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Low molecular weight heparin biosimilars: how much similarity for how much clinical benefit?

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Abstract

The development of biosimilar versions of low molecular weight heparins (LMWHs) raises real medical concerns. To illustrate this, we have chosen as an example the specific clinical setting of antithrombotic management of acute coronary syndromes (ACS). In this indication, the LMWH enoxaparin has consistently shown its superiority in terms of efficacy when compared to unfractionated heparin (UFH) and in a number of direct or indirect comparisons to other LMWHs. For this reason, enoxaparin has become the gold standard for anticoagulation in cardiology, recommended by practice guidelines and extensively used in everyday practice. We are concerned by the fact that some patients might be treated with a biosimilar copy of enoxaparin, on the basis of simplified criteria that are not specific enough to differentiate between different available LMWHs and are thus unable to differentiate between enoxaparin and a biosimilar. In the absence of evidence from clinical trials, especially in ACS, we believe that it is difficult to ensure that the benefit/risk ratio of enoxaparin and its copy are equivalent. In addition to efficacy, safety issues also have to be taken into consideration, since biosimilars consist of glycan chain mixtures that exhibit specific immunoallergic features. Contamination of raw material with other glycans or xenobiotic material during extraction and fractionation may trigger potentially harmful immune reactions.

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References

  1. Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman S et al (1997) A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous enoxaparin in Non-Q-Wave coronary events study group. N Engl J Med 337(7):447–452

    Article  PubMed  CAS  Google Scholar 

  2. Montalescot G, Cohen M, Goldstein P et al (2010) ATOLL An international randomized study comparing IV enoxaparin to IV UFH in primary PCI. ESC, Stockholm – Hotline session August 30. http://www.escardio.org/congresses/esc-2010/congress-reports/Pages/707-4-ATOLL.aspx. 2010

  3. Anderson JL et al (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of cardiology/American heart association task force on practice guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable angina/Non-ST-elevation myocardial infarction) developed in collaboration with the American college of emergency physicians, the society for cardiovascular angiography and interventions, and the society of thoracic surgeons endorsed by the American association of cardiovascular and pulmonary rehabilitation and the society for academic emergency medicine. J Am Coll Cardiol 50(7):e1–e157

    Article  PubMed  Google Scholar 

  4. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernandez-Aviles F et al (2007) Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 28(13):1598–1660

    Article  PubMed  CAS  Google Scholar 

  5. Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM et al (2009) 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of cardiology foundation/American heart association task force on practice guidelines. J Am Coll Cardiol 54(23):2205–2241

    Article  PubMed  Google Scholar 

  6. Van de Werf F et al (2008) Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the task force on the management of ST-segment elevation acute myocardial infarction of the European society of cardiology. Eur Heart J 29(23):2909–2945

    Article  PubMed  Google Scholar 

  7. Walenga JM, Prechel M, Jeske WP, Bakhos M (2005) Unfractionated heparin compared with low-molecular-weight heparin as related to heparin-induced thrombocytopenia. Curr Opin Pulm Med 11(5):385–391

    Article  PubMed  CAS  Google Scholar 

  8. Alban S, Luhn S, Schiemann S, Beyer T, Norwig J, Schilling C et al (2011) Comparison of established and novel purity tests for the quality control of heparin by means of a set of 177 heparin samples. Anal Bioanal Chem 399(2):605–620

    Article  PubMed  CAS  Google Scholar 

  9. FDA (2010) http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm220037.htm. 2010

  10. European Medicines Agency Committee for medicinal products for human use March 2009. Guidelines on non clinical and clinical development of similar biological medicinal products containing low molecular weight heparin. http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003927.pdf. 2009

  11. The World Health Organization Expert Committee on Biological Standardization. Guidelines on evaluation of similar biotherapeutic products (SBPs). http://www.who.int/entity/bio¬logicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEBj2APRIL20. 2009

  12. Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein D et al (1999) Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 100(15):1593–1601

    PubMed  CAS  Google Scholar 

  13. Antman EM, Morrow DA, McCabe CH, Murphy SA, Ruda M, Sadowski Z et al (2006) Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 354(14):1477–1488

    Article  PubMed  CAS  Google Scholar 

  14. Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman S et al (2004) Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 292(1):45–54

    Article  PubMed  CAS  Google Scholar 

  15. Gallo R, Steinhubl SR, White HD, Montalescot G (2009) Impact of anticoagulation regimens on sheath management and bleeding in patients undergoing elective percutaneous coronary intervention in the STEEPLE trial. Catheter Cardiovasc Interv 73(3):319–325

    Article  PubMed  Google Scholar 

  16. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS et al (2000) ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American college of cardiology/American heart association task force on practice guidelines (committee on the management of patients with unstable angina). J Am Coll Cardiol 36(3):970–1062

    Article  PubMed  CAS  Google Scholar 

  17. Montalescot G, Bal-dit-Sollier C, Chibedi D, Collet JP, Soulat T, Dalby M et al (2003) Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction (the ARMADA study). Am J Cardiol 91(8):925–930

    Article  PubMed  CAS  Google Scholar 

  18. Drouet L, Bal dit Sollier C, Martin J (2009) Adding intravenous unfractionated heparin to standard enoxaparin causes excessive anticoagulation not detected by activated clotting time: results of the STACK-on to ENOXaparin (STACKENOX) study. Am Heart J 158(2):177–184

    Article  PubMed  CAS  Google Scholar 

  19. Weitz JI (1997) Low-molecular-weight heparins. N Engl J Med 337(10):688–698

    Article  PubMed  CAS  Google Scholar 

  20. Linhardt RJ, Gunay NS (1999) Production and chemical processing of low molecular weight heparins. Semin Thromb Hemost 25(Suppl 3):5–16

    PubMed  CAS  Google Scholar 

  21. Rudolph TK, Rudolph V, Witte A, Klinke A, Szoecs K, Lau D et al. Liberation of vessel adherent myeloperoxidase by enoxaparin improves endothelial function. Int J Cardiol 140(1):42–7

  22. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C et al (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(11):793–800

    Article  PubMed  CAS  Google Scholar 

  23. Hull RD, Schellong SM, Tapson VF, Monreal M, Samama MM, Nicol P et al (2010) Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 153(1):8–18

    PubMed  Google Scholar 

  24. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W et al (2006) Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 332(7537):325–329

    Article  PubMed  CAS  Google Scholar 

  25. Jeske W, Neville B, Ma Q et al (2004) Effect of 1,6-anhdro bicyclic ring structure on the pharmacokientic behavior of low molecular weight heparin. Blood 104:abstract 1868

    Google Scholar 

  26. Fareed J, Ma Q, Florian M, Maddineni J, Iqbal O, Hoppensteadt DA et al (2004) Differentiation of low-molecular-weight heparins: impact on the future of the management of thrombosis. Semin Thromb Hemost 30(Suppl 1):89–104

    PubMed  Google Scholar 

  27. Planes A, Samama MM, Lensing AW, Buller HR, Barre J, Vochelle N et al (1999) Prevention of deep vein thrombosis after hip replacement–comparison between two low-molecular heparins, tinzaparin and enoxaparin. Thromb Haemost 81(1):22–25

    PubMed  CAS  Google Scholar 

  28. Michalis LK, Katsouras CS, Papamichael N, Adamides K, Naka KK, Goudevenos J et al (2003) Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: the EVET trial. Am Heart J 146(2):304–310

    Article  PubMed  CAS  Google Scholar 

  29. Katsouras C, Michalis LK, Papamichael N, Adamides K, Naka KK, Nikas D et al (2005) Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: results of the enoxaparin versus tinzaparin (EVET) trial at 6 months. Am Heart J 150(3):385–391

    Article  PubMed  CAS  Google Scholar 

  30. Ramaciotti E, Gomez M, Walenga J et al (2010) Differential immunogenic responses of branded and generic versions of low molecular weight heparins. FASEB J (Meeting Abstract Supplement) 24:951–956

    Google Scholar 

  31. Mazoyer E, Enjolras O, Bisdorff A, Perdu J, Wassef M, Drouet L (2008) Coagulation disorders in patients with venous malformation of the limbs and trunk: a case series of 118 patients. Arch Dermatol 144(7):861–867

    Article  PubMed  Google Scholar 

  32. Warkentin TE, Greinacher A (2009) Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf 8(2):129–144

    Article  PubMed  CAS  Google Scholar 

  33. Assmann A, Boeken U, Feindt P, Schurr P, Akhyari P, Lichtenberg A (2010) Heparin-induced thrombocytopenia type II after cardiac surgery: predictors and outcome. Thorac Cardiovasc Surg 58(8):463–467

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

Ludovic Drouet has participated on National or International expert committees in the field of thrombosis and anticoagulation for Sanofi-Aventis, Pfizer, BMS, Boehringer-Ingelheim, The Medicine Company and Bayer, and has been invited as a speaker at conferences or symposia by Sanofi-Aventis, GSK, Leo-Pharma, Bayer, the Medicine Company and Boehringer-Ingelheim.

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Authors and Affiliations

  1. Angio-hématologie et Clinique des Anticoagulants « CREATIF », Hôpital Lariboisière, AP–HP Paris, Faculté de Médecine Paris-VII, Paris, France

    Ludovic Drouet

  2. Laboratoire de Thrombose et d’Athérosclérose, Institut des Vaisseaux et du Sang, Hôpital Lariboisière, Paris, France

    Ludovic Drouet

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  1. Ludovic Drouet
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Correspondence to Ludovic Drouet.

Additional information

This paper is an updated translation of Drouet L (2011) Biosimilaires d’héparine de bas poids moléculaire : quel degré de similarité pour quel bénéfice clinique ? Oncologie 13(5):239–246

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Drouet, L. Low molecular weight heparin biosimilars: how much similarity for how much clinical benefit?. Targ Oncol 7 (Suppl 1), 35–42 (2012). https://doi.org/10.1007/s11523-011-0194-5

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