Statin Therapy: Not Just for Cholesterol Anymore?
Statin Therapy: Not Just for Cholesterol Anymore?
Abstract & Commentary
By Andrew M. Luks, MD, Pulmonary and Critical Care Medicine, University of Washington, Seattle, is Associate Editor for Critical Care Alert.
Dr. Luks reports no financial relationship to this field of study.
Synopsis: This retrospective cohort study demonstrated that statin use was associated with a reduction in mortality in patients with severe sepsis (APACHE II > 24), but had no effect on mortality in those with less severe disease.
Source: Dobesh PP, et al. Reduction in mortality associated with statin therapy in patients with severe sepsis. Pharmacotherapy 2009;29:621-630.
In addition to their cholesterol-lowering properties, hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, commonly referred to as statins, have been shown to modify inflammatory and immunologic pathways. Given the role that inflammation and immune responses play in the pathophysiology of sepsis, questions have been raised about whether these medications may have a role in the management of patients with this disorder. Building on earlier retrospective studies suggestive of a benefit in this regard,1,2 Dobesh and colleagues sought to determine whether statin exposure affected mortality in patients with severe sepsis.
To investigate this question, they conducted a single-center, retrospective cohort study. They reviewed data from patients 40 years or older with a confirmed diagnosis of sepsis admitted to a medical-surgical ICU over a 2-year period. Patients < 40 years of age were excluded because they were unlikely to be on statin therapy. Potential cases were identified based on ICD-9 CM codes noting the presence of infection and acute organ dysfunction. Patients from that group were then selected for inclusion in the study if they had two or more criteria for SIRS (systemic inflammatory response syndrome) within a 24-hour period. All septic patients at the institution were treated with a standard approach using a protocolized version of early goal-directed therapy. Patients were considered exposed to statins if they were receiving a statin-containing product at the time of admission or if they were prescribed one during hospitalization. The primary outcome measure was inpatient mortality, while secondary outcomes included hospital and ICU length of stay and total hospital costs. Severity of illness was measured using APACHE II scores, and multiple potential confounding variables including age, comorbid conditions, concomitant drugs, vital signs, and laboratory values were controlled for in the statistical analysis.
A total of 188 patients (4.9% of admissions) had sepsis during the study period and were included in the analysis. Sixty (32%) of these patients were exposed to statins while the remaining 128 (68%) had no exposure. The two groups were relatively well matched, but the statin-exposed group had more hypertension, diabetes, chronic kidney disease, and coronary artery disease and the non-exposed group had more liver disease. In-hospital mortality was significantly lower in the statin-exposed group (31.7% vs 48.4%; P = 0.04). The mortality benefit was also observed in multivariate analysis, as the adjusted odds ratio for mortality with statin exposure was 0.42 (95% confidence interval, 0.21-0.84; P = 0.014). When the authors analyzed outcomes based on the severity of illness, however, a mortality benefit was only observed in those patients with APACHE II scores > 24; no significant differences were observed in those with less severe disease. Of note, even in those patients in whom statins were discontinued at the time of admission, there was a nonsignificant trend toward improved mortality compared to those with no statin exposure (27.6% vs 48.4%; P = 0.06). There were no differences in hospital or ICU length of stay and hospital costs between the statin-exposed and non-exposed patients.
Commentary
I must admit that I have often looked askance at residents I am supervising when they report during morning rounds that they continued many outpatient medications on admission that seemed unrelated to the patient's severe acute illness. The study by Dobesh and colleagues suggests that perhaps there are benefits to continuing one class of medications that I usually lump into this group — statins — as they may lead to improvements in mortality in patients with severe sepsis.
Continuing a previously prescribed medication, however, is a far cry from ordering statins for all of our septic patients and at present, there are still no data to support this practice. In addition to the fact that this was a relatively small, single-center study with important differences in baseline characteristics between the two groups, it must be remembered that this study, as well as the other studies that have examined the role of statins in sepsis, used a retrospective design. As the story of estrogen-replacement therapy in postmenopausal women has well demonstrated, many therapies that looked great in retrospective analysis have subsequently not passed muster when subjected to rigorous prospective testing. Nevertheless, the data from these retrospective studies are intriguing and provide a solid rationale for proceeding with prospective, multicenter studies to further investigate the role of this widely used class of medications in a major form of critical illness.
Should prospective, multicenter trials demonstrate a benefit on mortality and other outcomes, statins could represent a useful tool for intensivists, as administering these medications once a day is substantially easier and less costly than, for example, another medication shown to be of benefit in patients with severe sepsis, recombinant human activated Protein C (APC). Unfortunately, at present, statins lack the type of prospective data that support the use of APC and we are simply left with the knowledge that by continuing these medications on admission we are at least not doing harm to our patients and may potentially provide some benefit.
References
- Liappis AP, et al. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 2001;33:1352-1357.
- Schmidt H, et al. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med 2006;32:1248-1251.
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