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Dalteparin

An Update of its Pharmacological Properties and Clinical Efficacy in the Prophylaxis and Treatment of Thromboembolic Disease

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Summary

Abstract

Dalteparin is a low molecular weight heparin (LMWH) with a mean molecular weight of 5000. Compared with unfractionated heparin (UFH), the drug has markedly improved bioavailability and increased plasma elimination half-life, and exerts a greater inhibitory effect on plasma activity of coagulation factor Xa relative to its effects on other coagulation parameters. Dalteparin also has less lipolytic activity than UFH.

Dalteparin 2500U once daily subcutaneously is of similar antithrombotic efficacy to UFH 5000IU twice daily, and 2 studies have shown superiority over UFH 2 or 3 times daily of dalteparin 5000U once daily in patients requiring surgical thromboprophylaxis. After total hip arthroplasty, dalteparin was superior to adjusted-dosage warfarin and was of greater thromboprophylactic efficacy when given for 35 than for 7 days.

Intravenous or subcutaneous dalteparin is as effective as intravenous UFH when given once or twice daily in the initial management of established deep vein thrombosis (DVT). The drug is also effective in long term home treatment. Dalteparin has been shown to be effective in combination with aspirin in the management of unstable coronary artery disease (CAD), with composite end-point data from 1 study suggesting benefit for up to 3 months. Current data indicate potential of the drug in the management of acute myocardial infarction (MI). Dalteparin is also of similar efficacy to UFH, with a single bolus dose being sufficient in some patients, in the prevention of clotting in haemodialysis and haemofiltration circuits.

Pharmacoeconomic data indicate that overall costs relative to UFH from a hospital perspective can be reduced through the use of dalteparin in patients receiving treatment for venous thromboembolism. Dalteparin has also been shown to be cost effective when used for surgical thromboprophylaxis.

Overall, rates of haemorrhagic complications in patients receiving dalteparin are low and are similar to those seen with UFH.

Conclusions: Dalteparin is effective and well tolerated when given subcutaneously once daily in the prophylaxis and treatment of thromboembolic disease. The simplicity of the administration regimens used and the lack of necessity for laboratory monitoring facilitate home or outpatient treatment and appear to translate into cost advantages from a hospital perspective over UFH or warfarin. Dalteparin also maintains the patency of haemodialysis and haemofiltration circuits, with beneficial effects on blood lipid profiles and the potential for prophylaxis with a single bolus injection in some patients. Data are also accumulating to show dalteparin to be an effective and easily administered alternative to UFH in patients with CAD.

Pharmacological Properties

Dalteparin inhibits coagulation factor Xa in human plasma in a dose-dependent manner, with anti-factor Xa activities 2 and 5 times those seen after an intravenous dose of UFH 5000IU being reported after intravenous doses of dalteparin 5000 and 10 000U, respectively. In contrast to UFH, anti-factor Xa activity exceeds anti-factor IIa activity in plasma of individuals who have received dalteparin. The drug also exerts significantly greater effects than UFH on plasma anti-factor Xa activity relative to its effects on other coagulation parameters [including activated partial thromboplastin time (aPTT) and thrombin time]. Dalteparin does not have any clinically relevant effects on plasma antithrombin levels, platelet counts or on the fibrinolytic system, although recent studies show inhibition of thrombin formation in patients with activated haemostatic systems.

Data from healthy volunteers and patients undergoing haemodialysis show less lipolytic activity with dalteparin than with UFH, with reductions in blood levels of total and low density lipoprotein cholesterol and triglycerides being shown with the LMWH.

Dalteparin has monoexponential, first order and dose-independent pharmacokinetic characteristics. Absorption is rate-limiting after subcutaneous administration: peak plasma concentrations (as measured by plasma anti-factor Xa activity) are attained after 2.8 to 4 hours, and the drug undergoes substantially less hepatic and renal deposition than UFH. Bioavailability is 87% and plasma elimination half-life (t½β) 2.4 to 4 hours. t½β after intravenous administration is approximately 2 hours. Elimination takes place predominantly via the kidneys.

The anticoagulant effects of a number of agents (e.g. aspirin, dipyridamole, vitamin K antagonists and non-steroidal anti-inflammatory drugs) may be enhanced by coadministration with dalteparin. The anticoagulant effect of dalteparin may be reduced by the presence of antihistamines, cardiac glycosides, tetracyclines or ascorbic acid.

Therapeutic Use

Surgical Thromboprophylaxis. Randomised and double-blind studies have shown consistently that dalteparin 2500U given subcutaneously once daily for 5 to 13 days is of similar thromboprophylactic efficacy to UFH 5000IU subcutaneously twice daily in patients undergoing general or orthopaedic surgery. Two studies, one in over 800 patients undergoing general surgery and the other with a 6-to 8-week follow-up in 122 patients undergoing orthopaedic surgery, showed dalteparin 5000U once daily subcutaneously to be superior to UFH 5000IU 2 or 3 times daily.

Recent studies have shown that dalteparin 5000U once daily subcutaneously reduces the frequency of venographically evident thromboembolism to a greater extent when given for 35 days than for 7 days in patients undergoing total hip arthroplasty. In 2 double-blind studies (each involving around 200 patients), reductions in incidence of DVT relative to 7-day prophylaxis of 54 and 63% were reported after 35 days’ administration. Dalteparin was also of superior thromboprophylactic efficacy to adjusted-dosage warfarin in patients undergoing total hip arthroplasty.

Two small single-blind studies have been carried out to compare dalteparin with the other LMWHs enoxaparin and nadroparin, but the results of these trials were inconclusive.

Thromboprophylaxis in Pregnancy. Dalteparin has been used successfully with no evidence of any adverse fetal effects in pregnant women at high risk of thromboembolic complications. Dosages were adjusted according to plasma anti-factor Xa activity in these patients. There was an apparently lower risk of bleeding with dalteparin than with UFH in a nonblind comparative study in 105 patients.

Treatment of Established Thromboembolic Disease. Comparative studies have shown intravenous or subcutaneous dalteparin (given once or twice daily) to be of equivalent efficacy in terms of Marder scores and venographic findings to aPTT-adjusted intravenous UFH in patients receiving initial heparin treatment for established DVT. Six-month follow-up data from 1 study showed no significant difference in Marder scores, symptoms or thrombus evolution between patients who received dalteparin 200 U/kg once daily subcutaneously or recipients of continuously infused aPTT-adjusted UFH for 5 to 10 days. Similar conclusions were reported after up to 14 years’ follow-up in patients from 3 Swedish clinical studies in which subcutaneous dalteparin adjusted according to anti-factor Xa activity had been compared with aPTT-adjusted intravenous UFH (either given for at least 5 days pending dosage titration of warfarin).

Noncomparative studies have demonstrated feasibility of initial outpatient treatment of established thromboembolic disease with dalteparin 200 U/kg once daily subcutaneously for at least 4 to 5 days. The drug was also effective and well tolerated when self-administered for 3 months at a dosage of 5000U once daily by patients not eligible for warfarin therapy. In a 3-month nonblind comparison, there was no statistically significant difference in efficacy between long term dalteparin 5000U once daily subcutaneously and warfarin in 86 patients with thromboembolic disease.

Coronary Artery Disease. Dalteparin 7500U once daily subcutaneously plus aspirin (n = 562) was of similar efficacy to aspirin alone (n = 561) in terms of a composite end-point of death, MI or recurrence of angina over 39 days of double-blind placebo-controlled treatment in a study in patients with unstable CAD. Equivalence of dalteparin 120 U/kg twice daily subcutaneously and aPTT-ad-justed UFH infusion (in terms of rates of death or MI, need for coronary revas-cularisation or recurrence of angina) was suggested by the results of an initial 6-day nonblind phase in 1482 patients.

In the first of 2 randomised double-blind studies carried out by the Swedish Fragmin and Fast Revascularisation in Coronary Artery Disease (FRISC) study group, significantly lower rates of death and new MI and reduced need for revascularisation or intravenous heparin were reported after 6 days’ treatment with dalteparin 120 U/kg subcutaneously twice daily (n = 746) than with placebo (n = 760). Subgroup analyses suggested maintenance of benefit at 40 days with dalteparin 7500 U/day in non-smokers, patients with non-Q-wave MI and those with body mass index below 26 kg/m2. There was no significant difference from placebo after 4 to 5 months.

A second study carried out by the FRISC group in 2267 patients with unstable CAD showed a 47% decrease (p = 0.002) relative to placebo in a combined end-point of death and MI after the first month of a 3-month period of double-blind treatment with dalteparin 5000 or 7500U twice daily. When a triple end-point of death, MI and need for revascularisation was considered for both the 3-month double-blind treatment period and an initial 5-to 7-day nonblind phase (in which all patients received dalteparin), there were significant differences in favour of dalteparin after 1 month and 3 months. Subgroup analyses have suggested a link between efficacy of dalteparin in the longer term and raised levels of the cardiac marker troponin-T.

Outcomes were not affected by dalteparin therapy in a further comparative study in which percutaneous coronary intervention was shown to be superior to non-invasive therapy in 2457 patients with unstable CAD.

In a randomised double-blind study in 517 patients with acute anterior MI, there was a statistically significant 35% reduction versus placebo in a combined end-point of left ventricular thrombus formation or arterial thromboembolism with dalteparin 150 U/kg twice daily subcutaneously for 7 to 11 days after thrombol-ysis with streptokinase. In another double-blind study in 101 patients with acute MI, dalteparin 100 U/kg before and 12 hours after streptokinase thro mbolysis had no effect on rates of death or reinfarction or other cardiac events, although significantly fewer dalteparin than placebo recipients had ECG evidence of ischaemia from 6 to 24 hours after starting treatment. Preliminary results from a study in 1128 patients with acute MI who were not eligible for thrombolysis indicate short term (3-day) but not long term (30-or 90-day) benefit of subcutaneous dalteparin 120 U/kg twice daily.

Haemodialysis and Haemofiltration. Dalteparin was of similar efficacy to UFH in the maintenance of patency of haemodialysis and haemofiltration circuits in studies in which heparin was administered as an intravenous bolus followed by continuous infusion. Initial doses of dalteparin ranged from 2500 to 5000U; those of UFH ranged from 2000 to 5000IU. Infusions were given at fixed hourly rates or were adjusted according to bodyweight or whole blood activated clotting times. Dalteparin prevented blood clot formation in dialysers to a similar extent to tinzaparin, and was associated with similar haemofilter survival times to nadroparin, in comparative studies. Data are also available to show equivalent efficacy of a single bolus of dalteparin (given at the start of haemodialysis) and continuously infused UFH.

Ischaemic Stroke. Dalteparin has not been shown to have any significant advantage over aspirin on cerebral end-points in patients with acute ischaemic stroke. Outcomes were similar in patients treated with dalteparin 100 U/kg twice daily subcutaneously and in those receiving aspirin 160mg daily (orally or rectally) in a recent placebo-controlled double-blind trial in 449 patients with atrial fibrillation and ischaemic stroke.

Pharmacoeconomic Considerations

A retrospective comparison using results from 434 patients, 80.2% of whom received home treatment with subcutaneous dalteparin 200 U/kg once daily for initial management of established DVT, showed a 34.5% reduction relative to inpatient treatment in Swedish mean hospital and treatment costs (1996 values). Australian researchers estimated overall per-patient treatment costs (year not stated) to be reduced by $A1239 when initial DVT treatment with dalteparin 200 U/kg once daily was given at home rather than in hospital.

Canadian and Spanish data indicate overall institutional cost savings when dalteparin is used in place of UFH in the initial management of DVT in hospital. In addition, a brief pharmacoeconomic report from a UK study in 105 patients showed a £900 per-patient overall cost saving when subcutaneous dalteparin 5000U once daily rather than laboratory-adjusted warfarin therapy was given for 3 months for the prevention of recurrence of DVT.

Significantly lower rates of DVT with subcutaneous dalteparin 5000U once daily than with laboratory-adjusted warfarin for a mean 7 days translated into similar average cost effectiveness of dalteparin and warfarin in terms of cost per event-free patient in a pharmacoeconomic analysis of 382 individuals receiving thromboprophylaxis after total hip arthroplasty. Overall costs per patient from a hospital perspective were similar under different treatment scenarios (short term (6-day) and long term (35-day) treatment started before or after surgery) for dalteparin and warfarin in a North American study in which 1130 patients were randomised to prophylaxis with either drug after total hip arthroplasty. Incremental cost effectiveness of dalteparin ranged from $US 1799 to $US4661 per patient (year of costing not stated) in this analysis.

Economic data from a 9-week time and motion study in 116 patients receiving aPTT-adjusted UFH infusion for acute CAD showed costs from a hospital perspective of $Can25.68 for UFH and $Can28.82 for dalteparin 120 U/kg twice daily subcutaneously. In this analysis, costs for dalteparin therapy were estimated using a projection based on assumptions regarding resource utilisation, staff activity and acquisition cost.

Tolerability

Overall, rates of haemorrhagic complications appear similar for dalteparin and UFH in patients receiving thromboprophylaxis and those undergoing treatment for established thromboembolic disease. Collated data from studies in surgical patients receiving subcutaneous thromboprophylaxis with dalteparin 2500 or 5000U or UFH 10 000IU daily show similar rates of bleeding with either heparin. Increased frequency of bleeding complications relative to placebo has been reported in patients undergoing treatment with dalteparin for up to 3 months for unstable CAD; in patients receiving acute treatment for MI in 1 study, major haemorrhage was reported in 2.9% of dalteparin recipients and 0.3% of those receiving placebo (p = 0.006). There have been no reports of excess bleeding relative to placebo in patients receiving extended (35-day) thromboprophylaxis with dalteparin after orthopaedic surgery, and the drug has not been associated with clinically significant haemorrhagic complications or adverse fetal or maternal outcomes in pregnant women.

The exact incidence of thrombocytopenia with dalteparin is not known, but has been reported to be less than 1% in patients receiving the drug for thromboprophylaxis.

Dosage and Administration

Patients at moderate risk of venous thromboembolism after surgery should receive dalteparin subcutaneously at a dosage of 2500U once daily; patients at high risk should receive 5000U once daily. A dosage of 200 U/kg once daily or 100 U/kg twice daily is recommended for the initial treatment of established thromboembolic disease, and 120 U/kg every 12 hours in addition to aspirin is indicated for patients with unstable CAD. An intravenous weight-adjusted bolus followed by continuous infusion is recommended for haemodialysis or haemo-filtration procedures lasting 4 hours or more; a single intravenous bolus may be suitable where sessions are of less than 4 hours’ duration. Subcutaneous administration of dalteparin should be via the abdomen or the lateral portion of the thigh.

Laboratory monitoring of the coagulation response is not necessary in most patients receiving dalteparin therapy. Plasma anti-factor Xa activity should be monitored in certain groups of individuals, however; these include those with acute or chronic renal failure, and those at high risk of bleeding who require treatment for established thromboembolic disease.

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    Christopher J. Dunn & Blair Jarvis

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Correspondence to Christopher J. Dunn.

Additional information

Various sections of the manuscript reviewed by: R.L. Bick, Department of Medicine and Pathology, University of Texas Southwestern Medical School, Dallas, Texas, USA; J. Fareed, Loyola University Medical Center, Maywood, Illinois, USA; E. Gurfinkel, Coronary Care Unit, Favaloro Foundation, Buenos Aires, Argentina; B.J. Hunt, The Rayne Institute, St Thomas’ Hospital, London, England; M.R. Lassen, Department of Orthopaedics, Hillerød Hospital, Hillerød, Denmark; P.J. Zed, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Data Selection

Sources: Medical literature published in any language since 1996 on dalteparin, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘dalteparin’ or ‘tedelparin’ or ‘dalteparin sodium’. EMBASE search terms were ‘dalteparin’ or ‘dalteparin sodium’ or ‘FR 860’ or ‘KABI 2165’ or ‘tedelparin’. AdisBase search terms were ‘dalteparin’ or ‘dalteparin sodium’ or ‘FR-860’ or ‘KABI 2165’ or ‘tedelparin’. Searches were last updated on 19th June 2000.

Selection: Studies in patients with or at risk of thromboembolic disease or on haemodialysis/haemofiltration who received dalteparin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Dalteparin, thromboprophylaxis, orthopaedic surgery, general surgery, pregnancy, deep vein thrombosis, pulmonary embolism, outpatient treatment, unstable coronary artery disease, myocardial infarction, haemodialysis, haemofiltration, pharmacodynamics, pharmacokinetics, pharmacoeconomics, tolerability, dosage and administration, therapeutic use.

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Dunn, C.J., Jarvis, B. Dalteparin. Drugs 60, 203–237 (2000). https://doi.org/10.2165/00003495-200060010-00010

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