New York Academy of Medicine Teaching Evidence Assimilation for Collaborative Healthcare The
New York, August 8, 2012
Yngve Falck-Ytter, MD, AGAF for the GRADE team Associate Professor, Case Western Reserve University, Case & VA Medical Center Chief of Gastroenterology, VA Medical Center, Cleveland 1
It’s evident – or is it?
Question to the audience Decisions in your medical practice are based on: A. Training, experience and knowledge of respected B. C. D. E.
colleagues Patient preferences Convincing evidence (non experimental) from case reports, case series, disease mechanism RCTs, systematic reviews of RCTs and meta-analyses All of the above 3
Evidence-based clinical decisions Patient values and preferences
Clinical circumstances
Expertise
Research evidence Haynes et al. 2002
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Are guidelines evidencebased?
1,275 recommendations evaluated from NGC Not reliably identifiable rec. in 32% Not executable as written Common problem: statement of fact only
Variability in recommendation strength: Absent 53%, inaccurate 7%
Why is it so hard?
Hussain T, Michel G, Schiffman R. Int J Med Inform 2009
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Before GRADE Level of evidence
Source of evidence
I
SR, RCTs
II
Cohort studies
Grades of recomend.
A B
III
Case-control studies
IV
Case series
C
V
Expert opinion
D
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Before GRADE Level of evidence
Source of evidence
Ia Ib
Meta-analysis RCTs
II
Cohort studies
Grades of recomend.
A B
III
Case-control studies
IV
Case series
C
V
Expert opinion
D
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Is there any guidance here? P: In patients with acute hepatitis C …
I : Should anti-viral treatment be used … C: Compared to no treatment … O: To achieve viral clearance?
Evidence Recommendation
Organization
B
Class I
AASLD (2009)
II-1
-/-
VA (2006)
1+
A
SIGN (2006)
-/-
“Most authorities…” AGA (2006)
IIb
B (firm evidence)
UK (2008)
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Question to the audience By now… A. …you are thoroughly confused B. …you start treatment because treatment is
recommended C. …you don’t start treatment because guidelines don’t recommend it D. …you look at the evidence yourself because past experience tells you that guidelines don’t help
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Just until recently… AASLD A
B
C
Multiple RCTs or meta-analysis
Single randomized trial, or nonrandomized studies
Only consensus opinion of experts, case studies, or standard-of-care
AGA
ACG
Good Consistent, well-designed, well conducted studies […]
1. Multiple published, well-controlled (?) randomized trials or a well designed systemic (?) metaanalysis
Fair Limited by the number, quality or consistency of individual studies […]
2. One qualitypublished (?) RCT, published welldesigned cohort/ case-control studies
Poor … important flaws, gaps in chain of evidence…
3. Consensus of authoritative (?) expert opinions based on clinical evidence or from well designed, but uncontrolled or non-rand. clin. trials
ASGE A. RCTs
B. RCT with important limitations
C. Observational studies
D. Expert opinion
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Institute of Medicine March 2011 report:
“Clinical Practice Guidelines We Can Trust” Establishing transparency Management of conflict of interest Guideline development group composition Evidence based on systematic reviews Method for rating strength of recommendations Articulation of recommendations External review Updating 11
Grades of Recommendations Assessment, Development and Evaluation
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60+ Organizations
2005
2006
2007
2008
2009
2010
2011 13
Where GRADE fits in Prioritize problems, establish panel Find/appraise or prepare: Systematic review Searches, selection of studies, data collection and analysis
Prepare evidence profile: Quality of evidence for each outcome and summary of findings Guidelines: Assess overall quality of evidence
GRADE
(Re-) Assess the relative importance of outcomes
Decide direction and strength of recommendation Draft guideline Consult with stakeholders and / or external peer reviewer Disseminate guideline Implement the guideline and evaluate
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GRADE is outcome-centric
Outcome #1
Quality
Outcome #2
Quality
Outcome #3
Quality
III
V
II
IB
Old system
GRADE
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Importance of outcomes Question (PICO) Should health care worker receive booster vaccination vs. not?
Intermediate outcomes Positive hepatitis B core antibody
Final health outcomes Mortality Liver cancer Liver cirrhosis
Amnestic response to re-challenge
Chronic hepatitis B infection
Loss of protective surface antibody
Acute symptom. infection 16
GRADE expands quality of evidence determinants Inconsistency of results
Risk of bias
Failure of blinding
Methodological limitations Allocation concealment
Incomplete reporting
Indirectness of evidence
Losses to follow-up Imprecision of results
Publication bias 17
GRADE: Quality of evidence For guidelines: The extent to which our confidence in an estimate of the treatment effect is adequate to support a particular recommendation. Although quality of evidence is a continuum, we suggest using 4 categories:
High Moderate Low Very low
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Determinants of quality  RCTs start high  Observational studies start low
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Quality of evidence: beyond risk of bias Definition: The extent to which our confidence in an estimate of the
treatment effect is adequate to support a particular recommendation Methodological limitations
Risk of bias: Allocation concealment Blinding Intention-to-treat Follow-up Stopped early
Inconsistency of results
Indirectness of evidence
Imprecision of results
Publication bias
Sources of indirectness: Indirect comparisons Patients Interventions Comparators Outcomes
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All phase II and III licensing trial for antidepressant drugs between 1987 and 2004 (74 trials – 23 were not published)
Quality assessment criteria Study design RCTs
Observational studies
Quality of evidence
Lower if…
High
Study limitations (design and execution)
Moderate
Inconsistency
Low
Indirectness
Very low
Imprecision
Higher if…
What can raise the quality of evidence?
Publication bias
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BMJ 2003;327:1459–61
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Question to the audience
A. B. C. D.
You review all colonoscopies for average risk screening in your health system and document a percentage of patient who developed a perforation after the procedure (evidence of free air on imaging). No comparison group without colonoscopy available. Rate the quality of evidence for the outcome perforation: High Moderate Low Very low 25
Question to the audience A systematic review of observational studies showed a relationship between front sleeping position (versus back position) and sudden infant death syndrome (SIDS): OR 2.93 (1.15, 7.47). Rate the quality of evidence for the outcome SIDS: A. High B. Moderate C. Low D. Very low 26
Quality assessment criteria Study design RCTs
Observational studies
Quality of evidence
Lower if…
Higher if…
High
Study limitations (design and execution)
Large effect (e.g., RR 0.5) Very large effect (e.g., RR 0.2)
Moderate
Inconsistency
Low
Indirectness
Very low
Imprecision Publication bias
Evidence of dose-response gradient All plausible confounding… … would reduce a demonstrated effect …would suggest a spurious effect when results show no effect
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Conceptualizing quality High
We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate
We are moderately confident in the estimate of effect: The true effect is likely to be close to the estimate of effect , but possibility to be substantially different.
Low
Our confidence in the effect is limited: The true effect may be substantially different from the estimate of the effect.
Very low
We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
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GRADE Evidence Profile Design
Inconsistency
Limitations
Imprecision
Indirectness
Publication bias
Relative and Absolute Risk
Importance
Overall Quality
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Critical
Outcome
Critical
Outcome
Important
Outcome
Important
Outcome
Less im po rt
an t
High rate Mode
Low
Very low
Overall quality of evidence
P I C O
Outcome
Grade down or up
n es nce a m stio t o e r po u tc l qu o m a i c t ni te lec e Cli Ra S
ing t a r lity es a s Qu com tudie t ou oss s acr
Formulate recommendations: •For or against (direction) •Strong or weak (strength) By considering: Quality of evidence Balance benefits/harms Values and preferences Revise if necessary by considering: Resource use (cost) 30
From evidence to recommendations Observational study
RCT
High level recommendation
Lower level recommendation
Old system
Quality of evidence
Balance between benefits, harms & burdens
Patients’ values & preferences
GRADE
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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.” Although the strength of recommendation is a continuum, we suggest using two categories: “Strong” and “Weak” 32
4 determinants of the strength of recommendation Factors that can weaken the strength of a recommendation
Explanation
Lower quality evidence
The higher the quality of evidence, the more likely is a strong recommendation.
Uncertainty about the balance of benefits versus harms and burdens
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 is a weak recommendation warranted.
Uncertainty or differences in patients’ values
The greater the variability in values and preferences, or uncertainty in values and preferences, the more likely weak recommendation warranted.
Uncertainty about whether the net benefits are worth the costs
The higher the costs of an intervention – that is, the more resources consumed – the less likely is a strong recommendation warranted. 33
Developing recommendations
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Implications of a strong recommendation Population: Most people in this situation would
want the recommended course of action and only a small proportion would not Health care workers: Most people should receive the recommended course of action Policy makers: The recommendation can be adapted as a policy in most situations
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Implications of a conditional recommendation Population: The majority of people in this situation
would want the recommended course of action, but many would not Health care workers: Be prepared to help people 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
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P I C O
Outcome
Critical
Outcome
Critical
Outcome
Important
Outcome
Less im
po rta n
of y t i l ua for q e e te Ra denc tcom RCT start high, evi h ou obs. data start low eac
High Moderate Low Very low t
Summary of findings & estimate of effect for each outcome
Systematic review
Grade down
es nce u a m q t o r e po u tc lat o m u i t rm te lec e Fo Ra S
file o r e ro at e p Cre denc ADEp evi h GR wit
1. 2. 3. 4. 5.
Grade up
ion t s e
es ies m tco tud Ou oss s acr
Risk of bias Inconsistency Indirectness Imprecision Publication bias
1. Large effect 2. Dose response 3. Confounders
Guideline development Rate overall quality of evidence across outcomes based on lowest quality of critical outcomes
Formulate recommendations: •For or against (direction) •Strong or weak (strength) By considering: Quality of evidence Balance benefits/harms Values and preferences Revise if necessary by considering: Resource use (cost)
• • • •
“We recommend using…” “We suggest using…” “We recommend against using…” “We suggest against using…” 37
GRADE’s limitations Evidence rating for alternative management
strategies, not risk or prognosis per se. Does not eliminate disagreements in interpreting the evidence – judgments on thresholds continue to be necessary Requires some training in methodology to be applied optimally
What GRADE isn’t Not another “risk of bias” tool Not a quantitative system (no scoring required) Not eliminate COI, but able to minimize Not “expensive” Builds on well established principles of EBM Some degree of training is needed for any system Proportionally adds minimal amount of extra time to
a systematic review
Evidence review stage What format of evidence do you use?
$$$
Using mainly systematic reviews (SR)
Have the resources
Do it inhouse
Outsource
Mainly using single study data
Don’t have the resources
Ready to use SR
Search for SR
Update SR
Ad hoc reviews
Utilize the full GRADE framework (Âą evidence Profiles)
$
Not ready to use SR Use GRADE without evidence profiles
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Conclusion Using internationally accepted and standardized rating system for evidence and recommendations (such as GRADE) adds value: 1. Criteria for evidence assessment across a range
of questions, settings and outcomes 2. Sensible, transparent, systematic 3. Balance between simplicity and methodological rigor 41
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