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(1)

Do statins improve outcomes of

patients with sepsis and pneumonia?

Jordi Carratalà

Department of Infectious Diseases

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(2)

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.

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(3)

Merx MW. Circulation 2004 Prior simvastatin

Yes No

Statin treatment improves survival in a murine model of sepsis

Merx MW. Circulation 2005 Statin after onset of sepsis

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(4)

Statins for the treatment of infections A systematic review and meta-analysis

Tleyjeh IM. Arch Intern Med 2009

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Effect of statins on outcomes in immunosuppressed patients with bloodstream infection (BSI)

Viasus D. Eur J Clin Microbiol Infect Dis 2011

• 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%)

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(6)

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

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No significant difference in LOS, ICU admissions, 28-day and 12-month readmissions or mortality was observed

Patel JM. Critical Care 2012

Conversion rate to severe sepsis

P = .007

%

Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients

(ASEPSIS Trial)

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(8)

A multicentre randomised trial of atorvastatin therapy in intensive care patients with severe sepsis

Kruger P. AJRCCM 2013

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

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Kruger P. AJRCCM 2013 De novo: no prior statin use Prior statin use

Atorvastatin

(n= 86) Placebo

(n= 87) P Atorvastatin

(n= 37) Placebo

(n=40) P

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

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16% 15% .78 11% 28% .06

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(10)

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

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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

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The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo-

controlled clinical trial

Novack V. Intensive Care Med Med 2009 TNF-α

IL-6

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)

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(13)

Statins for CAP?

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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)

Thomsen RW. Arch Intern Med 2008 Mortality % 30 d 90 d

10.7 15.7

16.8 22.4

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Chalmers JD. Am J 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)

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Chalmers JD. Am J Med 2008

Admission C-reactive protein levels and statin use

*P < .0001

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Proportion of surviving patients hospitalized with CAP by use of statin or ACE inhibitor versus non-use

Mortensen EM. Eur Respir J 2008

Using statin (n= 1567)

Not using statin (n= 7085)

P < .001

Using ACE inhibitor (n= 2930)

Not using ACE inhibitor (n= 5722)

P < .0001

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(18)

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

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The Role of Statins in Prevention and Treatment of Community Acquired Pneumonia: A Systematic Review and Meta-Analysis

Khan AR. Plos One 2013

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Assessed for Eligibility (n= 381) Randomly Assigned (n= 34)

Allocated to simvastatin

(n= 19) 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)

Viasus D ( Submitted)

The effect of simvastatin (20 mg/day) in CAP Randomized double-blind placebo-controlled trial

ISRCTN 91327214

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TNF-α

P = .58

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)

IL-6

P = .64

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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.

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