3 th Workshop Prctica Clinica Baseada em Evidncias

3 th Workshop Práctica Clinica Baseada em Evidências Rio de Janeiro, 2009 SYSTEMATIC REVIEWS AND META-ANALYSIS Dra. Luz María Letelier Saavedra. Associate Professor, Internal Medicine Faculty of Medicine Pontificia Universidad Católica de Chile

Sailing arround SRs. . . Sa § What is a SR & why are they useful. § How to use / analyze a SR. § Where to find SRs.

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 index 1530 new articles each day. Haynes, ACP 2005

How about RCTs. . . – Cochrane Library gathers 20. 000 new RCTs a year. (58/ day) » Haynes ACP 2005 – Keeps growing. . . .

Dilemma • Need to: Handle large amounts of information in order to deliver the best possible care to our patients • Difficult to: Collect and appraise all these information • FRUSTRATION frustrar-se

Why do we have trouble with information? Difficulties finding the right information • Knowledge and skills for efficient searches • Knowledge of different databases

Lets assume 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.

SEARCHING FOR EVIDENCE VITAMIN A AND LUNG CANCER PREVENTION

Using Pub. Med Search Terms Beta-carotene or vitamin A Hits 2003 33. 000 (Beta-carotene 751 or vitamin A) and lung cancer Hits 2006 40. 065 Hits 2009 45. 656 875 1107

At this point. . Use a more efficient searching tool. Clinical Query: Therapy & specific 94 hits Let’s quickly scan through 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 • CONCLUSIONS: We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alphatocopherol 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 • CONCLUSIONS: 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). • CONCLUSIONS: The PHS found no overall effect of beta-carotene on total cancer, or the three most common site-specific cancers. The possibility of risk reduction within specific subgroups remains.

BETA-CAROTENE AND LUNG CANCER PREVENTION Am J Clin Nutr 2000 Oct; 72(4): 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(8): 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 Recapitulação Summarizing: • 2 studies show benefit • 2 studies show possible harm • 2 studies show neither benefit or harm EVEN WHICH RESULTS DO YOU APPLY?

BETA-CAROTENE AND LUNG CANCER PREVENTION Are the studies similar? v. In their risk of bias (validity) v. In their results v. In their applicability

ENTÃO • Besides handling large amounts of information • How to decide which results to believe. . and apply to our patient?

SOLUÇÃO Destroy the evidence

SOLUÇÃO Collect some information and give your best opinion. “Narrative Review” or expert opinion Better solution? ? ?

SOLUÇÃO • Gather all available information using an explicit, reproducible and systematic method SYSTEMATIC REVIEW

DEFINIÇÃO DEFINI 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 methods to summarize the results of a Systematic Review

REVIEWS Narrative Systematic Ø Review a topic in several different aspects. Ø No explicit method for searching the evidence. Ø No explicit method for selecting information. Ø No explicit method for appraising information Ø Should not have statistical analysis. Ø Answers a specific question. Ø Explicit method for searching the evidence Ø Explicit method for selecting information. Ø Explicit method for appraissing information. Ø Might have statistical analysis.

Sailing arround SRs. . . Sa ü What are SR & why are they useful. § How to appraise a SR. § Where to find SRs.

Appraising a SR STEP 1 DEFINING THE QUESTION: SENSIBLE AND SPECIFIC Ø Ø Any antibiotic for any infection Any macrolide for any respiratory infection Claritromicine for Community Acquired Pneumonia (CAP) ATS I&II Claritromicine 250 vs 500 bid for CAP in 20 years old patients with asthma and allergy to penicillin. NOT TOO BROAD NOT TOO NARROW

Appraising a SR STEP 2 INCLUSION - EXCLUSION CRITERIA Ø Explicit and related to the question Ø Easy to apply by different reviewers Ø Applied before knowing studies’s results

Appraising a SR STEP 3 SEARCH FOR ALL AVAILABLE EVIDENCE Ø Sensitive search strategy: Ø Several databases. Ø Hand search: Ø References Ø Grey literature: abstracts from conferences Ø Ask experts and researchers on the topic, for unpublished data. AVOID PUBLICATION BIAS

Appraising a SR STEP 4 CRITICAL APPRAISAL OF INCLUDED STUDIES Ø Very important Ø Could be done: ØDescriptive ØQuantitative: Scores (ie. Jadad score)

Appraising a SR STEP 5 REPRODUCIBILITY OF PROCESS 2 Reviewers: ØSelection ØInclusion ØCritical Appraisal REDUCE BIAS AND RANDOM ERROR

Appraising a SR STEP 6 STATISTICAL ANALYSIS (META – ANALYSIS) Ø Establish possible sources of heterogeneity, a priori. Ø Test for heterogeneity: Q, chi square, I 2 Ø Decide whether to pool or not

I 2=4, 21% I 2=8, 45%

EBM: The explicit, conscientious, judicious use of the best available evidence in clinical decision making. . . HIERARQY OF EVIDENCE Systematic Review of RCT Bias + Precision ++ Bias +++ Randomized Trials (RCT) Observational Studies Clinical Experience or Case Reports

SYSTEMATIC REVIEW Best evidence only if method is correct. Should be critically appraised.

Hormonal replacement therapy to prevent coronary events in postmenopausal women: Meta-analysis of observational studies 1992 Annals of Internal Medicine versus RCTs HERS WHI 1998 2002

SYSTEMATIC REVIEWS

Sailing arround SRs. . . Sa ü What are SR & why are they useful. ü 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) 5. 676 (2009) Database of Abstracts of Reviews of Effectiveness • 3. 075 (2004) • 6. 019 (2006) • 9. 403 (2009)

Back to our question. . 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 The Cochrane Database of Systematic Reviews 2006 Issue 2 • 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.

RECAPITULAÇÃO SYSTEMATICS REVIEWS : ü Summarizes evidence regarding a specific question. ü Should have explicit methods to minimize bias. ü Should be critically appraised by users. ü If methodologically well done = highest level of evidence. ü Important tool to evidence based health care as they help handling large amounts of information.

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