Common Antihypertensive Linked to Lung Cancer

image of CT of lungs


 A new study has shown a popular class of medication may be associated with an increased risk of lung cancer. 

We should like to stress that the risk if real, is VERY SMALL and if you are taking these medications you should continue to do so. 

Stopping them suddenly is very dangerous - if you are concerned, please make an appointment.  You should not stop taking the medication without discussing it with us first.

Angiotensin Converting Enzyme Inhibitors (ACEI) are one of the most commonly prescribed medications for blood pressure.  In our practice the most commonly prescribed members of this class are Cilazapril and Enalapril, though we have a small number of patients taking Quinapril and a few others.  If your drug name ends in -pril then there is a high probability it is an ACEI.

These drugs have been very effective as they help dilate blood vessels and lower blood pressure.  They are the most likely choice of first medication for high blood pressure as they have really good evidence for prevention of heart attacks and strokes.  They are also very useful in patients with heart failure and significantly help symptoms for some patients.  One of the side effects of the medication is that it causes a build-up of bradykinin in the lungs.  This is the cause of the annoying dry cough that a some patients taking the drug experience.  Bradykinin is thought to increase the risk of lung cancer so there has been a lot of interest in this class of drugs.

Overall the study, published in the BMJ and available to read free of charge - Angiotensin Converting Enzyme Inhibitors and Lung Cancer Risk - shows that ACEI might be associated with up to 4 extra lung cancers per 10,000 patient-years of use of the medication.  This is about 4 times the 'acceptable' level of risk of 1:10,000 which is the risk of dying on the roads each year.

Right now there is no need to take any action.  If you are using one of these medications please continue to do so as you are far more likely to have a stroke or heart attack if you stop it suddenly than you are to develop lung cancer as a result of taking it and there are a number of problems with the study that mean the level of risk may be very different from that reported.  Certainly there is no measurable risk from using the medication for a few more weeks whilst you think it throuugh and discuss it with your doctor.  If you feel you would like to stop using the medication anyway, we have a range of suitable alternatives which we will be pleased to discuss with you when you make an appointment.

For those interested in more detail, an analysis of the paper follows:

Researchers analysed the records of 990,000 patients over a 6 year period, comparing patients taking ACEI with those taking another class of drugs, Angiotensin 2 Receptor Antagonists (A2RA).  A2RA work on the same biological system as ACEI, but at a later point and do not increase bradykinin levels.  On average they found that for every 10,000 years of use of ACEI as opposed to A2RA, there would be an extra 4 lung cancers seen.  In context, an average patient might take the medication for up to 30 years, so perhaps up to 1 chance in 83 in a lifetime of taking the medication of a lung cancer that might not otherwise have occurred.  This is a very small risk but is far from insignificant and if it turns out to be a real finding as opposed to a spurious one then it would be well worthwhile making changes to practice, especially for younger patients.

The study had a common flaw of observational cohort studies in that the populations were not similar.  Patients taking ACEIs were noticeably more likely to have alcohol disorders, be male, be obese and to be smokers (past and present) than the A2RA group.  This is difficult to avoid in this study design but can easily lead to error as efforts to correct for the differences can also introduce error and not all the differences have known correction factors.  Alcohol for instance increases cancer in smokers but may not do so in non-smokers, or it might, depending on which study you read. Obesity also increases cancer risk but data for specific cancers is limited.

The authors note that ACEI may cause cough, which can lead to a greater chance of cough being investigated in ACEI patients, potentially increasing the diagnosis of lung cancer in this group.  Whilst wise to mention, this is unlikely to be significant but there is no data available to confirm or refute the hypothesis.  It is more likely that the higher proportion of smokers would lead to more investigation however, and this may have had a small effect. 

A possible protective effect of A2RA was considered and rejected by comparing the use of ACEI with another class of antihypertensive (thiazides) and the same effect was found.

A commonly occurring error also found in the study was the Law of Small Numbers error.  Lung cancer is not that common and there were only 266 cancers in the group taking A2RA.  It would require only a small number more cancers to be diagnosed in the A2RA group in order for the apparent difference to disappear.  It is actually very probable that this has skewed the findings and it is possible that the observed difference is entirely due to this.   Conversely, it is possible that the observed difference is smaller than the real difference for the same reason.  The ancillary comparison with thiazides showed the same trend, though figures for this are not supplied.  This would suggest that Small Numbers Error is likely to be small though could still be in the range required to invalidate the key findings.

Despite the assertion that A2RA are prescribed at the same stage of hypertension as ACEI, they were very expensive and new at the time they were introduced.  Evidence supported greater benefit for patients with diabetes and renal disease who are of course more likely to die younger and therefore not to live long enough to get lung cancer.  It is incorrect to assume as the researchers have done that the medications were necessarily prescribed for the same reason.  In fact it is highly probable that the patients selected for A2RA were quite different from the ACEI group.  This is borne out by the relatively higher proportion of patients on multiple medications in the ACEI group.  These people are sicker than the A2RA patients.

A lack of ability to control for key factors inherent in cancer risk such as family history, diet, radon, asbestos and socioeconomic status also limit the validity of the study.

On the face of it, with all these problems, it is tempting to dismiss the findings, but in reality the large scale of the study and the quality of the analysis at the very least warrant further research into this matter.  It would be wrong to say definitively on the basis of this study that ACEI cause lung cancer, but it would be foolish indeed to dismiss the possibility out of hand.

Currently it seems wise to consider alternative treatments as first line for new patients, to consider transitioning younger patients onto A2RA and to leave patients with a life expectancy under 15 years on their current medication.

Calculated risks based on the published figure on 0.4/1000 patient years show a 0.2% risk for every 5 years of use of the medication.  As this is a very small percentage, it is valid enough to use this for at least up to 50 years of use without it significantly changing the assessment.  So a 2% risk over 50 years of use might make a difference to a 30 year old with hypertension, but a 0.4% risk would probably not deter a 75 year old.



Lung Abscess Image:  Yale Rosen Yes, we know the article is about cancer, but this was just a better illustration of lungs.

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