Kardiolunch, 11.2.2014 Meta-analysen Methodik für Mediziner PD Dr Matthias Briel Basel Institute for Clin Epi & Biostats, Switzerland McMaster University, Hamilton, Canada
Agenda SystematischeReviews & Meta-analysen I. Was istdas? II. Wozubrauchtman das? III. Wieliestman das? IV. Wiemachtman das?
What is a Systematic Review and what is a Meta-analysis?
Feature Narrative Review Systematic Review Question Not explicit/broad Focused Search strategy Not specified Reproducible Selection criteria Absent Clearly defined Methodological appraisal of primary studies Possible/No Yes Synthesis of results Uncommon/ qualitative Quantitative (Meta-analysis)
Lancet. 2007 Aug 18;370(9587):604-18. Review. Bsp. Narrativer Review oder Experten-Review
Feature Narrative Review Systematic Review Question Not explicit/broad Focused Search strategy Not specified Reproducible Selection criteria Absent Clearly defined Methodological appraisal of primary studies Possible/No Yes Synthesis of results Uncommon/ qualitative Quantitative (Meta-analysis)
ForestPlot -Example Study Risk ratio (95% CI) % Weight Morice (2002) 1.97 (0.50,7.68) 18.7 Schofer (2003) 0.81 (0.22,2.96) 30.6 Moses (2003) 1.55 (0.60,3.96) 43.5 Grube (2003) 2.91 (0.12,68.66) 3.1 Park (2003) 1.53 (0.06,36.88) 4.1 Overall (95% CI) Favors DES Favors BMS 1.44 (0.77,2.70).1 1 10 Risk ratio
Why do Systematic Reviews?
Whydo SystematicReviews? Synthesis ofavailableevidence in preparation for own study aspartofa grantsubmission to inform decisions in clinical practice and policy (clinical guidelines) as scientific publication
Howtoreada SystematicReview?
Criteria for Systematic Reviews 1. Are the results valid (internal validity)? - Explicit & focused clinical question
Example: Study Question P I C O In Patients with heartdisease(chd) whatistheeffectofdifferent lipid-modifying Interventions coronary Compared with placebo or no intervention on patient-relevant Outcomes(mortality, myocardialinfarction(mi), stroke)?
Criteria for Systematic Reviews 1. Are the results valid (internal validity)? - Explicit & focused clinical question - Explicit & appropriate eligibility criteria
Example: EligibilityCriteria Inclusion criteria: RCTs - comparing any lipid-modifying agent or diet with placebo or usual care - targeting reduction in CV risk - reporting mortality data -follow-upofatleast 6 months Exclusion criteria: - outdated interventions: hormones, ileal bypass surgery - combination of lipid-lowering interventions - restricted to heart transplant recipients
Criteria for Systematic Reviews 1. Are the results valid (internal validity)? - Explicit & focused clinical question - Explicit & appropriate eligibility criteria - Study search detailed& exhaustive
Example: SystematicSearch Electronic databases - MEDLINE, EMBASE, CENTRAL Handsearching - conference proceedings, thesis registries Reference lists/bibliographies - identified articles, reviews on the topic Trial registries for ongoing studies Contacting experts, companies, etc.
Criteria for Systematic Reviews 1. Are the results valid (internal validity)? - Explicit & focused clinical question - Explicit & appropriate eligibility criteria - Study search detailed& exhaustive - Methodological quality of primary studies
Methodologic Quality risk of bias from design, conduct Randomization allocation concealment Blinding patients caregivers adjudicators of outcome Loss to follow-up minimal
Why we err Two fundamental reasons studies mislead 1. Random error 2. Bias (systematic error) due to poor methodological quality Garbage in, garbage out
Criteria for Systematic Reviews 1. Are the results valid (internal validity)? - Explicit & focused clinical question - Explicit & appropriate eligibility criteria - Study search detailed& exhaustive - Methodological quality of primary studies - Assessments reproducible Keywords: 2 reviewers independent & in duplicate, κ or φ statistic
Criteria for Systematic Reviews 2. What are the results? - Overall results of the review? - Precision of the results?
Criteria for Systematic Reviews 2. What are the results? - Overall results of the review? - Precision of the results? -Resultssimilarfromstudytostudy? (homogeneity vs heterogeneity)
Homogenous If this result, what next? Relative Risk (95% CI) 0.73 (0.49, 1.07) 0.74 (0.59, 0.94) 0.76 (0.51, 1.12) 0.71 (0.56, 0.90) 0.73 (0.61, 0.88) p=0.99 for heterogeneity I 2 =0% 0.5 1
Heterogeneous If this result, what next? Relative Risk (95% CI) 0.44 (0.30, 0.65) 0.45 (0.36, 0.60) 1.25 (0.84, 1.84) 1.17 (0.92, 1.49) 0.73 (0.61, 0.88) p-value for heterogeneity < 0.001 I 2 =89% 0.5 1
Explaining heterogeneity Magnitude of effect in studies with and without characteristic (subgroups, stratification) Patient baseline characteristic Concealment, blinding, loss to follow-up Other trial characteristics (e.g. geographic area)
Heterogeneous Explaining factors: Relative Risk (95% CI) Diabetic { 0.44 (0.30, 0.65) 0.45 (0.36, 0.60) Non-Diabetic { 1.25 (0.84, 1.84) 1.17 (0.92, 1.49) 0.73 (0.61, 0.88) p-value for heterogeneity < 0.001 I 2 =89% 0.5 1
Heterogeneous Explaining factors: Relative Risk (95% CI) Unblinded { 0.44 (0.30, 0.65) 0.45 (0.36, 0.60) Blinded { 1.25 (0.84, 1.84) 1.17 (0.92, 1.49) 0.73 (0.61, 0.88) p-value for heterogeneity < 0.001 I 2 =89% 0.5 1
Criteria for Systematic Reviews 3. How to apply results to patient care(external validity)? - All patient important outcomes considered? - Effects clinically relevant? - Results applicable to my patient? - Values & preferences of my patient? -Benefitsworththecostsandpotential harms/risks?
Conductofa Systematic Review Summary
General Process/Summary (1) Clear studyquestion(pico) Systematicliteraturesearch Determiningeligibilityusingexplicit criteria -screeningoftitles& abstracts -fulltextscreening
Example: Trial flow 10,532 potentially relevant articles identified and screened for retrieval 572 articles retrieved in full text for more detailed evaluation 158 potentially appropriate RCTs to be included in the meta-analysis 108 RCTs included in the metaanalysis 9,960 articles excluded based on title and abstract using inclusion criteria 414 articles excluded, with reason: 10 not aiming at cardiovascular risk 21 no parallel-group RCT 173 not reporting deaths or MIs per group 134 follow-up < 6 months 76 duplicates, protocols, substudies of trials 50 RCTs excluded, with reasons: no follow-up values reported for LDL- and HDL-cholesterol 108 RCTs with usable information, by outcome Briel, Ferreira-Gonzalez et al. BMJ 2009
General Process/Summary (1) Clear study question(pico) Systematic literature search Determining eligibility using explicit criteria - screening of titles& abstracts - full text screening Assessing methodological quality Extracting relevant data Seeking unpublished data if needed
General Process/Summary (2) If possible, quantitative pooling using appropriate methods Meta-analysis (fixed vs random effects model) Assessing& explaining heterogeneity Reporting (PRISMA statement) Moheret al. Ann Intern Med 2009
Andreas Möller: Wir sind an ein Limit gekommen, wo es im Moment nicht drübergeht
Referenz Nordmann AJ, Kasenda B, Briel M. Meta-analyses: what they can and cannot do. Swiss Med Wkly2012;142:w13518
Vielen Dank! matthias.briel@usb.ch