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Evidence & Recommendations – Seeking a Standard. The New York Academy of Medicine Teaching Evidence Assimilation for Collaborative Healthcare New York, August 8 , 2012. Yngve Falck-Ytter , MD, AGAF for the GRADE team

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Evidence recommendations seeking a standard

Evidence & Recommendations – Seeking a Standard

The New York Academy of Medicine

Teaching Evidence Assimilation for Collaborative Healthcare

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


It s evident or is it

It’s evident – or is it?


Question to the audience

Question to the audience

Decisions in your medical practice are based on:

  • Training, experience and knowledge of respected 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


Evidence based clinical decisions

Evidence-based clinical decisions

Clinical circumstances

Patient values and preferences

Expertise

Research evidence

Haynes et al. 2002


Are guidelines evidence based

Are guidelines evidence-based?

  • 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


Before grade

Before GRADE

Source of evidence

Grades of recomend.

Level of evidence

I

SR, RCTs

A

II

Cohort studies

B

III

Case-control studies

IV

Case series

C

V

Expert opinion

D


Before grade1

Before GRADE

Source of evidence

Grades of recomend.

Level of evidence

Ia

Ib

Meta-analysis

RCTs

A

II

Cohort studies

B

III

Case-control studies

IV

Case series

C

V

Expert opinion

D


Is there any guidance here

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)

IIb

-/-

“Most authorities…”

B (firm evidence)

AGA (2006)

UK (2008)


Question to the audience1

Question to the audience

By now…

  • …you are thoroughly confused

  • …you start treatment because treatment is recommended

  • …you don’t start treatment because guidelines don’t recommend it

  • …you look at the evidence yourself because past experience tells you that guidelines don’t help


Just until recently

Just until recently…

AGA

AASLD

ACG

ASGE

1. Multiple published, well-controlled (?) randomized trials or a well designed systemic (?) meta-analysis

AMultiple RCTs or meta-analysis

A. RCTs

Good Consistent, well-designed, well conducted studies […]

B. RCT with important limitations

BSingle randomized trial, or non-randomized studies

FairLimited by the number, quality or consistency of individual studies […]

2. One quality-published (?) RCT, published well-designed cohort/ case-control studies

C. Obser-vational studies

3. Consensus of authoritative (?) expert opinions based on clinical evidence or from well designed, but uncontrolled or non-rand. clin. trials

C Only consensus opinion of experts, case studies, or standard-of-care

Poor… important flaws, gaps in chain of evidence…

D. Expert opinion


Institute of medicine

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


Evidence recommendations seeking a standard

Grades of Recommendations Assessment, Development and Evaluation


60 organizations

60+ Organizations

2008

2010

2006

2005

2007

2009

2011


Where grade fits in

Where GRADE fits in

Prioritize problems, establish panel

Find/appraise or prepare: Systematic review

Searches, selection of studies, data collection and analysis

(Re-) Assess the relative importance of outcomes

Prepare evidence profile: Quality of evidence for each outcome and summary of findings

GRADE

Guidelines: Assess overall quality of evidence

Decide direction and strength of recommendation

Draft guideline

Consult with stakeholders and / or external peer reviewer

Disseminate guideline

Implement the guideline and evaluate


Grade is outcome centric

GRADE is outcome-centric

Outcome #1

Quality

Outcome #2

Quality

Outcome #3

Quality

I B

II

V

III

Old system

GRADE


Importance of outcomes

Importance of outcomes

Final health outcomes

Mortality

Liver cancer

Liver cirrhosis

Chronic hepatitis B infection

Acute symptom. infection

Question (PICO)

Should health care worker receive booster vaccination vs. not?

Intermediate outcomes

Positive hepatitis B core antibody

Amnestic response to re-challenge

Loss of protective surface antibody


Grade expands quality of evidence determinants

GRADE expands quality of evidence determinants

Inconsistency of results

Risk of bias

Failure of blinding

Methodological limitations

Incomplete reporting

Indirectness of evidence

Losses to follow-up

Allocation concealment

Imprecision of results

Publication bias


Grade quality of evidence

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


Determinants of quality

Determinants of quality

  • RCTs start high

  • Observational studies start low


Quality of evidence beyond risk of bias

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

Inconsistency of results

Indirectness of evidence

Imprecision of results

Publication bias

Sources of indirectness:

Indirect comparisons

Patients

Interventions

Comparators

Outcomes

Risk of bias:

Allocation concealment

Blinding

Intention-to-treat

Follow-up

Stopped early


Evidence recommendations seeking a standard

All phase II and III licensing trial for antidepressant drugs between 1987 and 2004 (74 trials – 23 were not published)


Evidence recommendations seeking a standard

Quality assessment criteria

Lower if…

Higher if…

Quality of evidence

Study design

Study limitations

(design and execution)

High

RCTs 

Observational studies 

Moderate

Inconsistency

What can raise the quality of evidence?

Low

Indirectness

Very low

Imprecision

Publication bias


Evidence recommendations seeking a standard

BMJ 2003;327:1459–61

23


Evidence recommendations seeking a standard

24


Question to the audience2

Question to the audience

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


Question to the audience3

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:

  • High

  • Moderate

  • Low

  • Very low


Evidence recommendations seeking a standard

Quality assessment criteria

Lower if…

Higher if…

Quality of evidence

Study design

Study limitations

(design and execution)

High

RCTs 

Observational studies 

Large effect (e.g., RR 0.5)

Very large effect (e.g., RR 0.2)

Moderate

Inconsistency

Evidence of dose-response gradient

Low

Indirectness

All plausible confounding… …would reduce a demonstrated effect

…would suggest a spurious effect when results show no effect

Very low

Imprecision

Publication bias


Conceptualizing quality

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.

Our confidence in the effect is limited: The true effect may be substantially different from the estimate of the effect.

Low

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.


Grade evidence profile

GRADE Evidence Profile

Design

Incon-

sistency

Imprecision

Relative and Absolute Risk

Importance

Limitations

Indirect-

ness

Publication bias

Overall Quality


Evidence recommendations seeking a standard

Quality rating outcomes across studies

Clinical question

Rate importance

Select outcomes

High

P

I

C

O

Outcome

Critical

Moderate

Outcome

Critical

Grade down or up

Outcome

Important

Overall quality of evidence

Low

Outcome

Important

Less

Outcome

Very low

important

Panel

  • 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)


From evidence to recommendations

From evidence to recommendations

RCT

Obser-vational study

Balance between benefits, harms & burdens

Quality of evidence

Patients’ values & preferences

High level recommen-dation

Lower level recommen-dation

Old system

GRADE


Strength of recommendation

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”


4 determinants of the strength of recommendation

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.


Developing recommendations

Developing recommendations


Implications of a strong recommendation

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


Implications of a conditional recommendation

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


Evidence recommendations seeking a standard

Create

evidence profile with GRADEpro

Summary of findings & estimate of effect for each outcome

Guideline development

Rate

overall quality of evidence

across outcomes based on lowest quality

of critical outcomes

Rate quality of evidence for each outcome

Outcomes across studies

Formulate question

Rate importance

Select outcomes

RCT start high,

obs. data start low

Risk of bias

Inconsistency

Indirectness

Imprecision

Publication bias

P

I

C

O

Outcome

Critical

High

Outcome

Critical

Moderate

Grade down

Low

Outcome

Important

Very low

Outcome

Less

important

Large effect

Dose response

Confounders

Grade up

Panel

  • 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)

Systematic review

  • “We recommend using…”

  • “We suggest using…”

  • “We recommend against using…”

  • “We suggest against using…”


Grade s limitations

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

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

Evidence review stage

What format of evidence do you use?

$$$

Using mainly systematic reviews (SR)

Mainly using single study data

Have the resources

Don’t have the resources

Ready to use SR

Not ready to use SR

Do it in-house

Search for SR

Out-source

Use GRADE without evidence profiles

Update SR

Ad hoc reviews

$

Utilize the full GRADE framework (± evidence Profiles)


Conclusion

Conclusion

Using internationally accepted and standardized rating system for evidence and recommendations (such as GRADE) adds value:

  • Criteria for evidence assessment across a range of questions, settings and outcomes

  • Sensible, transparent, systematic

  • Balance between simplicity and methodological rigor


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