Effect of statin therapy on mortality from infection and sepsis: a meta-analysis of randomized and observational studies
© Wan et al.; licensee BioMed Central Ltd. 2014
Received: 24 December 2013
Accepted: 25 March 2014
Published: 11 April 2014
Observational data have suggested that statin therapy may reduce mortality in patients with infection and sepsis; however, results from randomized studies are contradictory and do not support the use of statins in this context. Here, we performed a meta-analysis to investigate the effects of statin therapy on mortality from infection and sepsis.
We searched electronic databases (PubMed and Embase) for articles published before November 2013. Randomized or observational studies reporting the effects of statin therapy on mortality in patients with infection or sepsis were eligible. Randomized and observational studies were separately pooled with relative risks (RRs) and random-effects models.
We examined 5 randomized controlled trials with 867 patients and 27 observational studies with 337,648 patients. Among the randomized controlled trials, statins did not significantly decrease in-hospital mortality (RR, 0.98; 95% confidence interval (CI), 0.73 to 1.33) or 28-day mortality (RR, 0.93; 95% CI, 0.46 to 1.89). However, observational studies indicated that statins were associated with a significant decrease in mortality with adjusted data (RR, 0.65; 95% CI, 0.57 to 0.75) or unadjusted data (RR, 0.74; 95% CI, 0.59 to 0.94).
Limited evidence suggests that statins may not be associated with a significant reduction in mortality from infection and sepsis. Although meta-analysis from observational studies showed that the use of statins was associated with a survival advantage, these outcomes were limited by high heterogeneity and possible bias in the data. Therefore, we should be cautious about the use of statins in infection and sepsis.
Sepsis is a complex syndrome caused by an uncontrolled systemic inflammatory response to infection. The manifestations of sepsis are multifaceted and ultimately result in multi-organ dysfunction. When accompanied by evidence of hypoperfusion or dysfunction of at least one organ system, sepsis progresses to “severe sepsis”. Moreover, if accompanied by hypotension or a need for vasopressors, the conditions further worsen to “septic shock”. Increasing severity correlates with increasing mortality, which increases from 25% to 30% for severe sepsis up to 40% to 70% for septic shock, and even if patients survive the acute phase of sepsis, clinical data indicate that surviving patients have higher mortality rates than patients who have not had sepsis[2–5].
Statins are used to lower cholesterol levels, and their cardiovascular benefits are widely accepted in medical practice. In addition, statins also have a wide variety of properties that are independent of their lipid-lowering ability, termed “pleiotropic effects”[6–8]. Many observational studies have demonstrated a significant protective effect from statins in patients with sepsis, and previous meta-analysis showed a similar outcome[9, 10]. However, at the time of that analysis, no appropriate studies describing the therapeutic effects of statins in randomized controlled trials had been published; therefore, we do not know whether statins truly have beneficial effects, or whether these results were observed due to the bias effect. One meta-analysis evaluating the prophylactic effects of statins found that statins did not reduce the risk of infections. However, this meta-analysis included only randomized controlled trials (RCTs) and did not describe the therapeutic effects of statins.
Because of the limited quantity and possible heterogeneity of RCTs, we also searched relevant observational studies as a supplement. Thus, in this manuscript, we present a meta-analysis of randomized and observational studies to investigate the effects of statin therapy on mortality from infection and sepsis.
Materials and methods
The systematic review and meta-analysis were performed according to the recently published Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Ethical approval and patient consent are not required since this is a meta-analysis of previously published studies.
Literature search and inclusion criteria
Electronic databases, including PubMed and Embase were searched from inception to November 2013 to identify relevant studies. We used a combination of keywords related to the type of statin (“hydroxymethylglutaryl coenzyme A reductase inhibitors” or “anticholesteremic agents” or “statin” or “simvastatin” or “rosuvastatin” or “pravastatin” or “atorvastatin” or “fluvastatin” or “cerivastatin” or “pitavastatin” or “lovastatin”) and the type of infection-associated disease (“infection” or “sepsis” or “bacteremia” or “pneumonia”). An English language restriction was imposed. We also evaluated the references in relevant review articles and meta-analyses to identify other potentially eligible studies. An RCT or an observational study was included if it met the following criteria: adult patients experienced infection or sepsis, statins compared with a control and data available on the mortality.
Data extraction and quality assessment
Data were extracted independently by two investigators (YDW and TWS). Discrepancies were resolved by consensus or a third author’s (FXG) adjudication. We separately extracted and pooled data from RCTs and observational studies. For RCTs, the following data were abstracted from each study: characteristics of the studies, characteristics of the included patients and outcomes of the studies. For observational studies only, we also extracted types of effect sizes (odds ratio (OR) or hazard ratio (HR)), adjusted covariates, data sources, financial support, study period and conclusion of the trials (see Additional files1,2 and3). For RCTs, the primary endpoint was mortality (in-hospital mortality and 28-day mortality). The secondary endpoints were the rates of mechanical ventilation (MV) usage, ICU admission and newly developed severe sepsis. For observational studies, we pooled the mortality (in-hospital mortality, 15-day mortality, 30-day mortality and 90-day mortality) with adjusted and unadjusted data.
The methodological quality of RCTs was evaluated using the Jadad scale[13, 14]. Because the observational studies were only used as a supplement for the RCTs, we did not evaluate the quality of the observational studies.
In examining the associations between statins and infection/sepsis mortality, results were expressed as relative risks (RRs) with 95% confidence intervals (CIs); risk ratios (RRs), ORs and HRs were included as eligible RRs without distinction because each provided effect sizes of similar magnitude. Heterogeneity across trials was assessed using a standard chi-squared test, with significance being set at P <0.10. Heterogeneity was also assessed by means of the I2 statistic, with significance being set at I2 > 50%. The random effects model was used for statistical analysis due to wide clinical and methodological variability across the trials. We further conducted subgroup analyses to explore possible explanations for heterogeneity. Publication biases were evaluated using Funnel plots and Egger’s tests. Statistical analysis was performed using STATA 12.0 (Stata Corp, Tong-Wen Sun, Zhengzhou, Henan province, China). A P- value of less than 0.05 was considered to represent statistical significance.
Study identification and selection
Main characteristics of RCTs included in the meta-analysis of statins for infection and sepsis
No. total (statins/non-statins)
Novak V et al./2009
Double-blind placebo controlled randomized clinical trial.
Not receiving statin therapy during the three months preceding the index admission, within 12 h of admission to a general medical ward with a suspected or documented bacterial infection, and prescribed intravenous antibiotics therapy by their physicians.
40 mg of simvastatin orally immediately following enrollment, and daily 20 mg of simvastatin after that, until hospital discharge or the development of severe sepsis.
Kruger PS et al./2011
Prospective randomized double-blind placebo-controlled trial
Patients with any of 97 potential infection-related diagnoses; admitted to both the general wards or the intensive care unit; preexisting statin therapy and the treating physician prepared to either continue or discontinue this therapy
20 mg of atorvastatin orally or via nasogastric tube at the earliest opportunity and was continued daily for the duration of hospital admission up to a maximum of 28 days.
Patel JM et al./2012
phase II randomized double-blind placebo-controlled trial
Documented new proven or suspected infection and the presence of any two of the signs and symptoms of infection (white blood cell >11 or <4 × 109/L, temperature >38°C or <36°C, heart rate >90 bpm, or respiratory rate >20/minute) for less than 24 hours.
Atorvastatin 40 mg daily was administered orally within 24 hours of randomization. Treatment continued for the duration of their hospital stay or 28 days if earlier
Kruger P et al./2013
Phase II, prospective, randomized, double-blind, placebo controlled trial
Critically ill, had strongly suspected or proven infection, fulfilled three or more of the features of systemic inflammatory response syndrome within the 48 hours and had an organ dysfunction of less than 24 hours duration
Take statins more than two weeks prior to hospital admission; Atorvastatin 20 mg was orally or via nasogastric tube given following randomisation then continued daily until Day 14 or until death or discharge from the intensive care unit
Papazian L et al./2013
Randomized, placebo-controlled, double-blind parallel-group trial
Received mechanical ventilation in the intensive care unit for at least two days and had suspected ventilator-associated pneumonia, statins therapy started on the same day as antibiotic therapy
Simvastatin 60 mg given via a nasogastric tube or orally from study inclusion to ICU discharge, death or Day 28
Outcome data of RCTs included in the meta-analysis of statin for infection and sepsis
Mean age (y) statin/ non-statin (mean ± SD)
Male sex (%) statin/non-statin
Need for MV or ICU admission
Severity of illness statin/non-statin (mean ± SD)
Length of hospital stay statin/non-statin
New development of severe sepsis
Novak V et al./2009
66.0 ± 17.2/72.7 ± 13.8
3/42 vs 5/41
APACHE II score (11.2 ± 4.3/8.9 ± 4.8)
0/42 vs 0/41
4 days (IQR 3 to 6)/4 days (IQR 2 to 6)
2/42 vs 2/41
Kruger PS et al./2011
68.2 ± 12.7/68.5 ± 11.9
13/75 vs 11/75
6/75 vs 4/75
7 days (IQR 4 to 12)/6 days (IQR 4 to 11)
Patel JM et al./2012
62.8 ± 21.2/64.0 ± 15.6
0/49 vs 2/51
APACHE II score (11.8 ± 5.6/11.9 ± 6.0)
2/49 vs 2/51
5 days (IQR 3 to 13)/6 days (IQR 4 to 12)
2/49 vs 12/51
Kruger P et al./2013
58 (44 to 67)/64 (50 to 75)*
123/123 vs 127/127
APACHE II score (22.1 ± 7.7/23.5 ± 7.8)
16/123 vs 23/127
12/123 vs 22/127
18.3 days (IQR 11.0 to 38.7)/22.7 days (IQR 12.4 to 37.0)
Papazian L et al./2013
60.0 ± 16.0/59.0 ± 17.0
146/146 vs 138/138
SOFA score (7.2 ± 3.6/6.7 ± 2.9)
43/146 vs 38/138
31/146 vs 21/138
37 days (IQR 21 to 59)/35 days (IQR 22 to 62)
Methodological quality assessment (risk of bias) of included studies by Jadad scale
Randomization (0 to 2 point(s))
Blinding (0 to 2 point(s))
Withdrawals and dropouts (0 to 1 point)
Total score (0 to 5 point(s))
No randomization or inappropriate randomization (0 point)
Described as randomized (1 point)
Method of randomization was described and appropriate (2 point)
No blind or inappropriate method of blinding (0 point)
Described as double blind (1 point)
Method of double blinding was described and appropriate (2 point)
Did not describe the follow-up (0 point)
A description of withdrawals and dropouts (1 point)
Novak V et al./2009
Kruger PS et al./2011
Patel JM et al./2012
Kruger P et al./2013
Papazian L et al./2013
Result from RCTs
Based on a meta-analysis of three studies[17–19] with 335 participants, there was no difference in the rates of mechanical ventilation (MV) usage or ICU admission for patients receiving statins (16/166) and placebo (18/169; RR, 0.94; 95% CI, 0.50 to 1.78), with low heterogeneity between studies (I 2 = 0.0%, P = 0.41). We also performed a meta-analysis of the rate of newly developed severe sepsis[17, 19] and found that compared with placebo (14/92), statins (4/91) did not have a beneficial effect (RR, 0.37; 95% CI, 0.07 to 1.99); significant heterogeneity was found among these two studies (I 2 = 50.8%; P = 0.15; Figure 2B).
Results from observational studies
Subgroup analyses of observational studies
Total sample size
RR (95% CI)
Heterogeneity I 2
0.65 (0.57 to 0.75)
Type of effect size
0.67 (0.57 to 0.78)
0.59 (0.38 to 0.91)
Type of mortality
0.72 (0.54 to 0.96)
0.93 (0.73 to 1.19)
0.57 (0.48 to 0.69)
0.07 (0.01 to 0.51)
0.18 (0.04 to 0.78)
0.64 (0.48 to 0.85)
0.65 (0.55 to 0.77)
0.49 (0.29 to 0.83)
0.70 (0.61 to 0.80)
0.75 (0.64 to 0.87)
0.43 (0.26 to 0.73)
0.51 (0.33 to 0.76)
0.66 (0.56 to 0.77)
0.61 (0.45 to 0.81)
Adjusted by propensity score
0.80 (0.70 to 0.91)
0.49 (0.38 to 0.64)
In this meta-analysis, the beneficial effects of statin treatment on mortality resulting from infection and sepsis were not found from RCTs and in one of the subgroups from the set of observational studies; these data were quite different from previously reported meta-analyses[9, 10]. However, while our meta-analysis of observational studies yielded a contradictory outcome, this may have resulted from the high heterogeneity and possible publication bias associated with these observational studies. This may indicate that the “pleiotropic effects” of statins may not be suitable for treatment of infection and sepsis.
The main findings from our meta-analysis of RCTs were inconsistent with those of observational studies. A major reason for this inconsistency may be the methodological differences between RCTs and observational studies. Observational studies are always at risk of unmeasured confounding variables, which are inherent to the study design and cannot be avoided. Among these biases, “healthy user” effects are a major source of such potentially confounding variables. In a population-based prospective cohort study by Majumdar et al., this assertion was supported by a propensity score. They observed that statin users were more likely to be former smokers and have up-to-date immunizations for pneumococcus and influenza and less likely to need advanced directives. Another possible explanation is that most observational studies primarily focus on statins as prophylaxis whereas the RCTs seem to evaluate statins as therapy. In observational studies, most patients receive statin therapy before their inpatient hospital course whereas RCT patients receive statin therapy after the onset of sepsis. Except for “healthy user” effects, other biases also exist in observational studies, including socioeconomic and health statuses and so on. Such biases are not present in meta-analyses of data from only RCTs. Based on this perspective, our meta-analysis of RCTs only demonstrated that statins have no therapeutic effects on infection and sepsis, and this is probably the more realistic result. Another limitation of meta-analyses of observational studies was the significant heterogeneity. We performed a subgroup analysis; however, we were still unable to completely remove heterogeneity. This may indicate that the most likely cause of heterogeneity was the type of statin therapy (different doses and types of statins) and the severity of the various infections (the APACHE II scores varied considerably across trials), which could not be adjusted for because of an insufficient amount of data. In spite of the disadvantage of observational studies, observational studies do provide valuable information. Observational studies are crucial to understanding how clinical trial-defined therapies are incorporated into routine clinical practice. In this manner, effectiveness as well as potentially uncommon adverse effects of statins can be examined over extended periods of time in “real-world” populations.
To the best of our knowledge, this is the first meta-analysis to explore the effects of statin therapy on mortality from infection and sepsis with high-quality RCT and observational data. Most previous meta-analyses have focused on observational studies[9, 10] because of the limitations of slow publication associated with RCTs. A meta-analysis conducted in 2010 by Janda et al., which included 19 observational studies and 1 RCT, found that statins provided a protective effect; however, we did not include this RCT because they only included patients after aneurysmal subarachnoid hemorrhage and infections were related to surgical complications. Additionally, the population did not meet our standards, and the researchers investigated preventive effects of statins instead of treatment effects. Additionally, in the meta-analysis by Janda et al., they found an asymmetrical funnel plot, but did not observe significant publication bias as assessed with Egger’s test (P = 0.052). In contrast, our analysis included eight more studies, and the publication bias was significant, exhibiting both an asymmetrical funnel plot and a significant Egger’s test result (P = 0.025). Uncorrectable heterogeneity, established publication bias, residual confounding variables, and healthy-user bias have always been deep concerns of investigators. These issues were examined more thoroughly in our meta-analysis, which had the greatest number of observational studies. Fortunately, our meta-analysis of RCTs removed most of these problems, and our results may provide some insights into further studies. More recently, a meta-analysis including five RCTs found statin therapy has no effect on mortality in septic patients. In order to control the overall quality, we excluded one conference paper included in this meta-analysis, and included one more large RCT and 27 observational studies[22–48]; thus, we found an interesting contradictory outcome between RCTs and observational studies.
Our meta-analysis of observational studies verified several previously proposed hypotheses suggested by RCTs. According to a study by Kruger et al., for the cohort as a whole there was no statistically significant difference in mortality. However, atorvastatin therapy in prior statin users was associated with lower baseline interleukin (IL)-6 levels and a statistically significant improvement in 28-day mortality, but this survival advantage did not appear in patients with no prior statin use. Similar outcomes were observed by Shyamsundar et al.. Therefore, Kruger et al. hypothesized that prior continued statin therapy may be associated with a significant special biological effect in critically ill patients with infection. It was further hypothesized that some of the pathways associated with the inflammatory response caused by infection and sepsis could be modulated by prior statin therapy. In order to test this theory, we conducted a special subgroup analysis with current statin users and former statin users. We observed that no clear differences were found between these groups, and current statin users still exhibited a survival advantage. We also conducted a novel subgroup analysis related to financial support, which was not investigated in previous meta-analyses. We expected that sources of financial support may be an important bias and may explain our observed publication bias. Unfortunately, the results were not consistent with our initial hypothesis, and there was no clear difference between studies with and without financial support.
Limitations of the study
One important limitation of this meta-analysis was the low number and sample size of RCTs, which made it difficult to carry out a subgroup analysis, and, thus, it was under-powered to detect a completely reliable conclusion. One important reason for the small sample size may have been the high refusal rate and slow recruitment[17–19] associated with RCTs. Another limitation to our meta-analysis was that we were unable to assess the impact of statins on other clinically meaningful end points because of the unsuitable pooled format of the data, such as length of hospital stay.
According to our analysis, the limited evidence suggested that statins may not be associated with a significant reduction in mortality from infection and sepsis. Though meta-analysis from observational studies showed a survival advantage of statins, these results were limited by the high heterogeneity and possible bias of the observational studies used in the analysis. Therefore, we should be cautious about the use of statins in patients with infection and sepsis.
Limited evidence from meta-analysis of RCTs suggested that statins may not be associated with a significant reduction in mortality from infection and sepsis.
Meta-analysis of observational studies showed the use of statins was associated with a survival advantage. However, these outcomes were limited by high heterogeneity and possible bias.
We should be cautious about the use of statins in patients with infection and sepsis.
- 95% CI:
95% Confidence intervals
- APACHE II:
Acute Physiology and Chronic Health Evaluation II
Randomized controlled trial
This study was supported by the National Natural Science Foundation of China (Grant No. 81370364), Innovative Investigators project grant from the Health Bureau of Henan Province, Program Grant for Science & Technology Innovation Talents in Universities of Henan Province (2012HASTIT001), Henan Provincial Science and Technology Achievement Transformation Project (122102310581), Henan Province of Medical Scientific Province & Ministry Research Project (201301005), Henan Province of Medical Scientific Research Project (201203027), China.
- Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 2001: 1250-1256.View ArticleGoogle Scholar
- Lever A, Mackenzie I: Sepsis: definition, epidemiology, and diagnosis. BMJ 2007, 335: 879-883. 10.1136/bmj.39346.495880.AEPubMed CentralView ArticlePubMedGoogle Scholar
- Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001, 29: 1303-1310. 10.1097/00003246-200107000-00002View ArticlePubMedGoogle Scholar
- Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003, 348: 1546-1554. 10.1056/NEJMoa022139View ArticlePubMedGoogle Scholar
- Perl TM, Dvorak L, Hwang T, Wenzel RP: Long-term survival and function after suspected gram-negative sepsis. JAMA 1995, 274: 338-345. 10.1001/jama.1995.03530040066043View ArticlePubMedGoogle Scholar
- Almog Y: Statins, inflammation, and sepsis: hypothesis. Chest 2003, 124: 740-743. 10.1378/chest.124.2.740View ArticlePubMedGoogle Scholar
- Jerwood S, Cohen J: Unexpected antimicrobial effect of statins. J Antimicrob Chemother 2008, 61: 362-364.View ArticlePubMedGoogle Scholar
- Arnaud C, Mach F: Potential antiinflammatory and immunomodulatory effects of statins in rheumatologic therapy. Arthritis Rheum 2006, 54: 390-392. 10.1002/art.21757View ArticlePubMedGoogle Scholar
- Tleyjeh IM, Kashour T, Hakim FA, Zimmerman VA, Erwin PJ, Sutton AJ, Ibrahim T: Statins for the prevention and treatment of infections: a systematic review and meta-analysis. Arch Intern Med 2009, 169: 1658-1667. 10.1001/archinternmed.2009.286View ArticlePubMedGoogle Scholar
- Janda S, Young A, Fitzgerald JM, Etminan M, Swiston J: The effect of statins on mortality from severe infections and sepsis: a systematic review and meta-analysis. J Crit Care 2010, 25: 656-657.View ArticlePubMedGoogle Scholar
- van den Hoek HL, Bos WJ, de Boer A, van de Garde EM: Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ 2011, 343: d7281. 10.1136/bmj.d7281PubMed CentralView ArticlePubMedGoogle Scholar
- Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009, 151: 264-269. W64 10.7326/0003-4819-151-4-200908180-00135View ArticlePubMedGoogle Scholar
- Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996, 17: 1-12. 10.1016/0197-2456(95)00134-4View ArticlePubMedGoogle Scholar
- Kjaergard LL, Villumsen J, Gluud C: Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001, 135: 982-989. 10.7326/0003-4819-135-11-200112040-00010View ArticlePubMedGoogle Scholar
- Davies HT, Crombie IK, Tavakoli M: When can odds ratios mislead? BMJ 1998, 316: 989-991. 10.1136/bmj.316.7136.989PubMed CentralView ArticlePubMedGoogle Scholar
- Egger M, Davey SG, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315: 629-634. 10.1136/bmj.315.7109.629PubMed CentralView ArticlePubMedGoogle Scholar
- Novack V, Eisinger M, Frenkel A, Terblanche M, Adhikari NK, Douvdevani A, Amichay D, Almog Y: The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial. Intensive Care Med 2009, 35: 1255-1260. 10.1007/s00134-009-1429-0View ArticlePubMedGoogle Scholar
- Kruger PS, Harward ML, Jones MA, Joyce CJ, Kostner KM, Roberts MS, Venkatesh B: Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. Am J Respir Crit Care Med 2011, 183: 774-781. 10.1164/rccm.201006-0955OCView ArticlePubMedGoogle Scholar
- Patel JM, Snaith C, Thickett DR, Linhartova L, Melody T, Hawkey P, Barnett AH, Jones A, Hong T, Cooke MW, Perkins GD, Gao F: Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial). Crit Care 2012, 16: R231. 10.1186/cc11895PubMed CentralView ArticlePubMedGoogle Scholar
- Kruger P, Bailey M, Bellomo R, Cooper DJ, Harward M, Higgins A, Howe B, Jones D, Joyce C, Kostner K, McNeil J, Nichol A, Roberts MS, Syres G, Venkatesh B: A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med 2013, 187: 743-750. 10.1164/rccm.201209-1718OCView ArticlePubMedGoogle Scholar
- Papazian L, Roch A, Charles PE, Penot-Ragon C, Perrin G, Roulier P, Goutorbe P, Lefrant JY, Wiramus S, Jung B, Perbet S, Hernu R, Nau A, Baldesi O, Allardet-Servent J, Baumstarck K, Jouve E, Moussa M, Hraiech S, Guervilly C, Forel JM: Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA 2013, 310: 1692-1700. 10.1001/jama.2013.280031View ArticlePubMedGoogle Scholar
- Rothberg MB, Bigelow C, Pekow PS, Lindenauer PK: Association between statins given in hospital and mortality in pneumonia patients. J Gen Intern Med 2012, 27: 280-286. 10.1007/s11606-011-1826-2PubMed CentralView ArticlePubMedGoogle Scholar
- Yende S, Milbrandt EB, Kellum JA, Kong L, Delude RL, Weissfeld LA, Angus DC: Understanding the potential role of statins in pneumonia and sepsis. Crit Care Med 2011, 39: 1871-1878. 10.1097/CCM.0b013e31821b8290PubMed CentralView ArticlePubMedGoogle Scholar
- Forrest GN, Kopack AM, Perencevich EN: Statins in candidemia: clinical outcomes from a matched cohort study. BMC Infect Dis 2010, 10: 152. 10.1186/1471-2334-10-152PubMed CentralView ArticlePubMedGoogle Scholar
- Thomsen RW, Riis A, Kornum JB, Christensen S, Johnsen SP, Sorensen HT: Preadmission use of statins and outcomes after hospitalization with pneumonia: population-based cohort study of 29,900 patients. Arch Intern Med 2008, 168: 2081-2087. 10.1001/archinte.168.19.2081View ArticlePubMedGoogle Scholar
- Donnino MW, Cocchi MN, Howell M, Clardy P, Talmor D, Cataldo L, Chase M, Al-Marshad A, Ngo L, Shapiro NI: Statin therapy is associated with decreased mortality in patients with infection. Acad Emerg Med 2009, 16: 230-234. 10.1111/j.1553-2712.2009.00350.xView ArticlePubMedGoogle Scholar
- Doshi SM, Kulkarni PA, Liao JM, Rueda AM, Musher DM: The impact of statin and macrolide use on early survival in patients with pneumococcal pneumonia. Am J Med Sci 2013, 345: 173-177. 10.1097/MAJ.0b013e3182639c26View ArticlePubMedGoogle Scholar
- Yeh PS, Lin HJ, Chen PS, Lin SH, Wang WM, Yang CM, Li YH: Effect of statin treatment on three-month outcomes in patients with stroke-associated infection: a prospective cohort study. Eur J Neurol 2012, 19: 689-695. 10.1111/j.1468-1331.2011.03608.xView ArticlePubMedGoogle Scholar
- Goodin J, Manrique C, Dulohery M, Sampson J, Saettele M, Dabbagh O: Effect of statins on the clinical outcomes of patients with sepsis. Anaesth Intensive Care 2011, 39: 1051-1055.PubMedGoogle Scholar
- Nseir W, Mograbi J, Abu-Elheja O, Bishara J, Assy N: The impact of prior long-term versus short-term statin use on the mortality of bacteraemic patients. Infection 2012, 40: 41-48. 10.1007/s15010-011-0190-9View ArticlePubMedGoogle Scholar
- Williams JM, Greenslade JH, Chu K, Brown AF, Paterson D, Lipman J: Prior statin use is not associated with improved outcome in emergency patients admitted with infection: a prospective observational study. Acad Emerg Med 2011, 18: 127-134. 10.1111/j.1553-2712.2010.00976.xView ArticlePubMedGoogle Scholar
- Myles PR, Hubbard RB, Gibson JE, Pogson Z, Smith CJ, McKeever TM: The impact of statins, ACE inhibitors and gastric acid suppressants on pneumonia mortality in a UK general practice population cohort. Pharmacoepidemiol Drug Saf 2009, 18: 697-703. 10.1002/pds.1769View ArticlePubMedGoogle Scholar
- Chalmers JD, Singanayagam A, Murray MP, Hill AT: Prior statin use is associated with improved outcomes in community-acquired pneumonia. Am J Med 2008, 121: 1002-1007. 10.1016/j.amjmed.2008.06.030View ArticlePubMedGoogle Scholar
- Mortensen EM, Nakashima B, Cornell J, Copeland LA, Pugh MJ, Anzueto A, Good C, Restrepo MI, Downs JR, Frei CR, Fine MJ: Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes. Clin Infect Dis 2012, 55: 1466-1473. 10.1093/cid/cis733PubMed CentralView ArticlePubMedGoogle Scholar
- Leung S, Pokharel R, Gong MN: Statins and outcomes in patients with bloodstream infection: a propensity-matched analysis. Crit Care Med 2012, 40: 1064-1071. 10.1097/CCM.0b013e31823bc9e7PubMed CentralView ArticlePubMedGoogle Scholar
- Yang KC, Chien JY, Tseng WK, Hsueh PR, Yu CJ, Wu CC: Statins do not improve short-term survival in an oriental population with sepsis. Am J Emerg Med 2007, 25: 494-501. 10.1016/j.ajem.2006.09.011View ArticlePubMedGoogle Scholar
- Kruger P, Fitzsimmons K, Cook D, Jones M, Nimmo G: Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med 2006, 32: 75-79. 10.1007/s00134-005-2859-yView ArticlePubMedGoogle Scholar
- Hsu J, Andes DR, Knasinski V, Pirsch J, Safdar N: Statins are associated with improved outcomes of bloodstream infection in solid-organ transplant recipients. Eur J Clin Microbiol Infect Dis 2009, 28: 1343-1351. 10.1007/s10096-009-0787-4View ArticlePubMedGoogle Scholar
- Mortensen EM, Pugh MJ, Copeland LA, Restrepo MI, Cornell JE, Anzueto A, Pugh JA: Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia. Eur Respir J 2008, 31: 611-617. 10.1183/09031936.00162006View ArticlePubMedGoogle Scholar
- Frost FJ, Petersen H, Tollestrup K, Skipper B: Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest 2007, 131: 1006-1012. 10.1378/chest.06-1997View ArticlePubMedGoogle Scholar
- Liappis AP, Kan VL, Rochester CG, Simon GL: The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 2001, 33: 1352-1357. 10.1086/323334View ArticlePubMedGoogle Scholar
- Mortensen EM, Restrepo MI, Anzueto A, Pugh J: The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia. Respir Res 2005, 6: 82. 10.1186/1465-9921-6-82PubMed CentralView ArticlePubMedGoogle Scholar
- Thomsen RW, Hundborg HH, Johnsen SP, Pedersen L, Sorensen HT, Schonheyder HC, Lervang HH: Statin use and mortality within 180 days after bacteremia: a population-based cohort study. Crit Care Med 2006, 34: 1080-1086. 10.1097/01.CCM.0000207345.92928.E4View ArticlePubMedGoogle Scholar
- Majumdar SR, McAlister FA, Eurich DT, Padwal RS, Marrie TJ: Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study. BMJ 2006, 333: 999. 10.1136/bmj.38992.565972.7CPubMed CentralView ArticlePubMedGoogle Scholar
- Dobesh PP, Klepser DG, McGuire TR, Morgan CW, Olsen KM: Reduction in mortality associated with statin therapy in patients with severe sepsis. Pharmacotherapy 2009, 29: 621-630. 10.1592/phco.29.6.621View ArticlePubMedGoogle Scholar
- Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A: Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation 2004, 110: 880-885. 10.1161/01.CIR.0000138932.17956.F1View ArticlePubMedGoogle Scholar
- Mortensen EM, Restrepo MI, Copeland LA, Pugh JA, Anzueto A, Cornell JE, Pugh MJ: Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy 2007, 27: 1619-1626. 10.1592/phco.27.12.1619View ArticlePubMedGoogle Scholar
- Park SW, Choi AR, Lee HJ, Chung H, Park JC, Shin SK, Lee SK, Lee YC, Kim JE, Lee H: The effects of statins on the clinical outcomes of Clostridium difficile infection in hospitalised patients. Aliment Pharmacol Ther 2013, 38: 619-627. 10.1111/apt.12439View ArticlePubMedGoogle Scholar
- Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AJ, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008, 359: 2195-2207. 10.1056/NEJMoa0807646View ArticlePubMedGoogle Scholar
- Makris D, Manoulakas E, Komnos A, Papakrivou E, Tzovaras N, Hovas A, Zintzaras E, Zakynthinos E: Effect of pravastatin on the frequency of ventilator-associated pneumonia and on intensive care unit mortality: open-label, randomized study. Crit Care Med 2011, 39: 2440-2446. 10.1097/CCM.0b013e318225742cView ArticlePubMedGoogle Scholar
- Thomsen RW, Johnsen SP, Olesen AV, Mortensen JT, Boggild H, Olsen J, Sorensen HT: Socioeconomic gradient in use of statins among Danish patients: population-based cross-sectional study. Br J Clin Pharmacol 2005, 60: 534-542. 10.1111/j.1365-2125.2005.02494.xPubMed CentralView ArticlePubMedGoogle Scholar
- Fang JC: Heart failure therapy: what should clinicians believe? JAMA 2012, 308: 2144-2146. 10.1001/jama.2012.45418View ArticlePubMedGoogle Scholar
- Tseng MY, Hutchinson PJ, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ: Effects of acute pravastatin treatment on intensity of rescue therapy, length of inpatient stay, and 6-month outcome in patients after aneurysmal subarachnoid hemorrhage. Stroke 2007, 38: 1545-1550. 10.1161/STROKEAHA.106.475905View ArticlePubMedGoogle Scholar
- Pasin L, Landoni G, Castro ML, Cabrini L, Belletti A, Feltracco P, Finco G, Carozzo A, Chiesa R, Zangrillo A: The effect of statins on mortality in septic patients: a meta-analysis of randomized controlled trials. PLoS One 2013, 8: e82775. 10.1371/journal.pone.0082775PubMed CentralView ArticlePubMedGoogle Scholar
- Shyamsundar M, McKeown ST, O'Kane CM, Craig TR, Brown V, Thickett DR, Matthay MA, Taggart CC, Backman JT, Elborn JS, McAuley DF: Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med 2009, 179: 1107-1114. 10.1164/rccm.200810-1584OCPubMed CentralView ArticlePubMedGoogle Scholar
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