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Three Part Question

In [patients with severe sepsis] does [use of statins during hospital stay] reduce [mortality]?

Clinical Scenario

A 65 years old male patient is admitted through your Emergency department with severe sepsis. Early Goal Directed Therapy (EGDT) was started within one hour of patient’s arrival. You are aware that sepsis has a very high mortality and you wonder is there anything else you can do to improve the chances of your patient surviving.
ITU registrar mentions the possible role of statins in the management of septic patients. On your search you realized that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors (statins), possess a number of pleiotropic effects that are thought to have a beneficial effect in septic patients. Data from animal models has shown promising results in improving survival in mice with sepsis, and you wonder if statins could be the new breakthrough drug in the management of these patients.

Search Strategy

A Comprehensive Literature search was carried out on Medline via Ovid interface.
Search trips used were exp sepsis, septic.ti, ab, septic shock, mortality.ti, ab, exp mortality, death*.ti, ab, statin*.ti, ab, (lovastatin* OR pravastatin* OR Simvastatin* OR atorvastatin* OR fluvastatin* OR rosuvastatin* ).ti, ab.


Studies looking at septic patients with specific co-morbidity were not included.
LIMITS : Human population and studies in English Language.

Search Outcome

Studies suggest that statin use might have a positive role in reducing mortality in sepsis. With 3 out of 5 studies appraised suggesting statin group to be associated with lower mortality, while the other two studies showed no difference. Weak evidence was seen in support of improved survival with use of statins. However evidence being weak as only one randomized controlled trial looking into the topic was found.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kruger et al 2000-03 Australia	438 patients, Inclusion criteria were Age > 18 years old with clinical features of infection and bacteremia. Patients were on statin at time of admission and as in patient.	Retrospective Cohort Study.	Statin use in septic patients over 28 day’s hospital mortality was looked at.	Statin use prior to admission showed reduced all-cause hospital mortality 7/66 patients (odds ratio 0.39; CI 95% 0.17, 0.91; p= 0.029) and reduced number of death attributed to bacteremia 4/66 (6.1% vs. 18.3%, p=0.014) continuing statin therapy during hospital stay also showed significantly reduced mortality {1/56 patients}	Small study, follow up was for only 28 days. Thirty seven patients were excluded from the original 475 number, Statin group had older patients with more coexisting diseases, There was no mention of how many patients fulfilled the criteria of severe sepsis.
Kruger et al 2006-08 Australia	Age >18 years and patients on statins admitted with 2 or more SIRS criteria.	Prospective randomized double blinded placebo control trial. Patients were on statins prior to admission and than either continued or given placebo. patients were divided into two groups 75 statin vs. 75 non statin group	No significant difference between the two groups.	Overall cohort had a hospital mortality of 6.6% with no significant difference	Study was not powered to assess mortality as end point. Patients admitted to the hospital over weekends and public holidays were excluded. Patients were followed till day 28, with no mention of the outcome in the remaining four patients, who were in patients at the end of 28 days.
Thomsen et al 1997-2002 Denmark	looked at 5,353 patients.Patients over the age 15 years with bacteremia were eligible to be included.	Population Based Cohort Study.	Looked at mortality rate at 30 and 180 days.	Not much difference in mortality between both groups at 30 days (Statin= 20.0% compare to non statin= 21.6%), However among survivors after 30 days users had substantially reduce mortality (8.4% vs. 17.5% adjusted mortality rate ratio 0.44, 95% confidence interval 0.24-0.80).	Only 2.8 % of the study population represented statin group. Once Bacteremia was confirmed Microbiologist informed the attending physician regarding positive culture which could lead to ‘surveillance Bias’. 30% patients in non-statin Group, had Medical indications to be on statin. suggesting a ‘Healthy user effect’ in statin group. No information is provided of how many patients fulfilled criteria for sepsis, or how many patients were admitted to ICU
Dobesh et al 2005-06 USA	> 40 years with two or more criteria of SIRS present and ICU admission.	188 patients in this Retrospective Cohort study. 60/188 patients were in the statin group {50 on statins which was continued during hospital stay and 10 were started on statin during hospital stay} non statin were 128/188 patients.	Statin group had 35% relative reduction in mortality	Statin group had 35% relative reduction in mortality (mortality rate 31.7% vs.	No power calculation Mean White cell count, arterial pressure and PH was worse in non statin Group, suggesting this group was more sick. Non statin group had patients with Myocardial Infarction/CABG (n=10) Coronary Artery disease (n=24) , percutaneous intervention PCI (n=7) suggesting healthy user effect in statin group.
Mortensen et al 1999-2002 USA	787 patients were recruited for this study. Inclusion criteria were >18 yrs age with diagnosis of Community Acquired Pneumonia which was confirmed Radio graphically.	Retrospective Cohort Study.	In septic patients, survival rate between statin users and non users was looked at.	Among statin group 110/787 (n=110) a higher survival at 30 days (p=0.001) was seen,use of statin at presentation (odds ratio 0.36, 95% confidence interval 0.14-0.92) was associated with decrease 30 day mortality.	Not a single patient in statin group had systolic BP < 90 mmHg, study fail to mention how many patients fulfill the criteria for sepsis, nor was there a subgroup analysis of mortality in the ICU group. Study shows 13.6% overall mortality at 90-days, however fails to address the sub-analysis of this group. No mention of duration of statin use and if statin was continued as in patient or not.
Forrest et al 2003-06 USA	Candidemia as a cause of SIRS in ICU setting in > 45 years old patients.	Retrospective matched cohort study,looking at patients with candidemia as a cause of infection in ICU patients. Statin group n=15 vs. matched non statin group n=30.	Statin group associated with lower mortality	Study demonstrated statin group to be associated with lower mortality on bivariable (OR 0.09, 95% CI 0.11- 0.75, P=0.03) and multivariable (OR 0.22, 95% CI 0.02-2.4, P=0.21) analysis.	Small study Patients in control group had higher APACHE 11 score (18.2 vs. 14.9) Patients with positive blood culture of other organisms within 24 hours or another active cause for (SIRS) or if they die before diagnosis or before receiving anti fungal therapy were excluded.
Liappis et al 1995-2000 USA	388 patients with Confirmed Staph Aureus and Gram negative bacteremia	Retrospective Cohort Study.	Mortality rate in statin and non statin groups with sepsis was looked at.	study showed a significant difference in mortality rate with 2 out 35 patients in statin group (6%) vs. (28%) 100 out of 353 patients in non statin group P= 0.002 , mortality directly attributed to infection was also lower (3% vs. 20%) in favour of statin users.	This was a small study. No mention of how many patients were septic in each group.Mortality rate was seen highest among Cirrhosis and hepatitis patients, with none of statin users suffering from the two co-morbidity.
Yang et al 2001-02 Taiwan	Retrospective Case control study in an Urban Medical centre. Inclusion criteria were hospital Record showing > 30days statin use and continue statin use during hospital stay with clinical diagnosis of sepsis and a positive blood result.	study demonstrates no beneficial or harmful effects of statins in terms of 30 days survivals in Oriental population.	Study demonstrates no beneficial or harmful effects of statins in terms of 30 days survivals in Oriental population.	Statin treatment was not seen associated with reduce mortality at 30 days (p=0.853; risk ratio, 0.95; 95% confidence interval, 0.53 -1.68)	No power calculation. Study looked at oriental population only.
Liappis et al 1995-2000 USA	Retrospective Case control study. patients included were confirmed cases of Staph Aureus and Gram negative bacteremia.	In this retrospective case control study looked at 388 patients with gram negative and staph aureus bacteremic episodes. 35 patients in statin vs. 353 in non statin group. Patients were followed till discharge from hospital.	Study showed significant difference in mortality rate, with improved survival in statin group.	study showed a significant difference in mortality rate with 2/35 patients in statin group (6%) vs. (28%) 100/353 patients in non statin group. Mortality directly attributed to infection was also lower (3% vs. 20%) in favour of statin users. Overall mortality in ICU admitted patients also showed improved survival in statin group.	99.5% patients in this study were male, with only 2 female patients. Hospital acquired bacteremia was the biggest cause of mortality 40/147 patient, all of these patients were not statin users.

Comment(s)

Given the effects related to many pathophysiological determinants of sepsis, statin therapy maybe the next logical step in the search for adjuvant therapy. Although having reviewed the data positive survival outcome is a possibility, no definite conclusions can be drawn from the data available to date as these studies are mainly retrospective and have several limitations.There has been only one randomized controlled trial with clinically relevant primary end points on this subject. Given the biological plausibility, there is a need for prospective studies and randomized control trials.

Clinical Bottom Line

I believe that further prospective and randomized control trials are warranted to determine the likely relationship between statin therapy and mortality in patients with sepsis. Looking at a huge amount of pathophysiological evidence in support of statins in septic patients, who knows statins might be the next big thing in the treatment of septic patients.

References

1. Kruger P, Fitzsimmons K, Cook D Statin therapy is associated with fewer deaths in patients with bacteremia. Intensive Care Med 2006;32:75-9.
2. Kruger PS, Harward ML, Jones MA, Joyce CJ et al Continuation of statn therapy in patients with presumed infection. American Journal of Respiratory and critical care Medicine 2011, 183:774-781
3. Thomsen RW, Hundborg H, Johnsen SP Statin use and mortality within 180 days after bacteremia: A population-based cohort study Critical Care Medicine 2006 ; 1080-86
4. Dobesh PP, Klepser DG, McGuire TR, Morgan CW, Olsen KM et al Reduction in mortality associated with statin therapy in patients with severe sepsis. Pharmacotherapy Jun 2009, vol./is. 29/6 (621-30)
5. Mortensen EM, Restrepo MI, Anzueto A The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia Respiratory Research journal 2005; 6:82
6. Graeme N Forrest, Angela M Kopack, Eli N Perencevich, et al Statins in Candidemia: clinical outcomes from a matched cohort study. BMC Infectious Diseases 2010;10:152
7. Liappis AP, Kan VL, Rochester CG The effect of statins on mortality in patients with bacteremia. clinical infectious diseases 2001;33:1352-7
8. Yang KC,Chien JY, Tseng WK, et al Statins do not improve short-term survival in oriental population with sepsis The American journal of Emergency Medicine 2007;25:494-501
9. Liappis AP, Kan VL, Rochester CG, et al. The effect of statins on mortality in patients with bacteremia. Clinical Infectious Diseases Journal 2001;33:1352-7