Group of Blood Pressure Drugs Linked to Lung Cancer

14% higher likelihood in users of ACE inhibitors; causal relationship unproven

by Mike Bassett

Patients using angiotensin converting enzyme inhibitors (ACEIs) to lower their blood pressure could be at increased risk of lung cancer, according to researchers.

And while the risk for individuals is "modest," the researchers suggested that these small relative effects could impact large numbers of patients because these drugs are so widely prescribed.

Furthermore, the researchers, led by senior author Laurent Azoulay, PhD, McGill University, Montreal, found the lung cancer risk was elevated for patients who have used the drug for more than five years.

In the study, published in The BMJ, Azoulay and his colleagues wanted to assess whether the use of ACEIs increased the risk of lung cancer compared to the use of angiotensin receptor blockers.

While ACEIs are widely used and have been shown to be effective in treating hypertension, the study authors noted that concerns have been raised about the increased risk of cancer associated with these drugs. This is primarily because their use causes a buildup of protein-like chemicals bradykinin and substance P, both of which have been reported to stimulate the growth of lung cancer.

However, the evidence from both preclinical and observational studies regarding the association of ACEIs and lung cancer is unclear.

Here, Azoulay and his colleagues conducted a large, population-based study using the U.K. Clinical Practice Research Datalink, comprising 15 million patients in the U.K. They identified and analyzed a cohort of nearly 1 million patients who were treated with a new antihypertensive drug between 1995 and 2015.

These patients were at least 18 years of age, had no previous history of cancer, and were followed for an average of 6.4 years.

During the follow-up period, 335,135 patients were treated with ACEIs, compared with 29,008 treated with angiotensin receptor blockers, and 101,637 treated with both groups of drugs.

The ACEIs most commonly used included ramipril (26%), lisinopril (12%), and perindopril (7%).

The researchers identified 7,952 cases of lung cancer within the study group for an incidence rate of 1.3 per 1,000 person years. After accounting for such factors as age, sex, weight, smoking, alcohol use, and history of lung diseases, Azoulay and his colleagues determined that compared with angiotensin receptor blockers, ACEIs were associated with a 14% greater risk of lung cancer (1.6 v. 1.2 per 1,000 person years, hazard ratio (HR) 1.14, 95% CI 1.01-1.29).

In addition, the researchers found that hazard ratios increased with five to 10 years of use (HR 1.22, 1.06 to 1.40), and continued to increase with more than 10 years of use (HR 1.31, 1.08 to 1.59).

"Although the magnitudes of the observed estimates are modest, these small relative effects could translate into large absolute numbers of patients at risk for lung cancer, so these findings need to be replicated in other settings," Azoulay and his colleagues concluded.

They did report several limitations to this study, such as an inability to adjust for some potential confounders, such as socioeconomic status, diet, exposure to asbestos or radon, and a family history of lung cancer. In addition, the researchers did not have complete information on smoking status, such as the duration and intensity of smoking.

"However, an analysis conducted within non-smokers produced results consistent with those of the primary analyses, with a clear duration-response association, providing reassurance that residual confounding by smoking did not materially affect our findings," Azoulay and his colleagues wrote.

An accompanying editorial by Deirdre Cronin-Fenton, PhD, of Aarhus University in Denmark, pointed out that the topic is undoubtedly controversial, with previous studies suggesting there is increased, decreased, or no association between ACEIs or angiotensin receptor blockers and lung cancer.

She noted that the study by Azoulay and his colleagues demonstrates the value of a big data approach to evaluating long-term outcomes, and agreed with the authors that while their finding of a 14% relative increase in lung cancer incidence "might not translate to a large absolute risk, the findings are important given the considerable use of ACEIs worldwide."

However, Cronin-Fenton added that for individual patients "concerns about the long-term risk of lung cancer should be balanced against gains in life expectancy associated with use of ACEIs."

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Comments

If this bears out, then it is scary. However, I rarely see cases of lung cancer in never smokers. "Non-smoker" status is just not good enough because once oncogenes are "turned on," it is only a matter of time and decline in the immune system with age until the lung cancer presents.

It would be interesting to see what percentage of the 7952 subjects that developed Lung Cancer using ACEIs were taking Lisinipril. As a Diabetic, I took Lisinipril for blood pressure and organ preservation for over 20 years. I am a never-smoker, but 1) my parents were both chain smokers, and 2) I spent extended periods of time (86 - 118 days continuously) confined in a submarine with 135 to 145 other individuals of which over half of them smoked.

This is absurd science at its best. Corrections for "weight, smoking, alcohol use, and history of lung diseases" are enormous. Small changes in the corrections for these larger effects (confounders) will lead to much greater than the 14% greater risk in lung cancer found in this study. Epidemiologists need to perform sensitivity analysis on the parameters used in their corrections.

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