Are statins protective in patients with severe respiratory infections? Two new studies from EuropeArchived

In recent years there have been a series of arguments and findings suggesting that Statins (HMG-CoA reductase inhibitors) which used widely to lower cholesterol levels may also be important in reducing the risk associated with severe infective conditions.[1]  Because the statins also have important general anti-inflammatory properties it is suggested that the risk of conditions where the inflammatory response in itself is suspected to be harmful inflammation are important ( including severe respiratory infections) may be reduced by their use. Since statins are widely used on a long term basis this has these has been examined through series of observational studies of their impact on risk of severe infection and their outcome.[1]

Pre-Admission Statin Use and In-Hospital Severity of 2009 Pandemic Influenza A(H1N1) DiseaseBrett SJ, Myles P, Lim WS, et al. PLoS ONE 2011; 6(4): e18120The authors of this first study examined the clinical course of patients admitted to hospital influenza attributed to A(H1N1) 2009 infection in the 2009 pandemic  according to whether or not they were taking statins at the time of admission. Methodologically, the study design used by the authors was a retrospective case-control study, performed using the United Kingdom Influenza Clinical  Information Network (FLU-CIN) database. The database fraction examined contained detailed information on over 1500 patients admitted to participating hospitals with confirmed 2009 influenza A(H1N1)2009 infection between April 2009 and January 2010. The analysis was performed for those older than 34 years. A univariate statistical analysis included factors affecting progression to severe outcome like high dependency of intensive care unit level support and death. In addition, multivariable logistic regression models were used examining age, sex, obesity and ‘indication for statin’ as variables.   In brief the study did not find a statistically significant association between pre-admission statin use and severity of outcome after adjustment for age and sex only [adjusted OR: 0.81; n=571]. Moreover, after adjustment for age, sex, obesity and ‘indication for statin’, the association between pre-admission statin use and severe outcome was still not statistically significant. However the authors noted that the point estimates they calculated were compatible with a small but clinically significant protective effect of statin use [adjusted OR: 0.72]. In light of these findings the authors conclude that, in the group of patients they selected hospitalized with 2009 pandemic influenza A(H1N1) infection, a significant beneficial effect of pre-admission statin use on the in-hospital course of illness was not identified.

Effect of statin treatment on short term mortality after pneumonia episode: cohort studyDouglas I, Evans S and Smeeth LBMJ 2011; 342:d1642 This larger study tried to clarify whether statins protect against all-cause mortality after a diagnosis of pneumonia. To do this, the authors designed a cohort study using a propensity score based method to control for differences between people prescribed and not prescribed statins. The data used were from the large United Kingdom Health Improvement Network database, which is a repository of electronic primary care medical records of more than 6 million patients. The study matched every patient starting treatment with a statin between 1995 and 2006 (total of nearly n=130,000) with up to five non-statin users. Similarly examined were about 9000 patients that had a recorded diagnosis of pneumonia nearly 1400 of whom were already using a statin. The main outcome measured was all-cause mortality within 6 months of the initial diagnosis of pneumonia.  The results found that, among users and non-users of statins with comparable propensity scores, 10.1% (95/942) of statin users and 19% (686/3615) of statin non-users died on the day that pneumonia was diagnosed. In the following 6 month period, 12.9% (109/847) of statin users died compared with 19.7% (578/2927) of statin non-users. The authors calculated that the resulting adjusted hazard ratio of 0.67 would mean in observed benefits during clinical practice that 15 patients would need to be treated with a statin for 6 months after pneumonia to prevent one extra death. As a result, compared with people who were not taking statins, the risk of dying in the 6 month period after pneumonia was substantially lower among people who were already established on a long-term statin treatment when the pneumonia occurred.  A caveat of this conclusion pointed out by the authors is the difficulty of determine whether some or all of this protective effect would be obtained if statin treatment began when a patient first developed pneumonia. 

ECDC Comment (5th May 2011):

Statins (or HMG-CoA reductase inhibitors) are a class of drug used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases (CVD), and statins are widely used in the prevention of these diseases. Randomized controlled trials suggest they are most effective in those already suffering from cardiovascular disease (secondary prevention), but they are also advocated and used extensively in those without previous CVD but with elevated cholesterol levels and other risk factors (such as diabetes and high blood pressure) that are associated with increased individual risk.

An editorial accompanying the Douglas et al article is cautious, pointing out the difficulty of excluding that there is a ‘healthy user’  effect  confounding by unmeasured variables such as better overall health in statin users such as frailty or socioeconomic status. Such information is usually unavailable in administrative databases and might explain the observed association between statin use and pneumonia. Even with the best statistics observational, retrospective and meta-analytical studies cannot eliminate such confounding biases.  Also observational studies examine the impact of continuous pre-admissoin statin use rather than the practical intervention of starting statins when severe infection is suspected or diagnosed.  Hence the editorial, the Douglas article and ECDC would argue the limits of these observational studies and that what is needed is a randomised controlled trial of use of statins by those developing severe respiratory infections.[1,2] The results of such a definitive study would be important as they would alter practice and potentially save many lives especially resulting from the acute respiratory distress syndrome observed with A(H1N1)2009.[3]  This is also important since though statins are generally considered safe they have rare but severe adverse effects, particularly muscle damage and should not be used without due reason.[4]  Arguably such a trial should have been undertaken during the 2009 pandemic. However given the enduring incidence of acute respiratory distress syndrome with seasonal influenza with A(H1N1)2009 as a seasonal influenza this trial may be possible in Europe through networks of intensive care units.[5,6]

References: 

1. Chopra V & Flanders S  Statins and pneumonia BMJ 2011;342:d1907 doi: 10.1136/bmj.d1907 http://www.bmj.com/content/342/bmj.d1907.full
2. Douglas I, Evans S, Smeeth L  Effect of statin treatment on short term mortality after pneumonia episode: cohort studyBMJ 2011;342:d1642 doi:10.1136/bmj.d1642
3. WHO Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, Clinical Aspects of Pandemic 2009 Influenza A (H1N1) Virus Infection N Engl J Med 2010 362: 1708-17
4. Armitage J. The safety of statins in clinical practice. Lancet2007;370:1781-90.
5. ECDC Risk Assessment Seasonal influenza 2010–2011 in Europe (EU/EEA countries)January 2011
6. Thomson G, Nicoll A. Responding to new severe diseases – the case for routine hospital surveillance and clinical networks in Europe. Euro Surveill. 2010;15(49):pii=19745.