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Statin Protection Against Influenza and COPD MortalityResponse FREE TO VIEW

David S. Fedson, MD
Author and Funding Information

Affiliations: Sergy Haut, France,  Lovelace Respiratory Research Unit, Albuquerque, NM

Correspondence to: David S. Fedson, MD, 57 chemin du Lavoir, 01630 Sergy Haut, France; e-mail: dfedson@wanadoo.fr



Chest. 2007;132(4):1406-1407. doi:10.1378/chest.07-0992
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It is difficult to interpret the report by Frost et al (April 2007)1 on statin-associated protection against influenza and COPD mortality. The authors used an administrative database that covered the 12-year period from 1992 to 2003. They defined a statin user as anyone for whom a statin was prescribed for ≥ 90 days. This means that, for example, someone could have received a statin from 1993 to 1996 and then discontinued treatment, only to die of influenza or COPD in 1998. How could a statin taken in the early period have affected the risk of mortality several years after it was stopped?

If received continuously over a prolonged period, statins could improve the overall health of the cardiopulmonary system, thus reducing the risk of death. Yet, most investigators2attribute the benefits of statins on outcomes of life-threatening infections to their antiinflammatory and immunomodulatory (pleiotropic) effects. These effects appear within a few days of initiating treatment and largely disappear soon after it is stopped. When statins are begun a day or two following acute myocardial infarction and major noncardiac surgery, rates of in-hospital morbidity and mortality are decreased. It is probably the acute effects of statin treatment, especially in hospital, that make a difference in patients with bacteremia.3 The same could be true for those with pneumonia and COPD, although this has not yet been demonstrated.

Two studies45 of outpatient-administered statins in pneumonia patients yielded conflicting results, but at least both studies documented that statin users were treated up to the moment of disease onset. In the study of Frost et al,1 this was not done, and we are left wondering whether the authors simply documented a “healthy user” effect.4 It is doubtful they have shown that statins reduced mortality in the patients they studied.

The author has no conflict of interest to disclose.

The author has no conflict of interest to disclose.

Frost, FJ, Petersen, H, Tollestrup, K, et al (2007) Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.Chest131,1006-1012. [PubMed] [CrossRef]
 
Terblanche, M, Almog, Y, Rosenson, RS, et al Statins and sepsis: multiple modifications at multiple levels.Lancet Infect Dis2007;7,358-368. [PubMed]
 
Kruger, P, Fitzsimmons, K, Cook, D, et al Statin therapy is associated with fewer deaths in patients with bacteremia.Intensive Care Med2006;32,75-79. [PubMed]
 
Majumdar, SR, McAlister, FA, Eurich, DT, et al Statins and outcomes in patients admitted to hospital with community acquired pneumonia: a population based prospective cohort study.BMJ2006;333,999-1004. [PubMed]
 
Schlienger, RG, Fedson, DS, Jick, SS, et al Statins and the risk of pneumonia: a population-based nested case-control study.Pharmacotherapy2007;27,325-332. [PubMed]
 
To the Editor:

We thank Dr. Fedson for his comments concerning our study.1 To clarify, we observed two groups of statin users after the subjects attained ≥ 90 days of statin use. The moderate-dose group received ≥ 4 mg/d of statins following initiation of treatment. Some participants may have stopped statin therapy before dying from influenza, but this should have only reduced the power of the study to detect an effect as opposed to creating an effect.

Our goal was to associate regular use of statins with each of the outcomes, not to relate medicine possession with outcomes. We assumed that if participants repeatedly refilled statins, then they were likely to be regular users of statins. Knowing only that a participant had the opportunity to take a statin near the time of illness onset or death likely overestimates exposure, especially since statin compliance tends to be very poor.23 In reality, it is virtually impossible to ensure that every participant classified as exposed was actually compliant in their use of medication.

Dr. Fedson asserts that statin-induced antiinflammatory/immunomodulatory effects occur and disappear quickly following initiation and discontinuation of statin therapy. This is not supported in a study by Rezaie-Majd et al,4 who demonstrated that statins significantly reduced serum cytokine levels by 6 weeks of therapy and that levels declined further by 6 months of therapy. Cytokine levels may have even declined further after additional months of treatment. It may, therefore, be unlikely that statins quickly reduce the risk of death from influenza or other inflammatory conditions. However, if a pill is occasionally missed, then these data suggest that inflammatory risks may not immediately return to baseline. Again, had we misclassified exposure, the effect should have been to reduce the power of the study rather than induce a spurious finding.

References
Frost, FJ, Petersen, H, Tollestrup, K, et al Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.Chest2007;131,1006-1012. [PubMed] [CrossRef]
 
Avorn, J, Monette, J, Lacour, A, et al Persistence of use of lipid-lowering medications: a cross-sectional study.JAMA1998;279,1458-1462. [PubMed]
 
Benner, JS, Glynn, RJ, Mogun, H, et al Long-term persistence in use of statin therapy in elderly patients.JAMA2002;288,455-461. [PubMed]
 
Rezaie-Majd, A, Maca, T, Bucek, R, et al Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients.Arterioscler Thromb Vasc Biol2002;22,1194-1199. [PubMed]
 

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Tables

References

Frost, FJ, Petersen, H, Tollestrup, K, et al (2007) Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.Chest131,1006-1012. [PubMed] [CrossRef]
 
Terblanche, M, Almog, Y, Rosenson, RS, et al Statins and sepsis: multiple modifications at multiple levels.Lancet Infect Dis2007;7,358-368. [PubMed]
 
Kruger, P, Fitzsimmons, K, Cook, D, et al Statin therapy is associated with fewer deaths in patients with bacteremia.Intensive Care Med2006;32,75-79. [PubMed]
 
Majumdar, SR, McAlister, FA, Eurich, DT, et al Statins and outcomes in patients admitted to hospital with community acquired pneumonia: a population based prospective cohort study.BMJ2006;333,999-1004. [PubMed]
 
Schlienger, RG, Fedson, DS, Jick, SS, et al Statins and the risk of pneumonia: a population-based nested case-control study.Pharmacotherapy2007;27,325-332. [PubMed]
 
Frost, FJ, Petersen, H, Tollestrup, K, et al Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.Chest2007;131,1006-1012. [PubMed] [CrossRef]
 
Avorn, J, Monette, J, Lacour, A, et al Persistence of use of lipid-lowering medications: a cross-sectional study.JAMA1998;279,1458-1462. [PubMed]
 
Benner, JS, Glynn, RJ, Mogun, H, et al Long-term persistence in use of statin therapy in elderly patients.JAMA2002;288,455-461. [PubMed]
 
Rezaie-Majd, A, Maca, T, Bucek, R, et al Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients.Arterioscler Thromb Vasc Biol2002;22,1194-1199. [PubMed]
 
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