Calcium Channel Blockers Don’t Promote Breast Cancer

Massive study finds no link between antihypertensive class and malignancy.

A long-simmering controversy over long-term use of calcium channel blockers to control high blood pressure and the effect that has on development of breast cancer may be settled, with researchers here reporting there is no link.

An adjusted hazard ratio for breast cancer among 107,337 women on calcium channel blockers was 0.96 when compared with 165,815 women not taking these agents (95% CI 0.90-1.03), a nonsignificant difference, said Sara Soldera, MD, a medical oncology fellow at McGill University Health Center, Montreal.

“We found that the long-term use of calcium channel blockers is not associated with an increased risk of breast cancer,” she told MedPage Todayat her poster presentation during the annual meeting of the American Society of Clinical Oncology. “Our finding is that this is just null — calcium channel blockers do not reduce your risk of breast cancer or increase your risk. They have no impact.”

Soldera and colleagues accessed the United Kingdom Clinical Research Datalink and included women enrolled in that database from 1995 to 2009 and then followed through the end of 2010. In that time period, 3,002 women who were not taking calcium channel blockers developed breast cancer over 1,075,336 person-years compared with 1,512 cases among the women whose records indicated treatment with this class of antihypertensive drug, over 491,768 person-years.

Soldera said that there had been a controversy over whether calcium channel blockers have an impact on breast cancer. “I got the idea to do the study when some of my patients brought up the question. I think that when a women is diagnosed with breast cancer, they look back to see if there is something that might have caused it,” Soldera said. “And they ask whether it was the calcium channel blockers.”

So she hit the medical literature books and “when I researched it, there was a lot of disparity — a lot of papers saying yes, and a lot of papers saying no. But these studies had small sample sizes and poor methodology.

“So we decided to do a larger study,” she said. “We thought that with the numbers of patients and patient-years in this study, if there was a signal, we would find it. We hoped that we could kind of settle the question with this study.”

Soldera noted that many women who develop breast cancer are overweight and may be taking calcium channel blockers to combat hypertension. She suggested they can be assured that taking the medication will help control blood pressure, but won’t be causative for breast cancer.

Tufia Haddad, MD, assistant professor of oncology at the Mayo School of Medicine, Rochester, Minn., told MedPage Today, “There has not been much discussion in the community of the possible link between calcium channel blockers and risk of breast cancer given that the study results to date have yielded such mixed results.

“There have been a number of small cohort or case-control studies evaluating this possible association, and some study results have suggested there is a possible association between usage and increased breast cancer risk while other study results suggest there is no association,” Haddad said.

“A recent meta-analysis of 17 studies evaluating this association did not find an increase in breast cancer risk between calcium channel blockers users and non-users. However, in subgroup analysis, long-term use — greater than 10 years of calcium channel blockers — [was] associated with an increase in breast cancer risk. That meta-analysis evaluated the data of approximately 150,000 women of whom over 53,000 were calcium channel blocker users,” she said.

“The current abstract is a well-designed, population-based cohort study of about 270,000 women who were newly started on an antihypertensive medication,” she said.

“Regardless of type of calcium channel blocker prescribed, long- or short-acting formulation of calcium channel blocker, or duration of calcium channel blocker use, there was no observed increase in the risk of breast cancer,” Haddad said. “The results were adjusted for other important breast cancer risk factors, and there was good long-term follow-up of these patients — more than 1.5 million person years.

“So there are no consistent data to support an association between calcium channel blocker use and breast cancer risk,” she said. “The negative findings of this contemporary, large, population-based cohort study are in agreement with that.”

Soldera, in her study, found that the hazard ratio of taking calcium channel blockers for less than 5 years was 0.96; the risk or taking the anti-hypertensive for 5 to10 years was 1.05, and the risk for taking calcium channel blockers for 10 or more years was 0.61 — but in none of these calculations was the finding statistically significant.

New Recommendations for Hypertension Management Released.

New recommendations published online in the Journal of the American Medical AssociationExternal Link aim to provide guidance on the management of patients with hypertension. More specifically, the recommendations focus on when medication should be started in patients, the best choices for medications to begin treatment; and communicating achievable blood pressure goals to patients.

“Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults,” the report authors note.

The report, written by panel members appointed to the Eighth Joint National Committee, notes there is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg. However, given insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, the panel recommends a BP of less than 140/90 mm Hg for those groups. “The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years,” the report notes.

In general, the report authors note that the 140/90 mm Hg definition from Joint National Committee 7 “remains reasonable” and recommend that lifestyle interventions be used for everyone with blood pressures in this range. “For all persons with hypertension, the potential benefits of a healthy diet, weight control, and regular exercise cannot be overemphasized,” they said. “These lifestyle treatments have the potential to improve BP control and even reduce medication needs.”

Also in the report, the authors note there is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. Additionally, there is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes.

Moving forward, the authors point out that an algorithm included as part of the recommendations will facilitate implementation and be useful to busy clinicians. They also suggest that “the strong evidence base of this report be used to inform quality measures for the treatment of patients with hypertension.”

Practice guidelines are traditionally promulgated by the government or by learned medical professional societies. The JAMA paper is a report of a group experts in the field of hypertension, but it does not carry the endorsement of any organized body. Moving forward, these recommendations will be taken into account in the coming year as the ACC/AHA Task Force on Practice Guidelines moves forward with developing the collaborative model to update the national hypertension guidelines in partnership with the National Heart, Lung, and Blood Institute (NHLBI). According to the ACC and the American Heart Association (AHA), once a writing group is appointed, there will be an extensive science and evidence review process, followed by draft recommendations that will undergo a peer and stakeholder review. Once the review process is complete, the ACC/AHA and partnering organizations will publish the guidelines in 2015 for clinicians to follow as the national standard for hypertension prevention and treatment.

The ACC, AHA and the Centers for Disease Control and Prevention released a scientific advisory on the effective approach to hypertension in November that encourages use of enhanced, evidence-based, blood pressure treatment systems for providers, including standardization of protocols and algorithms, incentives for improved performance based on achieving and maintaining patients at blood pressure goals, and technology-facilitated clinical decision support and feedback.

Some Antihypertensives Linked to Breast Cancer Risk.

 The first observational study of long-term antihypertensive use and breast cancer risk has found that calcium-channel blockers are associated with a more than 2-fold increased risk and that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk.

These findings come from a study published online August 5 inJAMA Internal Medicine.

Women who had taken calcium-channel blockers for 10 years or more had more than double the usual risk for invasive ductal breast carcinoma (IDC) (odds ratio [OR], 2.4) and for invasive lobular breast carcinoma (ILC) (OR, 2.6). The researchers also observed a possible association between the long-term use of ACE inhibitors and reduced risks for both IDC (OR, 0.7) and ILC (OR, 0.6), although the risk estimate for IDC was within the limits of chance.

No Changes in Clinical Practice Recommended Yet

“We don’t think this should change clinical practice in any way. It was the first study of long-term antihypertensive use. It was an observational study, not a clinical trial. We can suggest an association, but we cannot infer any causal relation at this point,” lead author Christopher Li, MD, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, told Medscape Medical News.

Dr. Li and colleagues interviewed women 55 to 74 years of age from the Puget Sound region — 880 with IDC, 1027 with ILC, and 856 without cancer (control group). Participants were interviewed in person to establish detailed histories of hypertension and heart disease and risk factors for cancer, including family history, obesity, smoking, and alcohol use. The researchers gathered data on the use of antihypertensive drugs, including beginning and end dates of use, drug names, dose, route of administration, pattern of use, and indication.

The antihypertensives included ACE inhibitors, angiotensin-receptor blockers, beta blockers, calcium-channel blockers, diuretics, and combination antihypertensive preparations, regardless of indication.

Calcium-channel blockers are among the most frequently prescribed medications in the United States; they accounted for nearly 98 million of the more than 678 million prescriptions filled in 2010.

Subjects who had used antihypertensives for 6 months or longer and were still using them were classified as current users, subjects who had used them for 6 months but were no longer using them were classified as former users, and subjects who had used them for less than 6 months were classified as short-term users.

In the regression analyses, potential confounders included age, county of residence, other commonly used medications, comorbid conditions (cardiovascular disease, diabetes, hyperlipidemia, depression), alcohol use, and estrogen-receptor status.

Increased Risk After 10 Years

“In examining duration effects for current users, we found an increased risk only in relation to the use of calcium-channel blockers for 10 years or longer, and an increased risk was observed for both IDC (OR, 2.4; 95% confidence interval [CI], 1.2 – 4.9; P = .04 for trend) and ILC (OR, 2.6; 95% CI, 1.3 – 5.3; P = .01 for trend). This association with 10 years or longer of current calcium-channel blocker use did not vary appreciably when results were further stratified by estrogen-receptor status,” the researchers report.

Dr. Li told Medscape Medical News that they were surprised by the magnitude of the risk associated with calcium-channel blockers and by the decrease associated with ACE inhibitors.

“We expected that we might see some increase in breast cancer risk with calcium-channel blockers, but not a more than doubling of the risk,” Dr. Li said. “The suggestion of an association between ACE inhibitors and reduction in breast cancer risk was a very unexpected finding and is worthy of follow-up.”

The mechanism behind the apparent calcium-channel blocker effect is not known, Dr. Li explained, but some researchers suspect that these drugs might increase cancer risk by inhibiting apoptosis.

“First-Rate Study,” But Confirmation Needed

“The data are persuasive because this was a first-rate study: it was population-based, large (1900 case patients and 856 controls), identified cases from the Seattle-area SEER surveillance system, had a high (80%) case response rate, and used best practices in ascertaining medication use from study participants,” Patricia F. Coogan, ScD, from the Slone Epidemiology Center at Boston University, writes in a related commentary.

“Given these results, should the use of calcium-channel blockers be discontinued once a patient has taken them for 9.9 years? The answer is no, because these data are from an observational study, which cannot prove causality and by itself cannot make a case for change in clinical practice,” Dr. Coogan explains.

“If the 2- to 3-fold increase in risk found in this study is confirmed, long-term calcium-channel blocker use would take its place as one of the major modifiable risk factors for breast cancer. Thus it is important that efforts be made to replicate the findings,” Dr. Coogan notes.

“We are cautious and don’t want to read too much into this, since this was the first study to look at long-term use of these medications. We need to see confirmation of the study before making any clinical recommendations,” Dr. Li emphasized.