Holger Schünemann, MD, PhD From Evidence to EMS Practice: Building the National Model Washington, September 4,

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 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.

3 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 values and preferences Clinical state and circumstances Expertise Equal for all Haynes 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

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 & 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 13

Another COPD guidelines 14

And another COPD guideline 15

What to do? 16

G rades of R ecommendation A ssessment, D evelopment and E valuation 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 *

Determinants of quality  RCTs start high  observational studies start low  what can lower quality? 1. detailed design and execution 2. inconsistency 3. indirectness 4. reporting bias 5. 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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 Evidence Table 5. Sources of likely indirectness of evidence Source of indirectnessQuestion of interestExample Indirect 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 H 1 -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 outcomes

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 criteria

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

Respiratory disease guidelines ?

Factors determining strength of recommendation

Determinants of the strength of recommendation

Conclusion  clinicians, policy makers, decision 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