4th Workshop Prática Clinica Baseada em Evidências Rio de Janeiro, 2010
REVISÕES SISTEMÁTICAS: Como interpretá-las? SYSTEMATIC REVIEWS: How to interpret them Luz M. Letelier Associate Professor, Internal Medicine Faculty of Medicine, Pontificia Universidad Católica de Chile
Navegando pelas RSs Sailing arround SRs.....
What is a SR & why are they useful. How to use / analyze a SR. Where to find SRs.
Estamos atualizados em relaçã rela o a conhecimento médico? Are we up-to-date on medical information?
• How many articles do you read a month? • How many should you read? • How big is the gap?
Informação disponíveis Available information Medline indexes 1530 new articles each day. Haynes, ACP 2005
Cochrane Library gathers 20.000 new RCTs a year. (58/day) Haynes ACP 2005 > 6200 SRs in the Cochrane Library (today)
Keeps growing…
Entã Ent o, tem algum problema? Are we in trouble?? • We need to handle large amounts of information in order to deliver the best care to our patients
• We find it difficult to collect and appraise all these information.
•FRUSTRAÇÃO •FRUSTRATION
Why do we have trouble collecting information?
• Huge amounts of information • Lack of skills for efficient searches….
During the workshop You are experts on efficient literature searches. CLINICAL SCENARIO Your last patient, a heavy smoker, asks if he should take vitamin A to prevent lung cancer.
√
SEARCH FOR EVIDENCE
• • • •
P: SMOKERS I: VITAMIN A C: NO TREATMENT O: REDUCE LUNG CANCER
Using PubMed Search Terms Hits 2003
Hits 2006
Hits 2009
Hits 2010
Beta-carotene or vitamin A
40.065
45.656
48.117
875
1107
1154
33.000
(Beta-carotene 751 or vitamin A) and lung cancer
At this point.... Use a more efficient searching tool‌. Clinical Query: Therapy & specific 99 hits Let’s quickly screen the titles and abstracts.....
BETA-CAROTENE AND LUNG CANCER PREVENTION • NEJM 1994; 330:1029-1035 • The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. Beta Carotene Cancer Prevention Study Group The Alpha-Tocopherol
• CONCLUSION: We found no reduction in the incidence of
lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.
BETA-CAROTENE AND LUNG CANCER PREVENTION • N Engl J Med 1996 May 2;334(18):1150-5 • Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease. CARET Study
• CONCLUSION: After an average of four years of
supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
BETA-CAROTENE AND LUNG CANCER PREVENTION Cancer Causes Control 2000 Aug;11(7):617-26 • Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians' Health Study (PHS). • CONCLUSION: The PHS found no overall effect of betacarotene on total cancer, or the three most common sitespecific cancers. The possibility of risk reduction within specific subgroups remains.
BETA-CAROTENE AND LUNG CANCER PREVENTION Am J Clin Nutr 2000 Oct;72:990-7 Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts CONCLUSION: Data from 2 cohort studies suggest that several carotenoids may reduce the risk of lung cancer.
BETA-CAROTENE AND LUNG CANCER PREVENTION Cancer Epidemiol Biomarkers Prev. 2006 ;15:1562-4. Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China. CONCLUSION: Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian, China.
BETA-CAROTENE AND LUNG CANCER PREVENTION Rev Med Suisse. 2010 May 26;6:1046-8, 1050-2. • Nutrition and physical activity: two targets for cancer prevention. The links between nutrition and cancer onset are now well established by epidemiological studies. The scientific evidence is presented in a report of the World Cancer Research Foundation (WCRF). Protective factors towards overall cancer risk are fruit and vegetable consumption and physical activity. Overweight and obesity, intakes of alcoholic beverage, fat, salt, high temperature cooked and processed red meat, increase cancer risk. In addition, beta-carotene systematic supplementation could increase lung cancer risk in smokers. As optimal controlling of these risk factors can decrease cancer mortality by 25%, nutritional counselling must be integrated in the global strategy of primary and secondary prevention of cancers.
Resumindo (Summarizing) BETA-CAROTENE AND LUNG CANCER PREVENTION • These supplements may have harmful as well as beneficial effects. 1994 • Vitamin A had no benefit and may have adverse effect on the incidence of lung cancer 1996 • No overall effect of beta-carotene on total cancer 2000 • Several carotenoids may reduce the risk of lung cancer. 2000 • Supplementation did not reduce lung cancer mortality 2006 • Beta-carotene supplementation could increase lung cancer risk in smokers 2010
QUAIS RESULTADOS EU DEVO APLICAR? WHICH RESULTS SHOULD I APPLY?
QUAIS RESULTADOS EU DEVO APLICAR? WHICH RESULTS SHOULD I APPLY?
a) b) c) d) e)
The last one All of them The biggest one The one in the best journal Another solution Are the studies similar? In their risk of bias (validity) In their results In their applicability
ENTﾃグ... SO....
Besides handling large amounts of information we need to decide which results to believe....and apply to our patient.
SOLUÇÃO (1) DESTROY THE EVIDENCE
SOLUÇÃO (2) Collect some information and give your best opinion.
“Narrative Review” or expert opinion Good solution???
SOLUÇÃO • Gather all available information using explicit, reproducible and systematic method
REVISÕES SISTEMÁTICAS SYSTEMATIC REVIEW
DEFINIÇÃO REVISÕES SISTEMÁTICAS SYSTEMATIC REVIEW Summary of ALL available information regarding a specific clinical question, using explicit methods towards reducing bias. Therapy / diagnosis / prognosis questions.
DEFINIÇÃO META - ANALYSIS Statistical method to summarize the results of a Systematic Review
REVISÕES Reviews Narrative Systematic Review a topic in several different aspects. No explicit method for searching the evidence. No explicit method for selecting information. No explicit method for appraising information Should not have statistical analysis.
Answers a specific question. Explicit method for searching the evidence Explicit method for selecting information. Explicit method for appraising information. Might have statistical analysis (Meta-analysis)
Navegando pelas RSs Sailing arround SRs…next STOP SRs what are they & why are they useful. How to use/appraise a SR Where to find SRs.
Appraising a SR STEP 1 IS THERE A SENSIBLE AND SPECIFIC QUESTION?
Any antibiotic for any infection Any macrolide for any respiratory infection Any dose of claritromicine for Community Acquired Pneumonia (CAP) ATS I&II Claritromicine 250 mg vs 500mg bid for CAP in patients 20 years old with asthma and allergy to penicillin. TO REMEMBER: NOT TOO BROAD NOT TOO NARROW
Appraising a SR STEP 2 INCLUSION - EXCLUSION CRITERIA Explicit and related to the question Easy to apply by different reviewers Applied regardless of studies’s results
Appraising a SR STEP 3 SEARCH FOR ALL AVAILABLE EVIDENCE Sensitive search strategy: Several databases. Hand search: References Grey literature: abstracts from conferences
Ask experts and researchers on the topic, for unpublished data.
AVOID PUBLICATION BIAS
Appraising a SR STEP 4 CRITICAL APPRAISAL OF INCLUDED STUDIES
Very important Avoid “garbage in”
“garbage out”
Could be done: Descriptive Quantitative: Scores (ie. Jadad score)
COCHRANE COLLABORATION’S APPROACH: Methodological quality summary: review authors’ judgments about each methodological quality item for each included study.
EBM: The judicious use of the best available evidence in clinical decision making
HIERARQY OF EVIDENCE Systematic Review of RCT Bias + Precision ++ Applicability ++
Randomized Clinical Trials (RCT) Bias +
Observational Studies Bias ++
Clinical Experience or Case Reports Bias +++
REVISÕES SISTEMÁTICAS SYSTEMATIC REVIEWS
Best evidence only if methods of the SR & of included trials avoid bias. Should be critically appraised.
Hormonal replacement therapy to reduce coronary events in post-menopausal women Meta-analysis of observational studies 1992 Annals of Internal Medicine RCTs
versus HERS 1998 WHI 2002
Appraising a SR STEP 5 REPRODUCIBILITY OF PROCESS 2 independent reviewers: Selection Inclusion Critical Appraisal REDUCE BIAS AND RANDOM ERROR
Appraising a SR STEP 6 STATISTICAL ANALYSIS (META – ANALYSIS) Establish a priori possible sources of heterogeneity. Test for heterogeneity: Q statistic chi square (χ2) I2
Decide whether to pool or not
I2=4,21%
I2=8,45%
O que fazer com esta informação? What would you do with this information?
O que fazer agora? What would you do now?
Remember
Always consider all posible outcomes. Consider patients values or preferences. SRs do not make decisions. SRs inform decisions.
Navegando pelas RSs Sailing arround SRs..... What are SR & why are they useful. How to appraise a SR. Where to find SRs.
Where to find SRs? • Pubmed: – Clinical Query SR – Límits: publication type: Meta-analysis
• Databases of SR
THE COCHRANE LIBRARY The Cochrane Database of Systematic Reviews • S. Reviews: 1.596 (2003) 4.320 (2006) 6.200 (2010) Database of Abstracts of Reviews of Effectiveness • 3.075 (2004) • 6.019 (2006) • 9.403 (2009)
Back to our question.... P: SMOKERS I: VITAMIN A C: NO TREATMENT O: REDUCE LUNG CANCER
Lung cancer prevention and betacarotene. Searching the Cochrane Database of Systematic Reviews.
BETA-CAROTENE AND LUNG CANCER PREVENTION
• Drugs for preventing lung cancer in healthy people. M Caraballoso, M Sacristan, C Serra, X Bonfill
Publication status and date: Edited (no change to conclusions), published in Issue 4, 2009. • Review content assessed as up-to-date: 30 January 2003
• Includes beta – carotene • Includes smokers
BETA-CAROTENE AND LUNG CANCER PREVENTION •
Drugs for preventing lung cancer in healthy people M Caraballoso, M Sacristan, C Serra, X Bonfill The Cochrane Database of Systematic Reviews 2006 Issue 2
Pre-defined method: • 4 RCTs • 109.304 participants • Beta-carotene alone or combined to other antioxidants • Placebo controlled • Duration of treatment 2 to 12 years • Follow up 2 a 5 years
Drugs for preventing lung cancer in healthy people M Caraballoso, M Sacristan, C Serra, X Bonfill The Cochrane Database of Systematic Reviews 2006 Issue 2
BETA-CAROTENE AND LUNG CANCER PREVENTION •
Drugs for preventing lung cancer in healthy people M Caraballoso, M Sacristan, C Serra, X Bonfill The Cochrane Database of Systematic Reviews 2006 Issue 2
• Authors' conclusions • There is currently no evidence to support recommending vitamins such as alpha-tocopherol, beta-carotene or retinol, alone or in combination, to prevent lung cancer. A harmful effect was found for beta-carotene with retinol at pharmacological doses in people with risk factors for lung cancer (smoking and/or occupational exposure to asbestos). More research from larger trials and with longer follow-up is needed to analyze the effectiveness of other supplements.
MENSAGENS PARA CASA TAKE HOME MESSAGES
CONCLUSÕES SYSTEMATICS REVIEWS : Summarizes evidence regarding a specific question. Should have explicit methods to minimize bias. Should be critically appraised by consumers (VOCE). If methodologically well done = highest level of evidence. Important tool to evidence based health care as they help handling large amounts of information.
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