Understanding the Potential Role of Statins in Pneumonia and Sepsis
Understanding the Potential Role of Statins in Pneumonia and Sepsis
Objective: To examine the association of statin use with clinical outcomes and circulating biomarkers in community-acquired pneumonia and sepsis.
Design: Multicenter inception cohort study.
Setting: Emergency departments of 28 U.S. hospitals.
Patients: A total of 1895 subjects hospitalized with community-acquired pneumonia.
Interventions: None.
Measurements and Main Results: Our approach consisted of two different comparison cohorts, each reflecting methods used in prior publications in this area. We first compared subjects with prior statin use (prior use cohort), defined as a history of statin use in the week before admission, with those with no prior use. We then compared prior statin users whose statins were continued inhospital (continued use cohort) with those with either no prior use or no inhospital use. We adjusted for patient characteristics, including demographics, comorbid conditions, and illness severity, and accounted for healthy user effect and indication bias using propensity analysis. We determined risk of severe sepsis and 90-day mortality. We measured markers inflammation (tumor necrosis factor, interleukin-6, interleukin-10), coagulation (antithrombin, factor IX, plasminogen activator inhibitor, d-dimer, thrombin antithrombin complex), and lymphocyte cell surface protein expression during the first week of hospitalization. There were no differences in severe sepsis risk between statin users and nonusers for prior (30.8% vs. 30.7%, p = .98) or continued statin use (30.2% vs. 30.8%, p = .85) in univariate analyses and after adjusting for patient characteristics and propensity for statin use. Ninety-day mortality was similar in prior statin users (9.2% vs. 12.0%, p = .11) and lower in continued statin users (7.9% vs. 12.1%, p = .02). After adjusting for patient characteristics and propensity for statin use, there was no mortality benefit for prior (odds ratio, 0.90 [0.63–1.29]; p = .57) or continued statin use (odds ratio, 0.73 [0.47–1.13]; p = .15). Only antithrombin activity over time was higher in statin subjects, yet the magnitude of the difference was modest. There were no differences in other coagulation, inflammatory, or lymphocyte cell surface markers.
Conclusions: We found no evidence of a protective effect for statin use on clinical outcomes and only modest differences in circulating biomarkers in community-acquired pneumonia, perhaps as a result of healthy user effects and indication bias.
HMG-CoA reductase inhibitors (statins) are the most prescribed class of drugs in the world and significantly improve survival in patients with cardiovascular disease. In addition to decreasing low-density lipoproteins, statins have diverse pharmacologic effects, including anti-inflammatory and antithrombotic properties. These effects have prompted speculation that statins may be useful in the treatment or prevention of severe sepsis, a syndrome defined as acute organ dysfunction secondary to infection and characterized by dysregulation of inflammation, coagulation, and other acute phase responses, yet this speculation is also tempered by the very real possibility of increased serious side effects that might occur with more frequent use of statins in acutely ill subjects.
A variety of observational studies have examined the role of statins in the prevention or treatment of infection and sepsis, as recently reviewed. Most suggest a clinical benefit for statins, yet others show no benefit and one shows possible harm. None of these has examined potential mechanisms of benefit. Furthermore, like all observation-based pharmacoepidemiologic studies, these studies are susceptible to a number of confounders and biases analogous to studies of hormone replacement therapy. Indeed, any "benefit" of statins on outcomes of infection may be the result of these and other biases.
Several randomized trials of statins in infection are planned, underway, or recently completed. Unfortunately, these are small studies that are underpowered to address mortality or other clinically meaningful end points. Thus, there remains an unmet need to better understand what, if any, clinical benefit statins may have after appropriate consideration of confounders and biases. Of equal importance is the need to better understand the influence of statins on potential pathophysiological mechanisms. We examined the association of statin use with clinical outcomes and measures of inflammation, coagulation, and lymphocyte cell surface protein expression in a large, multicenter inception cohort study, Genetic and Inflammatory Markers of Sepsis (GenIMS). GenIMS was specifically designed to explore risk factors, including statin use, for the development and progression of severe sepsis and death in patients hospitalized with community-acquired pneumonia (CAP), the most common cause of severe sepsis. Our a priori hypotheses were that statin use would be associated with decreased rates of severe sepsis and death, reduced dysregulation of plasma markers of inflammation and coagulation, and changes in lymphocyte cell surface protein expression but that some of these differences would be explained by patient characteristics, illness severity, indication bias, and healthy user effects.
Abstract and Introduction
Abstract
Objective: To examine the association of statin use with clinical outcomes and circulating biomarkers in community-acquired pneumonia and sepsis.
Design: Multicenter inception cohort study.
Setting: Emergency departments of 28 U.S. hospitals.
Patients: A total of 1895 subjects hospitalized with community-acquired pneumonia.
Interventions: None.
Measurements and Main Results: Our approach consisted of two different comparison cohorts, each reflecting methods used in prior publications in this area. We first compared subjects with prior statin use (prior use cohort), defined as a history of statin use in the week before admission, with those with no prior use. We then compared prior statin users whose statins were continued inhospital (continued use cohort) with those with either no prior use or no inhospital use. We adjusted for patient characteristics, including demographics, comorbid conditions, and illness severity, and accounted for healthy user effect and indication bias using propensity analysis. We determined risk of severe sepsis and 90-day mortality. We measured markers inflammation (tumor necrosis factor, interleukin-6, interleukin-10), coagulation (antithrombin, factor IX, plasminogen activator inhibitor, d-dimer, thrombin antithrombin complex), and lymphocyte cell surface protein expression during the first week of hospitalization. There were no differences in severe sepsis risk between statin users and nonusers for prior (30.8% vs. 30.7%, p = .98) or continued statin use (30.2% vs. 30.8%, p = .85) in univariate analyses and after adjusting for patient characteristics and propensity for statin use. Ninety-day mortality was similar in prior statin users (9.2% vs. 12.0%, p = .11) and lower in continued statin users (7.9% vs. 12.1%, p = .02). After adjusting for patient characteristics and propensity for statin use, there was no mortality benefit for prior (odds ratio, 0.90 [0.63–1.29]; p = .57) or continued statin use (odds ratio, 0.73 [0.47–1.13]; p = .15). Only antithrombin activity over time was higher in statin subjects, yet the magnitude of the difference was modest. There were no differences in other coagulation, inflammatory, or lymphocyte cell surface markers.
Conclusions: We found no evidence of a protective effect for statin use on clinical outcomes and only modest differences in circulating biomarkers in community-acquired pneumonia, perhaps as a result of healthy user effects and indication bias.
Introduction
HMG-CoA reductase inhibitors (statins) are the most prescribed class of drugs in the world and significantly improve survival in patients with cardiovascular disease. In addition to decreasing low-density lipoproteins, statins have diverse pharmacologic effects, including anti-inflammatory and antithrombotic properties. These effects have prompted speculation that statins may be useful in the treatment or prevention of severe sepsis, a syndrome defined as acute organ dysfunction secondary to infection and characterized by dysregulation of inflammation, coagulation, and other acute phase responses, yet this speculation is also tempered by the very real possibility of increased serious side effects that might occur with more frequent use of statins in acutely ill subjects.
A variety of observational studies have examined the role of statins in the prevention or treatment of infection and sepsis, as recently reviewed. Most suggest a clinical benefit for statins, yet others show no benefit and one shows possible harm. None of these has examined potential mechanisms of benefit. Furthermore, like all observation-based pharmacoepidemiologic studies, these studies are susceptible to a number of confounders and biases analogous to studies of hormone replacement therapy. Indeed, any "benefit" of statins on outcomes of infection may be the result of these and other biases.
Several randomized trials of statins in infection are planned, underway, or recently completed. Unfortunately, these are small studies that are underpowered to address mortality or other clinically meaningful end points. Thus, there remains an unmet need to better understand what, if any, clinical benefit statins may have after appropriate consideration of confounders and biases. Of equal importance is the need to better understand the influence of statins on potential pathophysiological mechanisms. We examined the association of statin use with clinical outcomes and measures of inflammation, coagulation, and lymphocyte cell surface protein expression in a large, multicenter inception cohort study, Genetic and Inflammatory Markers of Sepsis (GenIMS). GenIMS was specifically designed to explore risk factors, including statin use, for the development and progression of severe sepsis and death in patients hospitalized with community-acquired pneumonia (CAP), the most common cause of severe sepsis. Our a priori hypotheses were that statin use would be associated with decreased rates of severe sepsis and death, reduced dysregulation of plasma markers of inflammation and coagulation, and changes in lymphocyte cell surface protein expression but that some of these differences would be explained by patient characteristics, illness severity, indication bias, and healthy user effects.
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