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Failures of meta-analyses: the evidence against the

evidences

Giuseppe Biondi-Zoccai, MD

Division of Cardiology, Department of Internal Medicine, University of Turin, Turin, Italy

Meta-analysis and Evidence-based medicine Training in Cardiology (METCARDIO), Turin, Italy


What brings you from this…

Levi et al, Lancet 1999


…to this?


Index

• How to define meta-analyses? Key concepts

• What comes first? Scientific hierarchy and The

Cochrane Collaboration

• Where’s the beef? Strenghts of meta-analyses

• Any toxic asset? When meta-analyses fail

• All that glitters is not gold. Appraising systematic

reviews


Why meta-analyses are important: exponential increase in pertinent PubMed citations on…

PubMed search strategy: ("2001"[PDAT] : "2005"[PDAT]) AND (("systematic"[title/abstract] AND "review"[title/abstract]) OR ("systematic"[title/abstract] AND "overview"[title/abstract]) OR ("meta-analysis"[title/abstract] OR "meta-analyses"[title/abstract]))

0

200

400

600

800

1000

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1400

-1974 1975-1979 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2009

14 4/2009 - PubMed query: (thrombosis OR hemostasis OR haemostasis OR coagulation OR clot* OR tranexamic OR aprotinin* OR rfviia OR desmopressin*) AND (meta-analy* OR metanalys* OR metaanalys* OR (systematic AND (review OR overview)))

…thrombosis, hemostasis, coagulation, tranexamic acid,

aprotinin, rFVIIa, or desmopressin


Why should you trust me?Meta-analyses or manuscript pertinent to meta-

analyses that I have co-authored since graduation

Total = 51


Famous quotes

“If I have seen further it is by standing on the shoulders of giants” Isaac Newton

“The great advances in science usually result from new tools rather than from new doctrines” Freeman Dyson


Famous quotes“I like to think of the meta-analytic process as similar to being in a helicopter.

On the ground individual trees are visible with high resolution.

This resolution diminishes as the helicopter rises, and in its place we begin to see patterns not visible from the ground” Ingram Olkin


Baby steps of meta-analysis• 1904 - Karl Pearson (UK): correlation between inoculation of

vaccine for typhoid fever and mortality across apparently conflicting studies

• 1931 – Leonard Tippet (UK): comparison of differences between and within farming techniques on agricultural yield adjusting for sample size across several studies

• 1937 – William Cochran (UK): combination of effect sizes across different studies of medical treatments

• 1970s – Robert Rosenthal and Gene Glass (USA), Archie Cochrane (UK): combination of effect sizes across different studies of, respectively, educational and psychological treatments

• 1980s – exponential development/use of meta-analytic methods


Minimal glossary• Review: viewpoint on a subject quoting different primary authors

• Overview: as above

• Qualitative review: deliberately avoids a systematic approach

• Systematic review: deliberately uses a systematic approach to study

search, selection, abstraction, appraisal and pooling

• Quantitative review: uses quantitative methods to appraise or synthesize

data

• Meta-analysis: uses specific statistical methods for data pooling and/or

exploratory analysis

• Individual patient data meta-analysis: uses specific stastistical

methods for data pooling or subgroup exploration exploiting individual patient data

→ Our key goal: systematic review (± meta-analysis)


Qualitative review

Elwood et al, Lancet 2009


Systematic review and meta-analyses

• What is a systematic review?

– A systematic appraisal of the methodological quality,

clinical relevance and consistency of published

evidence on a specific clinical topic in order to provide

clear suggestions for a specific healthcare problem

• What is a meta-analysis?

– A quantitative synthesis that, preserving the identity of

individual studies, tries to provide an estimate of the

overall effect of an intervention, exposure, or diagnostic

strategy


Systematic review (w/o meta-analysis)

Berntorp et al, Eur J Haematol Suppl 2008


Systematic review and meta-analysis

Agostoni et al, J Am Coll Cardiol 2004


Index







reviews


EBM hierarchy of evidence1. N of 1 randomized controlled trial

2. Systematic reviews of homogeneous randomized trials

3. Single (large) randomized trial

4. Systematic review of homogeneous observational studies addressing patient-important outcomes

5. Single observational study addressing patient-important outcomes

6. Physiologic studies (eg blood pressure, cardiac output, exercise capacity, bone density, and so forth)

7. Unsystematic clinical observationsGuyatt and Rennie, Users’ guide to the medical literature, 2002


Parallel hierarchy of scientific studies in cardiovascular medicine

Biondi-Zoccai, Ital Heart J 2003

Qualitative reviews

Systematic reviews

Meta-analyses from individual non-

randomized studies

Meta-analyses from individual patient data from randomized studies

Case reports and series

Observational studies

Observational controlled studies

Randomized controlled trials

Multicenter randomized controlled trials

Meta-analyses from individual randomized

studies


The Cochrane Collaboration

Mission Statement:

The Cochrane Collaboration is an world-wide organization that aims to help people make well informed decisions about healthcare by preparing, maintaining and promoting the accessibility of systematic reviews of the effects of healthcare interventions


The Cochrane Collaboration• Over 6000 contributors & over 5000

reviews• 50 Collaborative Review Groups (CRGs)• 12 centers throughout the world• 9 fields• 11 Methods Groups• 1 Consumer Network• The Campbell Collaboration (focusing on

education/social sciences)


The Cochrane Collaboration• Over 6000 contributors & over 5000

reviews• 50 Collaborative Review Groups (CRGs)• 12 centers throughout the world• 9 fields• 11 Methods Groups• 1 Consumer Network• The Campbell Collaboration (focusing on

education/social sciences)

Thus currently the best reviews available (but still

far from perfection)!


Index






• All that glitters is not gold Appraising systematic

reviews


Pros• Application to any clinical research question

• Systematic searches for clinical evidence

• Explicit and standardized methods for search and selection

of evidence sources

• Thorough appraisal of the internal validity of primary studies

• Quantitative synthesis with increased statistical power

• Increased external validity by appraising the effect of an

intervention (exposure) across different settings

• Test subgroup hypotheses (eg with patient-level reviews)

• Explore clinical and statistical heterogeneity

Lau et al, Lancet 1998


Any application feasible: meta-analysis of intervention studies

Landoni et al, Am J Kidney Dis 2006


Any application feasible: meta-analysis of diagnostic studies

Hamon et al, JACC 2006


Any application feasible: meta-analysis of prognostic studies

Biondi-Zoccai et al, Eur Heart J 2006


Thorough appraisal of internal validity and quality of selected studies

Landoni et al, J Cardiothorac Vasc Anesth 2007


Increasing statistical power and external validity

Agostoni et al, J Am Coll Cardiol 2003


Explore small study effects

Abbate et al, J Am Coll Cardiol 2008

Review: Late percutaneous coronary intervention for infarct-related artery occlusionComparison: 01 Late percutaneous coronary intervention vs best medical therapy for infarct-related artery occlusion Outcome: 01 Death

0.1 0.2 0.5 1 2 5 10

0.0

0.4

0.8

1.2

1.6

SE(log OR)

OR (fixed)


Index







reviews


Reasons for meta-analysis failure • Duplicate efforts may lead to discordant results

• Funding or conflicts of interest may bias

• Studies/events might not be found

• Studies may be of low quality/internal validity

• Studies may be heterogeneous/inconsistent, ie “mixing

apples with oranges” provides unreal fruits

• Studies may not be relevant to current individual practice

• Selection based on publication may bias

• Analysis with highly sensitive but unrobust tests may biasLeLorier et al, New Engl J Med 1997; Lau et al, Lancet 1998;

Rosen, BMC BMC Health Services Research 2009


What if meta-analyses disagree?

Biondi-Zoccai et al, BMJ 2006


What if there is financial bias?

Barnes et al, JAMA 1998


What if there low quality studies are included?

Henry et al, CDSR 2009; Rosen, BMC BMC Health Services Research 2009


What if there low quality studies are included?

Henry et al, CDSR 2009


What if I mix apples and oranges…

Hsia et al, Ann Surg 2008


What if I mix apples and oranges…

Hsia et al, Ann Surg 2008

P for effect

Incosistency

P for heterogeneity


What if small positive studies are selectively published?

Pre

cisi

on

(sta

ndar

d e

rror

of

log

rel

ativ

e ris

k)

Effect(relative risk)

P<0.001 at Egger testP<0.001 at Peters test

0.01 0.1 1 10 100

0.0

0.4

0.8

1.2

1.6

Favours cilostazol Favours control

Biondi-Zoccai et al, Am Heart J 2008


Index







reviews


Internal validity of primary studies

• Many scales for the quality of included studies have been reported, but none is reliable or robust

• The recommended approach is to individually appraise the potential risk of the 4 biases (eg A-low, B-moderate, C-high, D-unclear from reported data):

– Selection bias (one group is different than the other)

– Performance bias (treatment is systematically different)

– Adjudication bias (outcome adjudication is selectively

different)

– Attrition bias (follow-up duration or completeness is

different)


Another common classification scheme for bias


Appraisal tools: QUOROM

Moher et al, Lancet 1999


Appraisal tools: Oxman and Guyatt’sEvaluates the internal validity of a review on 9 separate questions for which 3 distinct answers are eligible (“yes”, “partially/can’t tell”, “no”):

Oxman et al, J Clin Epidemiol 1991

1. Where the search methods used to find evidence stated?

2. Was the search for evidence reasonably comprehensive?

3. Were the criteria for deciding which studies to include in the overview reported?

4. Was bias in the selection of studies avoided?

5. Were the criteria used for assessing the validity of the included studies reported?

6. Was the validity of all studies referred to in the text assessed using appropriate criteria?


Appraisal tools: Oxman and Guyatt’s7. Were the methods used to combine the findings of the

relevant studies reported?

8. Were the findings of the relevant studies combined appropriately relative to the primary question the overview addresses?

9. Were the conclusions made by the author(s) supported by the data and/or analysis reported in the overview?

10. This summarizes the previous ones and, specifically, asks to rate the scientific quality of the review from 1 (being extensively flawed) to 3 (carrying major flaws) to 5 (carrying minor flaws) to 7 (minimally flawed).

If the “partially/can’t tell” answer is used one or more times in questions 2, 4, 6, or 8, a review is likely to have minor flaws at best and is difficult to rule out major flaws (ie a score≤4). If the “no” option is used on question 2, 4, 6 or 8, the review is likely to have major flaws (ie a score≤3). Oxman et al, J Clin Epidemiol 1991


A few references• Biondi-Zoccai GGL et al. Parallel hierarchy of scientific studies in cardiovascular medicine. Ital Heart J 2003; 4: 819-20• Biondi-Zoccai GGL et al. Compliance with QUOROM and quality of reporting of overlapping meta-analyses on the role of

acetylcysteine in the prevention of contrast associated nephropathy: case study. BMJ 2006;332:202-209• Biondi-Zoccai GGL et al. A practical algorithm for systematic reviews in cardiovascular medicine. Ital Heart J 2004;5:486 -7• Bucher HC et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J

Clin Epidemiol 1997;50:683– 9• Cappelleri JC et al. Large trials vs meta-analysis of smaller trials: how do their results compare? JAMA 1996; 276: 1332-8• Clarke M et al, eds. Cochrane reviewers’ handbook 4.2.0. (www.cochrane.org/resources/handbook/handbook.pdf)• Cooper H et al, eds. The handbook of research synthesis. New York, NY: Russell Sage Foundation, 1994• Cucherat M et al. EasyMA: a program for the meta-analysis of clinical trials. Comput Methods Programs Biomed

1997;53:187- 90• Egger M et al, eds. Systematic reviews in health care: meta-analysis in context. 2nd ed. London: BMJ Publishing Group,

2001• Glass G. Primary, secondary and meta-analysis of research. Educ Res 1976;5:3-8• Glasziou P et al. Systematic reviews in health care. A practical guide. Cambridge: Cambridge University Press, 2001• Guyatt G et al, eds. Users’ guides to the medical literature. A manual for evidence-based clinical practice. Chicago, IL: AMA

Press, 2002• Higgins JPT et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557 – 60• Lau J et al. Summing up evidence: one answer is not always enough. Lancet 1998;351:123 -7• Moher D et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUORUM statement.

Lancet 1999; 354: 1896-900• Petitti DB. Meta-analysis, decision analysis, and cost-effectiveness analysis: methods for quantitative synthesis in medicine.

New York, NY: Oxford University Press, 2000• Song F et al. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analysis. BMJ 2003;326:472• Thompson SG et al. How should meta-regression analyses undertaken and interpreted? Stat Med 2002;21:1559-73


Take home messages


Take home messages• The validity of a meta-analysis refers to the

soundness of the original studies and the

procedures used to combine them

• Dozens of potential validity threats have been

identified, and should always be borne in mind

• Given its current pivotal role in the hierarchy of

clinical evidence, all clinical decision-makers

should have a working knowledge of how to

appraise them


Take home messages

The three rules of thumb to decide whether a

meta-analysis can be trusted are:

Were the included studies all based on proper

randomization?

Were the included studies clinically and

statistically homogeneous?

Are there at least 100 event in any of the two

treatment groups for the end-point of interest?


Thank you for your attention!

For any correspondence: [email protected]

For further slides on these topics feel free to visit the metcardio.org website:

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[email protected] failures of meta-analyses: the evidence against the evidences giuseppe...

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