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Stephen Padilla
07 Nov 2018

Use of angiotensin converting enzyme inhibitors (ACEIs) appears to increase the risk of lung cancer, particularly among people using ACEIs for more than 5 years, suggests a recent study.

“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,” researchers said.

A total of 7,952 incident lung cancer events (crude incidence, 1.3 per 1,000 person-years; 95 percent CI, 1.2–1.3) occurred over a mean follow-up of 6.4 years. [BMJ 2018;363:k4209]

Overall, use of ACEIs vs angiotensin receptor blockers correlated with an increased risk of lung cancer (incidence rate, 1.6 vs 1.2 per 1,000 person-years; hazard ratio [HR], 1.14; 1.01–1.29). Longer durations of use led to a gradual increase in HRs, with an association evident after 5 years of use (HR, 1.22; 1.06–1.40) and peaking after more than 10 years of use (HR, 1.31; 1.08–1.59). There were similar findings seen with time since initiation.

Meta-analyses of randomized controlled trials found no association between ACEI use and cancer overall, or lung cancer in particular, but these trials were not designed to assess such outcomes and did not have sufficient follow-up to assess long-term adverse events such as cancer. [J Hypertens 2011;29:623-635; Lancet Oncol 2011;12:65-82]

“To our knowledge, although several observational studies reported on the association between ACEIs and lung cancer incidence, only one study was specifically designed to investigate this association,” researchers said. [PLoS One 2012;7:e50893; BMJ 2012;344:e2697; J Clin Oncol 2011;29:3001-3007; Cancer 2001;92:2462-2470; Br J Clin Pharmacol 2012;74:180-188; Lancet 1998;352:179-184; Circulation 2011;123:1729-1736]

This one well-conducted study found no association between ACEI use and an increased risk of lung cancer (HR, 0.99; 0.84–1.16), compared with angiotensin receptor blockers. [Pharmacoepidemiol Drug Saf 2016;25:512-520]

“However, as this study had a maximum follow-up of 5 years, its conclusion is not incompatible with our finding suggesting no association in the first 5 years of use (HR, 1.10; 0.96–1.25),” researchers said.

“The association between ACEIs and lung cancer is biologically plausible. In addition to angiotensin I, angiotensin converting enzyme also metabolizes bradykinin, an active vasodilator. Thus, the use of ACEIs results in the accumulation of bradykinin in the lung,” they explained. [Eur Respir J 1993;6:576-587; Endocr Rev 2003;24:261-271]

Bradykinin receptors have been found on several cancerous tissues including lung cancer, according to researchers. In addition, it may directly stimulate growth of lung cancer. [Eur Respir J 1993;6:576-587; Cancer Res 1991;51:3621-3623; Hippokratia 2007;11:124-128]

The present population-based cohort study identified a total of 992,061 patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2015. Participants were followed until 31 December 2016.

Researchers used Cox proportional hazards models to estimate adjusted HRs with 95 percent CIs 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.

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