GRADE INTRODUCTION

Holger Schünemann, MD, PhDProfessor

Utrecht, NLSeptember 18 - 19, 2008

1

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

11

A COPD guidelines

12

Another COPD guidelines

13

And another COPD guideline

14

What to do?

15

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”

34

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

42

Another COPD guidelines

43

And another COPD guideline

44

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