2. Using evidence-based clinical practice guidelines: Examples from the ACCP Antithrombotic and Thrombolytic Therapy Conference Holger Schünemann, MD, PhD Deborah Cook, MD, MSc Roman Jaeschke, MD, MSc Janek Brozek, MD Gordon Guyatt, MD, MSc

4. Where would you prefer to live?

5. ← Option 1 Option 2 →

6. ← Option 1 (pink card) Option 2 → (green card)

7. 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

8. Intro: Clinical Practice Guidelines 1

9. 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

10. 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

11. 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

12. The leaky pipeline from research to practice If 80% achieved at each stage then 0.8 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 Valid Research

13. Do you use guidelines in your practice?

14. Where do you get your guidelines from? www.guidelines.gov

16. “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

17. What makes Guidelines Evidence-Based in 2005? 2

18. 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 2001 Seventh conference held in 2003 87 panel members, 22 chapters Across subspecialties 565 recommendations, 230 new Translated: Polish, Spanish, Italian, French Background: ACCP Antithrombotic and Thrombolytic Therapy Guidelines

19.  Evidence – recommendation:transparent link  Explicit inclusion criteria  Comprehensive search  Standardized considerationof study quality  Conduct/use meta-analysis  Grade recommendations  Acknowledge values andpreferences underlyingrecommendations What makes guidelines evidence based in 2005? Schünemann et al. Chest 2004

20. A bit more practice using the voting instrument….

21. ← Option 1 (pink card) Option 2 → (green card) Remember

22. You are hiking. Which of the following animals would you prefer to encounter?

23. ← Option 1 (pink card) Option 2 → (green card)

24. You are buying an ice cream. Which flavor do you prefer?

25. ← Option 1 (pink card) Option 2 → (green card) Chocolate Strawberry

26. You are buying a new car. Which one would you buy?

27. ← Option 1 (pink card) Option 2 → (green card) Yellow fox Red Ferrari

28. What determines your choices? pleasure social responsibilities Risk taking Life crisis Resources Safety Past experiences Expectations Ongoing cost/inconvenience impuls control/politics

29. 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?

30. 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

31. Transparent link between evidence and recommendations & Explicit inclusion criteria Albers et al. Chest 2004

32. CAPRIE Trial Aspirin 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

33. CAPRIE* trial results Absolute risk * * Clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996 NNT 200

34. CAPRIE* trial results Relative risk reduction Clopidogrel better (Aspirin better) STROKEMI PAOD Total p = 0.260.66 0.0028 0.043 Clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996

35. 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)

36. Audience at a prior thrombosis meeting

37. Strong vs. weak recommendation 3

38. ACCP Recommendations? Stronger recommendations strong methods large precise effect benefits much greater than downsides, or downsides much greater than benefits one size fits all expect uniform clinician and patient behavior Grade 1 Weaker recommendations weaker methods imprecise estimate small effect benefits not clearly greater or smaller than downsides expect action to vary Grade 2

39. Case scenario 65 year old female with history of hypertension and DM type 2 complaining of chest pain. Diagnosed as unstable angina.

40. Who would recommend aspirin for our patient? YES (pink) No (green)

41. Strong vs. weak recommendation 4

42. Evidence weak or strong? Study design basic detailed design and execution Consistency Directness secure 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)

43. Grades of recommendation Methodological 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

44. Example: Stroke prevention In 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: This recommendation places a relatively high value on a small absolute risk reduction in stroke rates, and a relatively low value on minimizing drug expenditures Albers et al. Chest 2004

45. 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).

46.  Evidence – recommendation:transparent link  Explicit inclusion criteria  Comprehensive search  Standardized considerationof study quality  Conduct/use meta-analysis  Grade recommendations  Acknowledge values andpreferences underlyingrecommendations What makes guidelines evidence based in 2005? Schünemann et al. Chest 2004

47. 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

48. 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

49. Grading system

50. GRADE G rades of R ecommendation A ssessment, D evelopment and E valuation System adopted by: ACCP UpToDate Urology associations Endocrine Society *Grade Working Group. CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005

51. 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

52. QUESTIONS?

53. End

54. Evidence alone does not make decisions Expert opinion is not evidence – expert opinion is an interpretation of the evidence

56. 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

57. 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

58. 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

59. Evidence –recommendation:transparent link Explicit inclusion criteria Comprehensive search Standard consideration ofstudy quality ( Conduct/use meta-analysis) Grade recommendations Acknowledge values andpreferences underlyingrecommendations

60. 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

61. 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

62. 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+)

63. 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

64. Why Grade Recommendations? Strong recommendation one size fits all expect uniform clinician and patient behavior Weaker recommendation expect action to vary

65. Factors that influence the strength of the recommendation IssueExample 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).

66. Quality of evidence The 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)

67. 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

68. Factors that influence the strength of the recommendation

69. 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+).

70. 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

71. 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.

72. Evidence weak or strong? study design basic detailed design and execution consistency directness secure 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)

73. Why Grade Recommendations? Strong recommendations strong methods large precise effect few downsides of therapy Weak recommendations weak methods imprecise estimate small effect substantial downsides

74. Why Grade Recommendations? Strong recommendations strong methods large precise effect few downsides of therapy one size fits all expect uniform clinician and patient behavior Weak recommendations weak methods imprecise estimate small effect substantial downsides

75. Why Grade Recommendations? Strong recommendations strong methods large precise effect few downsides of therapy one size fits all expect uniform clinician and patient behavior Weak recommendations weak methods imprecise estimate small effect substantial downsides expect action to vary

76. Chapter authors Develop the Clinical Question Organize by patient groups or conditions Examples 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

77. 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

78. 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

80. 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 results Used Endnote ® software e.g. 490 citations on thrombolysis in acute stroke

83. 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

86. 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

87. 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.

88. Schünemann et al. Chest 2004

89. Schünemann HJ et al. Chest 2004