Do statins improve outcomes of patients with sepsis and pneumonia? Jordi Carratalà Department of Infectious Diseases
Statins for sepsis & community-acquired pneumonia Sepsis and CAP are major healthcare problems, affecting millions of people around the world each year. The mortality associated with these infection remains high. Excessive inflammatory response is one of the major causes of poor outcome in patients with sepsis and CAP. It has been suggested that statins may be useful to improve outcomes of patients with these infections.
Statin treatment improves survival in a murine model of sepsis Prior simvastatin Statin after onset of sepsis No Yes Merx MW. Circulation 2004 Merx MW. Circulation 2005
Statins for the treatment of infections A systematic review and meta-analysis Tleyjeh IM. Arch Intern Med 2009
Effect of statins on outcomes in immunosuppressed patients with bloodstream infection (BSI) Observational analysis of cancer patients and transplant recipients (2006-2009) 688 consecutive episodes of BSI in 476 patients were recorded 59 (12.4%) pts were receiving statins. No differences in mortality (15% vs 24%) Viasus D. Eur J Clin Microbiol Infect Dis 2011
Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) Objective: to determine if the administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis Setting: Birmingham Heartlands Hospital (UK) Intervention: atorvastatin 40 mg daily (n= 49) or placebo (n=51) for the duration of their hospital stay up to a maximum of 28-day Primary end point: the rate of sepsis progressing to severe sepsis during hospitalization Patel JM. Critical Care 2012
Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial) % Conversion rate to severe sepsis P =.007 No significant difference in LOS, ICU admissions, 28-day and 12-month readmissions or mortality was observed Patel JM. Critical Care 2012
A multicentre randomised trial of atorvastatin therapy in intensive care patients with severe sepsis Objective: To test whether atorvastatin therapy affects biological and clinical outcomes in critically ill patients with severe sepsis Setting: 21 Intensive Care Units across Australia and New Zealand (2007-2010) Intervention: atorvastatin, 20 mg daily (n= 123) or placebo (n= 127) Primary end point: plasma IL-6 levels Secondary end points: C-reactive protein, lipid profile, plasma atorvastatin levels and clinical outcomes Kruger P. AJRCCM 2013
De novo: no prior statin use Atorvastatin (n= 86) Placebo (n= 87) P Atorvastatin (n= 37) Prior statin use Placebo (n=40) ICU admission 7% 8%.23 8% 20%.14 Hospital mortality 14% 14%.98 11% 28%.06 28-day mortality 12% 13%.86 5% 28%.01 90-day mortality 16% 15%.78 11% 28%.06 P Kruger P. AJRCCM 2013
Continuation of Statin Therapy in Patients with Presumed Infection A Randomized Controlled Trial Objective: to test the hypothesis that continuation of therapy with statins influences the inflammatory response to infection Setting: Princess Alexandra Hospital, Brisbane, Australia Intervention: atorvastatin 20 mg (n=75) or placebo (n=75) in patients on preexisting statin therapy hospitalized for infection Primary end point: progression or regression of sepsis during hospital admission Secondary end points: 28-day mortality, ICU admission, and changes in biomarkers of inflammation and lipid profile Kruger PS. AJRCCM 2011
Rates of severe sepsis Atorvastatin Placebo Total Baseline 24 of 75 24 of 75 150 Day 3 12 of 56 11 of 56 112 Day 14 1 of 20 0 of 19 39 Day 28 0 of 2 0 of 2 4 Kruger PS. AJRCCM 2011
The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebocontrolled clinical trial Objective: to determine if statin therapy reduces the incidence of severe sepsis and the levels of inflammatory cytokines in patients with acute bacterial infection Setting: Soroka University Medical Center (2004), Israel Intervention: 40 mg of simvastatin orally, followed by 20 mg/day (n= 42) or placebo (n= 41) IL-6 TNF-α Novack V. Intensive Care Med Med 2009
Statins for CAP?
Preadmission use of statins and outcomes after hospitalization with pneumonia Population-based cohort study of 29,900 adults hospitalized with pneumonia for the first time between 1997 and 2004 in Denmark Current statin users: 1370 (4.6%) Statin users YES NO 30 d OR 0.69 (95% CI, 0.58 0.82) 90 d OR 0.75 (95% CI, 0.65 0.86) Mortality % 30 d 90 d 10.7 15.7 16.8 22.4 Thomsen RW. Arch Intern Med 2008
Cardiovascular drugs and 30-day mortality in 1007 adults hospitalized with community-acquired pneumonia Patients receiving one or more cardiovascular drugs (n= 458) Chalmers JD. Am J Med 2008
Admission C-reactive protein levels and statin use *P <.0001 Chalmers JD. Am J Med 2008
Proportion of surviving patients hospitalized with CAP by use of statin or ACE inhibitor versus non-use Using statin (n= 1567) P <.001 Not using statin (n= 7085) Using ACE inhibitor (n= 2930) P <.0001 Not using ACE inhibitor (n= 5722) Mortensen EM. Eur Respir J 2008
Statins and outcomes in patients admitted to hospital with CAP: population based prospective cohort study In-hospital mortality or admission to an ICU 624 / 3.415 (18%) patients Use of statins YES 50 / 325 (15%) NO 574 / 3090 (19%) OR 0.80 Adjusted OR: 1.10 (95% CI, 0.76 1.60) Majumdar SR. BMJ 2006
The Role of Statins in Prevention and Treatment of Community Acquired Pneumonia: A Systematic Review and Meta-Analysis Khan AR. Plos One 2013
The effect of simvastatin (20 mg/day) in CAP Randomized double-blind placebo-controlled trial Assessed for Eligibility (n= 381) Allocated to simvastatin (n= 19) Randomly Assigned (n= 34) Allocated to placebo (n = 15) Excluded (n= 347) Use of statins (91) Use of drugs metabolized by the CYP3A4 enzyme system (71) ATBs prior to enrollment (85) Immunosuppressed (35) Other (21) ISRCTN 91327214 Viasus D ( Submitted)
TNF-α P =.58 IL-6 P =.64 Time to clinical stability Median (days) IQR (days) Placebo (n=15) 3 (2-5) Simvastatin (n=19) 3 (2-5) Prior statin use (n=71) 4 (2-8.5) P = >.05 for all comparisons Viasus D (Submitted)
Summary Most observational studies on statin treatment for sepsis and CAP have shown some beneficial effects on clinical outcomes. Nevertheless, the healthy user bias and other methodological limitations make it difficult to interpret these observational studies. Few randomized trials have been performed to determine whether statins may improve outcomes of patients with sepsis and CAP.
Summary Moreover, the majority of these studies have not found a significant reduction on inflammatory cytokines. In addition, the most appropriate time to administer statins and the type and dose are still unknown. Caution is warranted in recommending the routine use of statins for treatment of sepsis and CAP.
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