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.
 
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Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study
BMJ 2018; 363 doi: 
 (Published 24 October 2018)Cite this as: BMJ 2018;363:k4209
 
Blánaid M Hicks, postdoctoral research fellow1 2 3, Kristian B Filion, assistant professor of epidemiology1 2 4, Hui Yin, statistician1, Lama Sakr, pulmonologist5, Jacob A Udell, cardiologist and assistant professor of cardiology6 7, Laurent Azoulay, associate professor of epidemiology and oncology1 2 8
 
 
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.
 
Any extra risk must be balanced against the mortality benefits of ACEI use
Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers are indicated for the treatment of hypertension, heart disease, renal insufficiency, and chronic kidney disease. ACEIs decrease the production of angiotensin II, whereas angiotensin receptor blockers selectively block its binding to angiotensin receptors.1 These drugs target the renin angiotensin aldosterone system, which may play a role in cancer development.23
 
In a linked paper, Hicks and colleagues (doi:10.1136/bmj.k4209) use registry data from the UK Clinical Practice Research Datalink (CPRD) to investigate the association of antihypertensive drugs with the risk of lung cancer.4Their study population included 992 061 people, newly treated with antihypertensive drugs between 1995 and 2015, with follow-up until end of December 2016. Their findings indicate an increased risk of lung cancer associated with the use of ACEIs compared with angiotensin receptor blockers; with the highest risk associated with more than 10 years of ACEI use. The authors propose that the underlying biological mechanism of this association involves the accumulation of bradykinin or substance P in the lungs, which are implicated in tumorigenesis.5
 
The study has several noteworthy strengths. The use of prospectively registered, population based CPRD data6eliminated recall bias and minimised selection bias. The validity of the cancer registration data in the CPRD is high.7The CPRD also enabled retrieval of data on potential confounders, including smoking. Although drugs registered in the CPRD are those prescribed by general practitioners and might not necessarily reflect drug consumption or adherence, repeat prescriptions over several years likely reflect actual use, and potential adherence bias in long term users seems unlikely to differ by antihypertensive drug class.
Hicks and colleagues comprehensively investigated the potential of bias in their study. Their new-user design reduced any prevalent user bias,8 and time varying modelling eliminated immortal time bias.9 Sensitivity analyses using marginal structural models and a disease risk score analysis diminished the possibility of residual and time dependent confounding due to the long follow-up period.10 Multiple imputation11 also suggested that missing data had little impact on the observed associations. A frequent limitation of pharmacoepidemiology studies is the potential for confounding by indication.12 By comparing users of ACEIs with users of angiotensin receptor blockers, Hicks and colleagues downplayed this potential. Furthermore, in sensitivity analysis, when the referent group was switched to thiazide diuretics as an active comparator drug (for both ACEIs and angiotensin receptor blockers), the increased risk of lung cancer associated with long term ACEI use remained.
 
Despite the rigorous analytical approach, the study has limitations, including being prone to residual confounding. Information on socioeconomic status was lacking, which may differ in users of ACEIs versus angiotensin receptor blockers. ACEIs became generically available in 1995,13 whereas the first generic angiotensin receptor blockers were marketed in 2010.14 Accordingly, socioeconomic differences might have influenced prescribing patterns and lung cancer risk over a long term period, even in the UK national healthcare setting. Likewise, residual confounding from other environmental exposures such as radon or asbestos might influence the observed association. Use of ACEIs is associated with a persistent cough, which may have prompted more frequent thorax imaging in ACEI users compared with angiotensin receptor blockers users, but data on such scans was not available in the current analysis. Critically, as different ACEIs have varying pharmacological properties and pleotropic effects, it remains unclear if a particular ACEI drove the observed associations.
 
Undoubtedly, this is a controversial topic: previous studies have suggested increased, decreased, or no association of ACEIs or angiotensin receptor blockers with cancer and lung cancer incidence.1516171819202122 For example, a previous study by Azoulay and colleagues, showed an increased risk of lung cancer associated with use of ACEIs but not angiotensin receptor blockers.19 Hallas and colleagues, however, saw little evidence of an association between lung cancer risk and at least five years use of ACEIs.21 Cancer outcomes have been investigated within antihypertensive trials, but these post hoc analyses lack information on dose and duration, and they may be prone to under-reporting of non-cardiovascular outcomes.1718
 
The study by Hicks and colleagues 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. 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 Hicks and colleagues 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.
 
Abstract
Objective To determine whether the use of angiotensin converting enzyme inhibitors (ACEIs), compared with use of angiotensin receptor blockers, is associated with an increased risk of lung cancer.
Design Population based cohort study.
 
Setting United Kingdom Clinical Practice Research Datalink.
 
Participants A cohort of 992 061 patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2015 was identified and followed until 31 December 2016.
 
Main outcome measures Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident lung cancer associated with the time varying use of ACEIs, compared with use of angiotensin receptor blockers, overall, by cumulative duration of use, and by time since initiation.
Results The cohort was followed for a mean of 6.4 (SD 4.7) years, generating 7952 incident lung cancer events (crude incidence 1.3 (95% confidence interval 1.2 to 1.3) per 1000 person years). Overall, use of ACEIs was associated with an increased risk of lung cancer (incidence rate 1.6 v 1.2 per 1000 person years; hazard ratio 1.14, 95% confidence interval 1.01 to 1.29), compared with use of angiotensin receptor blockers. Hazard ratios gradually increased with longer durations of use, with an association evident after five years of use (hazard ratio 1.22, 1.06 to 1.40) and peaking after more than 10 years of use (1.31, 1.08 to 1.59). Similar findings were observed with time since initiation.
 
Conclusions In this population based cohort study, the use of ACEIs was associated with an increased risk of lung cancer. The association was particularly elevated among people using ACEIs for more than five years. Additional studies, with long term follow-up, are needed to investigate the effects of these drugs on incidence of lung cancer.
 
Introduction
Angiotensin converting enzyme inhibitors (ACEIs) are effective drugs used in the treatment of hypertension.1Although these drugs have been shown to be relatively safe in the short term, concerns have been raised that their long term use may be associated with an increased risk of cancer. These concerns have been subject to debate, with observational studies producing mixed findings,234 including with respect to lung cancer.24 Some biological evidence exists for a possible association between ACEIs and risk of lung cancer. The use of ACEIs causes an accumulation of bradykinin in the lung,5 which has been reported to stimulate growth of lung cancer.56 ACEI use also results in accumulation of substance P, which is expressed in lung cancer tissue and has been associated with tumor proliferation and angiogenesis.7
Meta-analyses of randomized controlled trials found no evidence of an increase in cancer incidence with ACEIs, but most had relatively small sample sizes and short durations of follow-up (median 3.5 years).89 The few observational studies that have investigated the association between ACEI use and lung cancer have reported mixed findings.1011121314151617 However, most of these studies were designed to assess the risk of cancer overall and not lung cancer specifically.10111213141516 Additionally, several of these studies had some methodological shortcomings, including short duration of follow-up (for example, median of 0.7 years),17 failure to account for cancer latency,12131517 and immortal time bias.15 Furthermore, results of some studies may have been influenced by the use of an inappropriate comparator group, introducing potential confounding by indication,14and the inclusion of prevalent users of antihypertensives.15
Thus, in light of the conflicting and limited evidence from both preclinical and observational studies, we conducted a large, population based study to determine whether the use of ACEIs, compared with use of angiotensin receptor blockers, is associated with an increased risk of lung cancer.
 
Discussion
In this large population based study of nearly one million patients, the use of ACEIs was associated with an overall 14% increased risk of lung cancer. Associations were evident after five years of use and increased with longer durations of use, particularly among patients who used ACEIs for more than 10 years (31% increased risk). Although the magnitudes of the observed associations are modest, ACEIs are one of the most widely prescribed drug classes; in the UK, 70.1 million antihypertensives are dispensed each year, of which approximately 32% are ACEIs.3839 Thus, small relative effects could translate into large absolute numbers of patients at risk for lung cancer. Given the potential impact of our findings, they need to be replicated in other settings, particularly among patients exposed for longer durations.
 
Comparison with previous studies
Although meta-analyses of randomized controlled trials found no evidence of an association between the use of ACEIs and cancer overall, or lung cancer specifically,89 these trials were not powered or designed to assess these outcomes. Moreover, with relatively short durations of follow-up (median duration of 3.5 (range 1.3-5.1) years), these trials did not have sufficient follow-up to assess long term adverse events such as cancer.89 This is particularly important given that an association between use of ACEIs and risk of lung cancer became evident after five years of use in our study. To our knowledge, although several observational studies reported on the association between ACEIs and lung cancer incidence,10111213141516 only one study was specifically designed to investigate this association.17 In this well conducted study, the use of ACEIs was not associated with an increased risk of lung cancer (hazard ratio 0.99, 0.84 to 1.16), compared with angiotensin receptor blockers. However, as this study had a maximum follow-up of five years, its conclusion is not incompatible with our finding suggesting no association in the first five years of use (hazard ratio 1.10, 0.96 to 1.25). Other observational studies have investigated this association, but their findings were part of secondary analyses and thus should be interpreted with caution. Overall, these studies produced mixed results, with some reporting increased risks,101116 others reporting null associations,121314 and one study reporting a 66% decreased risk.15 However, the latter study may have been affected by immortal time bias, which resulted from the misclassification of unexposed person time as exposed person time.40 The other studies had other limitations, such as the inclusion of prevalent users of antihypertensive drugs,15 confounding by indication,14 and not accounting for cancer latency in their analyses.12131517
 
The association between ACEIs and lung cancer is biologically plausible. In addition to angiotensin I, angiotensin converting enzyme also metabolizes bradykinin, an active vasodilator.41 Thus, the use of ACEIs results in the accumulation of bradykinin in the lung.5 Bradykinin receptors have been located on various cancerous tissues including lung cancer,542 and bradykinin may directly stimulate growth of lung cancer.56 Bradykinin has been shown to stimulate the release of vascular endothelial growth factor, thus promoting angiogenesis,4344 as well as having indirect effects on lung cancer by enhancing vascular permeability, via the activation of matrix metalloproteinase, facilitating tumor invasion and metastases.44 Moreover, ACEI use also results in accumulation of substance P, which is expressed in lung cancer tissue and is associated with tumor proliferation and angiogenesis.7
 
The results of this study also raise important questions about the new angiotensin receptor/neprilysin inhibitor sacubitril/valsartan. Neprilysin inhibition results in increases in vasoactive and other peptides including bradykinin and substance P.45 The recent PARADIGM-HF trial reported clinical benefits for cardiovascular outcomes and death; however, cancer events were not reported.46 Therefore, whether these new renin-angiotensin system inhibitors may also increase the risk of lung cancer in the long term remains unknown. Moreover, these results also raise questions about recent evidence suggesting that ACEIs may protect against radiation induced pneumonitis in patients with lung cancer.47 Although limited studies have suggested improvements in survival in patients with lung cancer receiving renin-angiotensin system inhibitors and tyrosine kinase inhibitors or chemotherapy, the effect of ACEIs specifically on lung cancer progression remains uncertain.4849
Strengths and limitations of study
 
This study has several strengths. Firstly, to our knowledge, with more than 990 000 patients followed for an average of 6.4 years (beyond the one year post-cohort entry lag period), this is the largest study to have been conducted to specifically assess this association. Secondly, we used a new-user design, thus minimizing biases related to the inclusion of prevalent users.50 Thirdly, we used a time varying exposure definition that eliminated immortal time bias, while also accounting for cancer latency. Finally, the use of the CPRD allowed us to adjust the models for several potential important confounders, including smoking status, which was not available in some of the previous studies.17
 
This study has some limitations. Firstly, although we were able to adjust for several important confounders, this study lacked information on other potential confounders such as socioeconomic status, diet, exposure to radon or asbestos, and family history of lung cancer.5152 Additionally, despite adjusting for smoking status, we lacked detailed information on duration and intensity of smoking, which have been shown to be associated with lung cancer incidence.5152 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. Secondly, prescriptions in the CPRD represent those written by general practitioners, so misclassification of exposure is possible if patients did not adhere to the treatment regimen or received prescriptions from specialists. However, as all patients entering the cohort were those newly treated with antihypertensive drugs, misclassification due to non-adherence should be minimal and likely non-differential between ACEI and angiotensin receptor blocker users.
 
Thirdly, we compared ACEIs with angiotensin receptor blockers, as the latter also act on the renin-angiotensin system and are used at the same disease stage but have not been associated with neuropeptide accumulation in the lung. However, angiotensin receptor blockers may also have an effect on lung cancer incidence,53 and a meta-analysis of observational studies reported a decreased risk with these drugs.37 Studies included in this meta-analysis had some limitations, and several compared angiotensin receptor blockers with ACEIs.37 Thus, the apparent protective effect of angiotensin receptor blockers may be the result of a deleterious effect of ACEIs on lung cancer incidence.37 Nevertheless, our study was designed to consider this possibility by comparing ACEIs with thiazide diuretics in ancillary analyses. Reassuringly, this analysis yielded consistent results, both in terms of overall association and by cumulative duration of use. Importantly, our analyses comparing angiotensin receptor blockers with thiazide diuretics produced null associations for both overall and cumulative duration of use; this suggests that the observed increased risk with ACEIs is unlikely to be attributable to the purported antitumor effects of angiotensin receptor blockers. Fourthly, misclassification of the outcome is possible; however, lung cancer has been shown to be well recorded in the CPRD when compared with the UK National Cancer Data Repository (concordance rate of 93%).23 Associations may also vary by subtypes of lung cancer, but this information was not available within the CPRD.
 
Finally, persistent cough is a common and well known side effect of ACEIs, raising the possibility that the observed association could be due to detection bias. Patients taking ACEIs may be more likely to undergo diagnostic evaluations, such as computerized tomography of the chest, leading to an increased detection of preclinical lung cancers. Information on chest investigations is not well recorded in the CPRD, so we could not account for this possibility in our analyses. However, a recent study found minimal evidence of differences in chest investigations after ACEI and angiotensin receptor blocker initiation.17 Moreover, an over-detection of lung cancer would be expected to be observed relatively soon after the start of treatment, which is one the reasons why our exposures were lagged by one year. Lengthening the exposure lag period to two and three years yielded similar findings to those observed for the primary analysis. Furthermore, associations between ACEI use and lung cancer risk were evident only with increasing durations of use (after at least five years of use). Taken together, these results do not corroborate the hypothesis of an over-detection of lung cancer among ACEIs
 
Conclusions
In this large, population based study, the use of ACEIs was associated with an elevated risk of lung cancer overall, along with evidence of a duration-response relation. 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.
 
What is already known on this topic
Biological evidence suggests that angiotensin converting enzyme inhibitors may increase the risk of lung cancer through the accumulation of bradykinin and substance P in the lungHowever, observational studies examining this association are limited and report inconsistent results
 
What this study adds
The use of angiotensin converting enzyme inhibitors was associated with a 14% increased risk of lung cancer
 
Associations were evident after five years of use and increased with longer durations of use, particularly in patients who used angiotensin converting enzyme inhibitors for more than 10 years
 
The magnitudes of the observed estimates are modest, but these small relative effects could translate into large absolute numbers of patients at risk, so these findings should be replicated in other settings
 
 
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