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Nadroparin Calcium

A Review of its Pharmacology and Clinical Applications in the Prevention and Treatment of Thromboembolic Disorders

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Abstract

Synopsis

Nadroparin calcium is a low molecular weight heparin with a mean molecular weight of 4.5kD. Compared with unfractionated heparin, nadroparin calcium has a greater ratio of anti-factor Xa/ anti-factor IIa activity. Nadroparin calcium has a longer half-life and greater bioavailability than unfractionated heparin and can be administered by subcutaneous injection once daily for prophylaxis and twice daily for treatment. In clinical trials, nadroparin calcium has been shown to be at least as effective as unfractionated heparin in preventing deep venous thrombosis (DVT) after various surgical procedures including major orthopaedic and abdominal surgery, and in maintaining the patency of the extracorporeal circulation in adults and children undergoing haemodialysis.

Nadroparin calcium is well tolerated, the most common adverse event associated with its use being the development of minor haematoma at the operative incision site. In postmarketing surveillance data to date, the incidence of major haemorrhage related to nadroparin calcium use has been very low (< 1%). Nadroparin calcium has also been associated with a very low incidence of thrombocytopenia (< 0.001%).

Thus, nadroparin calcium is an effective alternative to unfractionated heparin in the prophylaxis or treatment of thromboembolic venous events, with the advantages of more convenient administration and a lower incidence of thrombocytopenia.

Pharmacodynamic Properties

Nadroparin calcium is a low molecular weight heparin prepared from porcine heparin by nitrous acid depolymerisation. Nadroparin calcium has a mean molecular weight of 4.5kD (range 1 to 10kD) and is less polydisperse than unfractionated heparin, with 50% of molecules having a molecular weight of 4 to 5.5kD. The anti-factor Xa activity of low molecular weight heparins has been standardised through development of the First International Standard, but nadroparin calcium is most often quantified in anti-factor Xa Institute Choay units (IGU); 1 ICU is approximately equivalent to 0.4 international standard units (IU). The standardised units provide a useful means of quantifying the activity of a single low molecular weight heparin, but anti-factor Xa activity provides only a partial measure of clinical activity and does not facilitate cross-referencing the activities of chemically distinct low molecular weight heparins.

In a nonhuman primate model, the extent and time course of nadroparin calcium-induced inhibition of factor IIa and factor Xa activity was related to route of administration. In platelet-poor plasma, nadroparin calcium is less potent gravimetrically than unfractionated heparin at inhibiting thrombin generation; nadroparin calcium 7500 ICU (3000IU)/day subcutaneously resulted in insignificant inhibition of factor Ha activity. In vitro evaluation demonstrated that 20 mg/L of nadroparin calcium caused near maximal inhibition of factor Xa generation in healthy volunteers. In animal models low doses of nadroparin calcium appear to inhibit thrombus growth more effectively than equigravimetric doses of unfractionated heparin; in high doses both nadroparin calcium and unfractionated heparin actually decreased thrombus size. While in some patients nadroparin calcium appeared to prevent the postoperative decrease in plasminogen levels, overall nadroparin calcium did not appear to have a global effect on fibrinolysis.

Pharmacokinetic Properties

Pharmacokinetic parameters of nadroparin calcium have generally been determined by assessment of anti-factor Xa activity in human plasma. Subcutaneous or intravenous administration of nadroparin calcium results in a dose-dependent increase in plasma anti-factor Xa activity, and in most cases large inter-patient variability is reported. The maximal plasma anti-factor Xa activity is approximately 3-fold higher following intravenous compared with subcutaneous administration, but the bioavailability of subcutaneous nadroparin calcium is estimated to be more than 98%. Some accumulation appears to be possible following twice daily subcutaneous administration of nadroparin calcium 7500 ICU, but this is minimised when nadroparin calcium 7500 ICU is given once daily. The apparent volume of distribution of nadroparin calcium in healthy volunteers is between 3 and 6.77 L/kg. The plasma elimination half-life of anti-factor Xa activity is between 2.2 and 3.6 hours following intravenous or subcutaneous administration. Plasma clearance is thought to involve nonsaturable renal mechanisms; it is significantly reduced in patients with varying degrees of renal impairment compared with healthy subjects (0.6 to 0.8 vs 1.17 L/ h), although it is uncertain whether there is a significant correlation between creatinine clearance and elimination half-life of anti-factor Xa activity. Accumulation of anti-factor Xa activity could potentially complicate nadroparin calcium therapy in patients with renal impairment.

Nadroparin calcium does not appear to cross the placenta and has been shown to have no effect on anti-factor Xa or anti-factor Ha activity in the fetal circulation.

Therapeutic Efficacy

Nadroparin calcium administered subcutaneously is effective for prevention of DVT and pulmonary embolus (PE) in both surgical and medical patients. Nadroparin calcium 100 to 200 ICU/ kg daily appears to produce a dose-proportional reduction in the incidence of DVT (detected either noninvasively, by fibrinogen uptake testing, or by phlebography) following orthopaedic surgery; however, to minimise the risk of haemorrhage, the minimal effective dosage should be employed. Compared with activated partial thromboplastin time (aPTT) adjusted-dose unfractionated heparin prophylaxis, nadroparin calcium 100 ICU/kg for 3 days followed by 150 ICU/ kg for 4 days resulted in a comparable global incidence of total phlebographically-detected DVT (12.6 vs 16%), but nadroparin calcium significantly reduced the incidence of proximal venous thrombosis (2.9 vs 13.1%); the incidence of haemorrhagic complications was similar between the 2 treatment groups. Prophylactic use of nadroparin calcium 7500 ICU/day following general surgery has been associated with an incidence of DVT (detected by radiolabelled-fibrinogen uptake tests) of 2.5 to 3.4%; in most studies this incidence increased to 6.3 to 6.8% in patients with malignancy. Proximal venous thromboses were detected in 0 to 0.5% of patients receiving nadroparin calcium and in one study the rate of proximal thrombosis was significantly lower in nadroparin calcium recipients (0.4%) compared with patients receiving unfractionated heparin (1.4%). The number of patients treated with nadroparin calcium for prophylaxis of DVT following other surgical procedures is too small to allow conclusions to be made regarding efficacy, but the preliminary results demonstrated a favourable risk: benefit ratio following nadroparin calcium prophylaxis in both ophthalmological and neurological surgery.

In general medical inpatients, prophylactic use of nadroparin calcium 7500 ICU/day resulted in a slightly lower incidence of DVT (detected by clinical diagnosis, ultrasound or fibrinogen uptake tests and confirmed by phlebography) and PE than placebo (2.93 vs 3.94% and 0.81 vs 1.36%, respectively). The incidence of DVT with nadroparin calcium (0 to 2%) was similar to that with unfractionated heparin (0.8 to 2%).

As treatment for established DVT, subcutaneous nadroparin calcium 225 ICU/kg twice daily improved the extent of venous thrombosis determined by phlebography compared with adjusted-dose intravenous unfractionated heparin. Subcutaneous nadroparin calcium 225 ICU/kg twice daily tended to decrease the recurrence rate of DVT or PE compared with unfractionated heparin; however, the difference between the 2 treatment groups was not statistically significant. Nadroparin calcium 400 ICU/kg daily subcutaneously was as effective as intravenous unfractionated heparin in the treatment of established PE.

Nadroparin calcium is effective at maintaining the extracorporeal circulation in adult and paediatric patients undergoing haemodialysis; a single intravenous bolus of 150 to 250 ICU/kg for adults and 300 ICU/kg for children (adjusted to achieve clinical efficacy) appeared to have an efficacy comparable to that of individualised dosages of unfractionated heparin.

Patients with heparin-induced thrombocytopenia and positive nadroparin calcium platelet aggregation tests in vitro should not be treated with nadroparin calcium.

Laboratory monitoring of anti-factor Xa activity is not required during prophylaxis with nadroparin calcium unless a patient has severe renal impairment. During treatment of established DVT or PE it is recommended that factor Xa activity is monitored to assess the individual response to nadroparin calcium, although monitoring may not prove to be necessary.

Tolerability

Nadroparin calcium appears to be well tolerated. Treatment was discontinued in 0.46% of patients as a result of adverse effects during prophylactic therapy. Haemorrhage is the most common adverse effect occurring in 4% of patients, but in most cases haemorrhagic effects were minor and did not require dosage adjustment or withdrawal of therapy. During postmarketing surveillance of an estimated 15 million patient treatments, nadroparin calcium was attributed with causing thrombocytopenia in < 0.001% of patients. Therefore, although the incidence of thrombocytopenia appears to be very low, it is recommended that the platelet count be monitored twice weekly. Postmarketing surveillance also reported cutaneous necrosis in isolated cases.

In clinical trials where nadroparin calcium was administered as treatment of DVT or as prophylaxis in medical patients, nadroparin calcium tended to cause slightly fewer haemorrhagic adverse effects than unfractionated heparin (0 to 2.3% vs 3.2 to 5%); however, these trials were not large enough to demonstrate any significant superiority of nadroparin calcium in this regard. When given as prophylaxis following surgical procedures, nadroparin calcium was associated with a risk of postoperative bleeding comparable to that observed following prophylaxis with unfractionated heparin, and greater than that following placebo.

Dosage and Administration

For prevention of DVT following orthopaedic surgery the recommended dosage of nadroparin calcium is 100 ICU/kg/day subcutaneously beginning 12 hours preoperatively and continued for 3 days, after which the dosage should be increased to 150 ICU/kg/day for at least 4 more days. For prevention of venous thromboembolic disease following general surgery subcutaneous administration of nadroparin calcium 7500 ICU daily is recommended; this dosage also appears to be effective in the prevention of DVT following ophthalmological and neurological surgery and in medical patients. Nadroparin calcium 450 ICU/kg/day is recommended for the treatment of DVT and appears to be effective in the treatment of PE. Nadroparin calcium 150 to 300 ICU/kg intravenously has been used to maintain the patency of the catheter and dialyser in the extra-corporeal circulation in adults and children undergoing haemodialysis; however, the dosage must be individualised. Nadroparin calcium dosage may need to be reduced in patients with renal impairment.

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References

  • Abildgaard U, Lindahl AK, Sandset PM. Heparin requires both antithrombin and extrinsic pathway inhibitor for its anticoagulant effect in human blood. Haemostasis 21: 254–257, 1991

    PubMed  CAS  Google Scholar 

  • Aiach M, Sié P. Surveillance biologique des traitements par les héparines de bas poids moléculaire. Annales de Biologie Clinique 46: 715–718, 1988

    PubMed  CAS  Google Scholar 

  • Albanese C, Bellani M, Longatti S, Mazzola C, Tammaro AE. Comparison of the local tolerability of two subcutaneous low molecular weight heparins: CY 216 and enoxaparine. Current Therapeutic Research 51: 469–475, 1992

    Google Scholar 

  • Amann FW. Efficacy and tolerance of Fraxiparine in reocclusion after percutaneous transluminal coronary angioplasty: preliminary data. XIth Meeting of the International Society of Haematology, European and African Division, Basel, Aug 31–Sept 6, pp. 37–40, 1991

  • Amar J, Caranobe C, Sie P, Boneu B. Antithrombotic potencies of heparins in relation to their antifactor Xa and antithrombin activities: an experimental study in two models of thrombosis in the rabbit. British Journal of Haematology 76: 94–100, 1990

    PubMed  CAS  Google Scholar 

  • Anon. Consensus conference. Prevention of venous thrombosis and pulmonary embolism. Journal of the American Medical Association 256: 744–749, 1986

    Google Scholar 

  • Aquino J-P, Gambier A, Ducros J-J. Prevention of thromboembolic accidents in elderly subjects with Fraxiparine®. Proceedings of the Second International Symposium on Fraxiparine, pp. 51–54, 1990

  • Aranda A, Páramo JA, Alfaro MJ, Rocha E. The influence of standard and low molecular weight heparin on fibrinolysis in patients undergoing major abdominal surgery. Biologia and Clinica Hematologica 9: 169–174, 1987

    Google Scholar 

  • Ball A, L’Huillier AM, Dreyfuss L, Porte JL, Barthel JC. Thrombopénie à la Fraxiparine. Une observation. Correspondence Presse Médicale 18: 1254, 1989

    CAS  Google Scholar 

  • Banssillon V, Dejour H, Besson L, Davidas JL, Rondelet B, et al. Prevéntion des thromboses veineuses profondes en chirurgie orthopédique pour mise en place d’une prothèse totale de hanche. Essai randomisé détermination de la posologie optimale. Annales de Chirurgie 41: 377–385, 1987

    PubMed  CAS  Google Scholar 

  • Barrowcliffe TW, Curtis AD, Johnson EA, Thomas DP. An international standard for low molecular weight heparin. Thrombosis and Haemostasis 60: 1–7, 1988a

    PubMed  CAS  Google Scholar 

  • Barrowcliffe TW, Merton RE, Gray E, Thomas DP. Heparin and bleeding: an association with lipase release. Thrombosis and Haemostasis 60: 434–436, 1988b

    PubMed  CAS  Google Scholar 

  • Bârzu T, Van Rijn JLML, Petitou M, Molho P, Tobelem G, et al. Endothelial binding sites for heparin. Specificity and role in heparin neutralization. Biochemical Journal 238: 847–854, 1986

    PubMed  Google Scholar 

  • Basic-Micic M, Breddin HK. Fraxiparine: new data on anticoagulant and platelet inhibiting activity. Proceedings of XIth Meeting of the International Society of Haematology, European and African Division, Basel, Aug 31–Sept 6, pp. 43–48, 1991

  • Béguin S, Wielders S, Lormeau JC, Hemker HC. The mode of action of CY216 and CY222 in plasma. Thrombosis and Haemostasis 67: 33–41, 1992

    PubMed  Google Scholar 

  • Bender N, Seidl C, Weichen W, Breddin HK. Evaluation of the biological effects of low-molecular-weight heparins. Haemostasis 18 (Suppl. 3): 23–32, 1988

    PubMed  CAS  Google Scholar 

  • Bendetowicz AV, Bara L, Samama MM. The inhibition of intrinsic prothrombinase and its generation by heparin and four derivatives in prothrombin poor plasma. Thrombosis Research 58: 445–454, 1990

    PubMed  CAS  Google Scholar 

  • Boisseau MR, Freyburger G, Dachary J, Vaissié JJ. Effect of CY 216 and standard heparin on hemorheological factors. Proceedings of the Second International Symposium on Fraxiparine, pp. 125–132, 1990

  • Bokarev IN, Ivanov OL, Gurdus VO, Yarovaya LD. Fraxiparin in the treatment of skin vasculitis. Abstract 2423 Thrombosis and Haemostasis. 65: 1361, 1991

    Google Scholar 

  • Boneu B, Caranobe C, Gabaig AM, Dupouy D, Sie P, et al. Evidence for a saturable mechanism of disappearance of standard heparin in rabbits. Thrombosis Research 46: 835–844, 1987

    PubMed  CAS  Google Scholar 

  • Brace LD, Fareed J. Heparin-induced platelet aggregation. II. Dose/ response relationships for two low molecular weight heparin fractions (CY 216 and CY 222). Thrombosis Research 59: 1–14, 1990

    PubMed  CAS  Google Scholar 

  • Caulin C. The influence of CY 216 administration on hospital mortality of general medical in-patients. International collaborative double-blind study: methods and preliminary results. Proceedings of the First International Symposium on Fraxaparine, Paris, October 30, 1987. pp. 147–152, 1989

    Google Scholar 

  • Chong BH. Heparin-induced thrombocytopenia. Australian and New Zealand Journal of Medicine 22: 145–152, 1992

    PubMed  CAS  Google Scholar 

  • Collignon F, Frydman A, Caplain H, Bouthier J, Thébault JJ. Comparative cross over study of pharmacokinetics of enoxaparin (Clexane™, Lovenox™), KABI 2165 (Fragmin™), and CY 216 (Fraxiparin™) in man. Abstract Thrombosis and Haemostasis 65: 925, 1991

    Google Scholar 

  • Dahan M, Boneu B, Renella J, Berjaud J, Bogaty J, et al. Prevention of deep venous thromboses in cancer thoracic surgery with a low-molecular-weight heparin: Fraxiparine®. A comparative randomized trial. Proceedings of the Second International Symposium on Fraxiparine, pp. 27–31, 1990

  • Dawes J, Prowse CV, Pepper DS. Absorption of heparin, LMW heparin and SP54 after subcutaneous injection, assessed by competitive binding assay. Thrombosis Research 44: 683–693, 1986

    PubMed  CAS  Google Scholar 

  • Doutremépuich C, Bonini F, Toulemonde F, Bertrand H, Bayrou B, et al. In vivo neutralization of low-molecular weight heparin fraction CY 216 by protamine. Seminars in Thrombosis and Hemostasis 11: 318–322, 1985

    PubMed  Google Scholar 

  • Doutremepuich C, Gestreau JL, Maury MO, Quilichini R, Boisseau MR, et al. Experimental venous thrombosis in rats treated with heparin and a low molecular weight heparin fraction. Haemostasis 13: 109–112, 1983

    PubMed  CAS  Google Scholar 

  • Doutremepuich C, Llido S, Laianne MC, Doutremepuich F. Modifications of biological activities of heparin and Fraxiparine induced by the size and the age of a thrombus. Experimental study. Thrombosis Research 59: 439–447, 1990

    PubMed  CAS  Google Scholar 

  • Doutremepuich C, Toulemonde F, Bousquet F, Bonini F. Comparison of the haemorrhagic effects of unfractionated heparin and a low molecular weight heparin fraction (CY 216) in rabbits. Thrombosis Research 43: 691–695, 1986

    PubMed  CAS  Google Scholar 

  • Drouet JC, Bernard JM, Bourreli B, Gunst JP. Low-molecular-weight heparin (Fraxiparine) to prevent deep vein thrombosis in patients undergoing orthopedic surgery. A clinical report of two regimens. Correspondence. Haemostasis 18: 135–136, 1988

    PubMed  CAS  Google Scholar 

  • European Fraxiparin Study Group. Comparison of a low molecular weight heparin and unfractionated heparin for the prevention of deep vein thrombosis in patients undergoing abdominal surgery. British Journal of Surgery 75 (11): 1058–1063, 1988

    Google Scholar 

  • Faivre R, Kieffer Y, Bassand JP, Maurant JP. Les thrombopenies graves a l’heparine: interêt de l’utilisation de l’heparine à bas poids moléculaire. A propos de 6 observations. Archives des Maladies du Coeur et des Vaisseau 78: 27–30, 1985

    CAS  Google Scholar 

  • Fareed J, Walenga JM, Kumar A, Rock A. A modified stasis thrombosis model to study the antithrombotic actions of heparin and its fractions. Seminars in Thrombosis and Hemostasis 11: 155–175, 1985a

    PubMed  CAS  Google Scholar 

  • Fareed J, Walenga JM, Williamson K, Emanuele RM, Kumar A, et al. Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments. Seminars in Thrombosis and Hemostasis 11: 56–74, 1985b

    PubMed  CAS  Google Scholar 

  • Fareed J, Walenga JM, Racanelli A, Hoppensteadt D, Huan X, et al. Validity of the newly established low-molecular-weight heparin standard in cross-referencing low-molecular-weight heparins. Haemostasis 18 (Suppl. 3): 33–47, 1988

    PubMed  CAS  Google Scholar 

  • Fareed J, Walenga JM, Hoppensteadt D, Ahsan A, Murphy R, et al. Molecular composition of depolymerized heparins: relevance to biochemical and pharmacologic effects. Proceedings of the Second International Symposium on Fraxiparine, pp. 134–156, 1990

  • Forestier F, Daffos F, Rainaut M, Toulemonde F. Absence de passage transplacentaire de la Fraxiparine (héparine de bas poids moléculaire) au cours du troisième trimestre de la grossesse Journal de Gynécologie, Obstetrique et Biologie de la Reproduction 16: 981–986, 1987

    PubMed  CAS  Google Scholar 

  • Freedman MD, Leese P, Prasad R, Hayden D. An evaluation of the biological response to Fraxiparine, (a low molecular weight heparin) in the healthy individual. Journal of Clinical Pharmacology 30: 720–727, 1990

    PubMed  CAS  Google Scholar 

  • Furie B, Furie BC. Molecular and cellular biology of blood coagulation. New England Journal of Medicine 326: 800–806, 1992

    PubMed  CAS  Google Scholar 

  • Gauthier O, Chatelan M, Laudette G, Devilleres E, Castano J. Efficacy and tolerance of CY 216 in the treatment of some types of leg ulcer. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 193–199, 1989

    Google Scholar 

  • Gensini GF, Fortini A, Lombardi A, Pesciullesi E, Pieroni C, et al. Binding of low-molecular-weight heparin to aortic endo-thelium in rabbits. Haemostasis 14: 466–472, 1984

    PubMed  CAS  Google Scholar 

  • Gouault-Heilmann M, Huet Y, Adnot S, Contant G, Bonnet F, et al. Low molecular weight heparin fractions as an alternative therapy in heparin-induced thrombocytopenia. Haemostasis 17: 134–140, 1987

    PubMed  CAS  Google Scholar 

  • Goudable C, Saivin S, Houin G, Sie P, Boneu B, et al. Pharmacokinetics of a low molecular weight heparin (Fraxiparine®) in various stages of chronic renal failure. Nephron 59: 543–545, 1991

    PubMed  CAS  Google Scholar 

  • Goudable C, Gabaig AM, Tonthat H, Durand D, Rostin M, et al. Pharmacokinetics of CY 216 in healthy subjects and in renal impairment. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 79–84, 1989

    Google Scholar 

  • Grau E, Sigüenza F, Madvell F, Linares M, Olaso MA, et al. Low molecular weight heparin (CY-216) versus unfractionated heparin in chronic hemodialysis. Nephron 62: 13–17, 1992

    PubMed  CAS  Google Scholar 

  • Gray E, Padilla A, Barrowcliffe TW. Inhibition of thrombin generation by heparin and low molecular weight heparins — comparison of intrinsic and extrinsic systems. Abstract 547 Thrombosis and Haemostasis 65: 844, 1991

    Google Scholar 

  • Guilbaud J, Carsin H, Braquet M, Houin G, Mersch SM. Pharmacokinetic study of CY 216 in burned patients. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 85–92, 1989

    Google Scholar 

  • Haas S, Biegholdt M. Prevention of thromboembolism in outpatients with low-molecular-weight heparin. Proceedings of the Second International Symposium on Fraxiparine pp. 41–50, 1990

  • Handeland GF, Abildgaard U. Assay of unfractionated and LMW heparin with chromogenic substrates: twin methods with factor Xa and thrombin. Thrombosis Research 35: 627–636, 1984

    PubMed  CAS  Google Scholar 

  • Harenberg J, Würzner B, Zimmermann R, Schettler G. Bioavail-ability and antagonization of the low molecular weight heparin CY 216 in man. Thrombosis Research 44: 549–554, 1986

    PubMed  CAS  Google Scholar 

  • Harenberg J, Stehle G, Augustin J, Zimmermarin R. Comparative human pharmacology of low molecular weight heparins. Seminars in Thrombosis and Hemostasis 15: 414–423, 1989

    PubMed  CAS  Google Scholar 

  • Heinrich D, Görg T, Schulz M. Effects of unfractionated and fractionated heparin on platelet function. Haemostasis 18 (Suppl. 3): 48–54, 1988

    PubMed  CAS  Google Scholar 

  • Hemker HC. A standard for low molecular weight heparin? Haemostasis 1: 1–4, 1989

    Google Scholar 

  • Hirsh J. Rationale for development of low-molecular-weight heparins and their clinical potential in the prevention of postoperative venous thrombosis. American Journal of Surgery 161: 512–518, 1991

    PubMed  CAS  Google Scholar 

  • Hirsh J, Levine MN. Low molecular weight heparin. Blood 79: 1–17, 1992

    PubMed  CAS  Google Scholar 

  • Hoppensteadt D, Breddin K, Fareed J, Walenga JM, Bender N. Relevance of anti Xa, anti Ha and other laboratory parameters to the clinical efficacy of Fraxiparin. Preliminary results of European Fraxiparine study. Abstract 220. Haemostasis 18 (Suppl. 2): 164–165, 1988

    Google Scholar 

  • Hoppensteadt D, Walenga JM, Fareed J. Relevance of laboratory parameters to the clinical efficacy of Fraxiparin®. Thrombotic and Haemorrhagic Disorders 4: 7–12, 1991

    Google Scholar 

  • Kaiser B, Kühnemuth G, Markwardt F. Pharmacological studies on the low molecular weight heparin derivative CY 216. Pharmazie 45: 522–524, 1990

    PubMed  CAS  Google Scholar 

  • Kakkar VV. Prevention of post-operative venous thromboem-bolism by a new low molecular weight heparin fraction. Nouvelle Révue Française d’Hématologie 26: 277–282, 1984

    PubMed  CAS  Google Scholar 

  • Kakkar VV, Murray WJG. Efficacy and safety of low-molecular-weight heparin (CY216) in preventing postoperative venous thrombo-embolism: a co-operative study. British Journal of Surgery 72: 786–791, 1985

    PubMed  CAS  Google Scholar 

  • Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clinical Pharmacokinetics 22: 359–374, 1992

    PubMed  CAS  Google Scholar 

  • Leroy J, Leclerc MH, Delahousse B, Guérois C, Foloppe P, et al. Treatment of heparin-associated thrombocytopenia and thrombosis with low molecular weight heparin (CY 216). Seminars in Thrombosis and Hemostasis 11: 326–329, 1985

    PubMed  CAS  Google Scholar 

  • Levesque H, Verdier S, Cailleux N, Elie Legrand MC, Gancel A, et al. Low molecular weight heparins and hypoaldosteronism. British Medical Journal 300: 1437–1438, 1990

    PubMed  CAS  Google Scholar 

  • Lewandowski K, Psuja P, Tokarz A, Zozulinska M, Sowier J, et al. Anticoagulant activity in the plasma after a single administration of nebulized heparin or LMW heparin fraction (Fraxiparine) in patients undergoing abdominal surgery. Thrombosis Research 58: 525–530, 1990

    PubMed  CAS  Google Scholar 

  • Leyvraz PF, Bachmann F, Hoek J, Büller HR, Postel M, et al. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. British Medical Journal 303: 543–548, 1991

    PubMed  CAS  Google Scholar 

  • Lindhout Th, Pieters J, Béguin S, Hemker HC. The mode of action of CY 216 on thrombin generation in the plasma. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 23–33, 1989

    Google Scholar 

  • Lopaciuk S, Meissner AJ, Filipecki S, Zawilska K, Sowier J, et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thrombosis and Haemostasis 68: 14–18, 1992

    PubMed  CAS  Google Scholar 

  • Lormeau J-C. Physiochemical and biological characteristics of CY 216. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 13–19, 1989

    Google Scholar 

  • Manciet G, Vergnes C, Vaissié JJ, Boisseau MR. A study on the efficacy and tolerance of Fraxiparine® during long-term therapy of the elderly. A randomised double-blind clinical trial. Proceedings of the Second International Symposium on Fraxiparine pp. 55–59, 1990

  • Marassi A, Mari G, Balzano G, Delia Valle P, Di Carlo V, et al. Prevention of postoperative isotopic deep vein thrombosis by low molecular weight heparin CY 216: a randomized study in cancer patients undergoing abdominal surgery. Abstract 826 Thrombosis and Haemostasis 65: 928, 1991

    Google Scholar 

  • Marcelli JM, Lalau JD, Abourachid H, Quiret JC, Quichaud J. Unlike heparin, low-molecular weight heparin does not suppress aldosterone production Hormone and Metabolic Research 21: 402, 1989

    PubMed  CAS  Google Scholar 

  • Morin Y, Limon S. Étude de la tolérance en chirurgie ophtalmologique du CY 216 employé pour la prévention des thromboses veineuses des membres inférieurs. Journal Français d’Ophtalmologie 11: 747–752, 1988

    PubMed  CAS  Google Scholar 

  • Morinière P, Dieval J, Bayrou B, Roussel B, Renaud H, et al. Low-molecular-weight heparin Fraxiparin® in chronic hemodialysis. A dose-finding study. Blood Purification 7: 301–308, 1989

    PubMed  Google Scholar 

  • Müting H, Biegholdt M. Low molecular weight heparin (CY 216/ FRAXIPARIN) for the prevention of deep vein thrombosis in patients with myocardial infarction. Abstract 25. Haemostasis 18 (Suppl. 2): 19, 1988

    Google Scholar 

  • Nenci GG, Parise P, Morini M, Rossini A, Agnelli G. Effect of unfractionated heparin and a low molecular weight heparin on clot sensitivity to tPA-induced lysis. Abstract. 12th International Congress on Thrombosis, Florence, May 18–23, 1992

    Google Scholar 

  • Ninet J, Bachet PH, Prandoni P, Ruol A, Vigo M, et al. A randomised trial of subcutaneous low molecular weight heparin (CY 216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. A Collaborative European Multicentre Study. Thrombosis and Haemostasis 65: 251–256, 1991

    Google Scholar 

  • Nurmohamed MT, ten Cate J, Stevens P, Hoek JA, Lins RL, et al. Long-term efficacy and safety of a low molecular weight heparin in chronic hemodialysis patients. A comparison with standard heparin ASAIO Transactions 37: M459–M461, 1991

    PubMed  CAS  Google Scholar 

  • Ockelford PA, Carter CJ, Mitchell L, Hirsch J. Discordance between the anti-factor Xa activity and the antithrombotic activity of an ultra-low molecular weight heparin fraction. Thrombosis Research 28: 410–409, 1982

    Google Scholar 

  • Ofosu FA, Birchall KJ, Buchanan MR. Preliminary report on a new approach to laboratory monitoring of the low molecular weight heparin CY 216. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 35–40, 1989

    Google Scholar 

  • Paoletti C, Maubec E, Raggueneau J-L, George B, Robine D, et al. Clinical tolerance of CY 216 D (Fraxiparine®) for throm-boembolic prophylaxis after neurosurgery. Agressologie 30: 363–366, 1989

    PubMed  CAS  Google Scholar 

  • Petitou M. Molecular basis for activity of CY 216. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 5–11, 1989

    Google Scholar 

  • Petitou M, Duchaussoy P, Lederman I, Choay J. Binding of heparin to antithrombin III. A chemical proof of the critical role played by a 3-sulfated 2-amino-deoxy-D-glucose residue. Carbohydrate Research 179: 163–172, 1988

    PubMed  CAS  Google Scholar 

  • Pezzuoli G, Neri Serneri GG, Settembrini P, Coggi G, Olivari N, et al. Prophylaxis of fatal pulmonary embolism in general surgery using low-molecular weight heparin CY 216. A multi-centre, double-blind, randomized, controlled, clinical trial versus placebo (STEP). International Surgery 74: 205–210, 1989

    PubMed  CAS  Google Scholar 

  • Pogliarti EM, Bucciarelli P, Bregani R, Chinea B, Longatti S. Effect on haemostasis of repeated subcutaneously administration of CY 216 in volunteers. Abstract 2410 Thrombosis and Haemostasis 65: 1358, 1991

    Google Scholar 

  • Pogliani EM, Casaroli I, Bolis S, Salvatore M, Corneo GM. Profibrinolytic effect of low-molecular-weight heparin (LMWH CY 216) in surgical patients. Abstract. Tenth International Congress on Thrombosis, The Mediterranean League against Thromboembolic Diseases, Athens, 1988

    Google Scholar 

  • Potron GM, Choisy H, Droulle CL, Nguyen PV, Vaissie JJ. Prospective post marketing follow-up of Fraxiparine in Reims. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 157–166, 1989

    Google Scholar 

  • Prandoni P, Lensing AWA, Büller HR, Carta M, Cogo A, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 339: 441–445, 1992

    PubMed  CAS  Google Scholar 

  • Prandoni P, Lensing A, Carletti E, Cuppini S, Ruol A. Low molecular-weight heparin CY 216 in the treatment of venous thrombosis in patients with heparin-associated major bleeding complications. Abstract 112. Tenth International Congress on Thrombosis, Athens, p. 53, 1988

    Google Scholar 

  • Racanelli A, Fareed J, Walenga JM, Coyne E. Biochemical and pharmacologic studies on the protamine interactions with heparin, its fractions and fragments. Seminars in Thrombosis and Hemostasis 11: 176–189, 1985

    PubMed  CAS  Google Scholar 

  • Rem JA, Gratzl O, Faes J-M. Feasibility of LMWH CY 216 in neurosurgery on patients undergoing lumbar disc operation. A randomised, prospective, double-blind pilot-study. Abstract 818 Thrombosis and Haemostasis 65: 926, 1991

    Google Scholar 

  • Rostin M, Montastruc JL, Hoiun G, D’Azemar PD, Bayrou B, et al. Pharmacodynamics of CY 216 in healthy volunteers: inter-individual variations. Fundamental and Clinical Pharmacology 4: 17–23, 1990

    PubMed  CAS  Google Scholar 

  • Roussi JH, Houbouyan LL, Goguel AF. Use of low-molecular-weight heparin in heparin-induced thrombocytopenia with thrombotic complications. Lancet 1 (8387): 1183, 1984

    PubMed  CAS  Google Scholar 

  • Salzman EW. Low-molecular-weight heparin Is small beautiful? New England Journal of Medicine 315: 957–959, 1986

    PubMed  CAS  Google Scholar 

  • Schmitt BP, Adelman B. Heparin associated thrombocytopenia (HAT). Abstract Clinical Research 40: 563A, 1992

    Google Scholar 

  • Schlegel N, Macher MA, Hurtaud MF, Maisin A, Bara L, et al. The use of CY 216 in paediatric haemodialysis. Proceedings of the First International Symposium on Fraxiparine, Paris, October 30, 1987. pp. 177–186, 1989

    Google Scholar 

  • Simon P, Kindermans A, Kempf JF, Postel M. Efficacité et tolérance d’une héparine de bas poids moléculaire dans la prévention des thromboses veineuses profondes lors des arthroplasties totales de hanche réglées. Essai prospectif, multicentrique. Journal of Chirurgie 127: 252–257, 1990

    CAS  Google Scholar 

  • Simon P, Kempf JF, Krauze D, Levy S, Hammer D, et al. Des progrès dans la prévention des thromboses veineuses profondes en orthopédie. Premiers résultats d’un essai pilote, ouvert, multicentrique avec une héparine de bas poids moléculaire. Journal de Médecine de Strasbourg 19: 241–243, 1988

    Google Scholar 

  • Stassen JM, Juhan-Vague I, Alessi MC, De Cock F, Collen D. Potentiation by heparin fragments of thrombolysis induced with human tissue-type plasminogen activator or human single-chain urokinase-type plasminogen activator. Thrombosis and Haemostasis 58: 947–950, 1987

    PubMed  CAS  Google Scholar 

  • Steinbach G, Bosc C, Caraman PL, Azoulay E, Olry L, et al. Utilisation en hémodialyse et en hémofiltration du CY 216 (Fraxiparine®) en bolus intraveineux, chez des patients insuffisants rénaux aigus et chroniques, avec et sans risque hémorragique. Néphrologie 11: 17–21, 1990

    PubMed  CAS  Google Scholar 

  • Tardy B, Page Y, Tardy-Poncet B, Comtet C, Zeni F, et al. Thrombopénie induite par une héparine de bas poids moléculaire Therapie 45: 453, 1990

    PubMed  CAS  Google Scholar 

  • Théry C, Simonneau G, Meyer G, Hélénon O, Bridey F, et al. Randomized trial of subcutaneous low-molecular-weight heparin CY 216 (Fraxiparine) compared with intravenous unfractionated heparin in the curative treatment of submassive pulmonary embolism. A dose-ranging study/Circulation 85: 1380–1389, 1992

    Google Scholar 

  • Vairel EG, Bouty-Boye H, Toulemonde F, Doutremepuich C, Marsh NA, et al. Heparin and a low molecular weight fraction enhances thrombolysis and by this pathway exercises a protective effect against thrombosis. Thrombosis Research 30: 219–224, 1983

    PubMed  CAS  Google Scholar 

  • Vairel EG, Brouty-Boyé H, Doutremepuich C, Toulemonde F. The thrombolytic activity of heparin LMW derivatives on constituted thrombosis. Abstract 0720. Thrombosis and Haemostasis 50 (1): 231, 1983

    Google Scholar 

  • Vergnes C, Manciet G, Bourdenx V, Roudaut MF, Lacombe F, et al. Standard heparin but not LMW heparin induces a concomitant increase of t-PA and PAI-1 without modification of global fibrinolysis: study after 60 days treatment. Thrombosis Research 63: 521–530, 1991

    PubMed  CAS  Google Scholar 

  • Verstraete M. Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins. Drugs 40: 498–530, 1990

    PubMed  CAS  Google Scholar 

  • Verstraete M, Boogaerts MA. Haematological disorders. In Speight TM (Ed.) Avery’s Drug Treatment. 3rd Edition (1987), ADIS Press Ltd. Auckland

    Google Scholar 

  • Vitoux JF, Aiach M, Roncato M, Fiessinger JN. Should thromboprophylactic dosage of low molecular weight heparin be adapted to patient’s weight? Thrombosis and Haemostasis. 59: 120, 1988

    PubMed  CAS  Google Scholar 

  • von Hugo R, Stengel U. Can low-molecular-weight heparin cross the placenta? Proceedings of the Second International Symposium on Fraxiparine pp. 119–123, 1990

  • Weichen W, Breddin HK. Effect of low-molecular weight heparins on laser-induced thrombus formation in rat mesenteric vessels. Haemostasis 18 (Suppl. 3): 55–63, 1988

    Google Scholar 

  • Wille-Jørgensen P. Prophylaxis of postoperative thromboembolism. Laegeforeningens Forlag, Copenhagen 1991

    Google Scholar 

  • Zawilska K, Elikowski W, Zozulinska M, Turowiecka Z, Psuja P, et al. Heparin and Fraxiparine mobilizable pool of platelet factor 4 in young survivors of myocardial infarction. Abstract 1653 Thrombosis and Haemostasis 65: 1155, 1991

    Google Scholar 

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    Lee B. Barradell & Micaela M. Buckley

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Various sections of the manuscript reviewed by: K. Breddin, Zentrum der Inneren Medizin, Klinikum der J.W. Goethe-Universität, Frankfurt, Federal Republic of Germany; J.F. Cade, Director of Intensive Care, Royal Melbourne Hospital, Melbourne, Victoria, Australia; C. Doutremepuich, Laboratoire d’Hématologie, Bordeaux, France; J. Fareed, Hemostasis and Thrombosis Research Laboratories, Loyola University Chicago, May wood, Illinois, USA; J. Harenberg, Medical Clinic, University of Heidelberg, Heidelberg, Federal Republic of Germany; J. Hirsh, Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada; R.J. Kondrotas, Department of Pharmacy Practice, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA; J.L. Montastruc, Laboratoire de Pharmacologie Médicale et Clinique, Faculté de Medecine, Hopitaux de Toulouse, Toulouse, France; P. Ockelford, Diagnostic Laboratory, Auckland, New Zealand; G. Pezzuoli, Clinica Chirurgica I, Università degli Studi di Milano, Milano, Italy; M. Verstraete, Center for Thrombosis and Vascular Research, Katholieke Universiteit Leuven, Leuven, Belgium.

Nadroparin calcium (CY-216) has previously been extensively referred to as ‘Fraxiparine’, which is in fact the registered proprietary name. The INN approved name (i.e. nadroparin calcium) will be used throughout this review.

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Barradell, L.B., Buckley, M.M. Nadroparin Calcium. Drugs 44, 858–888 (1992). https://doi.org/10.2165/00003495-199244050-00010

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