3th WorkshopPráctica 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.....

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 Are we up to date on medical information?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.......

DilemmaDilemma

• 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

•FRUSTRATIONFRUSTRATIONfrustrar-sefrustrar-se

Why do we have trouble with Why do we have trouble with information?information?

Difficulties finding the right information• Knowledge and skills for efficient searches

• Knowledge of different databases

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 assumeLets assume

SEARCHING FOR EVIDENCESEARCHING FOR EVIDENCE

VITAMIN A

AND LUNG CANCER PREVENTION

Using PubMedUsing PubMed

Search Terms Hits

2003

Hits

2006

Hits

2009Beta-carotene or vitamin A

33.000 40.065 45.656

(Beta-carotene or vitamin A)

and lung cancer

751 875 1107

At this point....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-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

• 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.

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

• 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-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).

• 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-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER CANCER PREVENPREVENTTIONION

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-CAROTENBETA-CAROTENEE ANDAND LUNGLUNG CANCER CANCER PREVENPREVENTTIONION

• 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

RecapitulaçãoSummarizing:

• 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?

In their risk of bias (validity)In their resultsIn 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

SYSTEMATIC REVIEW

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

Therapy / diagnosis / prognosis questions.

META - ANALYSIS

Statistical methods to summarize the results of a Systematic Review

DEFINIÇÃO

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.

Sailing arround SRs.....

What are SR & why are they useful.

How to appraise a SR.

Where to find SRs.

Appraising aAppraising 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

Appraising aAppraising 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

Appraising aAppraising 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 aAppraising a SR

STEP 4

CRITICAL APPRAISAL OF INCLUDED STUDIES

Very importantCould be done:

DescriptiveQuantitative: Scores (ie. Jadad score)

Appraising aAppraising a SR

STEP 5

REPRODUCIBILITY OF PROCESS

2 Reviewers:SelectionInclusionCritical Appraisal

REDUCE BIAS AND RANDOM ERROR

Appraising aAppraising a SR

STEP 6

STATISTICAL ANALYSIS (META – ANALYSIS)

Establish possible sources of heterogeneity, a priori. Test for heterogeneity: Q, chi square, I2

Decide whether to pool or not

I2=4,21%

I2=8,45%

HIERARQY OF EVIDENCE

Clinical Experience or Case ReportsBias +++

Observational StudiesBias ++

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.....

SYSTEMATIC REVIEW

Best evidence only if method is correct.

Should be critically appraised.

Hormonal replacement therapy to prevent coronary events in post-menopausal women:

Meta-analysis of observational studies

1992 Annals of Internal Medicine versus RCTs HERS 1998

WHI 2002

SYSTEMATIC REVIEWS

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)

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 beta-carotene.

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 BonfillThe 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 BonfillThe 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.

RECAPITULAÇÃORECAPITULAÇÃO

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.

OBRIGADA

PERGUNTASCOMMENTSCOMPLAINTS