ACE-inhibitors may inc lung cancer risk

​A recent article found an increase in lung cancer in those on ACEIs (see htn ace-i inc lung ca bmj2018 in dropbox, or doi.org/10.1136/bmj.k4209).

Details:

--992,061 patients, newly treated with antihypertensive drugs from 1995-2015 and followed til end of 2016, from the UK Clinical Practice Research Datalink

--mean age 56, 46% male, 7% alcohol related disorders, 22% current smokers/23% past smokers/48% never smokers, BMI <25 in 31%/25-30 in 31% />30 in 23%, mean duration of htn treatment 1.5 years, 17% on statins

--335,135 patients were treated with ACEIs, 29,008 with angiotensin receptor blockers (ARBs), and 101,637 with both ACEIs and ARBs

--ACEIs used: ramipril (26%; 257,420 patients), lisinopril (12%; 120;641 patients), and perindopril (7%; 70,955 patients).

--those on ACEIs were more likely to be male, have alcohol-related disorders, be current smokers, have a higher BMI, more likely to be on statins and other meds

--main outcome: incident lung cancer, comparing ACEIs vs ARBs, by cumulative duration of use, and by time since initiation

--followed for a mean of 6.4 years

Results:

--7952 incident lung cancer events, at rate of 1.3 per 1000 person years

--ACEIs vs ARBs were associated with a 14% increased lung cancer incidence, 1.6 v 1.2 per 1000 person years, adjusted HR 1.14 (1.01 to 1.29),  all HR's adjusted by sex, age, BMI, smoking status, alcohol related disorders, history of lung disease

--HR gradually increased with longer durations of use

    --after five years of use, 22% increase with HR 1.22 (1.06 to 1.40)

    -- after >10 years of use, 31% increase with HR 1.31 (1.08 to 1.59).

-- HR also increased by the time since ACEIs were first use

    --after five years, 14% increase with HR 1.14 (0.99 to 1.30)

    -- after >10 years , 29% increase with HR 1.29 (1.10 to 1.51).

--smoking status did not affect the above results [but, see below]

--compared with thiazides, ACEIs were associated with a 6% increase in lung cancer, HR 1.06 (1.00-1.13), but up to 23% increase if >10 years of use.

    --no difference in risk between thiazides and ARBs

Commentary:

--prior studies are mixed on the relationship between ACEIs and risk of lung cancer, perhaps in part from small size or limited followup (and this really large study found no association unless at least 5 years of followup)

--there is some biological evidence for a possible association between ACEIs and risk of lung cancer. The ACEI-related increase in bradykinin in the lung has been reported to stimulate growth of lung cancer.  And the bradykinin may stimulate the release of vascular endothelial growth factors and promote angiogenesis as well as increasing vascular permeability and perhaps increasing tumor invasion and metastases. 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.

--there are several limitations to this study

    --one really big one is the lack of data on the intensity of cigarette smoking, which does affect lung cancer risk (no data on number of pack-years of smoking, just on whether current or past smokers). And even for past smokers, there is a big difference between those who stopped smoking in the past year (perhaps spurred on by the recent diagnosis of hypertension) vs those who stopped >15 years before (when the risk of lung cancer reverts to almost that of non-smokers). and there may have been important but undetected differences between the groups.a

    --another is the co-morbidities (eg, those smokers with COPD, for example, are at much higher risk of lung cancer than those without COPD, even controlling for amount of smoking)

    --other potentially related variables were not included, eg socioeconomic status, occupation and exposures, family history, diet, exercise,…

    --one interesting potential mediator of the association is the likely increase in cough in those on ACEIs, which can happen at any time in the course of ACEI therapy, and might lead to more chest xrays and more incidental pickups of lung cancer, exaggerating the associations

--the increase in risk is pretty small, and given the limits of the study (including data on intensity of cigarette smoking) this association may not be real.  but,

   --this was a really large study, which tends to equilibrate the differences between groups (though systematic biases can still be present, such as differences in underlying conditions, they did try to decrease some of these, eg by only looking at patients newly on anti-hypertensives)

    --huge numbers of patients are on ACEIs (of the 70.1 million scripts for antihypertensives in the UK, 32% are for ACEIs)

    --there was a dose-response curve: the longer on the ACEIs, the more likely to get lung cancer (though we have no information on the dose/intensity of ACEIs perscribed)

    ​--and, even a 10% increased risk of lung cancer would translate into lots of cases

--one comment by the researchers is that the new heart failure drug sacubitril/valsartan could also be associated with lung cancer, since neprilysin inhibition also increases bradykinin and substance P levels

--also, i am not sure how to explain the rather frequent co-prescriptions of ACEI and ARB: it has been pretty clear that this combo has more adverse effects, overwhelming its potential benefit, and has continued to be specifically targeted by guidelines as a no-no (eg see http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html ​ )

--but, the elephant in the room: the vast majority of chronic diseases, and the ones we in primary care treat and give meds for, result from the quality of our social environment and lifestyle issues (and meds would not be needed in a more healthful environment). for many of us, we have  poor access to high quality foods (most foods are distorted by current farming and industrial practices: use of chemicals to improve vegetable growth, antibiotics for animal growth, effluent of toxic chemicals in the water, food deserts in many urban and rural areas with lack of access to better foods and more access to junk and fast foods), lack exercise (our high intensity social existences leading to little time to exercise, lack of safe venues to exercise, overwhelming influence of TV/screen-time on our lives), high stress living overall, menial and low-paying jobs (with increasing demands on workers, leading to musculoskeletal problems, and also many workers needing to work 2+ jobs to live and also leaving no time to cook, or exercise), climate change (spread of new microbes/diseases, morbidity/mortality/stress of adverse weather), increasing levels of environmental and occupational toxins (industry, increasingly unregulated, using thousands of new chemicals every year; often polluting workers using them as well as the environment broadly, and these chemicals are `rarely tested for their potential harm to us and the environment), direct toxins promoted by government and social acceptance/advertising/life stressors (cigarettes, alcohol, and now opiates….)... So, we (myself certainly included) resort frequently to drugs to help treat these fundamentally socially-driven issues, and typically drugs are not-so-targeted/do affect the larger biological system that we are (hence, the often unanticipated adverse reactions, in this case lung cancer), alter the normal homeostatic mechanisms that humans have evolved for eons, etc.

So, given the above-noted limitations of this study, I am not ready to change my practice drastically.  Overall I have been using more amlodipine as my first antihypertensive, since it has a long duration of action and decreases blood pressure variability the most [ACEIs seem to be associated with more strokes, for example, perhaps because their effects wear off and many strokes happen in the early AM hours; and hydrochlorothizide, in particular, has about ½ the 24-hour effect of just about any other antihypertensive (see http://gmodestmedblogs.blogspot.com/2016/04/chlorthalidone-is-better-than-hctz-for.html   and http://gmodestmedblogs.blogspot.com/2017/11/new-aha-hypertension-guidelines.html )]. And, with the potential association of ACEIs and lung cancer, maybe the better part of valor is to lean a bit further from prescribing them to patients who are smokers or who have underlying lung disease that clearly increase their risk of lung cancer.

geoff​

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