Holger Schünemann, MD, PhDProfessor

From Evidence to EMS Practice: Building the National ModelWashington, September 4, 2008

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Disclosure

In the past three years, Dr. Schünemann received no personal payments for service from the pharmaceutical industry. He received research grants and - until April 2008 - fees and/or honoraria that were deposited into research accounts from AstraZeneca, Chiesi Foundation, Lily, Pfizer, Roche and UnitedBioSource for development or consulting regarding quality of life instruments for chronic respiratory diseases or as lecture fees related to the methodology of evidence based practice guideline development and/or research methodology. He is documents editor for the American Thoracic Society and senior editor of the ACCP Antithrombotic and Thrombolytic Therapy Guidelines. Institutions or organizations that he is affiliated with likely receive funding from for-profit sponsors that are supporting infrastructure and research that may serve his work.

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Why is the GRADE approach emerging as the most useful approach to guideline development in health care?

Content

Study design – bias Levels/quality of evidence - GRADE

Guidelines/Recommendations

Content

Study design – bias Levels/quality of evidence - GRADE

Guidelines/Recommendations

Confidence in evidence

There always is evidence “When there is a question there is

evidence” Better research greater confidence

in the evidence and decisions Evidence alone is never sufficient to

make a clinical decision

Evidence based clinical decisions

Research evidence

Patient valuesand preferences

Clinical state and circumstances

Expertise

Equal for allHaynes et al. 2002

Hierarchy of evidence

STUDY DESIGN

Randomized Controlled Trials

Cohort Studies and Case Control Studies

Case Reports and Case Series, Non-systematic observations

BIAS

Expert Opinion

Exp

ert O

pin

ion

Expert Opinion

Can you explain the following? Concealment of randomization Blinding (who is blinded in a double

blinded trial?) Intention to treat analysis and its

correct application Why trials stopped early for benefit

overestimate treatment effects? P-values and confidence intervals

Reasons for grading evidence? People draw conclusions about the

quality of evidence and strength of recommendations

Systematic and explicit approaches can help protect against errors, resolve disagreements communicate information and fulfil needs

Change practitioner behavior However, wide variation in approaches

GRADE working group. BMJ. 2004 & 2008

Which grading system?

Evidence Recommendation B Class I A 1 IV C

Organization AHA ACCP SIGN

Recommendation for use of oral anticoagulation in patients with atrial fibrillation and rheumatic mitral valve disease

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A COPD guidelines

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Another COPD guidelines

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And another COPD guideline

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What to do?

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Grades of Recommendation Assessment,

Development and Evaluation

CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005, AJRCCM 2006, Chest 2006, BMJ 2008

About GRADE

Since 2000 Researchers/guideline developers with

interest in methodology Aim: to develop a common,

transparent and sensible system for grading the quality of evidence and the strength of recommendations

Evaluation of existing systems

GRADE Uptake

World Health Organization Allergic Rhinitis in Asthma Guidelines (ARIA) American Thoracic Society British Medical Journal Infectious Disease Society of America American College of Chest Physicians UpToDate American College of Physicians Cochrane Collaboration National Institute Clinical Excellence (NICE) Infectious Disease Society of America European Society of Thoracic Surgeons Clinical Evidence Agency for Health Care Research and Quality (AHRQ) Over 20 major organizations

Limitations of existing systems

confuse quality of evidence with strength of recommendations

lack well-articulated conceptual framework

criteria not comprehensive or transparent GRADE unique

breadth, intensity of development process wide endorsement and use conceptual framework comprehensive, transparent criteria

Focus on all important outcomes related to a specific question and overall quality

GRADE Evidence Profiles

The GRADE approach

Clear separation of 2 issues:1) 4 categories of quality of evidence:

very low, low, moderate, or high quality? methodological quality of evidence likelihood of bias by outcome and across outcomes

2) Recommendation: 2 grades - weak or strong (for or against)? Quality of evidence only one factor

*www.GradeWorking-Group.org

Determinants of quality

RCTs start high

observational studies start low

what can lower quality?1. detailed design and execution2. inconsistency3. indirectness4. reporting bias5. imprecision

1. Design and Execution

limitations Randomization lack of concealment intention to treat principle violated inadequate blinding loss to follow-up early stopping for benefit

Example: the evidence for the effect of sublingual immunotherapy in children with allergic rhinitis on the development of asthma, comes from a single randomised trial with no description of randomisation, concealment of allocation, and type of analysis, no blinding, and 21% of children lost to follow-up. These very serious limitations would warrant downgrading the quality of evidence by two levels (i.e. from high to low).

1. Design and Execution From Cates , CDSR 2008

CDSR 2008

1. Design and Execution

Overall judgment required

2. Consistency of results Look for explanation for inconsistency

patients, intervention, comparator, outcome, methods

Judgment variation in size of effect overlap in confidence intervals statistical significance of heterogeneity I2

3. Directness of Evidence

indirect comparisons interested in A versus B have A versus C and B versus C

differences in patients interventions outcomes

Directness of EvidenceTable 5. Sources of likely indirectness of evidenceSource of indirectness Question of interest ExampleIndirect comparison Early emergency department

systemic corticosteroids to treat acute exacerbations in adult patients with asthma

Both oral and intravenous routes are effective but there is no direct comparison of these two routes of administration in adults.

Differences in populations

Anti-leukotrienes plus inhaled glucocorticosteroids vs. inhaled glucocorticosteroids alone to prevent asthma exacerbations and nighttime symptoms in patients with chronic asthma and allergic rhinitis.

Trials that measured asthma exacerbations and nighttime symptoms did not include patients with allergic rhinitis.

Differences in intervention

Avoidance of pet allergens in non-allergic infants or preschool children to prevent development of allergy.

Available studies used multifaceted interventions directed at multiple potential risk factors in addition to pet avoidance.

Differences in outcomes of interest

Intranasal glucocorticosteroids vs. oral H1-antihistamines in

children with seasonal allergic rhinitis.

In the available study parents were rating the symptoms and quality of life of their teenage children, instead the children themselves.

4. Reporting Bias

reporting bias reporting of studies

publication bias number of small studies

reporting of outcomesExample: a systematic review of topical treatments for seasonal allergic conjunctivitis showed that patients using topical sodium cromoglycate were more likely to perceive benefit than those using placebo. However, only small trials reported clinically and statistically significant benefits of active treatment, while a larger trial showed a much smaller and a statistically not significant effect (Owen 2004 [53]). These findings suggest that smaller studies demonstrating smaller effects might not have been published.

5. Imprecision

small sample size small number of events

wide confidence intervals uncertainty about magnitude of effect

What can raise quality?3 Factors large magnitude can upgrade one level

very large two levels common criteria

everyone used to do badly almost everyone does well

Epinephrin in allergic shock dose response relation

(higher INR – increased bleeding) Residual confounding unlikely to be

responsible for observed effect

Quality assessment criteriaQuality assessment criteria Quality of evidence

Study design Lower if Higher if

High Randomised trial Study quality: Serious limitations Very serious limitations I mportant inconsistency Directness: Some uncertainty Major uncertainty Sparse or imprecise data High probability of reporting bias

Strong association: Strong, no plausible confounders Very strong, no major threats to validity Evidence of a Dose response gradient All plausible confounders would have reduced the eff ect

Moderate

Low Observational study

Very low Any other evidence

Strength of recommendation

“The strength of a recommendation reflects the extent to which we can, across the range of patients for whom the recommendations are intended, be confident that desirable effects of a management strategy outweigh undesirable effects.”

Strong or weak

Quality of evidence & strength of recommendation Linked but no automatism Other factors beyond the quality of

evidence influence our confidence that adherence to a recommendation causes more benefit than harm

Systems/approaches failed to make this explicit

GRADE separates quality of evidence from strength of recommendation

Evaluating desirable and undesirable effects

Desirable << Undesirable Effects Desirable ?< Undesirable Effects Desirable ?> Undesirable Effects Desirable >> Undesirable Effects

Formulating a recommendation

Against For

Strong

1

Weak ? 2

Weak ? 2

Strong

1

Respiratory disease guidelines ?

Factors determining strength of recommendation

Factors that can strengthen a recommendation

Comment

Quality of the evidence The higher the quality of evidence, the more likely is a strong recommendation.

Balance between desirable and undesirable effects

The larger the difference between the desirable and undesirable consequences, the more likely a strong recommendation warranted. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a weak recommendation.

Values and preferences The greater the variability in values and preferences, or uncertainty in values and preferences, the more likely weak recommendation warranted.

Costs (resource allocation) The higher the costs of an intervention – that is, the more resources consumed – the less likely is a strong recommendation warranted

Conclusion

clinicians, policy makers need summaries quality of evidence strength of recommendations

explicit rules transparent, informative

GRADE four categories of quality of evidence two grades for strength of recommendations transparent, systematic by and across outcomes applicable to diagnosis wide adoption

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Values & Preferences

Patients’ perspectives, beliefs, expectations, and goals for health and life.

Underlying processes used in considering the benefits, harms, costs, and inconveniences patients will experience with each management option and the resulting preferences for each option.

Guideline panels should be explicit about the relative value they place on the range of relevant patient-important outcomes. If values and preferences vary widely, a strong recommendation becomes less likely

Example: Patients vary widely in their view of how aversive they find the risk of a stroke versus the risk of a gastrointestinal bleed when deciding about oral anticoagulation for atrial fibrillation.

Relative importance of outcomes and management approaches

Desirable and undesirable effects desirable effects

Mortality improvement in quality of life, fewer

hospitalizations reduction in the burden of treatment reduced resource expenditure

undesirable consequences deleterious impact on morbidity, mortality

or quality of life, increased resource expenditure