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      Systematic Review and Meta-Analysis on the Association between Outpatient Statins Use and Infectious Disease-Related Mortality

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          Abstract

          Background

          To update and refine systematic literature review on the association between outpatient statins use and mortality in patients with infectious disease.

          Materials and Methods

          We searched articles published before September 31, 2012, on the association between statins and infectious disease-related mortality through electronic databases. Eligible articles were analyzed in Review Manager 5.1. We conducted stratification analysis by study design, infection types, clinical outcomes and study locations.

          Results

          The pooled odds ratio (OR) for death (statins use vs. no use) across the 41 included studies was 0.71 (95% confidence interval: 0.64, 0.78). The corresponding pooled ORs were 0.58 (0.38, 0.90), 0.66 (0.57, 0.75), 0.71 (0.57, 0.89) and 0.83 (0.67, 1.04) for the case-control study, retrospective cohort studies, prospective cohort studies and RCTs; 0.40 (0.20, 0.78), 0.61 (0.41, 0.90), 0.69 (0.62, 0.78) and 0.86 (0.68, 1.09) for bacteremia, sepsis, pneumonia and other infections; 0.62 (0.534, 0.72), 0.68 (0.53, 0.89), 0.71 (0.61, 0.83) and 0.86 (0.70, 1.07) for 30-day, 90-day, in-hospital and long-term (>1 year) mortality, respectively.

          Conclusions

          Outpatient statins use is associated with a lower risk of death in patients with infectious disease in observational studies, but in a less extent in clinical trials. This association also varies considerably by infection types and clinical outcomes.

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          Most cited references 46

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          Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.

          Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331.) 2009 Massachusetts Medical Society
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            Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.

            Large observational studies, small prospective studies and post-hoc analyses of randomised clinical trials have suggested that statins could be beneficial in patients with chronic heart failure. However, previous studies have been methodologically weak. We investigated the efficacy and safety of the statin rosuvastatin in patients with heart failure. We undertook a randomised, double-blind, placebo-controlled trial in 326 cardiology and 31 internal medicine centres in Italy. We enrolled patients aged 18 years or older with chronic heart failure of New York Heart Association class II-IV, irrespective of cause and left ventricular ejection fraction, and randomly assigned them to rosuvastatin 10 mg daily (n=2285) or placebo (n=2289) by a concealed, computerised telephone randomisation system. Patients were followed up for a median of 3.9 years (IQR 3.0-4.4). Primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00336336. We analysed all randomised patients. 657 (29%) patients died from any cause in the rosuvastatin group and 644 (28%) in the placebo group (adjusted hazard ratio [HR] 1.00 [95.5% CI 0.898-1.122], p=0.943). 1305 (57%) patients in the rosuvastatin group and 1283 (56%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR 1.01 [99% CI 0.908-1.112], p=0.903). In both groups, gastrointestinal disorders were the most frequent adverse reaction (34 [1%] rosuvastatin group vs 44 [2%] placebo group). Rosuvastatin 10 mg daily did not affect clinical outcomes in patients with chronic heart failure of any cause, in whom the drug was safe.
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              Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site.

              The beta2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1-mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                17 December 2012
                : 7
                : 12
                Affiliations
                [1 ]Department of Epidemiology and Biostatistics, School of Public Health, Key Laboratory of Tropical Diseases Control Research, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong Province, PR China
                [2 ]Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, United States of America
                [3 ]Department of Epidemiology and Biostatistics, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong Province, PR China
                [4 ]School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong Province, PR China
                [5 ]Laboratory Animal Center, Sun Yat-Sen University, Guangzhou, Guangdong Province, PR China
                University of Hong Kong, Hong Kong
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YM XZW JHL JP ZMG. Performed the experiments: YM JP YL ZMG. Analyzed the data: YM XZW ZMG JHL. Contributed reagents/materials/analysis tools: YM JP YL. Wrote the paper: YM.

                Article
                PONE-D-12-17556
                10.1371/journal.pone.0051548
                3524177
                23284711

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 14
                Funding
                This project was supported by the Natural Science Foundation of China (NSFC) [grant No. 81172735] ( http://159.226.244.22/portal/Proj_List.asp). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Cardiovascular
                Atherosclerosis
                Clinical Research Design
                Meta-Analyses
                Systematic Reviews
                Critical Care and Emergency Medicine
                Sepsis
                Epidemiology
                Clinical Epidemiology
                Infectious Disease Epidemiology
                Infectious Diseases
                Bacterial Diseases
                Bacteremia
                Bacterial Pneumonia
                Septicemic Plagues
                Viral Diseases
                Influenza
                Infectious Disease Control

                Uncategorized

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