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Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy |
Cannon C P, Steinberg B A, Murphy S A, Mega J L, Braunwald E |
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CRD summary The authors concluded that intensive statin treatment offers greater benefits than standard-dose treatment, mainly for nonfatal cardiovascular events. The review appears to support the authors' conclusions, but the poor reporting of review methods and the lack of an assessment of study quality mean that the reliability of the conclusions is uncertain. Authors' objectives To compare the effects of intensive versus standard-dose statin treatment on cardiovascular outcomes. Searching PubMed was searched and references of original studies and reviews and were screened. The dates searched and search terms used were not reported. Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) that had more than 1,000 patients and were adequately powered to detect clinical end points were eligible for inclusion. The duration of the included studies was reported as a mean of 24 months or as a median ranging from 721 days to 4.9 years. Specific interventions included in the reviewStudies that compared intensive with standard-dose statin treatment were eligible for inclusion. The reviewers accepted the original authors' classification of intensive and standard-dose treatment. The included studies compared 40 mg pravastatin versus 80 mg atorovastatin, 10 mg versus 80 mg atorovastatin, placebo followed by 20 mg simvastatin versus 40 mg simvastatin followed by 80 mg simvastatin, and 20 mg simvastatin titrated to 40 mg versus 80 mg atorovastatin. Participants included in the reviewStudies of patients with stable coronary artery disease or acute coronary syndromes (ACS) were eligible for inclusion. In the included studies, about one quarter of all patients (range: 0% to 75.5%) had previously been taking statins. Outcomes assessed in the reviewStudies that reported clinical outcomes were eligible for inclusion. The review assessed the combined outcome of coronary death or nonfatal myocardial infarction (MI), the combined outcome of coronary death or any cardiovascular event (MI, stroke, hospitalisation for unstable angina and revascularisation), stroke, and the combined outcome of cardiovascular, non-cardivascular and all-cause mortality. The review also assessed low-density lipoprotein (LDL) cholesterol values and severe adverse events. Individual studies used different definitions for coronary death and any adverse cardiovascular outcome. How were decisions on the relevance of primary studies made?The authors did not state how the papers were selected for the review, or how many reviewers performed the selection. Assessment of study quality The authors did not state that they assessed validity. Data extraction The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. For each study, baseline LDL values and end point LDL values (on-treatment means for the study duration based on intention-to-treat populations), event rates for each treatment arm, and odds reductions for outcomes of interest were presented. To ensure similarity of definitions across all studies, the reviewers included revascularisation at any time and only coronary death in the combined outcome of all cardiovascular events. Methods of synthesis How were the studies combined?Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed-effect Mantel-Haenszel model. Odds reductions were also presented. How were differences between studies investigated?Analyses were repeated using a random-effects model. Results of the review Four RCTs (n=27,548) were included. The mean difference in the reduction in LDL cholesterol from baseline between intensive and standard-dose statin treatment was 25.7% (101 versus 75 mg/dL). Compared with standard-dose statin treatment, intensive statin treatment was associated with a statistically significant reduction in coronary death or MI (9.4% with standard dose versus 8.0% with intensive treatment; OR 0.84, 95% CI: 0.77, 0.91, p<0.00001), coronary death or adverse cardiovascular events (32.3% versus 28.8%; OR 0.84, 95% CI: 0.80, 0.89, p<0.0000001), stroke (2.8% versus 2.3%; OR 0.82, 95% CI: 0.71, 0.96, p=0.012) and coronary heart disease death or MI (16.5% odds reduction; OR 0.835, 95% CI: 0.77, 0.91, p<0.0001). Intensive statin treatment was also associated with a non-statistically significant reduction in cardiovascular mortality (3.8% with standard dose versus 3.3% with intensive treatment; OR 0.88, 95% CI: 0.78, 1.00, p=0.054) and all-cause mortality (6.2% versus 5.9%; OR 0.94, 95% CI: 0.85, 1.04, p=0.20). Severe adverse effects reported included rhabdomyolysis (similar incidence in both treatment arms), and elevated creatine kinase or aspartate aminotransferase/alanine aminotransferase levels (higher incidence in high-dose treatment arms). Authors' conclusions Intensive statin treatment offers greater benefits than standard-dose treatment, mainly for nonfatal cardiovascular events. CRD commentary The review addressed a clear question that was defined in terms of the participants, intervention, outcomes and study design. Only one database was searched, the search strategy was not completely described, and no specific attempts to minimise either publication or language bias were reported. However, the limited search was likely to have identified most studies with the large required minimum sample size. The methods used to select the studies and extract the data were not described, so it is not known whether any efforts were made to reduce reviewer errors and bias. Only large RCTs were included but, since study validity was not assessed, the results from these studies and any synthesis may not be reliable. The studies were appropriately pooled using a meta-analysis and forest plots were presented. The review appears to support the authors' conclusions, but the lack of reporting of review methods and the lack of an assessment of study quality mean that the reliability of the conclusions is uncertain. Implications of the review for practice and research Practice: The authors stated that review findings support the National Cholesterol Education Program 2004 amendment to the Adult Panel III Guidelines (see Other Publications of Related Interest, nos.1-2). They also recommended that intensive statin treatment should be considered for secondary prevention on the same basis as other proven treatments, and that clinicians should ensure that a higher percentage of eligible patients receive the appropriate evidence-based dose of statins. Research: The authors did not state any implications for further research. They stated that there were ongoing trials evaluating cost-benefits and more intensive regimens. Bibliographic details Cannon C P, Steinberg B A, Murphy S A, Mega J L, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. Journal of the American College of Cardiology 2006; 48(3): 438-445 Other publications of related interest 1. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39. 2. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2002;285:2486-97. Indexing Status Subject indexing assigned by NLM MeSH Cardiovascular Diseases /prevention & Coronary Disease /drug therapy; Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors /administration & Randomized Controlled Trials as Topic; Syndrome; Treatment Outcome; control; dosage /therapeutic use AccessionNumber 12006003733 Date bibliographic record published 30/09/2007 Date abstract record published 30/09/2007 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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