Modest Association of Long-Term ACE Inhibitor Treatment With Lung Cancer: The Promise and Pitfalls of Epidemiological Drug-Safety Analyses

Results of the carefully executed Evaluation of Treatment with Angiotensin Converting Enzyme Inhibitors and the Risk of Lung Cancer (ERACER) study, reported in this issue, echo those of several previous observational analyses of the association of long-term angiotensin-converting enzyme (ACE) inhibitor use with incident lung cancer. These epidemiological drug-safety analyses merit cautious interpretation. First, the number needed to harm (NNH) of 6667 reported in ERACER for ACE inhibitors compared with angiotensin-2 receptor blockers (ARBs) after approximately 12 years of follow-up should be balanced against therapeutic benefits. Previously reported meta-analyses of randomized controlled trials (RCTs) over a mean 4.3-year follow-up suggested number needed to treat (NNT) of 67 for all-cause mortality, 116 for cardiovascular mortality, and 86 for a composite of myocardial infarction (MI) and stroke for ACE inhibitors, compared with nonsignificant benefits for ARBs on the mortality outcomes and NNT of 157 for ARBs on the MI/stroke composite. Second, confounding by indication is possible because until 2013, ACE inhibitors, not ARBs, were first-line medications for heart failure, which is associated with incident lung cancer. Third, findings may be compromised by detection bias due to investigation of ACE inhibitor-induced cough, or by residual confounding due to influential factors not measurable in the available data, such as socioeconomic status (SES) or smoking history. The important questions raised by ERACER and similar drug-safety analyses should be addressed in long-term RCTs or in enhanced large-database pharmacoepidemiological analyses, measuring both NNH and NNT and controlling for SES, indication, medication, and dosage.