Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? Proceedings of an Ad Hoc Working Group Meeting

Abstract

Physicians and patients consider the balance between benefits and risks of treatment when making decisions about the use of anticoagulants for the prevention of venous thromboembolism (VTE). The results of early trials demonstrating the efficacy of heparin compared with placebo or no thromboprophylaxis for the prevention of a fatal pulmonary embolism (PE) led to the adoption of routine anticoagulant prophylaxis in patients considered to be at an increased risk of VTE. More recent trials comparing new anticoagulants with heparin have most commonly used the composite outcome, asymptomatic (or ‘silent’) deep vein thrombosis (DVT), detected by screening venography, and symptomatic (or ‘patient-important’) VTE, as the primary measure of efficacy [1.National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital, 2010.http://www.nice.org.uk/nicemedia/pdf/CG92FullGuideline.pdf. Accessed 21 October 2011.Google Scholar, 2.Struijk-Mulder M.C. Ettema H.B. Verheyen C.C. Büller H.R. Comparing consensus guidelines on thromboprophylaxis in orthopedic surgery.J Thromb Haemost. 2010; 8: 678-83Crossref PubMed Scopus (70) Google Scholar, 3.Guyatt G.H. Eikelboom J.W. Gould M.K. Garcia D.A. Crowther M. Murad M.H. Kahn S.R. Falck-Ytter Y. Francis C.W. Lansberg M.G. Akl E.A. Hirsh J. Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: american College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 2: e185S-94SAbstract Full Text Full Text PDF Scopus (143) Google Scholar]. The advantage of including an asymptomatic DVT detected by screening venography in the primary efficacy outcome of post-surgical prophylaxis trials is that it is much more common than symptomatic VTE, thus allowing much smaller sample sizes than would be required if the primary outcome was based on symptomatic VTE. The disadvantage is that physicians and patients do not know how to trade off an asymptomatic DVT against bleeding because asymptomatic events are of uncertain importance for patients [4.American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline, Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty.http://www.aaos.org/research/guidelines/VTE/VTE_full_guideline.pdf. Accessed 21 October 2011.Google Scholar]. A working group comprising clinicians, methodologists, regulators from the European Medicine Agency (EMA) and the Food and Drug Administration (FDA), and representatives from the pharmaceutical industry (see Appendix for list of delegates) met in Washington in 2009 to consider the balance between the benefits and risks of anticoagulants for the prevention of VTE. The objectives of this 1-day meeting were to (i) consider the validity of an asymptomatic DVT as a surrogate for symptomatic VTE and (ii) evaluate the trade-off between the prevention of VTE and risk of bleeding in trials of anticoagulant prophylaxis. This paper summarizes the meeting proceedings. A silent DVT detected by screening venography has the potential to be a valuable surrogate in thromboprophylaxis trials because it can be measured more easily and occurs much more frequently than the symptomatic VTE [5.Bucher H.C. [Surrogate endpoint trials: benefit and pitfalls for clinical decision making].Internist (Berl). 2008; 49: 681-7Crossref Scopus (4) Google Scholar]. The disadvantage of including an asymptomatic DVT in the assessment of efficacy is that its relationship to outcomes of importance to patients (VTE that requires treatment with anticoagulants, a fatal PE and post-thrombotic syndrome) is difficult to quantify [6.Bucher H.C. Guyatt G.H. Cook D.J. Holbrook A. McAlister F.A. Users' guides to the medical literature: XIX Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points. Evidence-Based Medicine Working Group.JAMA. 1999; 282: 771-8Crossref PubMed Scopus (282) Google Scholar, 7.Fleming T.R. De Mets D.L. Surrogate end points in clinical trials: are we being misled?.Ann Intern Med. 1996; 125: 605-13Crossref PubMed Scopus (1357) Google Scholar]. The acceptance of an asymptomatic DVT as a valid surrogate measure for symptomatic VTE is based on: (i) the biological link between an asymptomatic and symptomatic VTE; (ii) the accuracy of venography for the diagnosis of an asymptomatic DVT; (iii) the similarity between pooled estimates of the relative effect of anticoagulant prophylaxis for an asymptomatic DVT and symptomatic VTE; and (iv) an assumption that we know the quantitative relationship between an asymptomatic DVT and symptomatic VTE. The biological link between an asymptomatic DVT and symptomatic VTE is supported by indirect comparisons of efficacy assessments based on DVT detected by screening radioactive fibrinogen leg scanning (FLS) and screening venography, and symptomatic VTE diagnosed by objective testing. Studies using FLS indicate that the incidence of a DVT in bed-ridden patients is high, that most DVT start in the calf [8.Kearon C. Natural history of venous thromboembolism.Circulation. 2003; 23: I22-30Google Scholar] and, if that untreated, these asymptomatic DVTs may either propagate or undergo spontaneous lysis. The incidence of a DVT on screening venography performed 1 week after major surgery is lower than that detected by FLS, presumably because venography only detects the larger DVTs that have not undergone spontaneous lysis. The incidence of symptomatic VTE is much lower than that of asymptomatic DVTs, and most symptomatic thrombi declare themselves after the first week and are larger than asymptomatic DVTs [8.Kearon C. Natural history of venous thromboembolism.Circulation. 2003; 23: I22-30Google Scholar]. PEs can be derived from either asymptomatic or symptomatic DVTs, but symptomatic (patient important) PEs tends to be associated with larger DVTs. Based on data derived from the above studies, it is reasonable to accept the view that symptomatic VTE originates from an asymptomatic DVT. Venography is regarded as the gold standard for the detection of a DVT. However, this may not necessarily be the case in all settings. While inter-observer agreement for a venographically-detected DVT is good within individual centers [9.Lensing A.W. Büller H.R. Prandoni P. Batchelor D. Molenaar A.H. Cogo A. Vigo M. Huisman P.M. ten Cate J.W. Contrast venography, the gold standard for the diagnosis of deep vein thrombosis: improvement in observer agreement.Thromb Haemost. 1992; 67: 8-12Crossref PubMed Google Scholar], rates reported in patients of similar age, undergoing the same type of operation and receiving the same thromboprophylaxis regimens differ by as much as two-fold between adjudication centers [10.Quinlan D.J. Eikelboom J.W. Dahl O.E. Eriksson B.I. Sidhu P.S. Hirsh J. Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery.J Thromb Haemost. 2007; 5: 1438-43Crossref PubMed Scopus (97) Google Scholar]. Pooled data from randomized trials indicate that on average, anticoagulant prophylaxis produces proportionately similar risk reductions in asymptomatic DVTs and symptomatic VTE [11.Eikelboom J.W. Karthikeyan G. Fagel N. Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients?.Chest. 2009; 135: 513-20Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar]. It is possible, however, for average effects to be the same but for true underlying effects in individual trials or sets of trials to show important discrepancies. Indeed, individual examples of large differences in the effect of post-surgical thromboprophylaxis on asymptomatic and symptomatic events exist [12.Lassen M.R. Bauer K.A. Eriksson B.I. Turpie A.G. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison.Lancet. 2002; 359: 1715-20Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar, 13.Lassen M.R. Raskob G.E. Gallus A. Pineo G. Chen D. Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.Lancet. 2010; 375: 807-15Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar]. More powerful than a demonstration of average effects being similar would be a very high level of agreement in individual trials or sets of trials. Moreover, estimates based on trials using screening venography are subject to two competing biases. On the one hand, patients known to have an asymptomatic DVT may be more likely to be diagnosed with symptomatic VTE than those with a normal venogram. On the other hand, patients diagnosed with an asymptomatic DVT may be less likely to develop symptomatic VTE because they receive anticoagulant treatment for the asymptomatic DVT. These potential biases reduce our confidence in the estimates of treatment effect from trials that include an asymptomatic DVT in the primary outcome. The incidence of an asymptomatic venographically detected DVT is much higher than the incidence of symptomatic VTE. Although various attempts have been made to quantify the numerical relationship between these two outcomes, the true relationship is uncertain, and without such knowledge, estimates of the trade-off between risks and benefits of anticoagulant prophylaxis are imprecise. Perspectives from guideline groups and agencies reflect uncertainty about the value of an asymptomatic DVT detected by screening venography as a surrogate for symptomatic VTE (Table 1) [1.National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital, 2010.http://www.nice.org.uk/nicemedia/pdf/CG92FullGuideline.pdf. Accessed 21 October 2011.Google Scholar, 4.American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline, Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty.http://www.aaos.org/research/guidelines/VTE/VTE_full_guideline.pdf. Accessed 21 October 2011.Google Scholar, 14.European Medicines Agency. Committee for medicinal products for human use. Guideline on clinical investigation of medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk. CPMP/EWP/707/98 Rev.1. May 2008. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003301.pdf. Accessed 21 October 2011.Google Scholar, 15.Qaseem A. Chou R. Humphrey L.L. Starkey M. Shekelle P. Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians.Ann Intern Med. 2011; 155: 625-32Crossref PubMed Scopus (201) Google Scholar, 16.Falck-Ytter Y. Francis C.W. Johanson N.A. Curley C. Dahl O.E. Schulman S. Ortel T.L. Pauker S.G. Colwell C.W. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 141: e278S-325SAbstract Full Text Full Text PDF PubMed Scopus (1581) Google Scholar]. The 2012 American College of Chest Physicians (ACCP) guidelines make strong recommendations for anticoagulant prophylaxis in hospitalized surgical and high-risk medical patients [16.Falck-Ytter Y. Francis C.W. Johanson N.A. Curley C. Dahl O.E. Schulman S. Ortel T.L. Pauker S.G. Colwell C.W. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 141: e278S-325SAbstract Full Text Full Text PDF PubMed Scopus (1581) Google Scholar, 17.Kahn S.R. Lim W. Dunn A.S. Cushman M. Dentali F. Akl E.A. Cook D.J. Balekian A.A. Klein R.C. Le H. Schulman S. Murad M.H. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 2: e195S-226SAbstract Full Text Full Text PDF Scopus (1263) Google Scholar] but rate down the quality of the evidence if the efficacy outcome from randomized controlled trials is based on an asymptomatic DVT. The UK National Institute for Health and Clinical Excellence (NICE) [1.National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital, 2010.http://www.nice.org.uk/nicemedia/pdf/CG92FullGuideline.pdf. Accessed 21 October 2011.Google Scholar] also rate down the quality of evidence if the efficacy outcome from randomized trials is based on an asymptomatic DVT. The 2011 American Association of Orthopedic Surgeons (AAOS) guidelines for the prevention of VTE in patients undergoing orthopedic surgery largely reject evidence from trials that use screening venography [4.American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline, Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty.http://www.aaos.org/research/guidelines/VTE/VTE_full_guideline.pdf. Accessed 21 October 2011.Google Scholar].Table 1Guideline and regulatory perspectives on an asymptomatic deep vein thrombosis (DVT) as an outcome in thromboprophylaxis trialsGuidelinePerspectiveNICE 2010 [1.National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital, 2010.http://www.nice.org.uk/nicemedia/pdf/CG92FullGuideline.pdf. Accessed 21 October 2011.Google Scholar]Accept both an asymptomatic and symptomatic DVT as valid outcomesDowngrade the quality of the evidence based on an asymptomatic DVTAAOS 2011 [4.American Academy of Orthopaedic Surgeons. American Academy of Orthopaedic Surgeons clinical practice guideline, Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty.http://www.aaos.org/research/guidelines/VTE/VTE_full_guideline.pdf. Accessed 21 October 2011.Google Scholar]Largely reject evidence from trials that use screening venographyACP 2011 [15.Qaseem A. Chou R. Humphrey L.L. Starkey M. Shekelle P. Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians.Ann Intern Med. 2011; 155: 625-32Crossref PubMed Scopus (201) Google Scholar]Reject evidence from an asymptomatic DVTACCP 2012 [16.Falck-Ytter Y. Francis C.W. Johanson N.A. Curley C. Dahl O.E. Schulman S. Ortel T.L. Pauker S.G. Colwell C.W. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 141: e278S-325SAbstract Full Text Full Text PDF PubMed Scopus (1581) Google Scholar]Downgrade the quality of the evidence based on an asymptomatic DVTUse an asymptomatic DVT to obtain best estimates of the effect of treatment on symptomatic eventsRegulatorPerspectiveEMA 2008 [14.European Medicines Agency. Committee for medicinal products for human use. Guideline on clinical investigation of medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk. CPMP/EWP/707/98 Rev.1. May 2008. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003301.pdf. Accessed 21 October 2011.Google Scholar]Recommend an asymptomatic proximal DVT but not an asymptomatic distal DVT as an appropriate outcome in therapeutic confirmatory trialsFDAAccept an asymptomatic DVT as a basis for drug approval Open table in a new tab The EMA has stated that it considers an asymptomatic proximal DVT but not asymptomatic distal DVT as an appropriate outcome for drug approval [14.European Medicines Agency. Committee for medicinal products for human use. Guideline on clinical investigation of medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk. CPMP/EWP/707/98 Rev.1. May 2008. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003301.pdf. Accessed 21 October 2011.Google Scholar]. The Food and Drugs Administration grants new drug approvals largely based on the results of randomized trials that report an asymptomatic DVT diagnosed by screening venography. They consider the totality of venographic data, including the clinical consequences associated with the location of the DVT. Physicians and patients need to take into account the incidence and consequences of VTE and bleeding when making decisions about the use of anticoagulant thromboprophylaxis. When symptomatic, a DVT causes leg pain and swelling. Both an asymptomatic and symptomatic DVT can result in a pulmonary embolism (PE). Patients who develop a DVT or PE are generally prescribed anticoagulant treatment for at least 3–6 months [18.Ginsberg J.S. Hirsh J. Julian J. Vander L.M. Magier D. MacKinnon B. Gent M. Prevention and treatment of postphlebitic syndrome: Results of a 3-part study.Arch Intern Med. 2001; 161: 2105-9Crossref PubMed Scopus (244) Google Scholar]. The long-term consequences of an asymptomatic DVT are uncertain but up to 40% of symptomatic DVTs are associated with the development of post-thrombotic syndrome, which is debilitating in about 15% of affected patients [19.Prandoni P. Lensing A.W. Cogo A. The long-term clinical course of acute deep vein thrombosis.Ann Intern Med. 1996; 125: 1-7Crossref PubMed Scopus (1934) Google Scholar, 20.Schulman S. Lindmarker P. Holmstrom M. Larfars G. Carlsson A. Nicol P. Svensson E. Ljungberg B. Viering S. Nordlander S. Leijd B. Jahed K. Hjorth M. Linder O. Beckman M. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months.J Thromb Haemost. 2006; 4: 734-42Crossref PubMed Scopus (368) Google Scholar]. The most important consequence of a PE is death, and in the long term ∼3% of PE patients develop thromboembolic pulmonary hypertension [21.Kearon C. Akl E.A. Comerota A.J. Prandoni P. Bounameaux H. Goldhaber S.Z. Nelson M.E. Wells P.S. Gould M.K. Dentali F. Crowther M. Kahn S.R. Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 2: e419S-94SAbstract Full Text Full Text PDF Scopus (2922) Google Scholar]. Bleeding at the operative wound site post-surgery is generally considered to be the most important adverse event associated with the use of anticoagulant prophylaxis. Wound bleeding can cause local pain and swelling and increase the risk of an infection, which may lead to the need for blood transfusion, often prolongs hospitalization and on rare occasions requires further surgery. Orthopedic surgeons have expressed concerns that anticoagulants cause bleeding into prosthetic joints and thereby impair functional outcomes but there are no reliable data on the frequency of this problem. In spite of making treatment recommendations based on the results of venographic trials, the NICE guidelines do not provide guidance on the assessment of the trade-off between an asymptomatic DVT and wound bleeding [1.National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital, 2010.http://www.nice.org.uk/nicemedia/pdf/CG92FullGuideline.pdf. Accessed 21 October 2011.Google Scholar]. Instead, the NICE guidelines take into account patient bleeding risk and stratify recommendations for thromboprophylaxis according to whether or not patients are considered to be at an elevated risk for bleeding. By largely disregarding the results of venographic trials, the 2011 AAOS guidelines avoid the need to trade-off a reduction in an asymptomatic DVT against bleeding. The 2012 ACCP guidelines offer explicit strategies for estimating the absolute risk reduction in symptomatic VTE when trials have focused on asymptomatic events and explicit tradeoffs between symptomatic VTE and bleeding [3.Guyatt G.H. Eikelboom J.W. Gould M.K. Garcia D.A. Crowther M. Murad M.H. Kahn S.R. Falck-Ytter Y. Francis C.W. Lansberg M.G. Akl E.A. Hirsh J. Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: american College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2012; 2: e185S-94SAbstract Full Text Full Text PDF Scopus (143) Google Scholar]. Based on the totality of the evidence, and particularly the evidence from trials demonstrating that anticoagulant prophylaxis prevents fatal PE, this class of agents has been widely accepted by regulators, guidelines, clinicians and patients for the prevention of VTE.