breast cancer.

Objective

• The objective of this study was to

determine whether the use of CCB is

associated with an increased risk of breast

cancer overall, and to assess whether this risk varies with cumulative duration of use.

Methods

• A cohort of 273,152 women newly treated with antihypertensive drugs between January 1, 1995 and December 31, 2009, followed until December 31, 2010, was identified using the UK Clinical Practice Research Datalink.

• A Cox proportional hazards model using a time-varying CCB exposure definition, lagged by one year for latency and reverse causality considerations, was used to estimate adjusted hazard ratios (HR) with 95% confidence intervals (CI) of incident breast cancer.

Methods (2)

• A secondary analysis was conducted to

assess whether the risk varied with

cumulative duration of use.

• All models were adjusted for various

potential confounders.

Results

• During 1,567,104 person-years of follow-up, 4520 women were newly-diagnosed with breast cancer.

• Compared with other antihypertensive drugs, the use of CCB was not associated with an increased risk of breast cancer.

• In a secondary analysis, the risk did not vary according to cumulative duration of use.

Characteristic Calcium channel blockers

Use No use

Total 107,337 165,815

Age, years (mean, SD) 62.6 (14.3) 58.0 (16.2)

Excessive alcohol use, n (%) 3,337 (3.1) 5,757 (3.5)

Smoking status, n (%)

Ever 37,033 (34.5) 59,456 (35.9)

Never 56,881(53.0) 86,944 (52.4)

Unknown 13,423 (12.5) 19,415 (11.7)

Body mass index, n (%)

<18.5 kg/m2 1,620 (1.5) 2,345 (1.4)

18.5-25 kg/m2 22,899 (21.3) 35,729 (21.6)

25-30 kg/m2 23,463 (21.9) 33,781 (20.4)

≥30.0 kg/m2 19,701 (18.4) 30,032 (18.1)

Unknown 39,654 (36.9) 63,928 (38.6)

Previous mammography screening, n (%) 94,909 (32.5) 46,910 (28.3)

Previous cancer, n (%) 6,958 (6.5) 10,619 (6.4)

Oophorectomy, n (%) 2,788 (2.6) 4,034 (2.4)

Anti-diabetic agents, n (%)

Metformin 3,121 (2.9) 6,173 (3.7)

Sulfonylureas 2,794 (2.6) 4,298 (2.6)

Thiazolidinediones 299 (0.3) 958 (0.6)

Insulins 1,359 (1.3) 2,791 (1.7)

Other anti-diabetic drugs 358 (0.3) 505 (0.3)

Aspirin, n (%) 18,015 (16.8) 25,423 (15.3)

Other NSAID, n (%) 51,501 (48.0) 80,048 (48.3)

Statins, n (%) 11,894 (11.1) 19,107 (11.5)

Hormone replacement therapy, n (%) 25,421 (23.7) 45,004 (27.1)

Oral contraceptives, n (%) 11,733 (10.9) 32,259 (19.5)

Antihypertensive drugs at cohort entry

Calcium channel blockers, monotherapy, n (%) 31,672 (29.5) 0 (0.0)

Beta-blockers, monotherapy, n (%) 19,348 (18.0) 42,851 (25.8)

Diuretics, monotherapy, n (%) 36,843 (34.3) 71,968 (43.4)

ACE inhibitors, monotherapy, n (%) 10,774 (10.0) 25,237 (15.2)

ARBs, monotherapy, n (%) 1,183 (1.1) 2,811 (1.7)

Other antihypertensive drugs, monotherapy, n (%) 1,512 (1.4) 16,182 (9.8)

Calcium channel blockers in combination, n (%) 3,328 (3.1) 0 (0.0)

Other combinations, n (%) 2,677 (2.5) 6,766 (4.1)

Table 1. Baseline demographics and

clinical characteristics according to use

of CCB

Conventional adjustment Time-varying adjustment

CCB use Events Person-

years Incidence rate

(95% CI) Crude HR HR (95% CI)

Marginal structural model HR (95% CI)

No use 3002 1,075,336 2.8 (2.7 to 2.9) 1 1.00 [Reference] 1.00 [Reference]

Use 1518 491,768 3.1 (2.9 to 3.2) 1.08 0.96 (0.90 to 1.03) 0.97 (0.89 to 1.05)

Table 2. Crude and adjusted HR for the association between the use of CCB and the risk

of breast cancer

CCBs exposure Events Person-

years

Incidence rate

(95% CI) Crude HR Adjusted HR (95% CI)

No use 3,002 1,075,336 2.8 (2.7 to 2.9) 1 1.00 [Reference]

CCB use, years

< 5 years 1,302 431,598 3.0 (2.9 to 3.2) 1.06 0.96 (0.90 to 1.03)

5 to 10 years 207 56,192 3.7 (3.2 to 4.2) 1.22 1.05 (0.90 to 1.22)

≥ 10 years 9 3,978 2.3 (1.0 to 4.3) 0.73 0.61 (0.32 to 1.20)

p-trend = 0.25

Long- and short-acting

Short-acting 119 43,070 2.8 (2.3 to 3.3) 0.98 1.03 (0.85 to 1.24)

Long-acting 1,291 414,139 3.1 (2.9 to 3.3) 1.09 0.96 (0.90 to 1.03)

Both 108 34,559 3.1 (2.6 to 3.8) 1.06 0.95 (0.79 to 1.16)

Dihydropyridines

Dihydropyridines 1,246 412,671 3.0 (2.9 to 3.2) 1.05 0.95 (0.88 to 1.02)

Non-dihydropyridines 191 54,975 3.5 (3.0 to 4.0) 1.22 1.12 (0.96 to 1.30)

Both 81 24,122 3.4 (2.7 to 4.2) 1.13 0.96 (0.77 to 1.21)

Table 3. Crude and adjusted HR for secondary analyses between CCB and the risk of

breast cancer

Discussion Strengths

• One of the largest observational studies investigating this question

• Use of new-user cohort eliminated biases related to the inclusion of prevalent users

• Models adjusted for multiple potential confounders

• Exposure definition considered latency and reverse causality, with sensitivity analyses yielding consistent results

Limitations

• Prescriptions issued by general practitioners; misclassification of exposure possible if non compliance or treatment by specialist

• Observational nature of the study; possible residual confounders

• Secondary analysis powered to rule out an increased risk of at least 20% in patients who used CCB for more than 10 years, which is below the point estimates observed in the study reporting an increased risk of breast cancer after more than 10 years of CCB use

Conclusion

• The results of this large population-based

study provide evidence that the use of

CCB is not associated with an increased

risk of breast cancer in women treated

with antihypertensive drugs.

• No association was observed according to

CCB subtype or by cumulative duration of

use.

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