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Inhaled Corticosteroids and Mortality in COPDResponseResponse FREE TO VIEW

Giora Netzer, MD, MSCE
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Affiliations: University of Maryland School of Medicine, Baltimore, MD,  Novi, MI,  University of Manitoba, Winnipeg, MB, Canada

Correspondence to: Giora Netzer, MD, MSCE, University of Maryland School of Medicine, MSTF Room 800, 685 W Baltimore St, Baltimore, MD 21201-1192; e-mail: gnetzer@medicine.umaryland.edu



Chest. 2007;131(3):939-940. doi:10.1378/chest.06-2473
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I appreciate the thoughtful discussion in a recent issue of CHEST (September 2006)1by Macie et al of the limitations of database analyses, as well as of the adjustments made in their study for the confounding factors of comorbid illness and other respiratory medications. However, their analysis may have overlooked potential confounding by indication, which may be highly significant in this population. The prescribing of inhaled corticosteroids may be reflective of the prescribers’ implementation of evidence-based medicine, and of the fact that patients to whom inhaled corticosteroids were prescribed for treatment of their COPD may have been more likely to have been prescribed aspirin, β-blockers, and angiotensin-converting enzyme inhibitors for treatment of their cardiovascular disease. Including these prescriptions in the multivariable model would account for this effect.2

The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

The author has no conflicts of interest to disclose.

The author has no conflict of interest to disclose.

Macie, C, Wooldrage, K, Manfreda, J, et al (2006) Inhaled corticosteroids and mortality in COPD.Chest130,640-646. [PubMed] [CrossRef]
 
Hak, E, Verheij, TJ, Grobbee, DE, et al Counfounding by indication in non-experimental evaluation of vaccine effectiveness: the example of prevention of vaccine complications.J Epidemiol Community Health2002;56,951-955. [PubMed]
 
To the Editor:

I read with interest the recent article by Macie and colleagues (September 2006).1I congratulate them on an exhaustive analysis of a well-designed observational study. I disagree, however, with the conclusion on several points. First, it is stated in the abstract that therapy “with ICSs [inhaled corticosteroids] reduced mortality in COPD patients.” Causality cannot be inferred from a case-control observational study no matter how well statistically modeled. Further, could undetected bias explain the association between ICS use and reduced mortality? The effect of ICSs on mortality may have been overestimated because of healthy user and provider selection bias.23 Could ICS users be a more robust group in terms of cardiovascular risk factors, or behavioral or lifestyle modifications? Further, providers might be more inclined to prescribe ICSs to less ill, more motivated COPD patients. The article supports this notion on several occasions. In Table 1, ICS users were more likely to receive other medications, visit physicians more frequently, and in older patients had less comorbidity. “In subjects who were > 65 years of age … who died had more comorbidities … received more prescriptions … other than ICSs than did control subjects.” It would have been instructive if the authors could have stratified the data on the basis of the percentage of patients in each group who received a prescription of ICSs but was later not dispensed. This would have provided insight into healthy user and provider selection bias. Examples of confounders not adjusted for in analyses include tobacco usage, body mass index, statin use, severity of COPD, social class, and physical activity. Model adjustments for complex social and behavioral factors are difficult and are outside the scope of observational studies in general.4 The patient out-of-pocket costs of medical therapy in COPD are considerable. It is incumbent on pulmonologists to parcel out the data carefully lest an ineffective therapy for reducing COPD-related mortality becomes the standard of care.

References
Macie, C, Wooldrage, K, Mandreda, J, et al Inhaled corticosteroids and mortality in COPD.Chest2006;130,640-646. [PubMed] [CrossRef]
 
Garbe, E, Suissa, S Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies.Hum Reprod2004;19,8-13. [PubMed]
 
Rosenberg, A, Hofer, T, Strachan, C, et al Accepting critically ill transfer patients: adverse effect on referral center’s outcome and benchmark measures.Ann Intern Med2003;138,882-890. [PubMed]
 
Lawlor, D, Smith, G, Bruchdorfer, K, et al Those confounded vitamins: what can we learn from the differences between observational versus randomized trial evidence?Lancet2004;363,1724-1727. [PubMed]
 
To the Editor:

We thank Drs. Netzer and Omron for their interest in our article. We agree that observational data such as we used are tricky and cannot consider all potential confounders. Confounding by indication is always the weakness of this kind of work. However, we tried to avoid this, and could not identify plausible causes for this kind of confounding. Dr. Netzer points out that we did not look at markers of cardiovascular disease, such as cardiac drugs, and she is right. However, in another study we have looked at cardiovascular morbidity as a function of respiratory drugs and found that inhaled steroids tended to be protective, but this effect was independent of interaction with cardiac drugs. Dr. Omron is not convinced that users of inhaled steroids were as sick as people who did not receive these drugs. We would argue that the evidence favors them being at least as sick; we regard frequent physician visits and multiple drugs as evidence of perceived severity, not the reverse. Further, we studied dispensed drugs only; we had no data regarding drugs that were prescribed but not dispensed. The fact that the steroid effect was most notable soon after dispensation we take as evidence favoring drug use.


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Tables

References

Macie, C, Wooldrage, K, Manfreda, J, et al (2006) Inhaled corticosteroids and mortality in COPD.Chest130,640-646. [PubMed] [CrossRef]
 
Hak, E, Verheij, TJ, Grobbee, DE, et al Counfounding by indication in non-experimental evaluation of vaccine effectiveness: the example of prevention of vaccine complications.J Epidemiol Community Health2002;56,951-955. [PubMed]
 
Macie, C, Wooldrage, K, Mandreda, J, et al Inhaled corticosteroids and mortality in COPD.Chest2006;130,640-646. [PubMed] [CrossRef]
 
Garbe, E, Suissa, S Hormone replacement therapy and acute coronary outcomes: methodological issues between randomized and observational studies.Hum Reprod2004;19,8-13. [PubMed]
 
Rosenberg, A, Hofer, T, Strachan, C, et al Accepting critically ill transfer patients: adverse effect on referral center’s outcome and benchmark measures.Ann Intern Med2003;138,882-890. [PubMed]
 
Lawlor, D, Smith, G, Bruchdorfer, K, et al Those confounded vitamins: what can we learn from the differences between observational versus randomized trial evidence?Lancet2004;363,1724-1727. [PubMed]
 
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