Elaboración de recomendaciones en las GPC
Sistema GRADE
Nicola MagriniNHS CeVEAS, Centre for the Evaluation of the Effectiveness of
Health Care, Modena, ItalyWHO Collaborating Centre for Evidence Based Research Synthesis
and Guideline Development
Contents of the presentation
• What are the defects of existing guidelines and systems of grading
• Why GRADE could help …• A three pillar method: the GRADE system to
evaluate quality of evidence and define the strength of a recommendation
• Three examples• Conclusions
Contents of the presentation
• What are the defects of existing guidelines and systems of grading
• Why GRADE could help …• A three pillar method: the GRADE system to
evaluate quality of evidence and define the strength of a recommendation
• Three examples• Conclusions
http://clinicalevidence.bmj.com/ceweb/about/knowledge.jsp 2011
Tendency of recent guidelines
Trends in guideline production(AHA guidelines, Tricoci JAMA 2009)
• Recommendations are increasing in size with every update (+48% form first version)
• Quality of evidence: only a minority of recommendations are based on good evidence (11%) and half (48%) on low quality evidence
• Recommendations with high quality evidence are mostly concentrated in class I (strong recommendation) but only 245 of 1305 class I recommendations have high quality evidence (median, 19%)
Guidelines reassessment …• … in ACC/AHA guidelines with at least 1 revision, the number of
recommendations increased 48% from the first guideline to the most recent version. If there is a main message in such guidelines, it is likely to be lost in the minutiae.
• Within a guideline document, individual recommendations also need to be prioritized.
• Finally, guidelines need flexibility. Recommendations should vary based on patient comorbidities, the health care setting, and patient values and preferences.
• Physicians would be better off making clinical decisions based on valid primary data.
Shaneyfelt TM, Centor RM.Reassessment of clinical practice guidelines
JAMA 2009
How to improve guideline quality
Present limitations:• Governance and composition of the guideline
committee (“what is to be decided is often already decided with the selection of the deciders”)
• Unanimity in guideline (not a natural component in research)
• Lack of independent review (outside the accepted procedures of scientific publications)
• Suboptimal management of Conflicts of interests
Sniderman AD, Furberg CD.Why guidelines making requires reform
JAMA 2009
Too many grading systems?Who is confused?
EvidenceRecommendation
B Class IC+ 1IV C
OrganizationAHAACCPSIGN
Recommendation for use of oral anticoagulation in patients with atrial fibrillation and rheumatic mitral valve disease
Contents of the presentation
• What are the defects of existing guidelines and systems of grading
• Why GRADE could help …• A three pillar method: the GRADE system to
evaluate quality of evidence and define the strength of a recommendation
• Three examples• Conclusions
Why using GRADE
GRADE is much more than a rating system • offers a transparent and structured process for
developing and presenting summaries of quality of evidence
• provides guideline developers with a comprehensive and transparent framework for carrying out the steps involved in developing recommendations
• specifies an approach to framing questions, choosing outcomes of interest and rating their importance, evaluating the evidence, and incorporating evidence with considerations of values and preferences of patients and society to arrive at recommendations
WHO guideline development processes
update 2010
1. Scoping the document: reasons for choosing the topic, problems with existing guidelines, variations and gaps,
2. Group composition (or consultations)
3. Conflict of interest
4. Formulations of the questions and choice of the relevant outcomes
5. Evidence retrieval, evaluation and synthesis (balance sheet, evidence
table)
6. Benefit/risk profile: integrating evidence with values and preferences,
equity and costs
7. Formulation of the recommendations
8. Implementation and evaluation of impact
9. Research needs or areas of further research
10. Peer-review process and updating
Title, responsible person, WHO Department - responsible of the clearance process, WHO Departments involved, CC
involved,
Standards for evidence: GRADE system
Reporting standard and process
Reporting standard and process
GRADE Working Group websiteand publications
www.gradeworkinggroup.org
Contents of the presentation
• What are the defects of existing guidelines and systems of grading
• Why GRADE could help …• A three pillar method: the GRADE system to
evaluate quality of evidence and define the strength of a recommendation
• Three examples• Conclusions
GRADE: a 3 pillars approach
1. Formulate the question, choose and rate your outcomes of interest and perform a systematic review (quality of evidence)
2. Risk benefit evaluation, consider patients values and preferences and also resource use and feasibility
3. Direction (positive/negative) and strength (strong/weak) of the recommendation
GRADE: a 3 pillars approach
1. Formulate the question, choose and rate the outcomes of interest and perform a systematic review (quality of evidence)
2. Risk benefit evaluation, consider patients values and preferences and also resource use and feasibility
3. Strength of the recommendation
Figure 1: Hierarchy of outcomes according to their patient-importance to assess the effect of enteral supplement nutrition for geriatric patientswith bed sores
Nutritional status 4
Importanceof endpoints
Microcirculationof the wound 1
2
Energy supply 3
5
Function 6
Quality of life 7
Healing of the 8bedsore
Mortality 9
Criticalfor decision making
Important, but not critical fordecision making
Not patient-important
Rating of outcomes
… example: patient with bed sores
WHO Recommendations for the Prevention of PPH, 2007
WHO Recommendations for the Prevention of PPH, 2007
Study design is important
Early systems of grading the quality of evidence focused almost exclusively on study design
Randomised trials provide, in general, stronger evidence than observational studies:–RCTs start at High Quality–Observational studies start at Low Quality
However, other factors may decrease or increase the quality of evidence
Quality assessment criteria: the big start
Factors that may decrease the quality of evidence
Study limitations (risk of bias) well established
– concealment– intention to treat principle observed– blinding– completeness of follow-up– Choice of comparator (standard/optimal
treatment)
more recent– early stopping for benefit– selective outcome reporting bias
Factors that may decrease the quality of evidence
Study limitations (risk of bias)Inconsistency among studiesIndirectness of evidence Imprecise results Reporting bias
Evidence synthesis (systematic review)
PICO
OutcomeOutcomeOutcomeOutcome
Formulate
question
Rate
importa
nce
Critical
Important
Critical
Not important
Create
evidence
profile with
GRADEpro
Summary of findings & estimate of effect for each outcome
Rate overall quality of
evidence across outcomes based on
lowest quality of critical outcomes
RCT start high, obs. data start
low
1. Risk of bias2. Inconsistency3. Indirectness4. Imprecision5. Publication
bias
Gra
de
dow
nG
rade
up
1. Large effect
2. Dose response
3. Confounders
Rate quality
of evidence
for each
outcomeSelect
outcomes
Very low
Low
ModerateHigh
Outcomes
across
studies
GRADE: a 3 pillars approach
1. Formulate the question, choose and rate your outcomes of interest and perform a systematic review (quality of evidence)
2. Risk benefit evaluation, consider patients values and preferences and also resource use and feasibility
3. Strength of the recommendation
Determining the benefit risk profile: positive/uncertain/unfavourable
Factors Impact on the strength of a recommendation
Balance between desirable and undesirable effects
Larger the difference between the desirable and undesirable effects, more likely a favourable benefit But differences can arise depending on the severuty of adverse events
Values and preferences
More variability in values and preferences, or more uncertainty in values and preferences, more likely an unfavourable profile.
Costs (resource use)
Higher the costs of an intervention – that is, the more resources consumed – less likely a favourable profile.
GRADE Step 2: risk benefit profile, values and preferences (1/3)
GRADE Step 2: risk benefit profile, values and preferences (2/3)
GRADE Step 2: risk benefit profile, values and preferences (3/3)
GRADE: a 3 pillars approach
1. Formulate the question, choose and rate your outcomes of interest and perform a systematic review (quality of evidence)
2. Risk benefit evaluation, consider patients values and preferences and also resource use and feasibility
3. Strength of the recommendation
Strength of recommendationThe degree of confidence that the
desirable effects of adherence to a recommendation outweigh the undesirable effects.
Desirable effects• health benefits• less burden• savings
Undesirable effects• harms• more burden• costs
Categories of recommendations
Although the degree of confidence is a continuum, we suggest using two categories: strong and weak.
Strong recommendation: the panel is confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects.
Weak recommendation: the panel concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but is not confident.
Recommend
Suggest
Why Grade Recommendations?
Strong recommendations– strong methods – large precise effect – few down sides of therapy
Weak recommendations– weak methods– imprecise estimate– small effect– substantial down sides
Evidence synthesis (systematic review)
Making recommendations (guidelines)
PICO
OutcomeOutcomeOutcomeOutcome
Formulate
question
Rate
importa
nce
Critical
Important
Critical
Not important
Create
evidence
profile with
GRADEpro
Summary of findings & estimate of effect for each outcome
Rate overall quality of
evidence across outcomes based
on lowest quality of critical outcomes
Panel
RCT start high, obs. data start
low
1. Risk of bias2. Inconsistency3. Indirectness4. Imprecision5. Publication
bias
Gra
de
dow
nG
rade
up
1. Large effect
2. Dose response
3. Confounders
Rate quality
of evidence
for each
outcomeSelect
outcomes
Very low
Low
ModerateHigh
Formulate recommendations:• For or against (direction)• Strong or weak (strength)
By considering:Quality of evidenceBalance 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…”
Outcomes
across
studies
Contents of the presentation
• What are the defects of existing guidelines and systems of grading
• Why GRADE could help …• A three pillar method: the GRADE system to
evaluate quality of evidence and define the strength of a recommendation
• Three examples• Conclusions
Recommendations using GRADE: Example 1
A flexible method:
quality of evidence independent from strength of recommendation
WHO avian flu guideline 2006
Schünemann HJ et al. Lancet Infect Dis 2007;7:21-31
For opioid agonist maintenance treatment, most patients should be advised to use methadone in adequate doses in preference to buprenorphine. – Strength of recommendation – Strong– Quality of evidence – High
WHO Guidelines for the Psychosocially Assisted Pharmacological Treatment of
Opioid Dependence (2009)
On average, methadone maintenance doses should be in the range of 60–120 mg per day. – Strength of recommendation – Strong– Quality of evidence – Low
Recommendations using GRADE: Example 2
Taking into account values and preferences … and local context
Values and preferences
Stroke guideline: patients with TIA clopidogrel over aspirin (Grade 2B).
Underlying values and preferences: This recommendation to use clopidogrel over aspirin places a relatively high value on a small absolute risk reduction in stroke rates, and a relatively low value on minimizing drug expenditures.
Values and preferences
peripheral vascular disease: aspirin be used instead of clopidogrel (Grade 2A).
Underlying values and preferences: This recommendation places a relatively high value on avoiding large expenditures to achieve small reductions in vascular events.
Recommendations using GRADE: Example 3
Weak recommendations …
a blurred vision or a clear one?
Recommendations and expected adoption rate
StrengthDefinition and implications
Expected adoption
rate
Strong positive
The drugs/interventions should offered to the vast majority of patients and could be used as an indicator of good quality of care > 60-70%
Weak positive
It has the wider range of uncertainty since it could mean only for a minority of patients (30%) or for a good proportion of them (50-60%). It is necessary to inform patients of the expected benefits and risks (and their magnitude), explore patients values and discuss potential alternative treatments
30-60%
Weak negative
In selected cases or a defined minority. The decision should go along with a detailed information to patient of the benefit risk profile (magnitude), patients values and expectations and the presentation of potential alternative treatments
5-30%
Strong negative
It should not be used neither routinely nor for a subgroup. Only in few very selected (and documented) cases can be used since the benefit/risk balance is negative/unknown and available alternative are preferable
< 5%
Contents of the presentation
• What are the defects of existing guidelines and systems of grading
• Why GRADE could help …• A three pillar method: the GRADE system to
evaluate quality of evidence and define the strength of a recommendation
• Three examples• Conclusions
GRADE … in short
• Have an overall view of the process (see WHO), a good-enough mandate and some governance of relevant CoI
• Make just a few (a reasonable number of) recommendations
• Use systematic reviews (if not available, review key, accessible evidence) – DO NOT meta-analyse if not done
• Use GRADE criteria for quality of evidence• Explain the reasons supporting the strength of
recommendations, including the benefit/risk profile and values and preferences
• … just be (more) transparent
Where am I?
You’re 30 metres
above the ground in a
balloon
You must be a
researcher
Yes. How
did you know?
Because what you told me is
absolutely correct but completely
useless
You must be a policy
maker
Yes, how did
you know? Because you
don’t know where you are, you
don’t know where you’re going, and
now you’re blaming me
from: Jonathan Lomas, 2008
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