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Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study

BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4209 (Published 24 October 2018) Cite this as: BMJ 2018;363:k4209

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Angiotensin converting enzyme inhibitors and risk of lung cancer

Re: Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study

Dear Editor,

We have read the article entitled “Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study” by Hicks et al. published on October 24, 2018, in which they show that users of angiotensin-converting enzyme inhibitors (ACEIs) have an increased risk of lung cancer (HR 1.14, 95% IC: 1.01-1.29) compared to users of angiotensin receptor blockers (ARBs), which are dependent on the accumulated time of use and increase risk of lung cancer up to 31% (HR 1.31, IC: 1.08-1.59) with uses longer than 10 years (1).

The authors support the plausibility of this association because ACEIs increase bradykinin, substance P, and vascular endothelial growth factor (VEGF) at the pulmonary level and inhibit matrix metalloproteinases, substances that have been associated with lung cancer. However, there is evidence that ACEIs decrease metalloproteinases, VEGF, and oxidative stress, which inhibits the development of tumors and tumor growth (2, 3). Additionally, researchers have demonstrated in vivo decrease of tumor growth and metastasis, inhibition of cancer cell proliferation, reduction of endothelial cell migration and angiogenesis (2), and a cytostatic effect (4). Therefore, there is contradictory evidence regarding the possibility of ACEIs’ relationship with lung cancer.

It would be very useful for this study to express the number needed to harm (NNH) to present a case of lung cancer associated with ACEIs. In this way, a comparison could be made with the number needed to treat (NNT) to prevent cardiovascular outcomes, taking into account that ACEIs have shown superior benefits to ARBs in terms of reducing cardiovascular mortality and all causes and result in a greater decrease in the incidence of myocardial infarction, stroke, and heart failure (5-7). These benefits confer superiority to ACEIs over ARBs, but this could be eclipsed by demonstrating a risk of developing lung cancer, hence the importance of comparing NNT with NNH and thus gaining a clearer picture regarding the risks/benefits.

A fundamental factor that was needed in the study of Hicks et al. was to determine the mortality in the users of ACEIs and BRAs. It has been shown that hypertensive patients who use ACEIs experience a 10% reduction in mortality from all causes, while in BRA users, no reduction has been observed (8). Based on this, it would be expected that in the present study, there would be less mortality in users of ACEIs, so the question arises: What if living longer, these patients are exposed to the risk of suffering from other diseases, including lung cancer?

References
1. Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ. 2018;363:k4209.
2. Lindberg H, Nielsen D, Jensen BV, Eriksen J, Skovsgaard T. Angiotensin converting enzyme inhibitors for cancer treatment? Acta Oncol. 2004;43(2):142-52.
3. Rosenthal T, Gavras I. Angiotensin inhibition and malignancies: a review. J Hum Hypertens. 2009;23(10):623.
4. Molteni A, Ward WF, Ts’ ao CH, et al. Cytostatic properties of some angiotensin I converting enzyme inhibitors and of angiotensin II type I receptor antagonists. Curr Pharm Des. 2003;9(9):751-61.
5. Savarese G, Costanzo P, Cleland JGF, et al. A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure. J Am Coll Cardiol. 2013;61(2):131-42.
6. Dézsi CA. Differences in the clinical effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a critical review of the evidence. Am J Cardiovasc Drugs. 2014;14(3):167-73.
7. Ferrari R, Rosano GM. Not just numbers, but years of science: putting the ACE inhibitor-ARB meta-analyses into context. Int J Cardiol. 2013;166(2):286-8.
8. van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin–angiotensin–aldosterone system inhibitors involving 158 998 patients. Eur Heart J. 2012;33(16):2088-97.

Competing interests: No competing interests

08 November 2018
Jorge E Machado-Alba
Physician, Researcher
Efrain Santiago Guzman-Bedoya. Manuel Enrique Machado-Duque
Grupo de Investigación en Farmacoepidemiología y Farmacovigilancia, Universidad Tecnológica de Pereira – Audifarma S.A
Calle 105 No. 14-140, Pereira. Colombia,