Statin use and risk of community acquired pneumonia in older people: population based case-control study
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b2137 (Published 16 June 2009) Cite this as: BMJ 2009;338:b2137
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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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Competing interests: No competing interests
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
Nicholas Moore, MD, PhD, FRCP(Edin)
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 ?
Competing interests: No competing interests
Re: We are not expecting statins to prevent pneumonia.
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
Competing interests: No competing interests