Treating hypertension with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) was associated with a reduced risk for colorectal cancer, according to findings from a large retrospective study.
However, another study reported just over a year ago suggested that ACE inhibitors, but not ARBs, are associated with an increased risk for lung cancer.
An expert approached for comment emphasized that both studies are observational, and as such they only show an association, and cannot infer causation.
In this latest study, published online today in the journal Hypertension, the use of ACE inhibitors/ARBs was associated with a 22% lower risk for colorectal cancer developing within 3 years after a negative baseline colonoscopy.
This is the largest study to date, with a cohort of more than 185,000 patients, to suggest a significant protective effect for these two common antihypertensive medications, the authors note.
The risk of developing colorectal cancer decreased with longer duration of ACE inhibitor/ARB use, with a 5% reduction in adjusted hazard ratio risk for each year of use.
However, this effect was limited to patients who had negative colonoscopies within a 3-year period and did not extend beyond that point.
Lead author Wai K. Leung, MD, clinical professor of medicine at the University of Hong Kong, explained that they are not advising patients to take ACE inhibitors simply to prevent cancer. "Unlike aspirin and statins, the potential chemopreventive role of ACE inhibitors on cancer has never been established," he told Medscape Medical News. "The study findings may favor the use of ACE inhibitors in the treatment of hypertension, over many other antihypertensives, in some patients for preventing colorectal cancer."
Increased or Reduced Risk?
There has been considerable debate about the potential carcinogenic effects of ACE inhibitors and ARBs, and the relationship with "various solid organ cancer risks have been unsettled," the authors note. Studies have produced conflicting results — showing no overall cancer risk and a modestly increased overall cancer risk — associated with these agents.
A recent study reported that ACE inhibitors, as compared with ARBs, increased risk for lung cancer by 14%. The risk for lung cancer increased by 22% among those using ACE inhibitors for 5 years, and peaked at 31% for patients who took ACE inhibitors for 10 years or longer.
The lead author of that lung cancer study, Laurent Azoulay, PhD, of McGill University in Montreal, Canada, offered some thoughts on the seemingly conflicting data now being reported showing a reduction in the risk of colorectal cancer.
"In a nutshell, this study has important methodologic issues that can explain the observed findings," he told Medscape Medical News.
Azoulay pointed out that in the univariate model, the use of ACE inhibitors/ARBs was associated with a 26% increased risk of colorectal cancer. "It is only after propensity score adjustment that the effect estimate reversed in the protective direction," he pointed out. "However, the variables included in the propensity score model were measured in the same time window as the exposure, which can lead to an overadjustment bias and generate spurious findings."
Another issue is that the study period did not begin at the time of the exposure, but rather at a distant point after treatment initiation — in this case, colorectal cancer screening. "As such, the authors excluded patients who were previously diagnosed with colorectal cancer prior to that point, which likely included patients exposed to ACE inhibitors/ARBs," he said. "This approach can lead to the inclusion of the 'survivors' for whom the risk of developing colorectal cancer is lower."
"But certainly," Azoulay added, "this possible association should be investigated using methodologically-sound approaches."
Take-Home Message for Physicians
Another expert emphasized the observational nature of both studies. Raymond Townsend, MD, director of the Hypertension Program and a professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia, said: "First and foremost, these are observational studies and cannot make inference about causality; they can only show associations." He pointed out that sometimes associations are truly present, whereas at other times there is bias or confounding that cannot be controlled for statistically because it is "unknown." That said, the size of this latest study is a plus, and there is a reasonable follow-up period.
"The take-home [message] for practitioners is that there may be a benefit in keeping older people on ACE inhibitors on the likelihood of developing colorectal cancer if your last colonoscopy was negative," Townsend, who was not involved in the study, told Medscape Medical News.
But there are some questions that remain unanswered regarding characteristics of the cohort, Townsend noted. "Who were the people having the colonoscopy in the first place? Were they a group at higher risk? Why were some on an ACE inhibitors/ARBs and many others not?"
There are other conclusions that clinicians can glean from this. "Make a choice of treatment for a patient based on your best estimate of what will lower their blood pressure and prevent hypertension-mediated organ damage," said Townsend, who is also an American Heart Association volunteer expert. "Keep in mind that patients hear about these studies, and read unreviewed blogs on the web, and so have questions."
He emphasized that it always comes back to two things. "One is that every treatment decision is inherently a risk–benefit scenario," he said. "And second is that most of our patients are adults, and if they choose to not be treated for their hypertension despite our best advice and reasoning with them, relinquish control and let them proceed as they wish, offering to renegotiate in the future when and if they reconsider."
In the latest study, Leung and colleagues conducted a retrospective cohort study and used data from an electronic healthcare database of the Hong Kong Hospital Authority. A total of 187,897 individuals aged 40 years and older had undergone colonoscopy between 2005 and 2013 with a negative result, and were included in the analysis.
The study's primary outcome was colorectal cancer that was diagnosed between 6 and 36 months after undergoing colonoscopy, and the median age at colonoscopy was 60.6 years. Within this population, 30,856 (16.4%) used ACE inhibitors/ARBs.
Between 6 months and 3 years after undergoing colonoscopy, 854 cases of colorectal cancer were diagnosed, with an incidence rate of 15.2 per 10 000 person-years. The median time between colonoscopy and diagnosis was 1.2 years.
ACE inhibitor/ARB users had a median duration of 3.3 years use within the 5-year period before their colonoscopy, and within this group, there were 169 (0.55%) cases of colorectal cancer. On univariate analysis, the crude hazard ratio (HR) of colorectal cancer and ACE inhibitor/ARB was 1.26 (P = .008), but on propensity score regression adjustment, the adjusted HR became 0.78.
The propensity score absolute reduction in risk for users was 3.2 per 10,000 person-years vs nonusers, and stratification by subsite showed an HR of 0.77 for distal cancers and 0.83 for proximal cancers.
In a subgroup analysis, the benefits of ACE inhibitors and ARBs were seen in patients aged 55 or older (adjusted HR, 0.79) and in those with a history of colonic polyps (adjusted HR, 0.71).
The authors also assessed if there was an association between these medications and other types of cancer. On univariate analysis, usage was associated with an increased risk of lung and prostate cancer, but lower risk of breast cancer. But after propensity score regression adjustment, the associations were no longer there.
The study was funded by the Health and Medical Research Fund of the Hong Kong SAR Government. Leung has received honorarium for attending advisory board meetings of AbbVie, Takeda, and Abbott Laboratories; coauthor Esther W. Chan has received funding support from Pfizer, Bristol-Myers Squibb, Bayer, Takeda, Janssen (a division of Johnson & Johnson); Research Grants Council of Hong Kong; Narcotics Division, Security Bureau; and the National Natural Science Foundation of China, all for work unrelated to the current study. None of the other authors have disclosed relevant financial relationships.
Azoulay has disclosed no relevant financial relationships. Townsend is employed by Penn Medicine.
Hypertension. Published online July 6, 2020. Abstract
Medscape Medical News © 2020
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