Skip to main content
SpringerLink
Log in

Design of the rivaroxaban for heparin-induced thrombocytopenia study

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Rivaroxaban is an ideal potential candidate for treatment of heparin-induced thrombocytopenia (HIT) because it is administered orally by fixed dosing, requires no laboratory monitoring and is effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT study is a prospective, multicentre, single-arm, cohort study evaluating the incidence of new symptomatic venous and arterial thromboembolism in patients with suspected or confirmed HIT who are treated with rivaroxaban. Methodological challenges faced in the design of this study include heterogeneity of the patient population, differences in the baseline risk of thrombosis and bleeding dependent on whether HIT is confirmed or just suspected, and heterogeneity in laboratory confirmation of HIT. The rationale for how these challenges were addressed and the final design of the Rivaroxaban for HIT study is reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG (1995) Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1330–1335

    Article  PubMed  CAS  Google Scholar 

  2. Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin TE, Eichler P (2005) Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 94:132–135

    PubMed  CAS  Google Scholar 

  3. Warkentin TE, Chong BH, Greinacher A (1998) Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 79:1–7

    PubMed  CAS  Google Scholar 

  4. Warkentin TE, Kelton JG (1996) A 14-year study of heparin-induced thrombocytopenia. Am J Med 101:502–507

    Article  PubMed  CAS  Google Scholar 

  5. Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF (1999) Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med 106:629–635

    Article  PubMed  CAS  Google Scholar 

  6. Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M (2000) Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 96:846–851

    PubMed  CAS  Google Scholar 

  7. Linkins LA, Warkentin TE (2011) Heparin-induced thrombocytopenia: real-world issues. Semin Thromb Hemost 37:653–663

    Article  PubMed  CAS  Google Scholar 

  8. Warkentin TE (2014) Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls. Expert Opin Drug Saf 13:25–43

    Article  PubMed  CAS  Google Scholar 

  9. Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H, de Greef R (2002) The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 41(Suppl 2):1–9

    Article  PubMed  CAS  Google Scholar 

  10. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366:1287–1297

    Article  PubMed  Google Scholar 

  11. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:883–891

    Article  PubMed  CAS  Google Scholar 

  12. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499–2510

    Article  PubMed  CAS  Google Scholar 

  13. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366:9–19

    Article  PubMed  CAS  Google Scholar 

  14. Walenga JM, Prechel M, Jeske WP, Hoppensteadt D, Maddineni J, Iqbal O, Messmore HL, Bakhos M (2008) Rivaroxaban—an oral, direct Factor Xa inhibitor—has potential for the management of patients with heparin-induced thrombocytopenia. Br J Haematol 143:92–99

    Article  PubMed  CAS  Google Scholar 

  15. Krauel K, Hackbarth C, Furll B, Greinacher A (2012) Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies. Blood 119:1248–1255

    Article  PubMed  CAS  Google Scholar 

  16. Warkentin TE (2011) How I diagnose and manage HIT. Hematol Am Soc Hematol Educ Program 2011:143–149

    Article  Google Scholar 

  17. Crowther MA, Cook DJ, Meade MO, Griffith LE, Guyatt GH, Arnold DM, Rabbat CG, Geerts WH, Warkentin TE (2005) Thrombocytopenia in medical–surgical critically ill patients: prevalence, incidence, and risk factors. J Crit Care 20:348–353

    Article  PubMed  Google Scholar 

  18. Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG (2008) The quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost 6:1304–1312

    Article  PubMed  CAS  Google Scholar 

  19. Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, Crowther M (2012) Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis: American College of Chest physicians evidence-based clinical practice guidelines. Chest 141:e495S–e530S

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Warkentin TE (2012) HITlights: a career perspective on heparin-induced thrombocytopenia. Am J Hematol 87(Suppl 1):S92–S99

    Article  PubMed  CAS  Google Scholar 

  21. Boyce SW, Bandyk DF, Bartholomew JR, Frame JN, Rice L (2011) A randomized, open-label pilot study comparing desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis: PREVENT-HIT study. Am J Ther 18:14–22

    Article  PubMed  Google Scholar 

  22. Boyce SW (2012) Challenges to the design and execution of controlled clinical studies of anticoagulants in patients with heparin-induced thrombocytopenia: lessons learned. J Thromb Thrombolysis 33:124–128

    Article  PubMed  Google Scholar 

  23. Price EA, Hayward CP, Moffat KA, Moore JC, Warkentin TE, Zehnder JL (2007) Laboratory testing for heparin-induced thrombocytopenia is inconsistent in North America: a survey of North American specialized coagulation laboratories. Thromb Haemost 98:1357–1361

    PubMed  CAS  Google Scholar 

  24. Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH (2011) Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost 9:2498–2500

    Article  PubMed  CAS  Google Scholar 

  25. Sheridan D, Carter C, Kelton JG (1986) A diagnostic test for heparin-induced thrombocytopenia. Blood 67:27–30

    PubMed  CAS  Google Scholar 

  26. Lee DH, Warkentin TE (2007) Frequency of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A (eds) Heparin-induced thrombocytopenia, 4th edn. Informa Healthcare USA, Inc., New York, pp 67–116

    Chapter  Google Scholar 

  27. Lo GK, Sigouin CS, Warkentin TE (2007) What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol 82:1037–1043

    Article  PubMed  CAS  Google Scholar 

  28. Cuker A (2011) Heparin-induced thrombocytopenia (HIT) in 2011: an epidemic of overdiagnosis. Thromb Haemost 106:993–994

    Article  PubMed  CAS  Google Scholar 

  29. Cuker A, Gimotty PA, Crowther MA, Warkentin TE (2012) Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood 120:4160–4167

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G (2005) Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 78:412–421

    Article  PubMed  CAS  Google Scholar 

  31. Weinz C, Schwarz T, Kubitza D, Mueck W, Lang D (2009) Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 37:1056–1064

    Article  PubMed  CAS  Google Scholar 

  32. Smythe MA, Warkentin TE, Stephens JL, Zakalik D, Mattson JC (2002) Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia. Am J Hematol 71:50–52

    Article  PubMed  Google Scholar 

  33. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A (2006) Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 4:759–765

    Article  PubMed  CAS  Google Scholar 

  34. Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG (2001) Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 103:1838–1843

    Article  PubMed  CAS  Google Scholar 

  35. Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG (2003) Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 163:1849–1856

    Article  PubMed  CAS  Google Scholar 

  36. Warkentin TE, Greinacher A, Koster A, Lincoff AM (2008) Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest physicians evidence-based clinical practice guidelines. Chest 133:340S–380S

    Article  PubMed  CAS  Google Scholar 

  37. Bucci C, Geerts WH, Sinclair A, Fremes SE (2011) Comparison of the effectiveness and safety of low-molecular weight heparin versus unfractionated heparin anticoagulation after heart valve surgery. Am J Cardiol 107:591–594

    Article  PubMed  CAS  Google Scholar 

  38. Schwann TA, Kistler L, Engoren MC, Habib RH (2010) Incidence and predictors of postoperative deep vein thrombosis in cardiac surgery in the era of aggressive thromboprophylaxis. Ann Thorac Surg 90:760–766

    Article  PubMed  Google Scholar 

  39. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N (1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in medical patients with Enoxaparin Study Group. N Engl J Med 341:793–800

    Article  PubMed  CAS  Google Scholar 

  40. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AG, Egberts JF, Lensing AW (2006) Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 332:325–329

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Cook D, Meade M, Guyatt G, Walter S, Heels-Ansdell D, Warkentin TE, Zytaruk N, Crowther M, Geerts W, Cooper DJ, Vallance S, Qushmaq I, Rocha M, Berwanger O, Vlahakis NE (2011) Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 364:1305–1314

    Article  PubMed  CAS  Google Scholar 

  42. Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW (2011) Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost 9:2389–2396

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

All authors have contributed to the drafting of this manuscript. The Rivaroxaban for HIT Study is funded by an investigator-initiated study Grant from Bayer Inc. In the past 5 years, Dr. Linkins has received honoraria for presentations from Pfizer. Dr. Warkentin has received lecture honoraria from Pfizer Canada and Instrumentation Laboratories, has provided consulting services to, and/or has received research funding from, GlaxoSmithKline, W. L. Gore, Immucor GTI Diagnostics, and Paringenix, and has provided expert witness testimony relating to HIT. In the last 5 years, Dr. Wells has received honoraria for presentations from Bayer Healthcare, Boehringer Ingelheim, Pfizer and Biomerieiux. He is the recipient of an investigator-initiated research Grant from Bristol Myers Squibb/Pfizer. Dr. Shivakumar has received lecture honoraria from Bayer Inc. Dr. Crowther discloses having sat on advisory boards for Leo Pharma, Pfizer, Bayer, Boehringer Ingelheim, Alexion, CSL Behring, Portola, Viropharm and AKP America; provided expert testimony for Bayer and Merck and has received research funding from Boehringer Ingelheim, Octapharm, Pfizer and Leo Pharma. Dr. Manji and Dr. Pai have no conflict of interest with this study.

Author information

Authors and Affiliations

  1. Department of Medicine, McMaster University, 1280 Main Street West, Juravinski Hospital Site, Rm A3-74, Hamilton, ON, L8S 4K1, Canada

    Lori-Ann Linkins

  2. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

    Theodore E. Warkentin, Menaka Pai & Mark A. Crowther

  3. Hamilton Regional Laboratory Medicine Program, McMaster University, Hamilton, ON, Canada

    Menaka Pai

  4. Department of Medicine, Dalhousie University, Halifax, NS, Canada

    Sudeep Shivakumar

  5. Cardiac Sciences Program, Department of Surgery, University of Manitoba, Winnipeg, MB, Canada

    Rizwan A. Manji

  6. Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada

    Philip S. Wells

  7. Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada

    Theodore E. Warkentin, Menaka Pai & Mark A. Crowther

Authors
  1. Lori-Ann Linkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theodore E. Warkentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Menaka Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sudeep Shivakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rizwan A. Manji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Philip S. Wells
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark A. Crowther
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lori-Ann Linkins.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Linkins, LA., Warkentin, T.E., Pai, M. et al. Design of the rivaroxaban for heparin-induced thrombocytopenia study. J Thromb Thrombolysis 38, 485–492 (2014). https://doi.org/10.1007/s11239-014-1064-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-014-1064-7

Keywords

Search

Navigation