Calcium channel blockers and cancer: Should we be worried?

Calcium channel blockers or CCBs such as amlodipine, diltiazem or verapamil are widely prescribed for the treatment of high blood pressure, angina and heart arrhythmias. Since these conditions make up a large part of a cardiologists workload most of us will have prescribed these medications to hundreds of people. Since the conditions they are used for are chronic patients are likely to be taking the medications for many years and this makes the long term safety of the medicines very important.

Over the last 20 years there have been a number of scares about the safety of CCBs. In 1995 it was the association between increased risk of heart attack that made headlines such as "Drug for Blood Pressure Linked to Heart Attacks: Researchers Fear 6 Million Are Imperiled” and this generated considerable public concern. This scare came and went and the prescription of CCBs continued. 

Skip forward 18 years and now we have another scare - CCBs are associated with an increase risk of breast cancer. A paper in JAMA Internal Medicine released on the 5th August reports that long-term current use of CCBs is associated with an increased risk of breast cancer. Except that this is not a new scare as there have been rumblings about an association of CCBs with cancer for many years. In the late nineties two papers reported increases in risk of all cancers among elderly people but both studies were small and subsequent larger studies failed to confirm the CCB-cancer association. In 3 randomized clinical trials over 5 years no cancer signal was seen and after this the CCB-cancer hypothesis gradually faded away that is until just recently.

So what does the current study show. There are two main types of invasive breast cancer - ductal and lobular. The researchers looked at women aged 55-74 years old. They took 1055 women with lobular and 905 women with ductal breast cancer type and compared then to 891 control women without a history of breast cancer.  The control women were matched for age and other known risk factors for breast cancer. About half the women in each group had a history of high blood pressure and the researchers noted the type and duration of anti-hypertensive medication.

In the control group 12 women had been taking a CCBs for more than 10 years. In the women with breast cancer 27 in the ductal group and 31 in the lobular group had been taking CCB for more than 10 years. In other words if you were a women with hypertension and breast cancer then you were more likely to be taking a CCB for 10 years or more. The results in the study are reported as odds ratios and this statistical measure gives an idea about the strength of association between the CCB exposure and breast cancer. When the authors looked at other blood pressure medication they did not find a significant association with increased risk of breast cancer. So essentially this studies shows a significant association between chronic CCB consumption and breast cancer risk but like all such studies it does not prove a causal relationship.

So far so good but what women on CCBs and their doctors want to know is how much is the individual patient's risk of breast cancer is increased. This is where it gets more difficult, but not impossible. First you need to think about the women's baseline risk of breast cancer. There are web-base calculators which allow us to predicted this. The lifetime risk of developing breast cancer is 1 in 8 for a women in the UK. The average 60 year women has a risk of developing breast cancer of 1.8% over 5 years. From this and the odds ratio in the paper it is possible to estimate that 18 women need to be treated with a CCBs for 10 years in order to produce one additional case of breast cancer. We call that the number needed to harm and 18 is a fairly low number. To place this in context treating people with raised cholesterol with statins to prevent heart disease has a number needed to treat of about 50 and we regard this as effective treatment.

So should we advise all our female patients who have been on CCBs for more than 10 years to stop taking them? Before we do this it is important to remember that the association with CCBs and breast cancer reported in this study were not seen when the same research group looked at a completely separate population of women. In their previous study they found that some other blood pressure tablets (thiazide and potassium-sparing diuretics) but not CCBs were associated with 40% and 60% increase in risk of breast cancer. In the California Teachers Study cohort they found that diuretic use for 10 years or longer was associated with a 16% increased risk, while use of CCBs and ACE inhibitors was not. A case-control analysis derived from the United Kingdom–based General Practice Research Database found no associations with use of ACE inhibitors, CCBs or β-blockers for 5 or more years.

Confused? You should be. How can all these differences be explained since there appears to be no consistency. These studies are all conducted in different populations with different methodology, correction factors and time periods and so it is not surprising differences are seen. One very important point is that the recently published study only found an association between breast cancer and the use of the CCB in women treated for 10 years or more. It is possible that the effects of CCBs take many years to develop and since most of the previously published studies looked at shorter time periods the effect was missed. 

This new study has generated a lot of interest because CCBs are one of the most  commonly prescribed class of drugs in the UK and breast cancer is the most commonly occurring cancer among women. If the CCBs do produce a 2-3 fold increase then long term CCB treatment would be a major modifiable risk factor for breast cancer. The results from this study are interesting and hypothesis generating. It is too early to recommend that all women who have been on CCBs for 9.9 years should be switched to alternative medications since the results from this study are not entirely consistent with other studies and need to be repeated and confirmed. However in the mean time cardiologists and GPs should be able to discuss the results of this study with patients and give appropriate advice perhaps by converting the odds ratios which are inherently difficult to understand into the number needed to harm. If an individual women has been on CCBs for a long time and is very anxious about continuing them then there are alternative treatments that can be offered and this should be discussed. 

Li et al., Use of Antihypertensive Medications and Breast Cancer Risk Among Women Aged 55 to 74 Years. JAMA Internal Medicine
Odds ratio to NNT converter

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