ArticlesStatins and sepsis in patients with cardiovascular disease: a population-based cohort analysis
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.
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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
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