Elsevier

The Lancet

Volume 367, Issue 9508, 4–10 February 2006, Pages 413-418
The Lancet

Articles
Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis

https://doi.org/10.1016/S0140-6736(06)68041-0Get rights and content

Summary

Background

Atherosclerosis and sepsis share several pathophysiological similarities, including immune dysregulation, increased thrombogenesis, and systemic inflammation. The relation between statins and risk of sepsis in patients with atherosclerosis is unknown.

Methods

We did a population-based cohort analysis through linked administrative databases in Ontario, Canada, with accrual from 1997 to 2002. We identified 141 487 patients older than 65 years who had been hospitalised for an acute coronary syndrome, ischaemic stroke, or revascularisation, who survived for at least 3 months after discharge. 46 662 (33%) were prescribed a statin within 90 days of discharge, 94 825 (67%) were not. Propensity-based matching, which accounted for each individual's likelihood of receiving a statin, yielded a cohort of 69 168 patients, of whom half (34 584) received a statin and half (34 584) did not.

Findings

Incidence of sepsis was lower in patients receiving statins than in controls (71·2 vs 88·0 events per 10 000 person-years; hazard ratio [HR] 0·81; 95% CI 0·72–0·91). Adjustment for demographic characteristics, sepsis risk factors, comorbidities, and health-care use gave similar results (HR 0·81; 95% CI 0·72–0·90). The protective association between statins and sepsis persisted in high-risk subgroups, including patients with diabetes mellitus, chronic renal failure, or a history of infections. Significant reductions in severe sepsis (HR 0·83; 95% CI 0·70–0·97) and fatal sepsis (0·75; 0·61–0·93) were also observed. No benefit was noted with non-statin lipid-lowering agents (0·95; 0·75–1·22).

Implications

Use of statins in patients with atherosclerosis is associated with a reduced risk of subsequent sepsis. Randomised trials of statins for prevention of sepsis are warranted.

Introduction

Sepsis is an enduring source of morbidity and mortality in the general population. More than a decade ago, a consensus committee of the Society of Critical Care Medicine and the American College of Physicians defined the disorder as the systemic inflammatory response to the presence of infection which, when severe, is accompanied by organ dysfunction or hypotension.1, 2 The prevention of sepsis has gained importance in recent years because sepsis is common and increasing in incidence, the disease carries a high case fatality rate, and the care of affected patients is extremely costly.3, 4

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are potent lipid-lowering agents that reduce the risk of cardiovascular events in patients with diabetes mellitus, coronary artery disease, and other forms of atherosclerosis.5 Although the major mechanism of action is cholesterol lowering, statins have several pleiotropic effects, including anti-inflammatory, immunomodulatory, antioxidant, antithrombotic, and endothelium-stabilising properties.6, 7, 8 These effects are of unknown importance, but might account for the benefits observed in clinical trials of statins in patients with multiple sclerosis, rheumatoid arthritis, and other inflammatory disorders.9, 10

Findings of studies in animals suggest that statins might also prevent sepsis.11, 12, 13, 14 Several therapeutic interventions for sepsis that have initially shown promise in studies with animals, however, have proven unsuccessful when tested in people. Two small observational studies have suggested a benefit of statins in patients with acute bacterial infection, including decreased progression to severe sepsis15 and reduced mortality attributable to sepsis.16 However, these studies were limited by small sample size, inadequate adjustment for confounding, brief follow-up duration, and absence of information on patient adherence. We postulated that statins reduce the incidence of sepsis in a high-risk population with atherosclerosis. We undertook a large-scale, multi-year, population-based cohort study with a comprehensive analysis of sepsis, propensity-based matching to minimise confounding, and tracer analyses to assess the specificity of the findings.

Section snippets

Setting and patients

We established a retrospective patient cohort by linking multiple administrative health-care databases over 5 years in the province of Ontario. Throughout the study, Ontario was Canada's most populous province with about 12 million inhabitants, of whom 1·5 million were aged 65 years or older. Elderly patients in Ontario had universal access to hospital care, physicians' services, and prescription drug coverage. Additionally, health-care records could be analysed using encrypted identifiers to

Results

During the 5-year accrual period, we identified 173 410 consecutive patients older than 65 years who were admitted for an acute coronary syndrome, ischaemic stroke, or arterial revascularisation. Of these, 22 101 individuals died during admission and a further 9822 died within 90 days after discharge. Of the 141 487 survivors, 46 662 (33%) received a statin within 90 days of discharge whereas 94 825 (67%) did not. Propensity-based matching then yielded a final cohort of 69 168 patients, of whom

Discussion

We observed that the use of statins in patients older than 65 years with atherosclerosis was associated with a 19% reduction in the risk of sepsis. The apparent protective association between statins and sepsis was consistent across several high-risk subgroups, was apparent throughout the entire follow-up period, and was amplified in analyses accounting for non-adherence and crossovers. Moreover, the observed association was in the range of known relative reductions in cardiovascular risk seen

References (49)

  • MM Levy et al.

    2001. SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference

    Crit Care Med

    (2003)
  • D Annane et al.

    Current epidemiology of septic shock: the CUB-Rea Network

    Am J Respir Crit Care Med

    (2003)
  • DC Angus et al.

    Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care

    Crit Care Med

    (2001)
  • MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial

    Lancet

    (2002)
  • JPJ Halcox et al.

    Beyond the laboratory: clinical implications for statin pleiotropy

    Circulation

    (2004)
  • U Landmesser et al.

    Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans

    Circulation

    (2005)
  • H Ando et al.

    Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis

    J Pharmacol Exp Ther

    (2000)
  • MW Merx et al.

    HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis

    Circulation

    (2004)
  • D Pruefer et al.

    Simvastatin inhibits inflammatory properties of Staphylococcus aureus alpha-toxin

    Circulation

    (2002)
  • A Giusti-Paiva et al.

    Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats

    Shock

    (2004)
  • Y Almog et al.

    Prior statin therapy is associated with a decreased rate of severe sepsis

    Circulation

    (2004)
  • AP Liappis et al.

    The effect of statins on mortality in patients with bacteremia

    Clin Infect Dis

    (2001)
  • CD Naylor et al.

    Cardiovascular health and services in Ontario: an ICES atlas

    (1999)
  • B Chan

    Supply of physicians' services in Ontario

    (1999)
  • Cited by (0)

    View full text