In this meta-analysis, we systematically reviewed 41 studies published during 2001–2012 on the association between statins use and infectious disease-related mortality. Overall, most observational studies found that statins were associated with lower mortality from infectious disease. Our pooled OR among these observational studies was similar to those in 3 previous meta-analyses by Tleyheh et al. 
, Surinder Janda et al. 
and Bjorkhem et al 
. However, we did not find conclusive evidence on this beneficial effect in clinical trials. In subgroup analysis, statins use was associated with lower 30-day, 90-day, and in-hospital mortality, but not with long-term mortality. Statins use was associated with lower mortality from bacteremia, pneumonia, and sepsis, but not with mortality from other infections and intensive care unit (ICU) patients.
We found that the magnitude of the association between statins use and infectious disease-related mortality tended to decrease with time, i.e. strongest for 30-day mortality followed by 90-day mortality and in-hospital mortality, and null for long-term mortality. This time trend suggests that the beneficial effect (if exists) of statins to lower infectious-disease related mortality may be short-term only. However, this time trend should be interpreted with caution due to potential misclassification of death outcome based on medical records, especially for in-hospital mortality. The substantial variation in hospitalization length posed a big challenge on estimating and interpreting pooled effect size of statins use, which can be confirmed by heterogeneity test within hospitalization period subgroup (I2 is 78%, P<0.0001).
We also found the magnitude of the association between statins use and mortality was strongest in patients with bacteremia. This suggests that the protective effect of statins may be superior for bacteremia than other types of infection. Alternatively, this may be partially explained by less use of antibiotics in patients with bacteremia: only 1 out of 6 studies on bacteremia patients, reported antibiotics use before the admission to hospital or during hospital, compared with most studies among patients with other types of infections (such as 100% in Kwong study and 20% in Yende study).
In this analysis, we found the reported effects of statins use varied strikingly by study design. Observational studies consistently supported the beneficial effect of statins in lowering infection disease mortality, while all RCTs showed null effects. Though RCTs often provide more valid results, these 10 RCTs can not completely outweigh the evidence on the beneficial effect of statins from observational studies. These “null-effect” RCTs are often criticized for small sample size 
. These criticisms usually are based on two factors. Firstly, the formal sample size calculations that compute the numbers of patients required prospectively, as if the trial had not yet been carried out. Secondly, the true power calculated when trial is over. Based on alpha level, sample size and actual rates of primary events among control and experimental patients, we did post-hoc analysis by re-calculating the power of 8 negative trials in 10 RCTs and found that only one trial’s retrospective power is bigger than 80% (Serrugs 81.5%), and all other 7 ones had power smaller than 80% (Fellstrom 8.9%, Kjekshus 25.5%, Wanner 14.3%, Stegmayr 47.3%, Holdaas 70.9%, Makris 60.5%). This under-power might be caused by the over-estimated event rate in control group and/or risk reduction level. In these 7 trials, investigator assumed the statins may reduce the risk of primary outcome by 20% to 50%, but the truth is the observed related risk reduction is obviously lower than 20% except for Makris study. This result indicated that the evidence to make a negative conclusion of statins is not sufficient and suggested retrospective sample size calculation is needed so as to add more representative patients in the trial. The sample size recalculation also showed that we still need 3–10 times of current number in each RCT to get positive result. Beside that, almost all these RCTs enrolled the patients who had existing cardiovascular disease. This could lead to misclassification of infection-related death, because of the difference between the primary and secondary infection. In addition, infection-related mortality is not a primary outcome in these studies on cardiovascular outcomes, and thus might not be measured accurately or appropriately.
Unexpectedly, we did not find significantly protective effect of statins against infection-related death in the 9 studies that focused on severe patient or patients admitted to ICU 
respectively in bacterenia (0.38, 0.15–1.01), in sepsis (0.65, 0.29–1.44), in pneumonia (0.95, 0.84–1.07), but not in other infections subgroup (0.64, 0.44–0.92). One explanation can be that those severe patients usually have many severe complications 
. These complications often lead to adverse outcome and significantly increase the risk of death, which may dim the moderate protective effects of statins. Most interested us is that the result from only one clinical trial in these 9 studies provided evidence supporting that statins might affect the course of critically ill patients and decrees the ICU mortality 
. Considering the differences in study design and implement between the observational studies and clinical trials, the most probable reason for this opposite result is the opportune moment of using statins. Patients in the observational studies might have already been using statins to treat high cholesterol (prevalent users). In clinical trials, however, statins were randomized to two groups after patients being recruited (new users). Another reason is the time difference between the progresses of critically ill and the onset time of statins. The immunomodulatory effects of statins can occur within 24 hours and thus acute treatment may down-regulate the level of pro-inflammatory cytokines 
. That is why the acute curative effect in clinical trial is better than long-term effect in observational studies. These findings suggest that long-term use of statins may not be able to protect severe ICU patients against death from infection as common or less severe patients. However, we need more evidence from RCTs to confirm the acute effect of statin in reducing the ICU mortality among ICU patient.
The moderate heterogeneity across the included 41 studies may come from 2 main sources: study population and methodology. The significantly lower I2 statistics in Europe studies than that in studies from other continents revealed the substantial difference in study population (e.g. ethnics and study locations), especially for limited source from Asia and Oceania population. For methodology, the low I2 statistics in clinical trails indicated better quality control and more reliable results than observational studies. Other methodological heterogeneity included type of patients, type of infection, and dose of statins use across different studies.
This meta-analysis had several strengths. First, we included much more RCTs than previous reviews (8 vs. 0 in Tleyjeh et al.’s, 0 in Kopterides’, 0 in Bjorkhem and 1 in Janda et al.’s). Inclusion of these RCTs can substantially improve the validity of our analysis. Secondly, we conducted subgroup analyses by 4 important factors, i.e. study design, types of infections, outcome measures, and study locations. These subgroups analyses can help us to better assess the sources of variation or inconsistency of findings, and also better understand the specific subgroups of patients that may benefit more or less from statins. Thirdly, we assessed the quality of each study by well-established score scales (NOS and Jadad Score). The relatively high quality of most included studies can improve our interpretation of the pooled effect estimates for stains use.
Several limitations of this meta-analysis needed to be mentioned. First, we only included electronic database and published articles. Both Egger’s test and asymmetry of funnel plotpotential suggested the existence of publication bias. Second, this meta-analysis included more observational studies (n
31) than clinical trials (n
10). We did not assign different weighting to included studies based on the validity of their study design (RCT vs. observational studies). Third, 6 of the 10 included RCTs were designed to test the effect of statins on cardiac outcomes rather than infectious disease-related mortality. So the validity of estimated associations from these RCTs may be comprised. Fortunately, several ongoing clinical trials 
(ID: NCT00528580, NCT00979121, NCT00702130, NCT00676897, http://www.clinicaltrials.gov
) aim to specifically examine the potential clinical benefit of statins in sepsis. We expect these studies will yield more conclusive evidence on this important topic in near future.
Based on this meta-analysis, we conclude that statins are associated with a lower risk of death in patients with infectious diseases in observational studies, but less in clinical trials. This beneficial effect tends to be short-term only. It seems to be stronger in patients with bacteremia but less for ICU patients with severe infection. More worldwide clinical trials specifically on this topic are urgently needed to provide more conclusive guideline for clinical practice.