GRADE

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 metaanalyses 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 P: In patients with acute hepatitis C … here?

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.

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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 f or 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…”

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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

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