Holger Schünemann, MD, PhD Professor McMaster University, Hamilton, Canada Madrid, Spain November 26, 2008 1.

Holger Schünemann, MD, PhD Professor McMaster University, Hamilton, Canada Madrid, Spain November 26, 2008 1

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

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 Expert Opinion

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

A COPD guidelines 11

Another COPD guidelines 12

And another COPD guideline 13

What to do? 14

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

G rades of R ecommendation A ssessment, D evelopment and E valuation CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005, AJRCCM 2006, Chest 2006, BMJ 2008

GRADE Working Group  David Atkins, chief medical officer a  Dana Best, assistant professor b  Martin Eccles, professor d  Francoise Cluzeau, lecturer x  Yngve Falck-Ytter, associate director e  Signe Flottorp, researcher f  Gordon H Guyatt, professor g  Robin T Harbour, quality and information director h  Margaret C Haugh, methodologist i  David Henry, professor j  Suzanne Hill, senior lecturer j  Roman Jaeschke, clinical professor k  Regina Kunx, Associate Professor  Gillian Leng, guidelines programme director l  Alessandro Liberati, professor m  Nicola Magrini, director n  James Mason, professor d  Philippa Middleton, honorary research fellow o  Jacek Mrukowicz, executive director p  Dianne O ’ Connell, senior epidemiologist q  Andrew D Oxman, director f  Bob Phillips, associate fellow r  Holger J Sch ü nemann, professor g,s  Tessa Tan-Torres Edejer, medical officer t  David Tovey, Editor y  Jane Thomas, Lecturer, UK  Helena Varonen, associate editor u  Gunn E Vist, researcher f  John W Williams Jr, professor v  Stephanie Zaza, project director w  a) Agency for Healthcare Research and Quality, USA  b) Children's National Medical Center, USA  c) Centers for Disease Control and Prevention, USA  d) University of Newcastle upon Tyne, UK  e) German Cochrane Centre, Germany  f) Norwegian Centre for Health Services, Norway  g) McMaster University, Canada  h) Scottish Intercollegiate Guidelines Network, UK  i) F é d é ration Nationale des Centres de Lutte Contre le Cancer, France  j) University of Newcastle, Australia  k) McMaster University, Canada  l) National Institute for Clinical Excellence, UK  m) Universit à di Modena e Reggio Emilia, Italy  n) Centro per la Valutazione della Efficacia della Assistenza Sanitaria, Italy  o) Australasian Cochrane Centre, Australia  p) Polish Institute for Evidence Based Medicine, Poland  q) The Cancer Council, Australia  r) Centre for Evidence-based Medicine, UK  s) National Cancer Institute, Italy  t) World Health Organisation, Switzerland  u) Finnish Medical Society Duodecim, Finland  v) Duke University Medical Center, USA  w) Centers for Disease Control and Prevention, USA  x) University of London, UK  Y) 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 systematic deviation from truth  by outcome 2) Recommendation: 2 grades - weak or strong (for or against)?  Quality of evidence only one factor *www.GradeWorking-Group.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  limitations in detailed design and execution  inconsistency  indirectness  reporting bias  imprecision  3 factors can increase the quality of evidence

Quality assessment criteria

Example: Design and Execution  limitations  inappropriate 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 likely to reduce (increase) observed (lack of) effect

From Evidence to Recommendation 28

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

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

Exercise! 36

A COPD guidelines 37

Another COPD guidelines 38

And another COPD guideline 39

The clinical question Population: In smokers with COPD Intervention: does beta-carotene suppl Comparison: 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)

Factors that can weaken the strength of a recommendation. Example: DecisionExplanation 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 recommendation Frequent “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.

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 limitations Imprecision Inconsistency of results Indirectness of evidence Publication bias likely Final rating of quality for each outcome: high, moderate, low, or very low (+) Large magnitude of effect Dose response Plausible 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 evidence Balance benefits/harms Values and preferences Decide if any revision of direction or strength is necessary considering: Resource use Rate overall quality of evidence (GRADE) (lowest quality among critical outcomes) S1S2S3S4 OC1OC2 OC3 OC4 OC1OC3 Critical outcomes OC4 Reevaluate estimate of effect for each outcome OC2 S5 *also labeled “conditional”

Guideline development process 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

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

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

Assessing the quality of evidence 56

1. Design and Execution  limitations  lack of concealment  intention to treat principle violated  inadequate blinding  loss to follow-up  early stopping for benefit  selective outcome reporting  Example: RCT suggests that danaparoid sodium is of benefit in treating HIT complicated by thrombosis  Key outcome: clinicians’ assessment of when the thromboembolism had resolved  Not blinded – subjective judgement

2. Inconsistency of results (Heterogeneity)  if inconsistency, look for explanation  patients, intervention, outcome, methods  unexplained inconsistency downgrade quality  Bleeding in thrombosis-prophylaxed hospitalized patients  seven RCTs  4 lower, 3 higher risk

Example: Bleeding in the hospital Dentali et al. Ann Int Med, 2007

 Judgment  variation in size of effect  overlap in confidence intervals  statistical significance of heterogeneity I2I2

Akl E, Barba M, Rohilla S, Terrenato I, Sperati F, Schünemann HJ. “Anticoagulation for the long term treatment of venous thromboembolism in patients with cancer”. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006650. Heparin or vitamin K antagonists for survival in patients with cancer

Non-steroidal drug use and risk of pancreatic cancer Capurso G, Schünemann HJ, Terrenato I, Moretti A, Koch M, Muti P, Capurso L, Delle Fave G. Meta-analysis: the use of non-steroidal anti-inflammatory drugs and pancreatic cancer risk for different exposure categories. Aliment Pharmacol Ther. 2007 Oct 15;26(8):1089-99.

3. Directness of Evidence  differences in  populations/patients (mild versus severe COPD, older, sicker or more co-morbidity)  interventions (all inhaled steroids, new vs. old)  outcomes (important vs. surrogate; long-term health- related quality of life, short –term functional capacity, laboratory exercise, spirometry)  indirect comparisons  interested in A versus B  have A versus C and B versus C  formoterol versus salmeterol versus tiotropium

Alendronate Risedronate Placebo Directness interested in A versus B available data A vs C, B vs C

4. Publication Bias & Imprecision  Publication bias  number of small studies

Egger M, Smith DS. BMJ 1995;310:752-54 66 I.V. Mg in acute myocardial infarction Publication bias Meta-analysis Yusuf S.Circulation 1993 ISIS-4 Lancet 1995

Egger M, Cochrane Colloquium Lyon 2001 67 Funnel plot Standard Error Odds ratio 0.10.313 3 2 1 0 100.6 Symmetrical: No publication bias

Egger M, Cochrane Colloquium Lyon 2001 68 Funnel plot Standard Error Odds ratio 0.10.313 3 2 1 0 100.6 Asymmetrical: Publication bias?

Egger M, Smith DS. BMJ 1995;310:752-54 69 I.V. Mg in acute myocardial infarction Publication bias Meta-analysis Yusuf S.Circulation 1993 ISIS-4 Lancet 1995

Egger M, Smith DS. BMJ 1995;310:752-54 70 Meta- analysis confirme d by mega- trials

71 Publication bias (File Drawer Problem)  Faster and multiple publication of “positive” trials  Fewer and slower publication of “negative” trials

5. Imprecision  small sample size  small number of events  wide confidence intervals  uncertainty about magnitude of effect  how to decide if CI too wide?  grade down one level?  grade down two levels?  extent to which confidence in estimate of effect adequate to support decision

Example: Bleeding in the hospital Dentali et al. Ann Int Med, 2007

Offer all effective treatments?  atrial fib at risk of stroke  warfarin increases serious gi bleeding  3% per year  1,000 patients 1 less stroke  30 more bleeds for each stroke prevented  1,000 patients 100 less strokes  3 strokes prevented for each bleed  where is your threshold?  how many strokes in 100 with 3% bleeding?

What can raise quality? 1. large magnitude can upgrade (RRR 50%)  very large two levels (RRR 80%)  common criteria  everyone used to do badly  almost everyone does well  oral anticoagulation for mechanical heart valves  insulin for diabetic ketoacidosis  hip replacement for severe osteoarthritis 2. dose response relation (higher INR – increased bleeding) 3. all plausible confounding may be working to reduce the demonstrated effect or increase the effect if no effect was observed

All plausible confounding would result in an underestimate of the treatment effect  Higher death rates in private for-profit versus private not-for-profit hospitals  patients in the not-for-profit hospitals likely sicker than those in the for-profit hospitals  for-profit hospitals are likely to admit a larger proportion of well-insured patients than not-for- profit hospitals (and thus have more resources with a spill over effect)

All plausible biases would result in an overestimate of effect  Hypoglycaemic drug phenformin causes lactic acidosis  The related agent metformin is under suspicion for the same toxicity.  Large observational studies have failed to demonstrate an association  Clinicians would be more alert to lactic acidosis in the presence of the agent

Hands-on exercise  Work in small groups  Select someone to report back to the whole group  Watch the time  Read the following instructions 1. Familiarize yourself with the review that you have been given (if you are not yet familiar with it): read the abstract 2. Identify the clinical question in the PICO (Population, Intervention, Comparison, Outcome) format. Work in your small group. 83

Hands-on exercise cont’d 3. Select up to 7 important outcomes for this comparison (consider the suggestions)  transfer them to a blank evidence profile or use GRADEpro (see worksheet 3 on page 6 of this handout or go to ). Work in your small group or in pairs. 4. Assess the quality of evidence for an outcome according to the GRADE approach 5. Move from evidence to recommendations using the evidence profile 84

Holger Schünemann, MD, PhD Professor 86

Evidence based clinical decisions Research evidence Patient values and preferences Clinical state and circumstances Expertise Equal for all Haynes et al. 2002

The GRADE approach 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 and across outcomes 2) Recommendation: 2 grades - weak or strong (for or against)?  Quality of evidence only one factor www.GradeWorkingGroup.org

Grades of recommendation: Strength of recommendations Strong recommendations  high quality methods with large precise effect  benefits much greater than downsides, or downsides much greater than benefits  we recommend  Grade 1 Weak/conditional recommendations  lower quality methods  benefits not clearly greater or smaller than downsides  values and preferences uncertain or very variable  we suggest  Grade 2

Case scenario A 13 year old girl who lives in rural Indonesia presented with flu symptoms and developed severe respiratory distress over the course of the last 2 days. She required intubation. The history reveals that she shares her living quarters with her parents and her three siblings. At night the family’s chicken stock shares this room too and several chicken had died unexpectedly a few days before the girl fell sick.

Relevant clinical question? Example from a not so common disease Clinical question: Population: Avian Flu/influenza A (H5N1) patients Intervention: Oseltamivir (or Zanamivir) Comparison: No pharmacological intervention Outcomes: Mortality, hospitalizations, resource use, adverse outcomes, antimicrobial resistance Schunemann et al. The Lancet ID, 2007

Methods – WHO Rapid Advice Guidelines for management of Avian Flu  Applied findings of a recent systematic evaluation of guideline development for WHO/ACHR  Group composition (including panel of 13 voting members):  clinicians who treated influenza A(H5N1) patients  infectious disease experts  basic scientists  public health officers  methodologists  Independent scientific reviewers:  Identified systematic reviews, recent RCTs, case series, animal studies related to H5N1 infection

Evidence Profile Oseltamivir for treatment of H5N1 infection: - -

Oseltamivir for Girl with Avian Flu Summary of findings:  No clinical trial of oseltamivir for treatment of H5N1 patients.  4 systematic reviews and health technology assessments (HTA) reporting on 5 studies of oseltamivir in seasonal influenza.  Hospitalization: OR 0.22 (0.02 – 2.16)  Pneumonia: OR 0.15 (0.03 - 0.69)  3 published case series.  Many in vitro and animal studies.  No alternative that is more promising at present.  Cost: ~ Euro 40$ per treatment course

Example: Oseltamivir for Avian Flu Recommendation: In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (????? recommendation, very low quality evidence). Schunemann et al. The Lancet ID, 2007

Example: Oseltamivir for Avian Flu Recommendation: In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence). Values and Preferences Remarks: This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places relatively low values on adverse reactions, the development of resistance and costs of treatment. Schunemann et al. The Lancet ID, 2007

Other explanations Remarks: Despite the lack of controlled treatment data for H5N1, this is a strong recommendation, in part, because there is a lack of known effective alternative pharmacological interventions at this time. The panel voted on whether this recommendation should be strong or weak and there was one abstention and one dissenting vote.

ACCP: Acute coronary syndrome Would a recommendation ignoring V & P be possible? For all patients presenting with NSTE ACS, without a clear allergy to aspirin, we recommend immediate aspirin, 75 to 325 mg po, and then daily, 75 to 162 mg po (strong recommendation, high quality evidence).

Value sensitive recommendation  Idiopathic deep venous thrombosis (DVT) is potentially life threatening condition  Patients usually receive blood thinners for one year  Continuing therapy will reduce a patients absolute risk for recurrent DVT by 7% per year for several years  The burdens include:  taking a blood thinner daily  keeping dietary intake of vitamin K constant  blood tests to monitor the intensity of anticoagulation  living with increased risk of minor and major bleeding

Value sensitive recommendations → Patients who are very averse to a recurrent DVT would consider the benefits of avoiding DVT worth the downsides of taking warfarin. Other patients are likely to consider the benefit not worth the harms and burden. For patients with idiopathic DVT, without elevated bleeding risk, we suggest long term warfarin therapy (weak recommendation, high quality evidence). Values and preferences: this recommendation ascribes a low value to bleeding complications and burden from therapy and a high value to avoiding DVTs

Quality assessment criteria

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.”  Strong or weak

Quality of evidence & strength of recommendation  Linked but no automatism  Other factors beyond the quality of evidence influence our confidence that adherence to a recommendation causes more benefit than harm  Systems/approaches failed to make this explicit  GRADE separates quality of evidence from strength of recommendation

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

Respiratory disease guidelines ?

Factors determining strength of recommendation

Values & Preferences  Patients’ perspectives, beliefs, expectations, and goals for health and life.  Underlying processes used in considering the benefits, harms, costs, and inconveniences patients will experience with each management option and the resulting preferences for each option.

 Guideline panels should be explicit about the relative value they place on the range of relevant patient- important outcomes. If values and preferences vary widely, a strong recommendation becomes less likely  Example: Patients vary widely in their view of how aversive they find the risk of a stroke versus the risk of a gastrointestinal bleed when deciding about oral anticoagulation for atrial fibrillation. Relative importance of outcomes and management approaches

Desirable and undesirable effects  desirable effects  Mortality  improvement in quality of life, fewer hospitalizations  reduction in the burden of treatment  reduced resource expenditure  undesirable consequences  deleterious impact on morbidity, mortality or quality of life, increased resource expenditure

Conclusion  clinicians, policy makers need summaries  quality of evidence  strength of recommendations  explicit rules  transparent, informative  GRADE  four categories of quality of evidence  two grades for strength of recommendations  transparent, systematic by and across outcomes  applicable to diagnosis  wide adoption

Questions for you  Are systematic reviews for every recommendation in your guidelines a reality/possibility?  What about cost – how do you deal with cost and how should we deal with it?

Content  Study design – bias  Levels/quality of evidence - GRADE  Guidelines/Recommendations

Confidence in evidence  There always is evidence  “When there is a question there is evidence”  Better research  greater confidence in the evidence and decisions  Evidence alone is never sufficient to make a clinical decision

Evidence based clinical decisions Research evidence Patient values and preferences Clinical state and circumstances Expertise Equal for all Haynes et al. 2002

About GRADE  Since 2000  Researchers/guideline developers with interest in methodology  Aim: to develop a common, transparent and sensible system for grading the quality of evidence and the strength of recommendations  Evaluation of existing systems

GRADE Evidence Profiles

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 and across outcomes 2) Recommendation: 2 grades - weak or strong (for or against)?  Quality of evidence only one factor *www.GradeWorking-Group.org

Determinants of quality  RCTs start high  observational studies start low  what can lower quality? 1. detailed design and execution 2. inconsistency 3. indirectness 4. reporting bias 5. imprecision