ACE Inhibitors Linked to Higher Lung Cancer Risk

The use of angiotensin-converting enzyme (ACE) inhibitors to lower blood pressure was associated with an overall increased risk for lung cancer of 14% compared to hypertension therapy with angiotensin receptor blockers (ARBs), a large, population-based cohort study shows.

Thanks to the widespread use of ACE inhibitors for the treatment of hypertension, this relatively modest association could result in large absolute numbers of patients at risk for lung cancer, the researchers warn.

An analysis of primary care records of almost one million patients in the United Kingdom showed that as treatment with ACE inhibitors continued, the risk for lung cancer increased. For patients who took ACE inhibitors for 5 years, the risk for lung cancer increased by 22% compared to those who took ARBs. The increased risk for lung cancer peaked at 31% for patients who took ACE inhibitors for 10 years or longer.

Secondary analyses showed that the use of ACE inhibitors for less than 5 years was not associated with an increased risk for lung cancer (hazard ratio [HR], 1.1). "This represents a novel finding that suggests a latent effect of the exposure on this cancer," said lead author Laurent Azoulay, PhD, of the Department of Epidemiology, Biostatistics and Occupational Health at McGill University in Montreal, Quebec, Canada.

"Given the potential impact of our findings, they need to be replicated in other settings, particularly among patients exposed for longer durations," the team comments.

"We believe that while physicians should be aware of this association, it would be premature at this stage to withhold this treatment in patients for whom there are known benefits," Azoulay told Medscape Medical News.

"Certainly, additional studies are needed to corroborate our findings. These need to have sufficient follow-up, given the long-term effect observed in our study," he added.

The study was published online October 24 in the BMJ.

In an accompanying editorial, Deirdre Cronin Fenton, PhD, associate professor in the Department of Clinical Epidemiology at Aarhus University, Denmark, agreed that long-term studies are needed to verify the safety of ACE inhibitors.

These drugs target the renin-angiotensin-aldosterone system, which may play a role in cancer development, she pointed out.

Like Azoulay, Fenton cautions against withholding ACE inhibitors from patients, noting that both ACE inhibitors and ARBs are indicated for the treatment of hypertension, heart disease, renal insufficiency, and chronic kidney disease.

"[I]n an individual patient, concerns about the long term risk of lung cancer should be balanced against gains in life expectancy associated with use of ACEIs," she writes.

Fenton also cautions that, despite the study's rigorous analytic approach, the findings may be limited by residual confounding. She notes that generic ACE inhibitors were available in 1995 but that generic ARBs did not enter the market until 2010. Socioeconomic changes during this period could have influenced prescribing patterns, and environmental exposures to radon or asbestos may have had an impact on lung cancer risk, she notes.

Study Details

More than 70 million antihypertensives are dispensed each year in the United Kingdom. Of these, about 32% are ACE inhibitors, the researchers note.

Although earlier observational studies reported similar estimates of risk with the use of ACEIs, none were specifically designed to assess lung cancer as an outcome, Azoulay and colleagues point out.

This latest study used data from the UK Clinical Practice Research Datalink for 992,061 patients who were newly treated with antihypertensive drugs between January 1995 and December 2015 and who were followed until December 2016.

A total of 335,135 patients were treated with ACE inhibitors: ramipril (Altace,Pfizer) was prescribed in 26% of patients; lisinopril (multiple brands) in 12%; and perindopril (multiple brands) in 7% of patients. A total of 29,008 patients were treated with ARBs, and 101,637 received both ACE inhibitors and ARBs.

None of the participants had a history of cancer at study entry. Patients who were prescribed ACE inhibitor were more likely to be male, to have alcohol-related disorders, to be smokers, and to have a higher body mass index (BMI) than patients treated with ARBs.

Patients taking ACE inhibitors were also more likely to have undergone treatment for hypertension for a shorter period and to have been prescribed statins and other drugs. The two groups were similar with respect to histories of pneumonia, tuberculosis, and chronic obstructive pulmonary disease.

During a median follow-up period of 6.4 years beyond the post-cohort latency period, there were 7952 cases of lung cancer, yielding in a crude incidence rate of 1.3 per 1000 person-years. After adjusting for age, sex, BMI, smoking history, alcohol-related disorders, and history of lung disease, the use of ACE inhibitors was associated with 1.6 cases of lung cancer per 1000 person-years. There were to 1.2 cases per 1000 person-years for patients treated with ARBs (HR, 1.14). After 5 years, the HR increased to 1.22, and after 10 years, to 1.31.

Similar findings were observed with time since starting ACE inhibitors; HRs peaked at more than 10 years following initiation of therapy (HR, 1.29).

The analysis also showed that smoking status did not significantly change the association between the use of ACE inhibitors and lung cancer risk. Overall, the results were consistent with the primary analyses; the HR was 1.64 after receiving ACE inhibitor therapy for 10 years or longer, the researchers report.

The study was funded by the Canadian Institutes of Health Research. Dr Azoulay and Dr Fentin have disclosed no relevant financial relationships. Study coauthor Jacob A. Udell, MD, has relationships with AstraZeneca, Janssen, Novartis, Sanofi, Amgen, Boehringer-Ingelheim, Merck, and Novartis.

BMJ. Published online on October 24, 2018. Full text, Editorial