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Nadroparin Calcium

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

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Abstract

Synopsis

Nadroparin (nadroparin calcium) is a low molecular weight heparin with a mean molecular weight of 4.5kD. Compared with unfractionated heparin (UFH), nadroparin has a greater ratio of anti-factor Xa to anti-factor IIa activity, greater bioavailability and a longer duration of action, allowing it to be administered by subcutaneous injection for prophylaxis or treatment of thromboembolic disorders.

In clinical trials conducted in older patients (mean age usually >60 years), nadroparin was at least as effective as UFH in preventing deep vein thrombosis (DVT) and pulmonary embolism after major general or orthopaedic surgery, and in bedridden medical patients. Nadroparin was also at least as effective as dalteparin or oral acenocoumarol in preventing thromboembolic events following general and orthopaedic surgery, respectively. When used for treatment of established DVT, nadroparin was at least as effective as intravenous UFH. Subcutaneous nadroparin, at dosages similar to those used for the treatment of DVT, produced promising results in older patients with pulmonary embolism, acute ischaemic stroke or unstable angina.

In 1 study, 75% of nadroparin-treated patients were able to complete their treatment at home and 36% did not require admission to hospital; the potential pharmacoeconomic implications of these results deserve further evaluation. Overall treatment costs (drug acquisition and monitoring costs) were similar for nadroparin and UFH in a French study, but nadroparin was associated with significantly less nursing time spent on treatment delivery.

Nadroparin is well tolerated by older patients. The most frequently reported adverse events in a large (n ≈ 4500) placebo-controlled study in general surgical patients were wound and injection site haematoma (11.8 and 10.2%, respectively, vs ≈6.5% for placebo). When used as prophylaxis, no significant differences in bleeding complications were noted between nadroparin and UFH or acenocoumarol recipients. Prophylactic nadroparin was associated with significantly fewer withdrawals because of adverse events than UFH in elderly bedridden medical patients. When used as treatment for DVT, nadroparin was generally associated with lower occurrences of major bleeding than intravenous UFH (0.5 to 2.3% vs 2 to 5%); however, trials were not large enough to demonstrate any significant differences between the 2 agents. Similarly, the incidence of thrombocytopenia was slightly, but generally not significantly, lower in nadroparin (<1%) than in UFH (≤3.5%) recipients.

Thus, nadroparin should be considered an effective and well tolerated alternative to UFH for prophylaxis and treatment of DVT in older patients, with the advantage of more convenient administration and decreased monitoring requirements.

Overview of Pharmacodynamic Properties

Nadroparin (nadroparin calcium) is a low molecular weight heparin (LMWH) with an average molecular weight of 4.5kD; it is produced from porcine heparin by nitrous acid depolymerisation. According to the World Health Organization (WHO) standard, the mean amidolytic anti-Xa activity of nadroparin is about 90 IU/mg in the presence of plasma and about 85 IU/mg in absence of plasma; its anti-factor IIa activity is 27 IU/mg. Nadroparin activity was originally quantified in anti-factor Xa Institute Choay units (ICU), where 1ICU is equivalent to 0.41IU.

The principal pharmacological properties of nadroparin include binding affinity for antithrombin III and consequently anti-factor IIa (antithrombin) and anti-factor Xa activity. Anti-factor Xa to anti-factor IIa ratios for standard unfractionated heparin (UFH) and nadroparin are reported to be 1: 1 (by definition) and ≈3.5: 1, respectively, reflecting the higher proportion of nadroparin molecules which bind to factor Xa compared with those which bind to factor Ha. Nadroparin exhibits dose-proportional inhibition of factor Xa. The relative importance of non-antithrombin Ill-mediated properties of nadroparin, including neutralisation by platelet factor 4, stimulation of tissue factor pathway inhibitor release, activation of fibrinolysis, and modification of haemorrheological parameters, remains to be fully determined.

In an ex vivo model of human venous thrombosis, both nadroparin and UFH at doses commonly prescribed for the treatment of venous embolism (6150 and 12 500IU, respectively) produced similar antithrombotic effects as assessed by fibrin deposition on activated endothelial cells and generation of markers of thrombin and fibrin formation.

Overview of Pharmacokinetic Properties

As with other LMWHs, the pharmacokinetic properties of nadroparin have most often been determined indirectly by measurement of plasma anti-factor Xa activity. The bioavailability of nadroparin has been reported to be ≥89% compared with 24% for UFH. Following single- or multiple-dose subcutaneous injection of nadroparin at doses of up to 185 IU/kg, peak plasma anti-factor Xa and anti-factor IIa activity (Amax) increased in a dose-proportional manner. Durations of anti-factor Xa and anti-factor IIa activity >0.1 IU/ml were also dependent on dose, and were 19.3 and 17.2 hours, respectively, after single subcutaneous doses of nadroparin 185 IU/kg. Some accumulation of antithrombotic activity appears to occur with nadroparin dosages above 6150 IU/day. Amax has generally been achieved within 3 to 5 hours after subcutaneous or intravenous administration of nadroparin.

The plasma elimination half-life of nadroparin, as measured by disappearance of anti-factor Xa activity, is 2.2 to 3.6 hours after intravenous and 2.3 to 5 hours after subcutaneous injection. Plasma clearance of nadroparin is thought to involve nonsaturable renal mechanisms, although recent data suggest that nadroparin undergoes metabolism in the liver before undergoing renal elimination. Plasma clearance was significantly reduced in older patients (median age 52 to 61 years) with varying degrees of renal impairment compared with healthy volunteers (0.59 to 0.78 vs 1.17 L/h). Thus, accumulation of antithrombotic activity is possible in nadroparin recipients with renal impairment, particularly in those receiving a relatively high dosage [e.g. patients with established deep vein thrombosis (DVT)].

Clinical Efficacy

Subcutaneous nadroparin demonstrated thromboprophylactic efficacy in studies in older patients (mean age ≥ 60 years) undergoing general or orthopaedic surgery and in bedridden medical patients. The incidence of venography-confirmed DVT was significantly lower in general surgical patients receiving subcutaneous nadroparin 3075IU once daily than after subcutaneous UFH 5000IU twice (2.5 vs 7.5%) or 3 times daily (2.8 vs 4.5%) or dalteparin 2500IU once daily (16.3 vs 32.3%). The unexpectedly high rate of DVT in the latter study was thought to be due to the high number of patients with multiple risk factors for DVT as well as more intensive evaluation of DVT.

In patients undergoing elective orthopaedic surgery (mostly hip replacement), similar incidences of DVT were observed with nadroparin compared with subcutaneous UFH or oral acenocoumarol. The incidence of proximal DVT was significantly lower in nadroparin- than in UFH-treated patients in 2 studies. In bedridden hospitalised medical patients, subcutaneous nadroparin 3075 IU/day was as effective as UFH 10 000 to 15 000 IU/day in the prevention of thromboembolic events.

A body weight-adjusted dosage of nadroparin 8200 to 18 400 IU/day in 2 divided doses was at least as effective as adjusted-dose intravenous UFH for the treatment of venography-confirmed DVT. The percentage of nadroparin-treated patients showing venographic improvement was significantly higher in 1 study (60 vs 43%), and similar in another study (56 vs 62%). In the latter study, nadroparin recipients showed significantly greater improvement in Arnesen (30.6 vs 16.4%) and Marder (28.9 vs 15.8%) venographic scores than UFH recipients. Data from a recent abstract suggest that once daily nadroparin is equivalent to twice daily nadroparin for the treatment of DVT. Preliminary results indicated that 8 days’ treatment with subcutaneous nadroparin 82 or 123 IU/kg twice daily and activated partial thromboplastin time (aPTT) adjusted-dose intravenous UFH produced similar reductions in pulmonary vascular obstruction in patients with non-massive acute pulmonary embolism.

Significantly fewer Chinese patients with acute ischaemic stroke had a poor 6-month outcome (death or dependency regarding daily living activities) after treatment with subcutaneous nadroparin 4100IU once (52%) or twice (45%) daily for 10 days than with placebo (65%). In patients with unstable angina, subcutaneous nadroparin 88 IU/kg twice daily plus aspirin (acetylsalicylic acid) was significantly more effective than adjusted-dose intravenous UFH plus aspirin 200 mg/day or aspirin alone in reducing adverse clinical events (recurrent angina, nonfatal myocardial infarction and urgent revascularisation procedure).

Although pharmacoeconomic studies involving LMWHs, including nadroparin, are scarce, recent data indicate that despite lower acquisition costs of UFH, LMWHs are more cost effective than UFH for prophylaxis or treatment of DVT, especially when the costs associated with antithrombotic failure and treating bleeding complications are considered. In a French study, overall treatment costs (drug acquisition and monitoring costs) were similar for nadroparin and UFH (FF345 vs FF337; 1992 values); use of nadroparin was, however, associated with significantly less nursing time spent on treatment delivery (42 vs 104 min/wk for UFH).

Outpatient treatment of DVT with subcutaneous nadroparin was also associated with considerably less hospital resource use than UFH (mean 2.7 vs 8.1 days in hospital) but required 2 outpatient nursing visits and 2.2 follow-up telephone calls per patient. Unfortunately, no cost data were applied to either inpatient or outpatient resource use.

Tolerability

Nadroparin was well tolerated in studies in older patients. In a large study of prophylaxis in general surgical patients (n = 4498), subcutaneous nadroparin 3075 IU/day was associated with a significantly higher incidence of excessive postoperative bleeding (7.7 vs 3.1 %) and wound (11.8 vs 6.3%) and injection site (10.2 vs 6.6%) haematoma than placebo. No significant difference in the incidence of bleeding complications was noted between subcutaneous nadroparin and subcutaneous UFH or oral acenocoumarol in patients undergoing general or orthopaedic surgery. In elderly bedridden hospitalised patients, 10 or 28 days’ prophylaxis with subcutaneous nadroparin 3075 IU/day appeared to be better tolerated than subcutaneous UFH 5000IU 2 to 3 times daily; incidences of local reactions, >3-fold elevations in liver transaminase levels, thrombocytopenia and withdrawals because of drug-related adverse events were significantly lower in nadroparin than in UFH recipients.

Nadroparin ≈185 IU/kg/day in 2 divided doses was associated with lower incidences of major bleeding than aPTT adjusted-dose intravenous UFH (0.5 to 2.3% vs 2 to 5%) in patients receiving treatment for DVT; however, the trials were not large enough to demonstrate any significant differences between nadroparin and UFH. Enrolment in patient groups receiving nadroparin 123 or 185 IU/kg twice daily for the treatment of submassive pulmonary embolism was discontinued because of a high incidence of clinically significant major bleeding.

In patients undergoing treatment for unstable angina, the incidence of spontaneous haematomas at injection sites was significantly lower in patients receiving nadroparin plus aspirin than in those receiving UFH plus aspirin (1.5 vs 14%). Local tolerability of nadroparin was significantly superior to that of enoxaparin in healthy volunteers and elderly bedridden hospitalised patients, with nadroparin recipients reporting significantly less injection site pain, haematoma, swelling, burning and itching than enoxaparin recipients.

Postmarketing assessment of spontaneous adverse event reports data based on >15 million nadroparin patient treatments in France indicated a low incidence of thrombocytopenia (<0.001%). In comparative clinical trials, the incidence of hepa-rin-induced thrombocytopenia was <1% in nadroparin recipients and ≥3.5% in UFH recipients.

Dosage and Administration

Drug dosages of nadroparin are usually expressed in injection volume in clinical practice; the currently available drug formulation contains 9500IU of nadroparin per 1ml of solution for injection. For prevention of venous thromboembolic disease following general surgery, subcutaneous nadroparin 0.3ml once daily is recommended; the same dosage was used in clinical studies in bedridden medical patients at risk for developing DVT. For prevention of DVT following orthopaedic surgery, the recommended dosages of nadroparin are 0.2, 0.3 and 0.4ml once daily subcutaneously for 3 days in patients weighing, respectively, <50, 50 to 69 and ≥70kg; this is followed by 0.3,0.4 and 0.6ml once daily from day 4 onwards. Drug administration should continue for at least 10 days or at least until the patient is ambulant.

In patients with DVT, nadroparin 0.4, 0.5, 0.6, 0.7, 0.8 and 0.9ml should be administered twice daily in patients weighing <50, 50 to 59, 60 to 69, 70 to 79, 80 to 89 and ≥90kg, respectively, for a usual duration of 10 days. Preliminary results support a similar dosage regimen for the treatment of pulmonary embolism, acute ischaemic stroke and unstable angina.

Although nadroparin is associated with a low incidence of thrombocytopenia, it is recommended that platelet counts be monitored twice weekly during treatment. Concomitant administration of nadroparin and drugs known to cause bleeding (e.g. nonsteroidal anti-inflammatory drugs, aspirin, ticlopidine) should be avoided or carefully monitored when such combinations cannot be avoided. The dosage of nadroparin may need to be reduced in patients with renal impairment although no specific dosage guidelines are available.

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    Rick Davis & Diana Faulds

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  1. Rick Davis
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Various sections of the manuscript reviewed by: S. Béguin, Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands; D. Bergqvist, Department of Surgery, Uppsala University, Uppsala, Sweden; L. Borris, Department of Orthopaedics, University Hospital of Aarhus, Aarhus, Denmark; P. Denoncourt, Frenchman Bay Orthopedics, Ellsworth, Maine, USA; J. Fareed, Department of Pathology and Pharmacology; Loyola University Medical Center, Chicago, Illinois, USA; B. Forette, Saint Périne Hospital, Paris, France; E. Gurfinkel, Institute of Cardiology and Cardiovascular Surgery, Buenos Aires, Argentina; J. Harenberg, Department of Medicine, University of Heidelberg, Heidelberg, Germany; D.C. Heaton, Haematology Department, Christchurch Hospital, Christchurch, New Zealand; R.J. Kandrotas, Department of Pharmaceutical Services, Miami Children’s Hospital, Miami, Florida, USA; R. Kay, Department of Medicine, Prince of Wales Hospital, Hong Kong; M. Koopman, Department of Haemostasis and Thrombosis, University of Amsterdam, Amsterdam, The Netherlands; T. Matsuo, Hyogo Prefectural Awaji Hospital, Sumoto, Japan; c. Théry, Department of Cardiology, University of Lille, Lille, France.

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Davis, R., Faulds, D. Nadroparin Calcium. Drugs & Aging 10, 299–322 (1997). https://doi.org/10.2165/00002512-199710040-00006

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