2. 3th 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

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

4. 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?

5. Informação disponíveis Available information Medline index 1530 new articles each day. Haynes, ACP 2005

6. How about RCTs... –Cochrane Library gathers 20.000 new RCTs a year. (58/ day) »Haynes ACP 2005 –Keeps growing.......

7. 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-seFRUSTRATION frustrar-se

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

9. 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. Lets assume

10. SEARCHING FOR EVIDENCE VITAMIN A AND LUNG CANCER PREVENTION

11. Using PubMed Search TermsHits 2003 Hits 2006 Hits 2009 Beta-carotene or vitamin A 33.00040.06545.656 (Beta-carotene or vitamin A) and lung cancer 7518751107

12. At this point.... Use a more efficient searching tool. Clinical Query: Therapy & specific 94 hits Let’s quickly scan through the titles and abstracts.....

13. 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 alpha- tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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?

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

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

21. SOLUÇÃO Destroy the evidence

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

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

24. DEFINIÇÃO SYSTEMATIC REVIEW Summary of ALL available information regarding a specific clinical question, using explicit methods towards reducing bias. Therapy / diagnosis / prognosis questions.

25. META - ANALYSIS Statistical methods to summarize the results of a Systematic Review DEFINIÇÃO

26. REVIEWS Narrative  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. Systematic  Answers a specific question.  Explicit method for searching the evidence  Explicit method for selecting information.  Explicit method for appraissing information.  Might have statistical analysis.

27. Sailing arround SRs..... What are SR & why are they useful.  How to appraise a SR.  Where to find SRs.

28. Appraising a Appraising a SR STEP 1 DEFINING THE QUESTION: SENSIBLE AND SPECIFIC  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

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

30. Appraising a 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

31. Appraising a Appraising a SR STEP 4 CRITICAL APPRAISAL OF INCLUDED STUDIES  Very important  Could be done:  Descriptive  Quantitative: Scores (ie. Jadad score)

32. Appraising a Appraising a SR STEP 5 REPRODUCIBILITY OF PROCESS 2 Reviewers:  Selection  Inclusion  Critical Appraisal REDUCE BIAS AND RANDOM ERROR

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

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

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

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

38. Hormonal replacement therapy to prevent coronary events in post- menopausal women: Meta-analysis of observational studies 1992 Annals of Internal Medicine versus RCTsHERS 1998 WHI2002

39. SYSTEMATIC REVIEWS

40. Sailing arround SRs..... What are SR & why are they useful. How to appraise a SR.  Where to find SRs.

41. Where to find SRs? Pubmed: –Clinical Query SR –Límits: publication type: Meta-analysis Databases of SR

43. 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)

45. Back to our question.... Lung cancer prevention and beta- carotene. Searching the Cochrane Database of Systematic Reviews.

46. 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

47. 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

48. 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

49. 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.

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

51. OBRIGADA PERGUNTAS COMMENTS COMPLAINTS