Download PDF
Thromb Haemost 2015; 114(05): 1049-1057
DOI: 10.1160/TH14-12-1006
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Lack of consistency in the relationship between asymptomatic DVT detected by venography and symptomatic VTE in thromboprophylaxis trials

Noel C. Chan   *
1   Population Health Research Institute, Hamilton, Ontario, Canada
,
Alexander C. Stehouwer   *
5   Division of Vascular Medicine, Department of Internal Medicine, University Medical Center Groningen, The Netherlands
,
Jack Hirsh
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Jeffrey S. Ginsberg
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Ashraf Alazzoni
4   Department of Cardiology, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
,
Michiel Coppens
6   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Gordon H. Guyatt
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
John W. Eikelboom
1   Population Health Research Institute, Hamilton, Ontario, Canada
2   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Received: 02 December 2014

Accepted after minor revision: 28 May 2015

Publication Date:
06 December 2017 (online)

    Permissions and Reprints

Summary

Asymptomatic deep-vein thrombosis (DVT) detected by mandatory venography, a surrogate outcome, comprises most of the efficacy outcome events in recent thromboprophylaxis trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in these clinical trials requires a consistent relationship between asymptomatic DVT and symptomatic venous thromboembolism (VTE). In this systematic review of high quality VTE prevention trials, we examined the consistency of the ratios of asymptomatic DVT to symptomatic VTE across a broad range of indications. Studies were identified from citations listed in the chapters on VTE prevention in the antithrombotic guidelines by the American College of Chest Physicians, 2012. A study was eligible if it: 1) was a randomised trial comparing an anticoagulant with standard of care; 2) included at least 500 participants; 3) reported asymptomatic or all DVT rates; and 4) re ported symptomatic VTE rates. Of the 26 eligible trials, 19 trials were conducted in orthopaedic patients, five in general surgery patients and two in general medical patients. The overall median rates (ranges) for asymptomatic DVT and symptomatic VTE were 9.11% (0.75 to 54.87%) and 0.49% (0.00 to 3.10%), respectively. The median ratio was 14.53, with a wide range (2.75 to 103.86). Wide variability in the ratios persisted despite indication- and anticoagulant-specific analyses. In VTE prevention trials of alternative anticoagulants, the wide variability in the ratios of asymptomatic DVT to symptomatic VTE precludes judging the trade-off between thrombotic and bleeding events on the basis of composite outcomes dominated by venographic DVT.

Keywords

Venography - surrogate marker - venous thrombosis - clinical trials - oral anticoagulants - heparins/LMWH

* Joint first authors.


 

  • References

  • 1 Collins R, Scrimgeour A, Yusuf S. et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. New Engl J Med 1988; 318: 1162-1173.
    CrossrefPubMedGoogle Scholar
  • 2 Falck-Ytter Y, Francis CW, Johanson NA. et al. 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-325S.
    CrossrefPubMedGoogle Scholar
  • 3 Guyatt GH, Eikelboom JW, Gould MK. et al. 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; 141: e185S-194S.
    CrossrefPubMedGoogle Scholar
  • 4 Berger J, Eikelboom JW, Quinlan DJ. et al. 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. J Thromb Haemost 2013; 11: 778-782.
    CrossrefPubMedGoogle Scholar
  • 5 Segers AEM, Prins MH, Lensing AWA. et al. Is contrast venography a valid surrogate outcome measure in venous thromboembolism prevention studies?. J Thromb Haemost 2005; 3: 1099-1102.
    CrossrefPubMedGoogle Scholar
  • 6 Quinlan DJ, Eikelboom JW, Dahl OE. et al. 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: 1438-1443.
    CrossrefPubMedGoogle Scholar
  • 7 Hirsh J, Ginsberg JS, Chan N. et al. Mandatory contrast-enhanced venography to detect deep-vein thrombosis (DVT) in studies of DVT prophylaxis: upsides and downsides. Thromb Haemost 2014; 111: 10-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Kahn SR, Lim W, Dunn AS. et al. 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; 141: e195S-e226S.
    CrossrefPubMedGoogle Scholar
  • 9 Gould MK, Garcia DA, Wren SM. et al. Prevention of VTE in non orthopedic surgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141: e227S-e277S.
    CrossrefPubMedGoogle Scholar
  • 10 Guyatt GH, Norris SL, Schulman S. et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141: 53S-70S.
    CrossrefPubMedGoogle Scholar
  • 11 Eriksson BI, Dahl OE, Huo MH. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105: 721-729.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Lassen MR, Gallus A, Raskob GE. et al. Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement. New Engl J Med 2010; 363: 2487-2498.
    CrossrefPubMedGoogle Scholar
  • 13 Kakkar AK, Brenner B, Dahl OE. et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372: 31-39.
    CrossrefPubMedGoogle Scholar
  • 14 Eriksson BI, Borris LC, Friedman RJ. et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. New Engl J Med 2008; 358: 2765-2775.
    CrossrefPubMedGoogle Scholar
  • 15 Eriksson BI, Dahl OE, Rosencher N. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949-956.
    CrossrefPubMedGoogle Scholar
  • 16 Lassen MR, Bauer KA, Eriksson BI. et al. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715-1720.
    CrossrefPubMedGoogle Scholar
  • 17 Turpie AGG, Bauer KA, Eriksson BI. et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721-1726.
    CrossrefPubMedGoogle Scholar
  • 18 Hull RD, Pineo GF, Francis C. et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Archives of internal medicine 2000; 160: 2208-2215.
    CrossrefPubMedGoogle Scholar
  • 19 Eriksson BI, Wille-Jorgensen P, Kalebo P. et al. A Comparison of Recombinant Hirudin with a Low-Molecular-Weight Heparin to Prevent Thromboembolic Complications after Total Hip Replacement. New Engl J Med 1997; 337: 1329-1335.
    CrossrefPubMedGoogle Scholar
  • 20 Hull R, Raskob G, Pineo G. et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. New Engl J Med 1993; 329: 1370-1376.
    CrossrefPubMedGoogle Scholar
  • 21 Lassen MR, Raskob GE, Gallus A. et al. Apixaban or Enoxaparin for Thromboprophylaxis after Knee Replacement. New Engl J Med 2009; 361: 594-604.
    CrossrefPubMedGoogle Scholar
  • 22 Lassen MR, Raskob GE, Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815.
    CrossrefPubMedGoogle Scholar
  • 23 Turpie AG, Lassen MR, Davidson BL. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673-1680.
    CrossrefPubMedGoogle Scholar
  • 24 Ginsberg JS, Davidson BL, Comp PC. et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24: 1-9.
    CrossrefPubMedGoogle Scholar
  • 25 Lassen MR, Ageno W, Borris LC. et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty. New Engl J Med 2008; 358: 2776-2786.
    CrossrefPubMedGoogle Scholar
  • 26 Eriksson BI, Dahl OE, Rosencher N. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5: 2178-2185.
    CrossrefPubMedGoogle Scholar
  • 27 Bauer KA, Eriksson BI, Lassen MR. et al. Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism after Elective Major Knee Surgery. New Engl J Med 2001; 345: 1305-1310.
    CrossrefPubMedGoogle Scholar
  • 28 Eriksson BI, Bauer KA, Lassen MR. et al. Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism after Hip-Fracture Surgery. New Engl J Med 2001; 345: 1298-1304.
    CrossrefPubMedGoogle Scholar
  • 29 Eriksson BI, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003; 163: 1337-1342.
    CrossrefPubMedGoogle Scholar
  • 30 ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg 1997; 84: 1099-1103.
    CrossrefPubMedGoogle Scholar
  • 31 McLeod RS, Geerts WH, Sniderman KW. et al. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery: results of the Canadian colorectal DVT prophylaxis trial: a randomized, double-blind trial. Ann Surg 2001; 233: 438-444.
    CrossrefPubMedGoogle Scholar
  • 32 Agnelli G, Bergqvist D, Cohen AT. et al. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005; 92: 1212-1220.
    CrossrefPubMedGoogle Scholar
  • 33 Turpie AG, Bauer KA, Caprini JA. et al. Fondaparinux combined with intermittent pneumatic compression vs. intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison. J Thromb Haemost 2007; 5: 1854-1861.
    CrossrefPubMedGoogle Scholar
  • 34 Kakkar VV, Balibrea JL, Martinez-Gonzalez J. et al. Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. J Thromb Haemost 2010; 8: 1223-1229.
    CrossrefPubMedGoogle Scholar
  • 35 Samama MM, Cohen AT, Darmon J-Y. et al. A Comparison of Enoxaparin with Placebo for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients. New Engl J Med 1999; 341: 793-800.
    CrossrefPubMedGoogle Scholar
  • 36 Cohen AT, Davidson BL, Gallus AS. et al., for the ARTEMIS Investigators Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. Br Med J 2006; 332: 325-329.
    CrossrefPubMedGoogle Scholar
  • 37 European Medicines Agency. Guideline on clinical investigation of medicinal products for prevention of venous thromboembolism (VTE) in patients undergoing high VTE-risk surgery. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143764.pdf Accessed 08/02/2015.
    PubMedGoogle Scholar