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How Much Did Biases in the Study of Chronic Obstructive Pulmonary Disease Medications and Mortality Affect the Outcome?
- Todd A. Lee, PharmD, PhD;
- A. Simon Pickard, PhD; and
- David H. Au, MD, MS
- From Hines Veterans Affairs Hospital, Hines, IL 60141; University of Illinois at Chicago, Chicago, IL 60637; and Veterans Affairs Puget Sound Health Care System, Seattle, WA 98174.
IN RESPONSE:
We thank the correspondents for their thoughtful comments. Drs. Suissa and Ernst raise 3 concerns about our article. First, to alleviate concerns that the observed risk for ipratropium and cardiovascular mortality was a result of an increased risk for exacerbations in the case patients, we conducted an analysis restricted to those without an exacerbation in the 180 days before their event date and found a level of risk (odds ratio, 1.45 [CI, 1.14 to 1.85]) similar to the results reported in the article. Second, unmeasured confounding and bias is a possible explanation for the discordant results between the TORCH study and our study. Among the other explanations, the difference in outcomes may be related to the patient populations. The population included in our analysis was older, had higher overall and cause-specific mortality rates, was nearly all male, had more coexisting conditions, and had differential respiratory medication use before entering the study. Third, we were able to measure medications used in the Veterans Administration health care system during inpatient stays, and thus the analysis was not subject to concerns about immeasurable time bias.
Dr. Gross raises concerns about observational studies and our ability to adjust for disease severity and smoking status. We acknowledged the inability to measure smoking status in our article, and the proportion of current smokers in the ipratropium group needed to be nearly 2.5 times higher than that in the comparator group to negate the observed association with ipratropium and cardiovascular mortality. We used COPD exacerbations and hospitalizations to characterize disease severity. The observed association with respiratory mortality and theophylline may have been related to residual confounding by severity, given its place in treatment guidelines. However, this is unlikely to be the case with ipratropium because it is used as a first-line medication in the treatment of COPD. We based the specific hypotheses tested in our study on past research, including a large prospective study of ipratropium that showed an increased risk for cardiovascular hospitalizations and deaths (1). In addition, our findings are consistent with a recent meta-analysis that reported similar risks with anticholinergics and cardiovascular outcomes (2).
Finally, Dr. Koga and colleagues note that socioeconomic status may confound the association between medication use and mortality. An advantage of conducting our analysis among U.S. veterans who received care from the Veterans Health Administration is the strong emphasis that the Veterans Administration places on equal access to health care, which probably minimizes the effects of socioeconomic status compared with other populations (3, 4).
A. Simon Pickard, PhD
University of Illinois at Chicago
Chicago, IL 60637
David H. Au, MD, MS
Veterans Affairs Puget Sound Health Care System
Seattle, WA 98174
Article and Author Information
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Potential Financial Conflicts of Interest: Honoraria: T.A. Lee (AstraZeneca, Novartis), D.H. Au (GlaxoSmithKline). Stock ownership or options (other than mutual funds): D.H. Au (Pfizer). Grants received: T.A. Lee (Altana, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, Schering-Plough, Sepracor, University of Kentucky). Other: D.H. Au (Assessing the Impact of Recent Updates for Advair and Serevent Special Issues Board).
