Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
The strange case of the disappearing gastroprotectors
- Ezgi Gulmez, Nicholas Moore (19 June 2009)
-
Statin use and risk of pneumonia.
- Luca Mascitelli, Francesca Pezzetta MD, Tolmezzo, Italy; Mark R Goldstein, Bonita Springs, FL, USA (23 June 2009)
-
Re: The strange case of the disappearing gastroprotectors
- Sascha Dublin, Michael L. Jackson, Jennifer C. Nelson, Noel S. Weiss, Eric B. Larson and Lisa A. Jackson (28 June 2009)
-
We are not expecting statins to prevent pneumonia.
- Konosuke Morimoto, Motoi Suzuki (28 June 2009)
-
Re: We are not expecting statins to prevent pneumonia.
- Sascha Dublin, Michael L. Jackson, Jennifer C. Nelson, Noel S. Weiss, Eric B. Larson and Lisa A. Jackson (8 July 2009)
|
|
|||
|
Ezgi Gulmez, Pharmacoepidemiologist 33076 University of Bordeaux, Nicholas Moore
Send response to journal:
|
Sir, We read with the greatest interest the paper by Sascha Dublin et al, (1) and were struck by an unfathomable mystery, that of the disappearing gastroprotectives. Proton pump inhibitors, the most widely used acid- supressing drugs, are a well-known cause of increased risk of community- acquired pneumonia (2, 3). The authors found an increased use of acid- suppressing drugs (ASD) in cases (22%) compared to controls (16%) (table 1, where incidentally they do not indicate statin use), and an increased use of ASD in statin users (23.2%) vs non users (14.8%) in controls. At this point we are anticipating some very nice confounding, and await with impatience the rest of the analyses, and the impact of ASD in the multivariate models, and lo ! to our greatest surprise there is not a trace of ASD in the multivariate analysis (table 4). This is extremely disappointing. Where have all the ASD gone ? We found no reason to remove them, and could find no explanation in text. It cannot be because the association was not significant. There are plenty of other associations in table 4 that are not significant. It can’t be because it finally wasn’t interesting : not finding a relation between PPI and pneumonia would be most interesting, anyhow, since most authors to date found an association (2-4 5) . Confirming a known association would be more trivial but still satisfactory. Willfully dropping a known risk factor for the outcome of interest from a multivariate analysis is something that is rarely seen. We remain baffled. Have these drugs been lost or kidnapped? will they reappear in a further episode? How does the story really end? Can the authors shed some light on this enigma? Most sincerely Ezgi Gulmez, MD, PhD
1. Dublin S, Jackson ML, Nelson JC, Weiss NS, Larson EB, Jackson LA. Statin use and risk of community acquired pneumonia in older people: population based case-control study. BMJ 2009;338:b2137. 2. Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med 2007;167(9):950-5. 3. Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292(16):1955-60. 4. Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Gibson JE. Risk of community-acquired pneumonia and the use of statins, ace inhibitors and gastric acid suppressants: a population-based case-control study. Pharmacoepidemiol Drug Saf 2009;18(4):269-75. 5. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008;149(6):391-8. Competing interests: Beyond a purely professional interest in this specific topic, the authors love a good whodunit, but this one is beyond them. Could Poirot or Holmes solve it ? |
|||
|
|
|||
|
Luca Mascitelli, Medical Officer Comando Brigata alpina Julia, Udine 33100, Italy, Francesca Pezzetta MD, Tolmezzo, Italy; Mark R Goldstein, Bonita Springs, FL, USA
Send response to journal:
|
Dublin and colleagues (1) found that statin use increased the risk of pneumonia among healthy, community dwelling older people (odds ratio 1.26, 95% confidence interval 1.01 to 1.56). Among the possible biological mechanisms of this detrimental action, they suggested that the well known immunomodulatory action of statins (2) might exert a significative role. We fully agree, and further suggest other mechanisms. In the study of Dublin and colleagues (1), swallowing disorder were increased in statin users. It is highly plausible that this disorder might be related to a deminished cough mechanism due to statin related muscle adverse effects (3). Indeed, it has been shown that cough, a well- characterised side-effect of ACE inhibitors, could be of some benefit in this setting in that it can decrease the risk of aspiration pneumonia in certain patients (4). Of note, it was found that cholesterol had graded inverse associations with some respiratory diseases, tending to be stronger in older individuals (5). Therefore, in clinical practice, caution is needed when giving statins for primary cardiovascular prevention to older people. 1. Dublin S, Jackson ML, Nelson JC, Weiss NS, Larson EB, Jackson LA. Statin use and risk of community acquired pneumonia in older people: population based case-control study. BMJ. 2009 Jun 16;338:b2137. doi: 10.1136/bmj.b2137. 2. Goldstein MR, Mascitelli L, Pezzetta F. The double-edged sword of statin immunomodulation. Int J Cardiol 2009;135:128-30. 3. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009;150:858-68. 4. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Gross MD, Sadler M, et al. Serum total cholesterol and risk of hospitalization, and death from respiratory disease. Int J Epidemiol 1997;26:1191- 202. 5. Rafailidis PI, Matthaiou DK, Varbobitis I, Falagas ME. Use of ACE inhibitors and risk of community-acquired pneumonia: a review. Eur J Clin Pharmacol 2008;64:565-73. Competing interests: None declared |
|||
|
|
|||
|
Sascha Dublin, Assistant Investigator Group Health, Seattle, WA 98101, Michael L. Jackson, Jennifer C. Nelson, Noel S. Weiss, Eric B. Larson and Lisa A. Jackson
Send response to journal:
|
We agree that the association between acid-suppressing drugs and community-acquired pneumonia is of great interest. We have repeated our primary analyses of statin use and risk of pneumonia including use of acid -suppressing drugs as a covariate, and our results change very little. The adjusted odds ratio for current statin use and risk of pneumonia is 1.25 (95% confidence interval, 1.01 to 1.55), and for cases requiring hospitalization, it is 1.61 (95% confidence interval, 1.08 to 2.40). Competing interests: Jennifer C Nelson did consulting work for GlaxoSmithKline |
|||
|
|
|||
|
Konosuke Morimoto, Associate Professor, Department of Clinical Medicine Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Japan 852-8523, Motoi Suzuki
Send response to journal:
|
Dublin and colleagues conclude that statins have no beneficial effect on community acquired pneumonia [1]. This argument is misleading. Firstly, substantial proportions of study participants have COPD (case 31.1%, control 10.5%). Because of its impaired mucociliary clearance and lower airway bacterial colonization, the mechanism of developing pneumonia in emphysematous lung is distinct from that in normal lung. Statins’ anti-inflammatory effects may protect the lung from development of COPD [2]. Thus, the effect of statins on pneumonia should be biologically modified by the level of lung function. This group should be analyzed separately. Secondly, and even more importantly, the authors’ research question - “do statins prevent the development of pneumonia?” - is not biologically plausible. This question is not relevant to that of cellular biologists who have been researching statins and pneumonia/sepsis. Biological studies have established that statins have immunomodulatory and anti-inflammatory effects [3], yet their protective effect on infections is not reported. They are, rather, known to inhibit the pulmonary clearance of bacteria [4] and to suppress Fc receptor mediated phagocytosis by macrophages due to inhibition of prenilation of Rho-GTPases [5]. It is rational that statins increase the risk of respiratory infections. Then why are we interested in the effect of statins on pneumonia/sepsis? Statins are expected to inhibit excess inflammatory responses derived from infections and to reduce the mortality among pneumonia/sepsis cases. The idea is similar to that of corticosteroids. Nobody thinks that corticosteroids prevent the occurrence of pneumonia. Statins’ beneficial effect on pneumonia should be found after the development of infections, and therefore, the space for “healthy user effect” is limited. We believe that any additional epidemiological studies using clinical records do not improve our knowledge about this issue. The randomised controlled trials to reveal the effect of statins on reducing mortality among pneumonia/sepsis patients are surely needed. Konosuke Morimoto, MD PhD Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan Motoi Suzuki, MD MSc candidate, London School of Hygiene and Tropical Medicine, London, UK References 1. Dublin S, Jackson ML, Nelson JC, Weiss NS, Larson EB, Jackson LA. Statin use and risk of community acquired pneumonia in older people: population based case-control study. BMJ 2009: 338: b2137. 2. Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax 2006: 61(8): 729-734. 3. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation 2004: 109(21 Suppl 1): II18-26. 4. Fessler MB, Young SK, Jeyaseelan S, Lieber JG, Arndt PG, Nick JA, Worthen GS. A Role for Hydroxy-Methylglutaryl Coenzyme A Reductase in Pulmonary Inflammation and Host Defense. Am J Respir Crit Care Med 2004. 5. Morimoto K, Janssen WJ, Fessler MB, McPhillips KA, Borges VM, Bowler RP, Xiao YQ, Kench JA, Henson PM, Vandivier RW. Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J Immunol 2006: 176(12): 7657-7665. Competing interests: None declared |
|||
|
|
|||
|
Sascha Dublin, Assistant Investigator Group Health, Seattle, WA 98101, Michael L. Jackson, Jennifer C. Nelson, Noel S. Weiss, Eric B. Larson and Lisa A. Jackson
Send response to journal:
|
We appreciate Drs. Morimoto and Suzuki’s interest in our research. They note that basic science experiments have demonstrated anti- inflammatory effects of statins, which in theory provide more support for a beneficial impact of statins after infection develops than for a role for statins in preventing infection initially. However, we believe our research is important because it addresses a question on which others have already published indicating that statins do reduce the risk of pneumonia.(1-3) These studies were likely to have been affected by uncontrolled confounding, particularly “healthy user” bias,(4,5) and so further examination of this question using more detailed data may be helpful. Beyond the specific focus on statins and pneumonia occurrence, we believe that our study illuminates the potential bias that can occur when studies rely on large databases that lack important information about some potential confounders – in this case, measures relevant to “healthy user” bias.(5,6) We do not agree that “healthy user” bias is unlikely to play an important role in observational studies examining outcomes after the development of infection (e.g. mortality after pneumonia or sepsis). On the contrary, “healthy user” bias may be at least as problematic, if not more so, in such studies as it is in studies which examine the risk of developing infection. Groups at particularly high risk for mortality—such as nursing home residents, persons with serious cancer or other terminal illness, or immunosuppressed persons—may be less likely to receive statin therapy prior to developing infection, which could result in “healthy user” bias in studies of mortality or other outcomes following acute infection. In addition, Drs. Morimoto and Suzuki suggest that the presence of COPD may modify the association of statins with pneumonia risk and that statin use may prevent development of COPD. Thus, they propose that analyses of the statin-pneumonia association should be stratified by COPD status. However, we believe that this approach would not be appropriate. The reasoning relates to how one should handle confounders that are also intermediate variables. If we felt that statin use protected against the development of COPD to a substantial degree, then it would be inappropriate to adjust for or in any way stratify on the presence of COPD in the analysis of statin use in relation to pneumonia risk (or even to restrict the analysis to persons without COPD). This is because according to that conceptual model, COPD is an intermediate in the causal pathway between statin use and pneumonia, and adjusting for an intermediate in the causal pathway is not appropriate. However, because we are unable to sort out the temporal relationship between statin use and COPD, and as a result do not know which of these came first, it would be hazardous NOT to adjust for the presence of COPD, given that it has the potential to serve as a strong confounding variable. We hope this response answers your questions about our study. Sincerely, Sascha Dublin, MD, PhD Michael L. Jackson, PhD Jennifer C. Nelson, PhD Noel S. Weiss, MD, DrPH Eric B. Larson, MD, MPH Lisa A. Jackson, MD, MPH References 1. Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Gibson JE. Risk of community-acquired pneumonia and the use of statins, ace inhibitors and gastric acid suppressants: a population-based case-control study. Pharmacoepidemiol Drug Saf. Apr 2009;18(4):269-275. 2. Schlienger RG, Fedson DS, Jick SS, Jick H, Meier CR. Statins and the risk of pneumonia: a population-based, nested case-control study. Pharmacotherapy. Mar 2007;27(3):325-332. 3. van de Garde EM, Hak E, Souverein PC, Hoes AW, van den Bosch JM, Leufkens HG. Statin therapy and reduced risk of pneumonia in patients with diabetes. Thorax. Nov 2006;61(11):957-961. 4. Glynn RJ, Schneeweiss S, Wang PS, Levin R, Avorn J. Selective prescribing led to overestimation of the benefits of lipid-lowering drugs. J Clin Epidemiol. Aug 2006;59(8):819-828. 5. Jackson LA, Jackson ML, Nelson JC, Neuzil KM, Weiss NS. Evidence of bias in estimates of influenza vaccine effectiveness in seniors. Int J Epidemiol. Apr 2006;35(2):337-344. 6. Jackson LA, Nelson JC, Benson P, et al. Functional status is a confounder of the association of influenza vaccine and risk of all cause mortality in seniors. Int J Epidemiol. Apr 2006;35(2):345-352. Competing interests: Jennifer C Nelson did consulting work for GlaxoSmithKline |
|||