Statins and Influenza/COPD Mortality

Abstract

We read with great interest the article by Frost et al1Frost FJ Petersen H Tollestrup K et al.Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.Chest. 2007; : 1006-1012Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar (April 2007), and although we concur in the need for measures to attenuate the effect of a potential influenza pandemic, we believe there might be other explanations for the apparent benefit of statins in the prevention of influenza/pneumonia and COPD-associated mortality. Study cohort members were classified as either statin exposed (moderate and low dose) or unexposed for the entire follow-up (ie, exposure status was fixed). Moreover, for statin users, the time from enrollment to initiation of statin therapy (phase 1) was necessarily free of events and contributed follow-up time in which statins were not taken. The inclusion of this “immortal time” would result in exposure misclassification and may artificially reduce the event rate in the statin-exposed group, producing an apparent benefit of statins.2Suissa S Immortal time bias in observational studies of drug effects.Pharmacoepidemiol Drug Saf. 2007; 16: 241-249Crossref PubMed Scopus (361) Google Scholar The classification of patients who used but did not accumulate 90 days of statin use is unclear. Their inclusion in the unexposed group would result in exposure misclassification, and their exclusion from the statin-exposed group would result in selection of a subgroup of patients (ie, with good tolerance to the drug). Allowing statin use to change after its initiation (time-varying exposure) would reduce exposure misclassification. Another consideration is the “healthy user” effect, in which statins use could be related to a constellation of healthy behaviors that were not included in the analysis.3Majumdar SR McAlister FA Eurich DT et al.Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study.BMJ. 2006; 333: 999-1001Crossref PubMed Scopus (231) Google Scholar Different designs using the same exposure definitions and covariates (eg, nested case control) will not account for this either. As the authors stated, unmeasured confounders could explain the observed benefits. Finally, logistic regression does not account for censoring.4Cox DR Oakes D Analysis of survival data. 1st ed. Chapman & Hall/CRC, Boca Raton, FL1984Google Scholar Data from clinical trials have failed to show benefits of statins in preventing mortality due to nonvascular respiratory causes.5Baigent C Keech A Kearney PM et al.Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2005; 366: 1267-1278Abstract Full Text Full Text PDF PubMed Scopus (5745) Google Scholar Meanwhile, the assessment of additional benefits of statins using observational studies requires the careful consideration of known sources of bias. Statins and Influenza/COPD Mortality: ResponseCHESTVol. 132Issue 4PreviewWe thank Drs. Grijalva, Arbogast, and Griffin for their observation that our study1 may have included an immortal time period such that participants were not permitted to die. Immortal time has been clearly demonstrated in the literature2 to cause substantial bias in observational studies when there is a difference in the application of immortal time between the exposed and unexposed groups. In our study, both the exposed and the individually matched unexposed participants were equally subject to immortal periods prior to the initiation of statins (12 months, phase 1) in order to estimate mortality risk differences. Full-Text PDF