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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

Systematic Reviews

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Presented by Luz Letelier at Rio Workshop 2010

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Page 1: Systematic Reviews

4th WorkshopPrática 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

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Navegando pelas RSsSailing arround SRs.....

What is a SR & why are they useful.

How to use / analyze a SR.

Where to find SRs.

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Estamos atualizados em relaEstamos atualizados em relação a o a conhecimento médico? conhecimento médico?

AreAre we up-to-date on medical information? 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?

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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…

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EntEntão, tem algum problema?o, tem algum problema?Are we in trouble??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.

•FRUSTRAFRUSTRAÇÇÃOO•FRUSTRATIONFRUSTRATION

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Why do we have trouble collecting information?Why do we have trouble collecting information?

• Huge amounts of information• Lack of skills for efficient searches….

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You are experts on efficient literature searches. √

CLINICAL SCENARIOYour last patient, a heavy smoker, asks if he should take vitamin A to prevent lung cancer.

During the workshopDuring the workshop

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SEARCH FOR EVIDENCESEARCH FOR EVIDENCE

• P: SMOKERS• I: VITAMIN A • C: NO TREATMENT• O: REDUCE LUNG CANCER

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Using PubMedUsing PubMed

Search Terms Hits2003

Hits2006

Hits2009

Hits2010

Beta-carotene or vitamin A

33.000 40.065 45.656 48.117

(Beta-carotene or vitamin A) and lung cancer

751 875 1107 1154

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At this point....At this point....Use a more efficient searching tool….

Clinical Query: Therapy & specific

99 hits

Let’s quickly screen the titles and abstracts.....

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BETA-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER CANCER PREVENPREVENTTIONION

• 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.

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BETA-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER CANCER PREVENPREVENTTIONION

• 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.

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BETA-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER CANCER PREVENPREVENTTIONION

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 beta-carotene on total cancer, or the three most common site-specific cancers. The possibility of risk reduction within

specific subgroups remains.

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BETA-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER CANCER PREVENPREVENTTIONION

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.

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BETA-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER PREVEN CANCER PREVENTTIONION

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.

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BETA-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER CANCER PREVENPREVENTTIONION

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.

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RResumindo (esumindo (Summarizing)Summarizing) BETA-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER PREVEN CANCER PREVENTTIONION

• 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?

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QUAIS RESULTADOS EU DEVO APLICAR?WHICH RESULTS SHOULD I APPLY?

a) The last oneb) All of themc) The biggest oned) The one in the best journale) Another solution

Are the studies similar? In their risk of bias (validity) In their results In their applicability

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ENTÃO...SO....

Besides handling large amounts of information we need to decide which results to believe....and apply to our patient.

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SOLUÇÃO (1)

DESTROY THE EVIDENCE

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SOLUÇÃO (2) Collect some information and give your best opinion.

“Narrative Review”or expert opinion

Good solution???

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SOLUÇÃO • Gather all available information using explicit,

reproducible and systematic method

REVISÕES SISTEMÁTICAS

SYSTEMATIC REVIEW

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DEFINIÇÃOREVISÕES SISTEMÁTICAS

SYSTEMATIC REVIEW

Summary of ALL available information regarding a specific clinical question, using explicit methods towards reducing bias.

Therapy / diagnosis / prognosis questions.

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META - ANALYSISStatistical method to summarize the results of a Systematic Review

DEFINIÇÃO

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REVISÕES 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

appraising information. Might have statistical

analysis (Meta-analysis)

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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.

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Appraising aAppraising a SRSTEP 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

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Appraising aAppraising a SRSTEP 2

INCLUSION - EXCLUSION CRITERIA

Explicit and related to the question Easy to apply by different reviewers Applied regardless of studies’s results

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Appraising aAppraising a SRSTEP 3

SEARCH FOR ALL AVAILABLE EVIDENCESensitive 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

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Appraising aAppraising a SRSTEP 4

CRITICAL APPRAISAL OF INCLUDED STUDIES

Very importantAvoid “garbage in” “garbage out”

Could be done:DescriptiveQuantitative: Scores (ie. Jadad score)

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COCHRANE COLLABORATION’S APPROACH:Methodological quality summary: review authors’ judgments about each methodological quality item for each included study.

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HIERARQY OF EVIDENCE

Clinical Experience or Case ReportsBias +++

Observational StudiesBias ++

Randomized Clinical Trials (RCT)

Bias +

Systematic Review of RCT Bias + Precision ++ Applicability ++

EBM: The judicious use of the best available evidence in clinical decision making

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REVISÕES SISTEMÁTICAS SYSTEMATIC REVIEWS

Best evidence only if methods of the SR & of included trials avoid bias.

Should be critically appraised.

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Hormonal replacement therapy to reduce coronary events in post-menopausal women

Meta-analysis of observational studies

1992 Annals of Internal Medicine versus

RCTs HERS 1998WHI 2002

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Appraising aAppraising a SRSTEP 5

REPRODUCIBILITY OF PROCESS2 independent reviewers:

SelectionInclusionCritical Appraisal

REDUCE BIAS AND RANDOM ERROR

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Appraising aAppraising a SRSTEP 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

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I2=4,21%

I2=8,45%

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O que fazer com esta informação?What would you do with this information?

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O que fazer agora?What would you do now?

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RememberRemember

Always consider all posible outcomes. Consider patients values or preferences. SRs do not make decisions. SRs inform decisions.

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Navegando pelas RSs Sailing arround SRs.....

What are SR & why are they useful.

How to appraise a SR.

Where to find SRs.

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Where to find SRs?• Pubmed:

– Clinical Query SR– Límits: publication type: Meta-analysis

• Databases of SR

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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)

THE COCHRANE LIBRARY

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Back to our question....

Lung cancer prevention and beta-carotene.

Searching the Cochrane Database of Systematic Reviews.

P: SMOKERSI: VITAMIN A C: NO TREATMENTO: REDUCE LUNG CANCER

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BETA-CAROTENE AND LUNG CANCER PREVENTION

• Drugs for preventing lung cancer in healthy people. M Caraballoso, M Sacristan, C Serra, X BonfillPublication 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

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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

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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

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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.

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MENSAGENS PARA CASAMENSAGENS PARA CASATAKE HOME MESSAGESTAKE HOME MESSAGES

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CONCLUSCONCLUSÕESÕESSYSTEMATICS 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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OBRIGADA

PERGUNTASCOMMENTSCOMPLAINTS