A meta-analysis summarizing the effects of statins on mortality in patients with infection and/or sepsis
] seems to support the hypothesis of a protective effect of statins during sepsis.
The analysis included 20 studies (18 cohort studies (12 retrospective and 6 prospective), 1 matched cohort study, and 1 randomized control trial). Of those 20 studies, 15 showed a decreased mortality in patients receiving statins with adjusted odds ratios (ORs) ranging from 0.06 to 0.75
]. Four studies showed a trend toward a benefit from statins although not reaching statistical significance
]. Only one study reported an increased mortality in patients taking statins
The primary meta-analysis regarding mortality from any cause at different time, according to 20 studies that pooled 265,558 patients, demonstrated a significant protective effect from statins in patients with infection and/or sepsis compared with no statin treatment or placebo (OR, 0.49; 95% CI, 0.37–0.61)
This meta-analysis supports the hypothesis of a protective effect of statins during sepsis
]. However, besides limitations regarding the heterogeneity and design of the analyzed studies and exposure definition, the handling of potential sources of bias and confounding, such as the healthy user effect or indication bias, limits the interpretation of these data. A recent prospective cohort study, specifically designed to avoid those bias, found no evidence of a protective effect for statin use on clinical outcomes
This study enrolled 1,895 subjects hospitalized with community-acquired pneumonia. It first compares subjects with prior statin use with those with no prior use and then compares continued in-hospital therapy with no prior use or no in-hospital use. There were no difference in severe sepsis risk between statin users and nonusers for prior (30.8% vs. 30.7%, P
0.98) or continued statin use (30.2% vs. 30.8%, P
0.85) in univariate analyses and after adjusting for patient characteristics and propensity for statin use. Interestingly, users whose statin was discontinued in the hospital had nearly twice the mortality of those whose statin was continued (15.3% vs. 7.9%, P
0.048). After accounting for likelihood of statin use by including a propensity score in each model, there was no detectable benefit of either prior (adjusted OR, 0.9; 95% CI, 0.63–1.29; P
0.57) or continued statin use (adjusted OR, 0.73; 95% CI, 0.47–1.13; P
First, in this study statin users were universally more likely to have healthy user indicators (being insured, living at home, being of good functional status, receiving vaccinations, taking daily aspirin, and quitting smoking) that can positively influence mortality in CAP. As these statin users’ characteristics are supported by other work in this area
], this healthy-user effect may account for better outcomes shown in previous studies
Second, this analysis refutes prior studies that support a protective effect of in-hospital ongoing statin therapy probably due to indication bias. Indeed, the decision to continue statin in the hospital depends on how sick the patient is and whether they are able to take medications by mouth. In this study, the inclusion of propensity for continued statin use in the mortality models universally moved the adjusted OR closer to unity and the p value toward greater degrees of insignificance, suggesting no association between 90-day mortality and cessation of statin therapy.
These findings seem to be confirmed by a randomized, placebo-controlled trial that does not support a beneficial role of continuing preexisting statin therapy on sepsis and inflammatory parameters
]. This small trial tested the hypothesis that continuation of therapy with statins influences the inflammatory response to infection and that cessation may cause an inflammatory rebound. One hundred and fifty patients on preexisting statin therapy requiring hospitalization for infection were randomized to receive atorvastatin (20 mg) or matched placebo. The primary end point was progression of sepsis during hospitalization. The rate of decline of severe sepsis was similar between the groups (odds ratio, 1.17 [0.56-2.47], P
0.7 day 3; 0.85 [0.21-3.34], P
0.8 day 14) and IL-6 and C-reactive protein declined in both groups with no statistically significant difference (P
0.7 and P
0.2, respectively). Hospital mortality was 6.6%, with no difference between the groups (6 [8%] of 75 statin group; 4 [5.3%] of 75 placebo group; not significant).
These observational trials studied the effects of chronic treatment before infection. The effect of statin treatment initiated just before the onset of sepsis a patients at-risk population or even after the onset of sepsis were not assessed. Obviously, prospective, randomized trials over acute statin therapy are needed.
Ongoing clinical trials
Simvastatin and severe sepsis trial (SIMSEPT) will be the first double-blind, randomized, placebo-controlled trial of simvastatin (40 mg) in the treatment of severe sepsis in humans. It will investigate the effect of simvastatin on important inflammatory markers and monitor the safety and feasibility of administering simvastatin to patients with severe sepsis
]. The STATInS trial is a phase II, randomised, placebo-controlled study of the safety, pharmacokinetics, and effect on inflammatory marker levels of atorvastatin in intensive care patients with severe sepsis
]. Two other phase II trials are evaluating simvastatin in adults hospitalized with sepsis with the primary outcome being time to clinical stability in one trial
] and time to shock reversal in the other