Plan GRADE backgroundGRADE background two stepstwo steps –quality of evidence –strength of recommendation quality and strength can differquality and strength.

Why Grade Why Grade Recommendations?Recommendations?

• strong recommendationsstrong recommendations– strong methods strong methods – large precise effect large precise effect – few down sides of therapyfew down sides of therapy

• weak recommendationsweak recommendations– weak methodsweak methods– imprecise estimateimprecise estimate– small effectsmall effect– substantial down sidessubstantial down sides

Which grading system to Which grading system to use?use?

• many availablemany available– Australian National and MRCAustralian National and MRC– Oxford Center for Evidence-based Oxford Center for Evidence-based

MedicineMedicine– Scottish Intercollegiate Guidelines (SIGN)Scottish Intercollegiate Guidelines (SIGN)– US Preventative Services Task ForceUS Preventative Services Task Force– American professional organizationsAmerican professional organizations

• AHA/ACC, ACCP, AAP, Endocrine society, etc....AHA/ACC, ACCP, AAP, Endocrine society, etc....

• cause of confusion, dismaycause of confusion, dismay

A common international A common international grading system?grading system?

• GRADE (GRADE (GGrades of rades of rrecommendation, ecommendation, aassessment, ssessment, ddevelopment and evelopment and eevaluation)valuation)

• international methodologists, guideline international methodologists, guideline developersdevelopers– Australian NMRC, SIGN, USPSTF, WHO, NICE, Oxford Australian NMRC, SIGN, USPSTF, WHO, NICE, Oxford

CEBM, CDC, CCCEBM, CDC, CC

• ~ 20 meetings over last eight years~ 20 meetings over last eight years• (~10 – 50 attendants)(~10 – 50 attendants)

• BMJ 2004, six part series 2008BMJ 2004, six part series 2008

GRADE UptakeGRADE Uptake

• UpToDate UpToDate World Health OrganizationWorld Health Organization• British Medical Journal British Medical Journal American Thoracic Society American Thoracic Society • American College of PhysiciansAmerican College of Physicians Cochrane CollaborationCochrane Collaboration• BMJ Clinical EvidenceBMJ Clinical Evidence KDIGOKDIGO• Polish Institute for EBMPolish Institute for EBM EBM Guidelines FinlandEBM Guidelines Finland• Society of Vascular SurgerySociety of Vascular Surgery Society of Pediatric EndocrinologySociety of Pediatric Endocrinology• European Respiratory SocietyEuropean Respiratory Society American Endocrine SocietyAmerican Endocrine Society• Society of Critical Care MedicineSociety of Critical Care Medicine Surviving sepsis campaignSurviving sepsis campaign• American College of Chest PhysiciansAmerican College of Chest Physicians European Soc of Thoracic SurgeonsEuropean Soc of Thoracic Surgeons• Allergic Rhinitis in Asthma Guidelines Allergic Rhinitis in Asthma Guidelines Society of Vascular SurgerySociety of Vascular Surgery• Infectious Disease Society of AmericaInfectious Disease Society of America• National Institute for Clinical Excellence (NICE)National Institute for Clinical Excellence (NICE)• Agency for Health Care Research and Quality (AHRQ)Agency for Health Care Research and Quality (AHRQ)• Swedish National Board of Health and WelfareSwedish National Board of Health and Welfare• Canadian Agency for Drugs and Technology in Health Canadian Agency for Drugs and Technology in Health • Ontario MOH Medical Advisory SecretariatOntario MOH Medical Advisory Secretariat• Agencia sanitaria regionale, Bologna, ItaliaAgencia sanitaria regionale, Bologna, Italia• The German Agency for Quality in Medicine The German Agency for Quality in Medicine • Evidence-based Nursing Sudtirol, Alta Adiga, ItalyEvidence-based Nursing Sudtirol, Alta Adiga, Italy• Norwegian Knowledge Centre for the Health ServicesNorwegian Knowledge Centre for the Health Services• University of Pennsylvania Health System Center for EB PracticeUniversity of Pennsylvania Health System Center for EB Practice • Journal of Infection in Developing Countries – InternationalJournal of Infection in Developing Countries – International• Japanese Society of Oral and Maxilofacial RadiologyJapanese Society of Oral and Maxilofacial Radiology• Emergency Medical Services for Children National Resource Center Emergency Medical Services for Children National Resource Center

What are we grading?What are we grading?

• two componentstwo components

• quality of body of evidencequality of body of evidence– confidence in estimate of effectconfidence in estimate of effect

• high, moderate, low, very lowhigh, moderate, low, very low

• strength of recommendationstrength of recommendation• strong and weakstrong and weak

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 (strong/weak*) of the recommendation considering:

Quality of the evidenceBalance of desirable/undesirable outcomes

Values and preferencesDecide if any revision of direction or strength is

necessary considering: Resource use*also labeled “conditional”or “discretionary”

Rate overall quality of evidence (lowest quality among critical outcomes)

S1 S2 S3 S4

OC1 OC2 OC3 OC4

OC1 OC3 Critical outcomes

OC4

Generate an estimate of effect for each outcome

OC2

S5

Structured questionStructured question

• patients: lymphoma patients at risk of developing chemotherapy-induced febrile neutropenia

• granulocyte colony-stimulating (G-CSF)

• alternative not using G-CSF

Need to define all patient-important outcomesand evaluate their importance

Design and ExecutionDesign and Execution

• well establishedwell established– concealmentconcealment– intention to treat principle observedintention to treat principle observed– blindingblinding– completeness of follow-upcompleteness of follow-up

• more recentmore recent– early stopping for benefitearly stopping for benefit– selective outcome reporting biasselective outcome reporting bias

Consistency of resultsConsistency of results

• consistency of resultsconsistency of results

• if inconsistency, look for explanationif inconsistency, look for explanation– patients, intervention, outcome, methodspatients, intervention, outcome, methods

• judgment of consistencyjudgment of consistency– variation in size of effectvariation in size of effect– overlap in confidence intervalsoverlap in confidence intervals– statistical significance of heterogeneitystatistical significance of heterogeneity– II22

Fluoroquinolone prophylaxis in neutropenia: infection-related mortality

Directness of EvidenceDirectness of Evidence

• differences in patients differences in patients – age, sex, ethnicity, condition – avian versus age, sex, ethnicity, condition – avian versus

regular influenzaregular influenza

• interventions interventions – dose, classdose, class

• outcomes outcomes – health-related quality of life, functional health-related quality of life, functional

capacity, laboratory exercisecapacity, laboratory exercise

Flatulence

Figure 6: Hierarchy of outcomes according to their patient-importance to assess Figure 6: Hierarchy of outcomes according to their patient-importance to assess the effect of phosphate lowering drugs in patients with renal failure and the effect of phosphate lowering drugs in patients with renal failure and hyperphophatemiahyperphophatemia

Importance of endpoints

Critical for decision making

Important, but not critical for decision making

Of low patient- importance2

5

Pain due to soft tissue Calcification / function 6

Fractures 7

Myocardial infarction 8

Mortality 9

3

4

1

Coronary calcification

Ca2+/P- Product

Surrogates of declining importance

Bone density

Ca2+/P- Product

Soft tissue calcification

Ca2+/P- Product

Lower by one level for

indirectness

Lower by two levels for

indirectness

Alendronate

Risedronate

Placebo

DirectnessDirectness

interested in A versus B interested in A versus B available data A vs C, B vs Cavailable data A vs C, B vs C

ImprecisionImprecision• small sample sizesmall sample size

– small number of eventssmall number of events

• wide confidence intervalswide confidence intervals– uncertainty about magnitude of effectuncertainty about magnitude of effect

• how to decide if CI too wide?how to decide if CI too wide?– grade down one level?grade down one level?– grade down two levels?grade down two levels?

• extent of confidence in estimate of effectextent of confidence in estimate of effect

Offer all effective treatments?Offer all effective treatments?• atrial fib at risk of strokeatrial fib at risk of stroke

• warfarin increases serious gi bleedingwarfarin increases serious gi bleeding– 3% per year 3% per year

• 1,000 patients 1 less stroke1,000 patients 1 less stroke– 30 more bleeds for each stroke prevented30 more bleeds for each stroke prevented

• 1,000 patients 100 less strokes1,000 patients 100 less strokes– 3 strokes prevented for each bleed3 strokes prevented for each bleed

• where is your threshold?where is your threshold?– how many strokes in 100 with 3% bleeding?how many strokes in 100 with 3% bleeding?

01.0%

01.0%

01.0%

01.0%

Publication biasPublication bias

• high likelihood could lower qualityhigh likelihood could lower quality

• reporting of studiesreporting of studies– publication biaspublication bias

• number of small studiesnumber of small studies• industry sponsoredindustry sponsored

What can lower quality?What can lower quality?

• detailed design and executiondetailed design and execution

• inconsistencyinconsistency

• indirectnessindirectness

• imprecisionimprecision

• publication biaspublication bias

What can raise quality?What can raise quality?

• large magnitude can upgrade one levellarge magnitude can upgrade one level– very large two levelsvery large two levels

• common criteriacommon criteria– everyone used to do badlyeveryone used to do badly– almost everyone does wellalmost everyone does well– quick actionquick action

• hip replacement for severe osteoarthritiship replacement for severe osteoarthritis

• dialysis vs no dialysis for prolonging lifedialysis vs no dialysis for prolonging life

Dose-response gradientDose-response gradient

• childhood lymphoblastic leukemiachildhood lymphoblastic leukemia

• risk for CNS malignancies 15 years after risk for CNS malignancies 15 years after cranial irradiationcranial irradiation

• no radiation: 1% (95% CI 0% to 2.1%) • 12 Gy: 1.6% (95% CI 0% to 3.4%) • 18 Gy: 3.3% (95% CI 0.9% to 5.6%).

Quality assessment criteriaQuality assessment criteria

Whipples procedure pancreatic cancerwith or without duodenectomy

Patients or population: Anyone taking a long flight (lasting more than 6 hours)Settings: International air travelIntervention: Compression stockings1

Comparison: Without stockings

Outcomes Illustrative comparative risks* (RANGE OF UNCERTAINTY)

Relative effect(95% CI)

Number of participants(studies)

Quality of theevidence(GRADE)

Comments

Assumed risk Corresponding risk

Without stockings With stockings(95% CI)

Symptomatic deep vein thrombosis (DVT)

See comment See comment Not estimable 2637(9 studies)

See comment 0 participants developed symptomatic DVT in these studies.

Symptomatic deep vein thrombosis –surrogate symptomless deep vein thrombosis

Low risk population 2 RR 0.10(0.04 to 0.25)

2637(9 studies)

Moderate3

Estimates of control group asymptomatic thrombosis from the primary studies range from 15 per 1,000 in low risk patients to 25 per 1,000 in high risk patients

5 per 10,000 0.5 per 10,000 (0 to 1)

High risk population 2

18 per 10,000 1.8 per 10,000 (0.5 to 4)

Superficial vein thrombosis

13 per 1000 6 per 1000 (2 to 15)

RR 0.45(0.18 to 1.13)

1804(8 studies)

Moderate4

Strength of RecommendationStrength of Recommendation

• strong recommendationstrong recommendation– benefits clearly outweigh risks/hassle/costbenefits clearly outweigh risks/hassle/cost– risk/hassle/cost clearly outweighs benefitrisk/hassle/cost clearly outweighs benefit

• what can downgrade strength?what can downgrade strength?– low quality evidence low quality evidence – close balance between up and downsidesclose balance between up and downsides

Risk/Benefit tradeoffRisk/Benefit tradeoff

• aspirin after myocardial infarctionaspirin after myocardial infarction– 25% reduction in relative risk25% reduction in relative risk– side effects minimal, cost minimalside effects minimal, cost minimal– benefit obviously much greater than benefit obviously much greater than

risk/costrisk/cost

• warfarin in low risk atrial fibrillationwarfarin in low risk atrial fibrillation– warfarin reduces stroke vs ASA by 50%warfarin reduces stroke vs ASA by 50%– but if risk only 1% per year, ARR 0.5%but if risk only 1% per year, ARR 0.5%– increased bleeds by 1% per yearincreased bleeds by 1% per year

Strength of Strength of RecommendationsRecommendations

Aspirin after MI – do itAspirin after MI – do it

Warfarin rather than ASA in Afib Warfarin rather than ASA in Afib -- probably do it-- probably do it

-- probably don’t do it-- probably don’t do it

Significance of strong vs Significance of strong vs weakweak

• variability in patient preferencevariability in patient preference– strong, almost all same choice (> 90%)strong, almost all same choice (> 90%)– weak, choice varies appreciablyweak, choice varies appreciably

• interaction with patientinteraction with patient– strong, just inform patientstrong, just inform patient– weak, ensure choice reflects valuesweak, ensure choice reflects values

• use of decision aiduse of decision aid– strong, don’t botherstrong, don’t bother– weak, use the aidweak, use the aid

• quality of care criterionquality of care criterion– strong, considerstrong, consider– weak, don’t considerweak, don’t consider

When evidence is low When evidence is low qualityquality

• choice more preference dependentchoice more preference dependent

• risk aversionrisk aversion

• steroids for pulmonary fibrosissteroids for pulmonary fibrosis– low quality evidence in support of low quality evidence in support of

benefitbenefit– high quality evidence of toxicityhigh quality evidence of toxicity

When evidence is low When evidence is low qualityquality

• recommendation to the hopeful patientrecommendation to the hopeful patient– I’m likely to deteriorateI’m likely to deteriorate– if something might work, let’s try itif something might work, let’s try it– damn the torpedoesdamn the torpedoes

• recommendation to the fearful patientrecommendation to the fearful patient– doctor, you mean you know it’s toxicdoctor, you mean you know it’s toxic

• diabetes, skin changes, body habitus, infection, diabetes, skin changes, body habitus, infection, osteoporosisosteoporosis

– you don’t know for sure it works?you don’t know for sure it works?– are you crazy?are you crazy?

• discretionary recommendation mandateddiscretionary recommendation mandated

Strong recommendation Strong recommendation when evidence is low when evidence is low

quality?quality?• recommendations againstrecommendations against

– uncertainty of benefituncertainty of benefit– confidence in down sidesconfidence in down sides

• whole body CT or MRI screeningwhole body CT or MRI screening– maybe benefit, maybe notmaybe benefit, maybe not– true positives some harmtrue positives some harm– false positive some harmfalse positive some harm


quality?quality?• known benefit, strong recommendation for known benefit, strong recommendation for

one of two alternativesone of two alternatives– antipyretics in children with chickenpoxantipyretics in children with chickenpox– but which one: ASA or acetaminophenbut which one: ASA or acetaminophen

• benefit: high quality evidence of equivalencebenefit: high quality evidence of equivalence

• harm: low quality evidence that harm differs harm: low quality evidence that harm differs appreciablyappreciably– Reye syndrome from ASAReye syndrome from ASA

• strong recommendation for acetaminophen?strong recommendation for acetaminophen?


quality?quality?• BlastomycosisBlastomycosis

– low quality evidence amphotericin low quality evidence amphotericin more effective than itraconazolemore effective than itraconazole

– high quality evidence more toxichigh quality evidence more toxic

• patients with life threatening blastopatients with life threatening blasto– life and death situationlife and death situation– strong recommendation for amphostrong recommendation for ampho

Value and preference Value and preference statementsstatements

• underlying values and preferences underlying values and preferences always presentalways present

• sometimes crucialsometimes crucial

• important to make explicitimportant to make explicit

Values and preferencesValues 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 preferencesValues 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.

Flavanoids for Flavanoids for HemorrhoidsHemorrhoids

• venotonic agentsvenotonic agents– mechanism unclear, increase venous returnmechanism unclear, increase venous return

• popularitypopularity– 90 venotonics commercialized in France90 venotonics commercialized in France– none in Sweden and Norwaynone in Sweden and Norway– France 70% of world marketFrance 70% of world market

• possibilitiespossibilities– French misguidedFrench misguided– rest of world missing outrest of world missing out

Systematic ReviewSystematic Review

• 14 trials, 1432 patients14 trials, 1432 patients

• key outcomekey outcome– risk not improving/persistent symptomsrisk not improving/persistent symptoms– 11 studies, 1002 patients, 375 events11 studies, 1002 patients, 375 events

– RR 0.4, 95% CI 0.29 to 0.57RR 0.4, 95% CI 0.29 to 0.57

• minimal side effectsminimal side effects

• is France right?is France right?

• what is the quality of evidence?what is the quality of evidence?


• detailed design and executiondetailed design and execution– lack of detail re concealmentlack of detail re concealment– questionnaires not validatedquestionnaires not validated

• rate down quality for study limitations?rate down quality for study limitations?

• indirectness – no problemindirectness – no problem

• inconsistency, need to look at the resultsinconsistency, need to look at the results

Review : Phlebotonics for hemorrhoidsComparison: 01 Venotonics vs placebp Outcome: 08 Overall improvement: no improvement/some improvement

Study RR (random) Weight RR (random)or sub-category log[RR] (SE) 95% CI % 95% CI

01 Up to seven daysChauvenet -0.8916 (0.2376) 12.67 0.41 [0.26, 0.65] Cospite -2.2073 (0.6117) 5.51 0.11 [0.03, 0.36] Thanapongsathorn -0.4308 (0.2985) 11.18 0.65 [0.36, 1.17]

Subtotal (95% CI) 29.36 0.37 [0.18, 0.77]Test for heterogeneity: Chi² = 6.92, df = 2 (P = 0.03), I² = 71.1%Test for overall effect: Z = 2.67 (P = 0.008)

02 Up to four w eeksAnnoni F -1.6094 (0.7073) 4.50 0.20 [0.05, 0.80] Clyne MB -0.9943 (0.3983) 8.94 0.37 [0.17, 0.81] Pirard J -1.1712 (0.3086) 10.94 0.31 [0.17, 0.57] Thanapongsathorn -1.1087 (1.1098) 2.18 0.33 [0.04, 2.91] Thorp 0.2624 (0.3291) 10.46 1.30 [0.68, 2.48] Titapan -0.8916 (0.3691) 9.56 0.41 [0.20, 0.85] Wijayanegara -0.5978 (0.1375) 14.97 0.55 [0.42, 0.72]

Subtotal (95% CI) 61.54 0.48 [0.32, 0.72]Test for heterogeneity: Chi² = 13.87, df = 6 (P = 0.03), I² = 56.7%Test for overall effect: Z = 3.57 (P = 0.0004)

03 Further than four w eeksGodeberg -1.7719 (0.3906) 9.10 0.17 [0.08, 0.37]

Subtotal (95% CI) 9.10 0.17 [0.08, 0.37]Test for heterogeneity: not applicableTest for overall effect: Z = 4.54 (P < 0.00001)

Total (95% CI) 100.00 0.40 [0.29, 0.57]Test for heterogeneity: Chi² = 28.66, df = 10 (P = 0.001), I² = 65.1%Test for overall effect: Z = 5.14 (P < 0.00001)

0.001 0.01 0.1 1 10 100 1000

Favours treatment Favours control

Publication bias?Publication bias?

• size of studiessize of studies– 40 to 234 patients, most around 10040 to 234 patients, most around 100

• all industry sponsoredall industry sponsored

Review : Phlebotonics for hemorrhoidsComparison: 01 Venotonics vs placebp Outcome: 08 Overall improvement: no improvement/some improvement

0.001 0.01 0.1 1 10 100 1000

0.0

0.4

0.8

1.2

1.6

RR (fixed)


• detailed design and executiondetailed design and execution– lack of detail re concealmentlack of detail re concealment– questionnaires not validatedquestionnaires not validated

• inconsistencyinconsistency– almost all show positive effect, trendalmost all show positive effect, trend– heterogeneity p < 0.001; Iheterogeneity p < 0.001; I22 65.1% 65.1%

• indirectnessindirectness

• imprecisionimprecision

– RR 0.4, 95% CI 0.29 to 0.57RR 0.4, 95% CI 0.29 to 0.57

• reporting biasreporting bias– 40 to 234 patients, most around 10040 to 234 patients, most around 100

Is France right?Is France right?

• nono

– recommend against userecommend against use

• strong or weak strong or weak

• yesyes– ensure venotonics availableensure venotonics available– recommend for use in individualsrecommend for use in individuals

• strong or weak?strong or weak?

Poldermans, NEJM, 1999Poldermans, NEJM, 1999

• elective vascular surgeryelective vascular surgery– positive dobutamine stress echopositive dobutamine stress echo

• compared bisoprolol to placebocompared bisoprolol to placebo– unblindedunblinded

• primary endpoint death or primary endpoint death or nonfatal MInonfatal MI

Poldermans NEJM 1999Poldermans NEJM 1999• planned sample size 266planned sample size 266

• prior planned single look at 100 ptsprior planned single look at 100 pts– stop if exceeded O’Brien-Fleming boundarystop if exceeded O’Brien-Fleming boundary

• p < 0.001p < 0.001

• stopped after 112 patientsstopped after 112 patients

• primary endpointprimary endpoint– 2 of 59 (3.4%) in bisoprolol group2 of 59 (3.4%) in bisoprolol group– 18 of 53 (34%) in placebo 18 of 53 (34%) in placebo

• RR 0.09, 95% CI 0.02 to 0.37, P< 0.001RR 0.09, 95% CI 0.02 to 0.37, P< 0.001

Final Recruitment8351 pts from 190 sites in 23 countries

3548

2005

1506

406

886

ValidityValidity

• randomization concealedrandomization concealed

• blindedblinded– patientspatients– cliniciansclinicians– date collectors date collectors – adjudicatorsadjudicators

• follow-up 99.8%follow-up 99.8%

• followed ITT principlefollowed ITT principle

Nonfatal MI – Fixed EffectsNonfatal MI – Fixed Effects

1 5 10 50 1000.5 0.1 0.05 0.01

Study Year Overall Event Rate Relative Risk (95% CI)

Jakobsen 1997 1 / 36 3.00 (0.13 to 69.09)

Poldermans 1999 9 / 112 0.05 (0.003 to 0.80)

Raby 1999 1 / 26 0.25 (0.01 to 5.62)

Zaugg 1999 3 / 63 0.07 (0.004 to 1.26)

Urban 2000 4 / 120 0.43 (0.07 to 2.81)

Pobble 2005 6 / 103 0.24 (0.04 to 1.39)

DIPOM 2006 5 / 921 1.39 (0.28 to 7.01)

MaVS 2006 38 / 496 1.02 (0.56 to 1.86)

Zaugg 2007 0 / 119 0.99 (0.02 to 49.51)

POISE 2007 366 / 8351 0.70 (0.57 to 0.86)

Fixed Effects Estimate 0.71 (0.59 to 0.86)

p=0.27 for heterogeneity, I²=19%

Quality AssessmentSummary of Findings

QualityRelative EffectRelative (95% CI) or WMD

Illustrative comparative risks

OutcomeNumber of

participants(studies)

Limitations Consistency Directness Precision Reporting Bias

Myocardial infarction

10,125(9)

No OK OK OK No High0.71

(0.57 to 0.86)5.1%

3.6%(2.9% to

4.4%)

Mortality – Fixed Effects

1 5 10 50 1000.5 0.1 0.05


Wallace 1998 6 / 200 1.84 (0.40 to 8.41)

Bayliff 1999 3 / 99 1.70 (0.23 to 12.39)

Poldermans 1999 11 / 112 0.24 (0.06 to 0.91)

Pobble 2005 5 / 103 1.23 (0.25 to 5.93)

DIPOM 2006 35 / 921 1.31 (0.69 to 2.51)

MaVS 2006 8 / 496 0.20 (0.04 to 1.16)

Zaugg 2007 1 / 219 2.97 (0.12 to 72.19)

POISE 2007 226 / 8351 1.33 (1.03 to 1.72)






OutcomeNumber of




10,125(9)


(0.57 to 0.86)5.1%

3.6%(2.9% to

4.4%)

Mortality10,205

(7)No Possible ↓ OK Imprecise No

Moderate or low

1.23(0.98 – 1.55)

2.3%2.8%

(2.2% to 3.6%)

Stroke – Fixed Effects

1 5 10 50 1000.5 0.1


Wallace 1998 5 / 200 3.06 (0.49 to 19.02)

Pobble 2005 1 / 103 2.63 (0.11 to 62.97)

DIPOM 2006 2 / 921 4.97 (0.24 to 103.19)

MaVS 2006 6 / 496 1.83 (0.39 to 8.50)

Zaugg 2007 1 / 119 2.97 (0.12 to 72.19)

POISE 2007 60 / 8351 2.13 (1.25 to 3.64)






OutcomeNumber of




10,125(9)


(0.57 to 0.86)5.1%

3.6%(2.9% to

4.4%)

Mortality10,205

(7)No Possible ↓ OK Imprecise No

Moderate or low

1.23(0.98 – 1.55)

2.3%2.8%(2.2% to 3.6%)

Stroke10,889

(5)No OK OK Possible ↓ No

High or moderate

2.21(1.37 – 3.55)

0.5%1.1

(0.69% to 1.8%)

Recommendations

• beta blockers– for– against

• Strength of recommendation– strong– weak

Acetylcysteine paracetamol Acetylcysteine paracetamol overdoseoverdose

• patients: acetaminophen overdosepatients: acetaminophen overdose

• intervention: aceteylcysteineintervention: aceteylcysteine

• comparator: no acetylcysteinecomparator: no acetylcysteine

• outcomesoutcomes– deathdeath– liver failureliver failure

Acetylcysteine Keays 1991Acetylcysteine Keays 1991• randomized trial fulminant hepatic failure after randomized trial fulminant hepatic failure after

paracetamol before acetylcysteineparacetamol before acetylcysteine

• loading dose and infusion of acetylcysteine until loading dose and infusion of acetylcysteine until resolution or death vs no acetylcysteineresolution or death vs no acetylcysteine

• treatment began 33 to 96 hours after ODtreatment began 33 to 96 hours after OD

• validityvalidity– concealment: envelopesconcealment: envelopes– blinding – noneblinding – none– LFUP – noneLFUP – none

• 12/25 (48%) acetylcysteine survived vs 5/25 (20%) of controls – (RR dying 0.65, 95% CI 0.43 to 0.99; p=0 037)

Quality of evidenceQuality of evidence

• RCT starts highRCT starts high– no study limitationsno study limitations– imprecise (CI too wide)imprecise (CI too wide)– directness (possibly indirect)directness (possibly indirect)

– consistency (no other RCT)consistency (no other RCT)– publication bias – no suggestionpublication bias – no suggestion

• overall moderate qualityoverall moderate quality

Acetylcysteine for paracetamol ODAcetylcysteine for paracetamol ODobservational studiesobservational studies

• Prescott BMJ 1979Prescott BMJ 1979– severe liver damage AST or ALT > 1,000severe liver damage AST or ALT > 1,000– 1/62 treated within 10 hours (2%)1/62 treated within 10 hours (2%)– retrospective series 22/57 (58%)retrospective series 22/57 (58%)

• Smilkstein NEJM 1988Smilkstein NEJM 1988– same criteria for damagesame criteria for damage– 32/537 (6.1%) treated in 10 hours32/537 (6.1%) treated in 10 hours– 247/935 (26.4%) treated 10 to 24 hours247/935 (26.4%) treated 10 to 24 hours

Acetylcysteine for paracetamol ODAcetylcysteine for paracetamol ODobservational studiesobservational studies

• observational studies start low observational studies start low qualityquality

• very large effectvery large effect– rate up 1 level to moderate or 2 to rate up 1 level to moderate or 2 to

highhigh

RecommendationsRecommendations

• acetylcysteineacetylcysteine– forfor– againstagainst

• strength of recommendationstrength of recommendation– strongstrong– weakweak

healthy asymptomatic postmenopausal healthy asymptomatic postmenopausal qomwn: HRT in 1992?qomwn: HRT in 1992?

Possible benefitsPossible benefits– CHD, Hip fracture, Colorectal cancerCHD, Hip fracture, Colorectal cancer

Possible harmsPossible harms– Breast cancerBreast cancer– StrokeStroke– ThrombosisThrombosis– Gall bladder diseaseGall bladder disease

Can GRADE lead to change?

Oestrogen + progestin for Oestrogen + progestin for prevention after WHI and HERSprevention after WHI and HERS

ConclusionConclusion

• clinicians, policy makers need summariesclinicians, policy makers need summaries– quality of evidencequality of evidence– strength of recommendationsstrength of recommendations

• explicit rulesexplicit rules– transparent, informativetransparent, informative

• GRADEGRADE– simple, transparent, systematicsimple, transparent, systematic– increasing wide adoptionincreasing wide adoption

Plan GRADE backgroundGRADE background two stepstwo steps –quality of evidence –strength of recommendation quality and strength can differquality and strength.

Documents

grade slide

grade recommendations

valuespreferences slide

dismay slide

clinical professor

attendants bmj

grading systems

group bmj