Long Term Usage of ACE Inhibitors as Blood Pressure Drugs Increases Risk of Lung Cancer

Based on results of an observational  study published earlier this week in The BMJ, angiotensin-converting-enzyme (ACE) inhibitors were associated with an increased risk of lung cancer, compared with a similar, but distinct type of blood pressure medication known as angiotensin-receptor blockers (ARBs).
Researchers evaluated patients from a U.K. primary care database and identified over 900,000 adults who began treatment with any type of blood pressure medication from 1995 through 2015. They excluded those with any history of cancer.
Over 335,000 patients were treated with ACE inhibitors, 29,000 with ARBs, and 101,000 with both an ACE and ARB inhibitor. Ramipril (26%) was the most common ACE noted in the study, along with lisinopril (12%) and perindopril (7%).

Over a follow-up period of 6 years, lung cancer was diagnosed in 0.8% (7,952) of this 900,000-person cohort. After taking into consideration smoking and other potential confounding factors, ACE inhibitor use was associated with a 14 % greater risk for lung cancer relative to ARB use (1.6 vs. 1.2 per 1000 person-years). In a secondary analysis, use of an ACE inhibitor for less than 5 years was not associated with an elevated risk for lung cancer.

However, the study noted that the levated risks did not become evident until a patient had been on an ACE inhibitor for 5 years, the , but did increase with greater than 10 years of use (31% increased risk).

In their study, researchers explained that use of ACE inhibitors results in accumulation of bradykinin in lungs, which "has been reported to stimulate growth of lung cancer.” ACE inhibitor use may also result in elevated levels of a compound known as substance P, produced in lung cancer cells and related to growth of the tumor and its associated blood vessels.

In light of such data, it’s important for the public to understand that this is only an observational study--not a randomized double blind placebo controlled study--making the absolute risk to patients low. But data indicates that ACE inhibitors account for nearly a third of all blood pressure medications prescribed in the UK, making the results a potential concern for a large number of patients.

While ACE inhibitors have been highly effective medications used to treat high blood pressure in the short term, there have been concerns raised about the safety of their long term use, specifically related to elevated risk of lung cancer.

Moreover, observational studies have led to mixed findings (related to actual lung cancer risk vs. overall risk of cancer), with no clear consensus to date, and meta-analyses of randomized controlled trials have not found evidence of elevated cancer risk, due to small sample size and length of follow-up (median of 3.5 years) compromising validity of findings.

Important limitations of the study that should be mentioned include lack of information about socioeconomic status, diet, exposure to asbestos or radon, as well as family history of lung cancer for patients enrolled in the study. The authors also did not have detailed information regarding number of pack-years of smoking, an important risk factor for incidence of lung cancer.
That said, there is biochemical evidence demonstrating a possible association between ACE inhibitor use and the risk of lu ng cancer with   elevated levels of bradykinin and substance P that could facilitate growth of lung cancer.

Certainly in any patient at risk for lung cancer, the benefits associated with taking an ACE inhibitor to reduce blood pressure and cardiac risk need to be weighed against risk for  lung cancer.

This view is echoed by one expert who expressed concern about the risks associated with ACE inhibitors.
"This high quality study shows that ACE inhibitors are a risk factor for lung cancer," saidKlaus Lessnau, M.D, a pulmonary and critical care specialist at Lenox Hill Hospital in New York City.

"The most important factor remains smoking, but implies that ACE inhibitors should be contraindicated in smokers and ex-smokers, armed with a study that reveals significant statistical association and biologic plausibility," offered Lessnau." "One wonders if they should be continued in nonsmokers," he added.

As a result, this study is important to highlight based on the large number of patients currently taking long term ACE inhibitors and the inherent concern they may have for elevated cancer risk--and the potential need to change their medication--based on the results of this study.

Again, it’s important to emphasize that this is an observational study and the overall risk to patients is relatively low.  Patients should have a discussion with their health care provider regarding the risks and benefits of remaining on an ACE inhibitor. One option might be to switch to an ARB if there is ongoing concern, since there has been no elevated risk of lung cancer observed thus far with this class of antihypertensives .  ARBs may, in fact, reduce risk of lung cancer with a protective effect, based on recent studies.

In an accompanying editorial in BMJ, Dr. Deirdre Cronin-Fenton, Associate Professor, Department of Clinical Epidemiology, Aarhus University in Denmark places validity in the findings, but recommends the need for ongoing and further studies to validate the findings of this prospective observational cohort study.

In her editorial, Cronin-Fenton writes the study "highlights the value of registry data and a 'big data' approach to evaluating long term outcomes, which may be challenging to investigate in clinical trials. Although 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."
Cronin-Fenton continues:  "Nonetheless, in 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. As [the authors] point out, further studies with long term follow-up are now needed to enhance the scientific evidence on the long term safety of these drugs."

ACE inhibitors certainly have been beneficial in controlling blood pressure in the clinical setting. While this study highlights a biochemical mechanism that does exist, the data still is observational in nature, and will require more in-depth study to definitively make a determination regarding the decision to discontinue and replacing it in favor of a new class of medications for managing blood pressure.

Reference: Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4209