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Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study
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BMJ 2018
What is already known on this topic
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⋅ 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 lung
⋅ However, 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
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.1 Although 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,14 and 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.
Results
The cohort included 992 061 patients (fig 1) followed for a mean of 6.4 (SD 4.7) years beyond the one year post-cohort entry latency period. During the follow-up period, 335 135 patients were treated with ACEIs, 29 008 with angiotensin receptor blockers, and 101 637 with both ACEIs and angiotensin receptor blockers. The three most commonly used ACEIs were ramipril (26%; 257 420 patients) lisinopril (12%; 120 641 patients), and perindopril (7%; 70 955 patients). Overall, 7952 patients were newly diagnosed as having lung cancer during 6 350 584 person years of follow-up, generating a crude incidence rate of 1.3 (95% confidence interval 1.2 to 1.3) per 1000 person years.
Table 1 shows baseline characteristics of the entire cohort and by use of ACEIs, angiotensin receptor blockers, and other antihypertensive drugs at cohort entry. Compared with angiotensin receptor blocker users, ACEI users were more likely to be male, to have alcohol related disorders, to be current smokers, and to have a higher body mass index. Additionally, ACEI users had a shorter duration of treated hypertension and were more likely to have used statins and other prescription drugs. ACEI and angiotensin receptor blocker users had a similar history of pneumonia, tuberculosis, and chronic obstructive pulmonary disease.
Table 2 shows the results from primary and secondary analyses. Compared with angiotensin receptor blockers, ACEIs were associated with an overall 14% greater risk of lung cancer (1.6 v 1.2 per 1000 person years; hazard ratio 1.14, 95% confidence interval 1.01 to 1.29). In secondary analyses, the use of ACEIs for less than five years was not associated with an increased risk of lung cancer (hazard ratio 1.10, 0.96 to 1.25). However, the hazard ratio was elevated with five to 10 years of use (1.22, 1.06 to 1.40) and continued to increase with more than 10 years of use (1.31, 1.08 to 1.59). Similar associations were observed for time since starting ACEI, with hazard ratios increasing with longer times since initiation, peaking at more than 10 years since initiation (hazard ratio 1.29, 1.10 to 1.51). We saw similar patterns in analyses using restricted cubic splines (supplementary figures A and B). Smoking status did not significantly modify the association between ACEI use and risk of lung cancer (P for interaction=0.40; supplementary table B). Supplementary table C shows analyses conducted within non-smokers. Overall, the results were consistent with those of the primary analyses, with the hazard ratio increasing with longer cumulative durations of use (>10 years cumulative use: hazard ratio 1.64, 1.02 to 2.64).
Sensitivity analyses
Results of sensitivity analyses are summarized in figure 2 and supplementary tables D-G. Overall, these yielded consistent results, generating hazard ratios ranging between 1.13 and 1.22. The latter estimate was from the marginal structural model that controlled for potential time dependent confounding.
Ancillary analyses
Compared with the use of thiazide diuretics, the use of ACEIs was associated with a 6% increased risk of lung cancer (hazard ratio 1.06, 1.00 to 1.13) (supplementary table H). Similar to the main analysis, use of ACEIs for less than five years was not associated with an increased risk of lung cancer, whereas hazard ratios were elevated with increasing use, peaking with more than 10 years of use (1.23, 1.04 to 1.44). Analysis comparing angiotensin receptor blockers with thiazide diuretics showed null associations overall (hazard ratio 0.93, 0.82 to 1.06) and by cumulative duration of use (supplementary table I).
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.17Moreover, 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.
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