GRADE INTRODUCTION
Holger Schünemann, MD, PhDProfessor
Utrecht, NLSeptember 18 - 19, 2008
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Disclosure
In the past three years, Dr. Schünemann received no personal payments for service from the pharmaceutical industry. His research group received research grants and - until April 2008 - fees and/or honoraria that were deposited into research accounts from Chiesi Foundation and Lily, as lecture fees related to research methodology. He is documents editor for the American Thoracic Society. 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.
Content
Background and rationale for revisiting guideline methodology
GRADE approach Quality of evidence Strength of recommendations
Content
Background and rationale for revisiting guideline methodology
GRADE approach Quality of evidence Strength of recommendations
Confidence in evidence
There always is evidence “When there is a question there is
evidence” Evidence alone is never sufficient to
make a clinical decision Better research greater confidence in
the evidence and decisions
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
Hierarchy of evidence
STUDY DESIGN Randomized Controlled
Trials Cohort Studies and
Case Control Studies Case Reports and Case
Series, Non-systematic observations
BIAS Exp
ert O
pin
ion
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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Content
Background and rationale for revisiting guideline methodology
GRADE approach Quality of evidence Strength of recommendations
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 WORKING GROUP
Grades of Recommendation Assessment,
Development and Evaluation
CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005, AJRCCM 2006, Chest 2006, BMJ 2008
GRADE Working GroupDavid Atkins, chief medical officera Dana Best, assistant professorb Martin Eccles, professord Francoise Cluzeau, lecturerx
Yngve Falck-Ytter, associate directore Signe Flottorp, researcherf Gordon H Guyatt, professorg Robin T Harbour, quality and information director h Margaret C Haugh, methodologisti David Henry, professorj Suzanne Hill, senior lecturerj Roman Jaeschke, clinical professork Regina Kunx, Associate ProfessorGillian Leng, guidelines programme directorl Alessandro Liberati, professorm Nicola Magrini, directorn
James Mason, professord Philippa Middleton, honorary research fellowo Jacek Mrukowicz, executive directorp Dianne O’Connell, senior epidemiologistq Andrew D Oxman, directorf Bob Phillips, associate fellowr Holger J Schünemann, professorg,s Tessa Tan-Torres Edejer, medical officert David Tovey, Editory
Jane Thomas, Lecturer, UKHelena Varonen, associate editoru Gunn E Vist, researcherf John W Williams Jr, professorv Stephanie Zaza, project directorw
a) Agency for Healthcare Research and Quality, USA b) Children's National Medical Center, USAc) Centers for Disease Control and Prevention, USAd) University of Newcastle upon Tyne, UKe) German Cochrane Centre, Germanyf) Norwegian Centre for Health Services, Norwayg) McMaster University, Canadah) Scottish Intercollegiate Guidelines Network, UKi) Fédération Nationale des Centres de Lutte Contre le Cancer, Francej) University of Newcastle, Australiak) McMaster University, Canadal) National Institute for Clinical Excellence, UKm) Università di Modena e Reggio Emilia, Italyn) Centro per la Valutazione della Efficacia della Assistenza Sanitaria, Italyo) Australasian Cochrane Centre, Australia p) Polish Institute for Evidence Based Medicine, Polandq) The Cancer Council, Australiar) Centre for Evidence-based Medicine, UKs) National Cancer Institute, Italyt) World Health Organisation, Switzerland u) Finnish Medical Society Duodecim, Finland v) Duke University Medical Center, USA w) Centers for Disease Control and Prevention, USAx) University of London, UKY) BMJ Clinical Evidence, UK
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
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
2) Recommendation: 2 grades - weak or strong (for or against)? Quality of evidence only one factor
*www.GradeWorkingGroup.org
GRADE Quality of Evidence
“Extent to which confidence in estimate of effect adequate to support decision”
high: considerable confidence in estimate of effect.
moderate: further research likely to have impact on confidence in estimate, may change estimate.
low: further research is very likely to impact on confidence, likely to change the estimate.
very low: any estimate of effect is very uncertain
Determinants of quality
RCTs start high
observational studies start low
5 factors lower the quality of evidence detailed design and execution inconsistency indirectness reporting bias Imprecision
3 factors can increase the quality of evidence
Quality 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
Example: Design and Execution
limitations Randomization lack of concealment intention to treat principle violated inadequate blinding loss to follow-up early stopping for benefit
Design and Execution From Cates , CDSR 2008
CDSR 2008
Design and Execution
Overall judgment required
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
Guideline development processPrioritise Problems, establish panel
Systematic Review
Evidence Profile
Relative importance of outcomes
Overall quality of evidence
Benefit – downside evaluation
Strength of recommendation
Implementation and evaluation of guidelines
GRADE
Prioritise Problems, establish panel
Systematic Review
Evidence Profile
Relative importance of outcomes
Overall quality of evidence
Benefit – downside evaluation
Strength of recommendation
Implementation and evaluation of guidelines
GRADE
Summary of Findings
Guideline development process
GRADE Profiles
Summary of Findings Tables
Health Care Question
(PICO)Systematic reviews
Studies
Outcomes
Important outcomes
Rate the quality of evidence for each outcome, across studies RCTs start high, observational studies start low(-)Study limitationsImprecisionInconsistency of resultsIndirectness of evidencePublication bias likely
Final rating of quality for each outcome: high, moderate, low, or very low
(+)Large magnitude of effectDose responsePlausible confounders would ↓ effect when an effect is present or ↑ effect if effect is absent
Decide on the direction (for/against) and grade strength of the recommendation (strong/weak*) considering:
Quality of the evidenceBalance benefits/harmsValues and preferences
Decide if any revision of direction or strength is necessary considering:
Resource useNorris 9/11/08
Rate overall quality of evidence (GRADE)(lowest quality among critical outcomes)
S1 S2 S3 S4
OC1 OC2 OC3 OC4
OC1 OC3 Critical outcomes
OC4
Reevaluate estimate of effect for each outcome
OC2
S5
*also labeled “conditional”
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The clinical scenario
A 68 year old male long-term patient of yours. He suffers from COPD but is unable to stop smoking after over 30 years of tobacco use. He has been taking beta-carotene supplements for several months because someone in the “healthy food” store recommended it to prevent cancer. He wants to know whether this will prevent him from getting cancer and whether he should use beta-carotene.
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.”
Desirable and undesirable effects
Desirable effects Mortality improvement in quality of life, fewer
hospitalizations/infections reduction in the burden of treatment reduced resource expenditure
Undesirable effects• deleterious impact on morbidity, mortality or
quality of life, increased resource expenditure
Determinants of the 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 certainty for that benefit, the more likely weak recommendation warranted.
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
Developing recommendations
Implications of a strong recommendation
Patients: Most people in this situation would want the recommended course of action and only a small proportion would not
Clinicians: Most patients should receive the recommended course of action
Policy makers: The recommendation can be adapted as a policy in most situations
Implications of a weak recommendation Patients: The majority of people in this
situation would want the recommended course of action, but many would not
Clinicians: Be prepared to help patients to make a decision that is consistent with their own values/decision aids and shared decision making
Policy makers: There is a need for substantial debate and involvement of stakeholders
A COPD guidelines
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Another COPD guidelines
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And another COPD guideline
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The clinical question
Population: In smokers with COPDIntervention: does beta-carotene supplComparison: compared to no suppl.Outcomes: reduce the risk of COPD
symptoms, lung cancer
and death and improve PFTs?
Two trials
1) The Alpha-Tocopherol Beta-Carotene (ATBC) trial randomly assigned 29,133 people to receive beta carotene, tocopherol, both, or placebo. Study participants averaged 57.2 years of age, 20.4 cigarettes per day, and 35.9 years of smoking. They were followed up for 5 to 8 years.
RR for lung cancer = 1.16 (95% CI 1.02-1.33)
Albanes et al, JNCI, 1996
Two trials
2) The Beta-Carotene and Retinol Efficacy Trial (CARET) evaluated high-risk current and former smokers with a 20–pack-year history of smoking (n = 14,254), ~ 60 years old. The participants were randomly assigned to receive either a combination of beta carotene and vitamin A or placebo. Mean length of follow up: 4 years.
RR for lung cancer = 1.28 (95% CI 1.04-1.57)
Determinants of the 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 certainty for that benefit, the more likely weak recommendation warranted.
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
Determinants of the strength of recommendation
Factors that can strengthen a recommendation
Comment
Quality of the evidence High
Balance between desirable and undesirable effects
Clear balance towards harm
Values and preferences Little variability
Costs (resource allocation) Lowering use of supplements will reduce resource use
Determinants of the strength of recommendation
Factors that can weaken the strength of a recommendation. Example:
Decision Explanation
Lower quality evidence □ Yes□ No
Uncertainty about the balance of benefits versus harms and burdens
□ Yes□ No
Uncertainty or differences in values □ Yes□ No
Uncertainty about whether the net benefits are worth the costs
□ Yes□ No
Table. Decisions about the strength of a recommendationFrequent “yes” answers will increase the likelihood of a weak recommendation
Your recommendation
Team up in pairs of two or three or four and formulate your recommendation for the guideline on COPD
I will collect your answers
Your recommendation
Our recommendation
In patients with COPD who continue to smoke, we recommend stopping beta-carotene supplementation.
OR:In patients with COPD who continue to
smoke, clinicians should stop beta-carotene supplementation.
Conclusions
GRADE is gaining acceptance as international standard
Criteria for evidence assessment across questions and outcomes
Criteria for moving from evidence to recommendations
Simple, transparent, systematic four categories of quality of evidence two grades for strength of recommendations
Transparency in decision making and judgments is key