using evidence-based clinical practice guidelines: examples from the accp antithrombotic and...
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Using evidence-based clinical practice guidelines:
Examples from the ACCP Antithrombotic and Thrombolytic Therapy Conference
Holger Schünemann, MD, PhDDeborah Cook, MD, MSc
Roman Jaeschke, MD, MScJanek Brozek, MD
Gordon Guyatt, MD, MSc
Where would you prefer to live?
← Option 1
Option 2 →
← Option 1 (pink card)
Option 2 → (green card)
Intro: Clinical practice guidelines
What makes guidelines evidence based in 2005?
Strong vs. weak recommendation
High vs. low quality evidence
Grading system
Today’s talk
Intro: Clinical Practice Guidelines1
Clinical Practice Guidelines
Systematically developed statements to assist practitioner and patient decisions about appropriate
health care for specific clinical circumstances
Users’ Guide to the Medical Literature, 2002
Why do clinicians need guidelines?
• Rising Healthcare Cost
• Increasing demand for care
• More expensive technologies
• Variations in service delivery among:
Providers, hospitals and geographical regions*
Assumption that this variation is a result of inappropriate (too much/too little) use of services
*BMJ 1999;318: 527
Clinical Practice Guidelines
…are a result of the desire:
• of healthcare workers to offer and of patients to receive the best possible care
• to make care more efficient and consistent by bridging the gap between what clinicians do and what the evidence shows
The leaky pipeline from research to practice
If 80% achieved at each stage then0.8 x 0.8 x 0.8 x 0.8 x 0.8 x 0.8 x 0.8 = 0.21
Glasziou and Haynes, ACP JC; 2005: 7-9
Aware Accept Target Doable Recall Agree Done
ValidResearch
Do you use guidelines in your practice?
Where do you get your guidelines from?
www.guidelines.gov
“Practice guidelines … have been demonstrated to improve patient
outcomes and lower cost”
S. Weingarten. Hospital Medicine 2005
…be based on sound scientific evidence and implemented in
an effective manner
What makes Guidelines Evidence-Based in 2005?2
First issue of ACCP guidelines in 1986 (CHEST)Initially aimed at consensus Methodologists involved since beginning Now formally convening every 2 to 3 years~200.000 copies in 2001Seventh conference held in 200387 panel members, 22 chapters Across subspecialties565 recommendations, 230 newTranslated: Polish, Spanish, Italian, French
Background: ACCP Antithrombotic and Thrombolytic Therapy Guidelines
Evidence – recommendation: transparent link
Explicit inclusion criteria Comprehensive search
Standardized consideration of study quality
Conduct/use meta-analysis
Grade recommendations
Acknowledge values and preferences underlying recommendations
What makes guidelines evidence based in 2005?
Schünemann et al. Chest 2004
A bit more practice using the voting instrument….
← Option 1 (pink card)
Option 2 → (green card)
Remember
You are hiking.
Which of the following animals would you prefer to encounter?
← Option 1 (pink card)
Option 2 → (green card)
You are buying an ice cream.
Which flavor do you prefer?
← Option 1 (pink card)
Option 2 → (green card)
Chocolate
Strawberry
You are buying a new car.
Which one would you buy?
← Option 1 (pink card)
Option 2 → (green card)
Yellow fox
Red Ferrari
What determines your choices?
• pleasure
• social responsibilities
•Risk taking
•Life crisis
•Resources
•Safety
•Past experiences
•Expectations
•Ongoing cost/inconvenience
• impuls control/politics
Case scenario and clinical question
75 year old men with history of hypertension presents to the ED with right upper extremity weakness and slurred speech for approximately two hours earlier in the day. Workup is negative. The symptoms are now resolved. Antihypertensive therapy is initiated.
Which antithrombotic treatment would you recommend?
In elderly men with TIA and hypertension, do antiplatelet agents compared to no antiplatelet agents reduce recurrent strokes?
ACCP Example: Stroke prevention
In patients with history of non-cardioembolic stroke or TIA…, we recommend treatment with an antiplatelet agent (Grade 1A). Aspirin, aspirin + XR dipyridamole or clopidogrel are all acceptable options for initial therapy.
Clopidogrel: Higher cost
If we had to make a choice between aspirin and clopidogrel, what would that choice be?
Albers et al. Chest 2004
Transparent link between evidence and recommendations
&Explicit inclusion criteria
Albers et al. Chest 2004
Table 1 Eligibility Criteria
Section Inclusion Criteria
Population Intervention(s) or Exposure Outcome Methodology
… … … … …
4.1. Patients with unstable
angina, MI, TIA and non-acute stroke
Any antiplatelet agent compared with placebo
or one or more other antiplatelet agents (s);
Death Stroke or recurrent stroke Other vascular events
Randomized controlled trials
4.2 Patients with
cardioembolic stroke Oral anticoaluation
Death Stroke or recurrent stroke
Randomized controlled trials
… … … … …
CAPRIE TrialAspirin vs clopidogrel in patients at risk for
cardiovascular event
19,185 patients, 3 subgroups with > 6,300 patients each (TIA/Stroke; myocardial infarction; peripheral arterial occlusive disease)
Mean duration of follow-up: 1.9 years
Primary outcome: ischemic stroke, myocardial infarction, or vascular death
Clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996
0
2
4
6
8
10
Absolute risk%
Clopidogrel 7.15 5.03 3.71 5.32
Aspirin 7.71 4.84 4.86 5.83
Stroke MI PAOD Total
CAPRIE* trial resultsAbsolute risk
**
Clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996
NNT 200
CAPRIE* trial resultsRelative risk reduction
7.3
-3.7
23.8
8.7
-30
-20
-10
0
10
20
30
40
Relative risk reduction
%Relative risk
Increase
Clopidogrel better
(Aspirin better)
STROKE MI PAOD Total
p = 0.26 0.66 0.0028 0.043
Clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996
Which of the following recommendations should one give?
1. Aspirin over clopidogrel in patients with prior history of TIA/Stroke?
OPTION 1 (pink)
2. Clopidogrel over aspirin in patients with prior history of TIA/Stroke?
OPTION 2 (green)
Audience at a prior thrombosis meeting
57% 43%
0%
20%
40%
60%
80%
100%
Aspirin Clopidogrel
Preferred recommendation
Strong vs. weak recommendation3
ACCP Recommendations?Stronger recommendations
strong methodslarge precise effect benefits much greater than downsides, or downsides much
greater than benefitsone size fits allexpect uniform clinician and patient behavior
Grade 1 Weaker recommendations
weaker methods imprecise estimatesmall effectbenefits not clearly greater or smaller than downsidesexpect action to vary
Grade 2
Case scenario
65 year old female with history of hypertension and DM type 2 complaining of chest pain. Diagnosed as unstable angina.
Who would recommend aspirin for our patient?
YES (pink)
No (green)
Strong vs. weak recommendation 4
Evidence weak or strong?Study design
basic
detailed design and execution
Consistency
Directnesssecure generalization?
populations (VKA for patients with A. fib and mitral valve stenosis)
interventions (Aspirin the same as clopidogrel?; LMWH)
outcomes (important versus surrogate outcomes; cholesterol)
comparison (A - C versus A - B & C - B)
Grades of recommendationMethodological quality
Grade A: consistent results from RCTs
Grade B: inconsistent results from RCTs or RCTs with
methodological limitations
Grade C: observational studies
Grade C+: observational studies with very strong
effects or secure generalization from RCTs
Example: Stroke preventionIn patients with history of non-cardioembolic stroke or
TIA…:
we recommend treatment with an antiplatelet agent (Grade 1A). Aspirin, aspirin and XR dipyridamole or clopidogrel are all acceptable options for initial therapy.
…, we suggest use of clopidogrel over aspirin (Grade 2B).
Underlying values and preferences:Underlying values and preferences:
This recommendation places a relatively This recommendation places a relatively high value on a small absolute risk reduction high value on a small absolute risk reduction in stroke rates, and a relatively low value on in stroke rates, and a relatively low value on minimizing drug expendituresminimizing drug expenditures
Albers et al. Chest 2004
Example: Acute coronary syndrome
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 (Grade 1A).
Evidence – recommendation: transparent link
Explicit inclusion criteria Comprehensive search
Standardized consideration of study quality
Conduct/use meta-analysis
Grade recommendations
Acknowledge values and preferences underlying recommendations
What makes guidelines evidence based in 2005?
Schünemann et al. Chest 2004
The ACCP Antithrombotic Therapy grading system
Clear separation of two issues:
Evidence: weak or strong?
methodological quality of evidence
likelihood of bias
Recommendation: weak or strong?
trade-off between benefits and downsides
Values and preferences
If available, they are integrated into recommendations and described by guideline developers
If unavailable, adequate representation of patients’ or society’s interests is assumed
To increase the likelihood of adequate representation, the process included review of recommendations by research methodologists, practicing generalists and specialists
Grading systemGrade of
recommendation Clarity of risk/benefit Strength of supporting evidence
1A Benefits clearly outweigh risk and burdens, or vice versa
Consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk.
1B Benefits clearly outweigh risk and burdens, or vice versa
Evidence from randomized, controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate.
1C Benefits appear to outweigh risk and burdens, or vice versa
Evidence from observational studes, unsystematic clinical experience, or from randomized, controlled trials with serious flaws. Any estimate of effect is uncertain.
2A Benefits closely balanced with risks and burdens
Consistent evidence from well performed randomized, controlled trials or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk.
2B Benefits closely balanced with risks and burdens; some uncertainty in the estimates of benefits, risks, and burdens
Evidence from randomized, controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate.
2C Uncertainty in the estimates of benefits, risks, and burdens; benefits may be closely balanced with risks and burdens
Evidence from observational studies, unsystematic clinical experience, or from randomized, controlled trials with serious flaws. Any estimate of effect is uncertain.
GRADE
Grades of Recommendation
Assessment, Development and
Evaluation
System adopted by:ACCP
UpToDateUrology associations
Endocrine Society
*Grade Working Group. CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005
Summary
Integration of values and preferences is challenging but critical for clinical practice guideline development and application
High transparency between evidence and recommendations required
GRADE approach to grading quality of evidence and strength of recommendations is gaining acceptance and application
QUESTIONS?
End
Evidence alone does not make decisions
Expert opinion is not evidence – expert opinion is an interpretation of the evidence
Finalization and harmonization of the guidelines
Preliminary versions formulated by authors and presented before and during conference
Controversial recommendations were presented during conference
Editors harmonized the chapters and facilitated discussion of contested recommendations
Limitations of guidelines
Possibility that some authors followed this methodology more closely than others
Possibility of missing relevant studies
No centralization of the methodological evaluation of all studies
Few meta-analysis conducted
Sparse data on patients’ values and preferences and resources utilization
Future directions of ACCP Guidelines
Tackle limitations mentioned above
Perform additional evaluations, supervised and coordinated centrally, of the quality of included trials
Formed “Cost” and “Grading” task forces
Merge with GRADE* approach
*Grading Recommendations Assessment, Development and Evaluation Working Group. BMJ 2004
Evidence – recommendation: transparent link
Explicit inclusion criteria Comprehensive search
Standard consideration of study quality
( Conduct/use meta-analysis)
Grade recommendations
Acknowledge values and preferences underlying recommendations
1.1. Patient group/condition, outcome, intervention
1.1. Discussion of eligible evidence answering the question
1.1. Statement of values and preferences if not obvious or particularly pertinent to the recommendation
1.1. Recommendation: Based on (quality) evidence, statement of recommendation with wording related to strength (GRADE STRENGTH/EVIDENCE QUALITY).
Summary of Recommendations
What we have achieved
Long Distance Travel
For long-distance travelers with other risk factors for VTE, we recommend the general strategies listed above. If active prophylaxis is considered, because of perceived increased risk of venous thrombosis, we suggest … single prophylactic dose of LMWH, injected prior to departure (Grade 2B).
Geerts et al. Chest 2004
Chronic limb ischemia
We recommend clopidogrel in comparison to no antiplatelet therapy (Grade 1C+), but suggest that 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.
We recommend clopidogrel over ticlopidine (Grade 1C+)
Evidence – recommendation: transparent link
Explicit inclusion criteria Comprehensive search Standard consideration of
study quality( Conduct/ use meta-analysis) Grade recommendations Acknowledge values and
preferences underlying recommendations
Knee Arthroscopy
For patients undergoing arthroscopic knee surgery we recommend against routine thromboprophylaxis, other than early mobilization (Grade 2B).
For patients undergoing arthroscopic knee surgery and who are at higher than usual risk, based on pre-existing VTE risk factors or following a prolonged or complicated procedure, we suggest thromboprophylaxis with LMWH (Grade 2B).
Geerts et al. Chest 2004
Why Grade Recommendations?
Strong recommendationone size fits all
expect uniform clinician and patient behavior
Weaker recommendation expect action to vary
Factors that influence the strength of the recommendation
Issue Example
Evidence for less serious event than one hopes to prevent
Preventing post-phlebitic syndrome with thrombolytic therapy in DVT rather than death from PE.
Smaller Treatment Effect
Clopidogrel versus aspirin leads to a smaller stroke reduction in TIA (8.7%% RRR) than anticoagulation versus placebo in AF (68% RRR)
Imprecise Estimate of Treatment Effect
ASA versus placebo in AF has a wider confidence interval than ASA for stroke prevention in patients with TIA
Lower Risk of Target Event
Some surgical patients are at very low risk of post-operative DVT and PE while others surgical patients have considerably higher rates of DVT and PE
Higher Risk of Therapy
ASA and clopidogrel in acute coronary syndromes have a higher risk for bleeding than ASA alone
Higher Costs
TPA has much higher cost than streptokinase in acute MI
Varying Values
Most young, healthy people will put a high value on prolonging their lives (and thus incur suffering to do so); the elderly and infirm are likely to vary in the value they place on prolonging their lives (and may vary in the suffering they are ready to experience to do so).
Quality of evidenceThe extent to which one can be confident that an estimate of effect or association is correct. This depends on the:
study design (e.g. RCT, cohort study, case series)
study quality (protection against bias; e.g. concealment of allocation,blinding, follow-up)
consistency of results
directness of the evidence including the
populations (those of interest versus similar; for example, older, sicker or more co-morbidity)
interventions (those of interest versus similar; for example, drugs within the same class)
outcomes (important versus surrogate outcomes)
comparison (A - C versus A - B & C - B)
Factors that influence the strength of the recommendation
• Evidence for less serious event than one hopes to prevent
• Smaller Treatment Effect
• Imprecise Estimate of Treatment Effect
• Low Risk of Target Event
• Higher Risk of Therapy
• Higher Costs
• Varying Values
• Higher Burden of Therapy
Factors that influence the strength of the recommendation
Peripheral arterial occlusive disease
We recommend lifelong aspirin therapy (75 - 162 mg/d) in comparison to no antiplatelet therapy in both patients with clinically manifest coronary or cerebrovascular disease (Grade 1A) and those without clinically manifest coronary or cerebrovascular disease (Grade 1C+).
We recommend clopidogrel in comparison to no antiplatelet therapy (Grade 1C+).
Which of the following options would you recommend?
1. Aspirin over clopidogrel in patients with PAOD?
OPTION 1
2. Clopidogrel over aspirin in patients with PAOD?
OPTION 2
PAOD
In patients with PAOD we suggest that 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.
Evidence weak or strong?study design
basic
detailed design and execution
consistency
directnesssecure generalization?
populations (VKA for patients with A.fib and mitral valve stenosis)
interventions (Aspirin the same as clopidogrel; LMWH)
outcomes (important versus surrogate outcomes; cholesterol)
comparison (A - C versus A - B & C - B)
Why Grade Recommendations?Strong recommendations
strong methods large precise effect few downsides of therapy
Weak recommendationsweak methodsimprecise estimatesmall effectsubstantial downsides
Why Grade Recommendations?Strong recommendations
strong methods large precise effect few downsides of therapyone size fits allexpect uniform clinician and patient behavior
Weak recommendationsweak methodsimprecise estimatesmall effectsubstantial downsides
Why Grade Recommendations?Strong recommendations
strong methods large precise effect few downsides of therapyone size fits allexpect uniform clinician and patient behavior
Weak recommendationsweak methodsimprecise estimatesmall effectsubstantial downsidesexpect action to vary
Chapter authors
Develop the Clinical Question
Organize by patient groups or conditionsExamples from chapter on Ischemic Stroke
Previous Now
Stroke Prevention Antiplatelet agents Non-cardioembolic stroke Cardioembolic stroke Oral Anticoagulation Cardioembolic stroke Non-cardioembolic stroke
Stroke Prevention Non-cardioembolic stroke Antiplatelet agents Oral Anticoagulation Cardioembolic stroke Oral Anticoagulation Antiplatelet agents
Explicit eligibility criteria
Example: Thrombolysis compared with no thrombolysis for acute stroke
Patients: Patients presenting with acute thrombotic stroke
Intervention: any thrombolytic regimen
Outcome: death, or validated functional status instrument
Methodology: randomized trials
Trombolisi confrontata con non trombolisi per stroke acuto
Questo quesito clinico orienta verso diverse raccomandazione:1.1. tPA per via intra-venosa in caso di stroke ischemico acuto
caratterizzato dalla presenza di sintomi per < 3 ore
1.2. tPA per via intra-venosa per stroke ischemico acuto caratterizzato dalla presenza di sintomi dalle 3 alle 6 ore
1.3. Streptokinase intravenoso in caso di stroke ischemico acuto caratterizzato dalla presenza di sintomi < 3 ore
1.4. Streptokinase intravenoso per stroke ischemico acuto caratterizzato dalla presenza di sintomi dalle 3 alle 6 ore
Evidence – recommendation: transparent link
Explicit inclusion criteria Comprehensive search Standard consideration of
study quality Conduct/ use meta-analysis Grade recommendations Acknowledge values and
preferences underlying recommendations
Role of librarians
Use questions to develop search strategy e.g. identify all search terms (MESH and keywords) for antiplatelet
agents or myocardial infarction
Search:Cochrane database of systematic reviews
Database of Abstracts of Reviews of Effectiveness
Cochrane Register of Controlled Trial
MEDLINE and Embase (1966 - Dec 2002)
ACP Journal Club
Provide search resultsUsed Endnote ® software
e.g. 490 citations on thrombolysis in acute stroke
Chapter authors
Identifying the Clinical Question:Prior experience
Prior recommendations
What matters in clinical practice
The questions:
Identify patients, interventions, and outcomes, but also methodological criteria
Methodological quality
Criteria for baseline risk studies in specific populations:
Cohort studies reporting of at least 200 participants
Control groups of RCTs reporting 200 participants
Focus in similar populations
Sufficient length of follow-up
Less than 20% loss to follow-up
Case scenario
A 67 year old engineer is brought to the ER with tachyarrhythmia and near syncope. An EKG reveals atrial fibrillation. Other workup is negative, but the patients states that he – on and off – felt his heart racing for several days. Together with your team you diagnose the patient with lone atrial fibrillation.
Schünemann et al. Chest 2004
Schünemann HJ et al. Chest 2004