New ACCP antithrombotic guidelines: overview & critical appraisal

Transcription

1 New ACCP antithrombotic guidelines: overview & critical appraisal Dr. A.T. Cohen Honorary Consultant Vascular Physician King's College Hospital, London, UK

2 ACCP 2012 New ACCP antithrombotic guidelines: overview & critical appraisal'. Dr Alexander (Ander) Cohen King s College Hospital, King s College London Dutch 'Vascular Internists Society 14 September 2012

3

4 Common books to set standards

5 Summary ACCP 2012 overview Background Orthopaedics Medical patients Treatment of VTE Conclusions

6 ACCP The good ACCP 2012 group have been very detailed, although variable in their approach to the guidelines but make many useful recommendations They should be congratulated in providing guidance in many areas in great detail However the recommendations are so numerous that they are often impenetrable and very difficult to navigate

7 What stops us from doing better?

8 Concerns - ACCP 2012 Methodology Terminology Bias

9 Concerns - ACCP 2012 the bad and the ugly Significant biases in many areas Publication bias Reviewer and author bias Therapeutic bias particularly with antiplatelet therapy Unfounded, inaccurate and potentially dangerous recommendations Unnecessary complication of simple recommendations Altered recommendations based on their own unvalidated assessment of clinical values which assume knowledge of patient preferences... Feeling thermometer Recommendations have been made in areas with no data and no recommendations in areas with significant data

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11 Summary Background Orthopaedics Medical patients Treatment of VTE Conclusions

12 Politicians Parties Common views Like changing everything Use politically correct language State the obvious Over complicate

13 ACCP Guidelines 2012 Evidence-based.. guidelines Without important intellectual conflicts No intellectual bias, seeking the truth 75% of the chapters has a first or last author from McMaster 92% of all chapters had at least one McMaster author Is that representative of the American or international expertise? Canadian? Ontario? Sounds a bit controlling, not representative and biased Guyatt GH et al. Chest 2012; 141; ad infinitum

14 Contraceptive Advice? Celibates

15 Medical Advice? Fisher Statisticians

16 Summary Background Orthopaedics Non-orthopaedic surgery Medical patients Treatment of VTE Conclusions

17 Surgery (Orthop and General) - Meta-analysis: Heparin vs Control 64% DVT rates in traumatic orthop surgery (p<0.0001) 70% DVT rates in elective orthop surgery (p<0.0001) 47% PE any form of surgery (p<0.0001) 66% Fatal PE in orthopaedic surgery (p=0.02) 21% Overall (all surgery) mortality (p=0.02). 30% Excessive bleeding or transfusion (orthop) Collins et al N Engl J Med, 1988

18 ACCP Guidelines 2012 Orthopaedic patients Evidence-based.. guidelines In patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA), we recommend use of one of the following for a minimum of 10 to 14 days rather than no antithrombotic prophylaxis: lowmolecular-weight heparin (LMWH), fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin (LDUH), adjusted-dose vitamin K antagonist (VKA), aspirin (all Grade 1B), or an intermittent pneumatic compression device (IPCD) (Grade 1C). Falck-Ytter Y et al. Prevention of VTE in Orthopaedic Surgery Patients. Chest 2012; 141; e278s-e325s

19 ACCP Guidelines 2012 Orthopaedic patients Evidence-based.. Guidelines In patients undergoing THA or TKA, irrespective of the concomitant use of an IPCD or length of treatment, we suggest the use of LMWH in preference to the other agents we have recommended as alternatives: fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH (all Grade 2B), adjusted-dose VKA, or aspirin (all Grade 2C). Falck-Ytter Y et al. Prevention of VTE in Orthopaedic Surgery Patients. Chest 2012; 141; e278s-e325s

20 ACCP Guidelines 2012 Orthopaedic patients Evidence-based.. Guidelines In patients undergoing major orthopaedic surgery and who decline or are uncooperative with injections or an IPCD, we recommend using apixaban or dabigatran (alternatively rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are unavailable) rather than alternative forms of prophylaxis (all Grade 1B). Falck-Ytter Y et al. Prevention of VTE in Orthopaedic Surgery Patients. Chest 2012; 141; e278s-e325s

21 Guff guff (ɡʌf) n [C19: Norwegian gufs puff of wind] Word Origin & History : guff "empty talk, nonsense," 1888, from earlier sense of "puff of air" (1825), of imitative origin.

22 Medical Advice? Fisher Statisticians

23 PEP Trial protocol title Pulmonary Embolism Prevention (PEP) trial. PROTOCOL Lancet WEBSITE 2000; (No longer available)

24 PEP Trial paper title No mention of mortality or major morbidity Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Lancet 2000; 355:

25 PEP Study authors and organisers Stephen MacMahon, and Anthony Rodgers - Clinical Trials Research Unit, University of Auckland, NZ Rory Collins - Clinical Trials Service Unit, University of Oxford Data Monitoring Committee - Richard Peto (Chair), Clinical Trials Service Unit, University of Oxford Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Lancet 2000; 355:

26 PEP Study Investigators Mislead us about the purpose of the trial Primary endpoints changed (Post-hoc) Sample size changed (Post-hoc) Negative study presented as a positive Diluted the safety data Made unfounded recommendations

27 Outcomes in the protocol Assess benefits / risks of 5 weeks of low dose aspirin (162 mg) on All vascular deaths during days 0-35 Major non-fatal vascular events (PE, MI, stroke) in hospital before day 35 Major bleeding complications in hospital Study powered to show mortality difference MacMahon S et. al. Antiplatelet therapy to prevent thrombosis after hip fracture. Rationale for a randomised trial. J Bone Joint Surg Br 1994; 76(4):

28 PEP Trial

29 Outcomes in the paper No clear definition given in the paper PE and DVT are emphasised DVT added to the primary outcome in the paper, no mention of vascular morbidity or vascular death Bleeding not defined as in protocol Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Lancet 2000; 355:

30 PEP Trial protocol sample size 6% placebo, 4% control Pulmonary Embolism Prevention (PEP) trial. Protocol previously on the Lancet website 2000.

31 Sample size in the paper With venous thromboembolism reported in 2.5% of patients assigned placebo, a study of 13-14,000 patients... to detect a reduction in risk of at least a third with aspirin. 2.5% down to 1.67% Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Lancet 2000; 355:

32 Presented Results - Efficacy VTE combined producing a RRR of 36% 1.6% vs 2.5% (p=0.0003) DVT added as a primary end point post-analysis Modest 29% RRR in-hospital DVT Definite and probable PE 43% RRR

33 ACCP Guidelines 2012 Orthopaedic patients PEP study This study has been criticised..perceived changes in the primary outcome...adjustments of sample size The PEP study, however, had considerable strengths... Conclusion...It is OK to cheat if you have strong methodology Falck-Ytter Y et al. Prevention of VTE in Orthopaedic Surgery Patients. Chest 2012; 141; e278s-e325s

34 True Results - Efficacy No effect on predefined major non-fatal vascular events vascular deaths (95% CI ) non-vascular deaths (95% CI ) overall mortality

35 Event Effects of aspirin on non-fatal vascular events and deaths in elective-arthroplasty patients Non-fatal vascular events Aspirin (n=2047) Placebo (n=2041) Hazard ratio (95% CI) Deep-vein thrombosis ( ) Pulmonary embolism ( ) Venous thromboembolism ( ) Myocardial infarction ( ) Stroke ( ) Vascular death Pulmonary embolism ( ) Ischaemic heart disease ( ) Stroke ( ) Other (including unknown) ( ) All vascular deaths ( ) Non-vascular death 1 0

36 ACCP Hip and knee arthroplasty No effect on VTE in 4088 elective patients HRR 19% (CI 53%-142%) No effect on pulmonary embolism (PE), 9 cases in the aspirin arm and 10 in the placebo arm No effect on total mortality 9 versus 11 respectively. ACCP 2012 combined the HFS data with the elective surgery data (HRR 28% for DVT and 22% for PE) On the basis of these results both the antiplatelet trialists and the ACCP recommend aspirin for thromboprophylaxis in this setting (ignored the specific results in a clinically distinct population)

37 Lies Damned Lies Statistics

38 The concern is not just about misleading doctors, it is about a lack of efficacy and safety

39 Heparin vs Aspirin RRR % Heparin 12,792 Aspirin 13,356 DVT PE Fatal PE Mortality 21 (p=0.02) 3 (NS) Bleeding Collins et al N Engl J Med, 1988 Rogers, MacMahon, Collins, Prentice, Lancet, 2000

40 Patient important VTE Neologism = Clinically presenting VTE Asymptomatic are not patient important However symptomatic start as and arise from asymptomatic

41 Not patient important

42 Not patient important

43 ALIVE

44 DEAD

45 Summary Background Orthopaedics Medical patients Treatment of VTE Conclusions

46 Medical patient revelations 2012 LMWH no effect on mortality (ACCP) All anticoagulants equally recommended for those at increased risk and not for those at low risk (1B formally 1A) Aspirin has an effect on VTE but the evidence is poor

47 Large Hadron Collider Higgs bosun or God particle

48 Sample size best case 8% (5-10%) mortality at 3 months 10% (6-14%) die from PE 0.8% of all deaths Thromboprophylaxis results in a 70% reduction in PE deaths (0.56%) (RR 0.93) Death rates 8% and 7.44% Alpha 5%, beta 0.2 (80% power) 72,000

49 Total Mortality in Nonsurgical Patients Am Coll Phys No. of studies ~patients Intervention n/n (%) Control n/n (%) Odds Ratio (95% CI) Medical patients 10 21, /10,466 (6.5) 679/10,251 (6.6) 0.94 (0.84 to 1.04) Patients with stroke 8 15, /5276 (9.4) 990/10,129 (9.8) 0.91 (0.70 to 1.18) All patients combined 18 36, /15,742 (7.5) 1669/20,380 (8.2) 0.93 (0.86 to 1.00) Lederle FA et al. Annals of Internal Medicine 2011;155:

50 Prince

51 The Artist Formerly Known As Prince

52 Prevention of VTE This is 1A General Medical Patients LDH (Grade 1A) LMWH (Grade 1A) Geerts et al. Chest

53 Prevention of VTE This is 1B Formerly known as 1A General Medical Patients LDH (Grade 1B) LMWH (Grade 1B) Khan S et al. Chest 2012

54 Prevention of VTE This is 1B Formerly known as 1A This is NOT science or evidence, this is the result of an existential crisis Years of evidence followed by touchy feely guff Khan S et al. Chest 2012

55 ACCP Guidelines 2008 Nonsurgical Patients For acutely ill medical patients admitted to hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, we recommend thromboprophylaxis with LMWH (Grade 1A), LDUH (Grade 1A), or fondaparinux (Grade 1A). Geerts W et al, ACCP 2008 Chest 2008

56 ACCP Guidelines 2012 Nonsurgical Patients For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thrombopropylaxis with LMWH, LDUH bid, LDUH tid, or fondaparinux (Grade 1B). Kahn SR et al. Prevention of VTE in Nonsurgical Patients. Chest 2012; 141(2) (Suppl);e195S-e226S

57 Risk Assessment Model: Padua observational study of 1180 patients Barbar S et al. J Thromb Haemost 2010; 8:

58 Risk Assessment Model: Padua Admission diagnoses Barbar S et al. J Thromb Haemost 2010; 8: *Patients with local or distant metastases and/or in whom chemotherapy or radiotherapy.. performed in the previous 6 mo. Anticipated bed rest with bathroom privileges (either because of patient s limitations or on physician s order) for at least 3 d. 58

59 ACCP Guidelines 2012 Nonsurgical Patients Evidence-based.. guidelines For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). Kahn SR et al. Prevention of VTE in Nonsurgical Patients. Chest 2012; 141(2) (Suppl);e195S-e226S

60 ACCP Guidelines 2012 Nonsurgical Patients Evidence-based.. guidelines American College of Chest Physicians Evidence- Based Clinical Practice Guidelines panelists used a feeling thermometer with anchors at 0 (representing death) and 100 (representing full health) to rate patient scenarios. Kahn SR et al. Prevention of VTE in Nonsurgical Patients. Chest 2012; 141(2) (Suppl);e195S-e226S

61 Feeling thermometer data Referenced to Guyatt GH ACCP S-70S Reflects the current science Without important intellectual conflicts In this chapter, section on Patient-important outcomes 2 references only Guyatt GH ACCP 2012 e185s-e194s Guyatt G, ACP Journal Club 2004

62 A feeling thermometer

63 Patient-important data is misleading In this chapter by Guyatt, section on Patient-important outcomes 2 references only Guyatt GH ACCP 2012 e185s-e194s Guyatt G, ACP Journal Club 2004 How many patients were consulted for the term patientimportant outcomes? Answer 0 Only academic clinicians in ACCP

64 ACCP Guidelines 2012 Nonsurgical Patients Evidence-based.. guidelines Patients who are particularly averse to the potential for skin complications, cost, and need for clinical monitoring of GCS and IPC use are likely to decline mechanical prophylaxis. Averse = having a strong feeling of opposition; repugnant Guff!! Kahn SR et al. Prevention of VTE in Nonsurgical Patients. Chest 2012; 141(2) (Suppl);e195S-e226S

65 Definition of Medical Patients Heart failure Respiratory failure Infections Inflammatory and rheumatological disorders Ischaemic Strokes Cancer requiring primary therapy or therapy for complications NOT Spinal cord paralysis, not AMI, not recurrent diseases (secondary prevention)

66 ACCP Nonsurgical Patients Aspirin or other antiplatelet drugs 9 trials of 555 patients DVT RR 0.65 CI (39 vs 61 events) PE RR 0.38 CI (3 vs 8 events) Bleeding rates not reported, few events, experimental drugs ACCP summary of ASA to prevent VTE in medical patients based on PEP study and the above medical patients Kahn SR et al. Prevention of VTE in Nonsurgical Patients. Chest 2012; 141(2) (Suppl);e195S-e226S

67 ACCP Guidelines 2012 Nonsurgical Patients Aspirin or other antiplatelet drugs DVT RR 0.71 CI PE RR 0.47 CI Mortality 0.97 CI Based medical patients and surgical patients (PEP study) No recommendations could be made Kahn SR et al. Prevention of VTE in Nonsurgical Patients. Chest 2012; 141(2) (Suppl);e195S-e226S

68 Medical Advice? Fisher Statisticians

69 Antiplatelet Trialists Collaboration Nine High Risk Medical Patients Trials Nos 1-4: unconfounded randomised comparisons Spinal chord injury: prophylaxis with calf compression, aspirin, and dipyridamole. Paraplegia, 1982;20: Effects of platelet suppressant, anticoagulant and fibrinolytic therapy in recurrent venous thrombosis. Clin Res 1976;24:abstract 573. Trial of dipyridamole-aspirin in recurring venous thrombosis. Lancet 1980;ii: Thromboses veineuses...des accidents vasculaires cérébraux.. (Thèèse pour les doctorat d etat en médicine.) Toulouse: Universite Paul Sabatier, ATC Oxford (Collins R...Peto R) BMJ 1994;308:

70 Antiplatelet Trialists Collaboration Nine High Risk Medical Patients Trials Nos 5-9: unconfounded randomised comparisons Ticlopidine in stroke patients (Sanofi internal report) ASA and RA-233 in decompensated heart disease (Proc ISTH 1972) Glaxo receptor antagonist against Nottingham DVT (Personal communication) Dazoxiben after myocardial infarction (MD thesis) Asasantin DVT nach myokardinfarkt 1981 (BI internal report) ATC Oxford (Collins R...Peto R) BMJ 1994;308:

71 ACCP 2012 Nonsurgical Patients - Cancer Evidence-based.. guidelines In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic dose LMWH or LDUH over no prophylaxis (Grade 2B) Additional risk factors for venous thrombosis in cancer outpatients include previous venous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide Interpretation: the majority of breast and prostate cancer patients on hormonal therapy should get anticoagulant prophylaxis. Kahn SR et al. Prevention of VTE in Nonsurgical Patients. Chest 2012; 141(2) (Suppl);e195S-e226S

72 Summary Background Orthopaedics Medical patients Treatment of VTE Conclusions

73 ACCP Therapy for VTE Disease 2004 (Buller) Recommendations 8 Remarks 2008 (Kearon) Recommendations 5 Remarks 2012 (Kearon) Recommendations 19 Remarks

74 What stops us from doing better?

75 Concerns - ACCP 2012 Methodology Terminology Bias

76 Chest 2012;141 :e419- e494 Weighing the benefits and risks of different durations of anticoagulant therapy : General consideration Weighing the benefits and risks of different durations of anticoagulant therapy Anticoagulant therapy for VTE should be continued until (1)the reduction of recurrent VTE < the increase in bleeding (2)patient preference to stop treatment even if the reduction in VTE > the increase in bleeding. Risk factors a for bleeding with anticoagulant therapy Age > 65 y Liver failure Poor anticoagulant control Age > 75 y Thrombocytopenia Comorbidity and reduced functional capacity Previous bleeding Previous stroke Recent surgery b Cancer Diabetes Frequent falls Metastatic cancer Anemia Alcohol abuse Renal failure Antiplatelet therapy

77 Concerns - ACCP 2012 Methodology Terminology Bias

78 Criteria used to decide on direction and strengths Criteria of recommendation of recommendations in extended anticoagulation in extended anticoagulation A strong recommendation against the estimated number of fatal bleeding events > the estimated number of fatal recurrent VTE prevented. To go from a strong recommendation against to weak recommendation against difference between the lower boundary of increased major bleeding and upper boundary of reduction in recurrent VTE < 2% (risk over 5 y averaged per year). To go from a weak recommendation against to a weak recommendation in favor of difference between point estimate of reduction of recurrent VTE and point estimate for increase in major bleeding is > 2% (risk over 5 y averaged per year) (2% to account for the burden and cost of VKA). To go from a weak recommendation for to strong recommendation for difference between the lower boundary of reduction in VTE and upper boundary of increased major bleeding > 4% (risk over 5 y averaged per year). Chest 2012;141 :e419-e494

79 Another way of interpreting the direction and strength of recommendation based on the number of deaths (related to either bleeding or recurrent VTE) Interpretation of recommendation in extended anticoagulation A strong recommendation against to be associated with an increase in deaths A weak recommendation against to be associated with from no effect on deaths to only a very small reduction in deaths (0-4/1,000 prevented over 5 y or <0.5%/patient-y) A weak recommendation for to be associated with a small reduction in deaths (5 to 9/1,000 prevented over 5 y or 0.5%-0.9%/patient-y) A strong recommendation for to be associated with a large reduction in deaths ( >10/1,000 prevented over 5 y or >1%/patient-y). Chest 2012;141 :e419-e494

80 Therapy for VTE Disease acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Grade 2C). Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day. Kearon C et al CHEST 2012, 141 (2) (Suppl):e419S-e494S

81 Therapy for VTE Disease acute DVT of the leg and whose home circumstances are adequate, we recommend initial treatment at home over treatment in hospital (Grade 1B). Remarks: The recommendation is conditional on the adequacy of home circumstances: well-maintained living conditions, strong support from family or friends... It is also conditional on the patient feeling well enough to be treated at home (eg, does not have severe leg symptoms or comorbidity). Kearon C et al CHEST 2012, 141 (2) (Suppl):e419S-e494S

82 Therapy for VTE Disease Abstract statement: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. Kearon C et al CHEST 2012, 141 (2) (Suppl):e419S-e494S

83 Therapy for VTE Disease with DVT and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C). ( no direct comparisons...evidence is low quality ) Kearon C et al CHEST 2012, 141 (2) (Suppl):e419S-e494S

84 Novel oral anticoagulants Hit the target

85 Therapy for VTE Disease There is a section of great interest missing in the recommendations In patients with DVT of the leg and no cancer, VKA therapy or rivaroxaban or dabigatran for long-term or extended therapy. (direct comparisons have been made, evidence 1B or 2B/C) These guidelines were out of date when published

86 Therapy for VTE Disease The direct antithrombin dabigatran and the direct factor Xa inhibitors apixaban and rivaroxaban have been evaluated for treatment of VTE and are now available in many countries. This statement is potentially misleading as it implies marketing authorization for these three NOACs for VTE. This is not the case other than for rivaroxaban (for DVT treatment only). Kearon C et al CHEST 2012, 141 (2) (Suppl):e419S-e494S

87 Therapy for VTE Disease acute symptomatic DVT of the leg, we suggest the use of compression stockings (Grade 2B). Remarks:... Patients who place a low value on preventing PTS or a high value on avoiding the inconvenience and discomfort of stockings are likely to decline stockings. Kearon C et al CHEST 2012, 141 (2) (Suppl):e419S-e494S

88 Annual risks of recurrent VTE after discontinuation of anticoagulation Recurrent VTE after discontinuation of anticoagulation Risk First VTE provoked by surgery 1% the first year assumed a 0.5% yearly risk thereafter (3% over 5 y) First episode of VTE provoked by nonsurgical factor 5% the first year assumed a 2.5% yearly risk thereafter (15% over 5 y) First episode of unprovoked VTE 10% the first year 11.0% over 1 y, 19.6% over 3 y, 29.1% over 5 y assumed a 5% yearly risk thereafter (30% over 5 y). Second episode of unprovoked VTE 15% the first year assumed that this inflicts 1.5 the risk of recurrent VTE relative to first episode of unprovoked VTE assumed a 7.5% yearly risk thereafter (45% over 5 y). Chest 2012;141 :e419-e494

89

90 Guidelines: ACCP, ACP, ICS, ESMO, ASCO etc

91 ACCP 2012 ACCP 2012 group have been very detailed, although variable in their approach to the guidelines but make many useful recommendations They should be congratulated in providing guidance in many areas in great detail However the recommendations are so numerous that they are often impenetrable and very difficult to navigate

92 Concerns - ACCP 2012 Significant biases in many areas Publication bias Reviewer and author bias Therapeutic bias particularly with antiplatelet therapy Unfounded, inaccurate and potentially dangerous recommendations Unnecessary complication of simple recommendations Altered recommendations based on their own unvalidated assessment of clinical values which assume knowledge of patient preferences... Feeling thermometer Recommendations have been made in areas with no data and no recommendations in areas with significant data

93 Say nothing more