April 30, 2004 EUROPEAN JOURNAL OF MEDICAL RESEARCH 215 Eur J Med Res (2004) 9: 215-224 © I. Holzapfel Publishers 2004 DALTEPARIN: PHARMACOLOGICAL PROPERTIES AND CLINICAL EFFICACY IN THE PROPHYLAXIS AND TREATMENT OF THROMBOEMBOLIC DISEASES Graham F. Pineo and Russell D. Hull University of Calgary, Thrombosis Research Unit, Foothills Hospital, Calgary, AB, Canada Abstract: Dalteparin is a low molecular weight rides or molecular weight of 5kD such as the heparin (LMWH) with a mean molecular weight LMWHs are unable to bind thrombin and anti- of approximately 5,000. As with the other low thrombin simultaneously resulting in an increase molecular weight heparins, dalteparin has certain in the ratio of anti-factor Xa to anti-factor IIa ac- advantages over unfractionated heparin (UFH) tivities [1, 2]. For dalteparin this ratio is 2.5:1 most important of which are improved bio-avail- compared with UFH which has an anti-factor Xa ability by subcutaneous injection, a prolonged to anti-factor IIa activity ratio of 1:1. antithrombotic activity which is highly correlated The antithrombotic effect of UFH is assessed with body weight permitting the once daily ad- by its ability to prolong the activated partial ministration of the drug. Other possible advantag- thromboplastin time (APTT). Prolongation of the es of LMWH including dalteparin include a lower APTT is associated with the higher molecular incidence of heparin induced thrombocytopenia weight fragments of LMWH and may reflect the and thrombosis and decreased tendency to pro- undesirable hemorrhage inducing properties of duce osteopenia on prolonged administration. heparin [2]. Because of the shorter side chain Dalteparin has been subjected to a large number lengths and the reduced anti-factor IIa effects of of well designed randomised clinical trials for the LMWH relative to UFH, the antithrombotic effi- prevention and treatment of venous thromboem- cacy of the LMWHs including dalteparin is meas- bolism. Based on data from the randomised clini- ured in terms of their ability to inhibit factor Xa, cal trials, dalteparin has been approved interna- [5, 6] although there is evidence that the activated tionally for a wide spectrum of clinical indica- clotting time may be useful for monitoring the tions. anti-coagulant [7] effect of low-molecular-weight heparin (dalteparin) during coronary artery inter- Key words: Low molecular weight heparin ventions. The doses of dalteparin for both preven- (LMWH); unfractionated heparin (UFH); venous tion and treatment of venous thomboembolism thromboembolism; deep vein thrombosis; pulmo- [3] or coronary indications [8] are expressed in nary embolism; acute anticoagulation; prophylaxis units of anti-factor Xa activity relative to the first International Standard for LMWHs, the reference DALTEPARIN: standard adapted for LMWH by the World INTRODUCTION TO THE COMPOUND Health Organization in 1988 [6]. Unfortunately the anti-Xa activity of a LMWH CHEMISTRY does not predict its anti-thrombotic or hemor- rhagic effects in patients being treated for venous Dalteparin sodium is a sulphated polysaccharide thromboembolism. It seems clear that the obtained by partial nitrous acid depolymerization LMWHs function through a mechanism only par- from standard UFH of porcine origin. The mean tially related to the anti-Xa and IIa activity of the molecular weight of dalteparin is approximately drug. The anti-thrombotic half-life of intravenous 5.7kD [1, 2]. The anticoagulant effect of LMWHs dalteparin in man as measured using the Wessler’s such as dalteparin differs from that of heparin. stasis technique is significantly longer than the The main anticoagulant effect of heparin is due to plasma half-life measured by the anti-Xa or anti- the presence of the pentasaccharide sequence with IIa activity (5 to more than 8 hours versus 1.6 to a high affinity for antithrombin [3, 4]. Heparin 2.4 hours for anti-Xa levels and 1 to 1.4 hours for must bind to antithrombin and thrombin simulta- anti-IIa respectively) [9]. Measurement of anti-Xa neously to form a ternary complex in order to in- levels have been recommended in certain clinical activate thrombin. The accelerated inactivation of circumstances such as in patients with mild to activated factor X (Xa) by heparin and antithrom- moderate renal failure, [10] patients who are mor- bin is less dependent on binding to the enzyme bidly obese and patients who bleed on LMWH [3]. Heparin molecules with fewer than 18 saccha- treatment. In a recent study in patients in inten- 216 EUROPEAN JOURNAL OF MEDICAL RESEARCH April 30, 2004 sive care units anti-Xa levels were measured 2-4 should be based on total body weight or adjusted hours after administration of 5,000 units of daltep- body weight but not on lean body weight [21]. arin to 13 consecutive patients with a wide range Further work is required to clarify this important of renal function [11]. Creatinine clearance was point. measured and compared with anti-Xa levels. The In a recent study patients treated for venous anti-Xa levels were consistently less than 0.5 thromboembolism with once daily therapeutic unit/s mL and there was no clear relationship to doses of dalteparin for at least 5 days were strati- creatinine clearance or bleeding events. The au- fied into three groups: thors concluded anti-Xa levels found 2-4 hours • Within 20% of ideal body weight (IBW) after injection of 5,000 units of dalteparin were • 20-40% over IBW consistently less than 0.5 units/mL and did not • >40% over IBW. vary significantly with renal function [11]. Anti-Xa levels (peak and trough) were similar Anti-Xa levels are not readily available in many in the three groups indicating no effect of body centres, and in clinical practice monitoring of weight on drug levels [22]. anti-Xa levels is seldom necessary. In the event of an accidental overdose of daltep- arin or if serious bleeding occurs during daltepar- PHARMACODYNAMICS in therapy, the slow intravenous infusion of pro- tamine sulfate is recommended [3]. Such treat- Doses of dalteparin used for therapy when admin- ments lead to a 74% decrease in factor Xa levels istered to healthy subjects do not produce signifi- and are thought to inhibit antithrombin activity cant changes in platelet aggregation, fibrinolysis by binding to fragments with longer side chains or global coagulation tests such as the prothrom- [23]. bin time, thrombin time or APTT [12]. Similarly, prophylactic doses of dalteparin i.e. 5,000 units PREVENTION OF VENOUS THROMBOEMBOLISM once or twice daily do not markedly affect APTT, platelet factor IV or lipoprotein lipase release [13]. Dalteparin has been extensively studied in the pre- Ongoing studies suggest that dalteparin prolongs vention of venous thromboembolism in patients the activated clotting time (ACT) in a dose related undergoing moderate to high-risk surgery and in fashion [7]. medical patients. The results of these clinical trials has been extensively reviewed recently [24]. PHARMACOKINETICS Furthermore, a comprehensive review of the pre- vention of venous thromboembolism was recently Dalteparin is rapidly absorbed after subcutaneous published [25]. administration (87% bio availability) with peak plasma concentrations being attained after 2.8 to 4 PREVENTION OF VENOUS THROMBOEMBOLISM IN hours and plasma elimination half-life being 2.4 to GENERAL SURGERY 4 hours [12-16]. Although the LMWHs are bound to red blood cells data with dalteparin suggest that Following initial dose findings studies a number erythrocyte binding does not interfere with the of pivotal studies were performed comparing dal- availability of the drug [17]. As with other teparin with UFH 5,000 units 2-3 times daily [26, LMWHs dalteparin is primarily eliminated by 27]. These studies showed dalteparin to be of renal clearance raising concern that there may be equal efficacy compared with UFH. The study by accumulation of the LMWHs in patients with Kakkar et al. was designed to detect a 50% reduc- moderate to severe renal failure [18]. Further tion in bleeding rates [27]. This study showed that work with the individual LMWHs is required to wound hematomas developed in fewer patients clarify this issue. treated with dalteparin than with UFH and a sig- For treatment of DVT the dalteparin dose is nificantly greater number of patients in the UFH capped at 18,000 units in Canada when the once group required reoperation for wound hematoma daily dosing is used. The rational for capping the or bleeding control. Severe bleeding occurred less dose is based on pharmacokinetic data suggesting frequently in the dalteparin group compared with that dalteparin distributes only in the plasma vol- the UFH group and there was a greater incidence ume, so that dosing should not be weight based in of minor bleeding in the UFH group mainly relat- obesity [19]. However, in the FRISC trial where ed to bruising at injection sights. A meta-analysis the higher dose of dalteparin was used (150 Xa of all studies comparing the use of the LMWH units per kg Q12H) the occurrence of bleeding with UFH has concluded that the two approaches and the median anti-factor Xa levels did not differ are of equal efficacy in patients undergoing ab- in patients with a high body weight or BMI (body dominal, gynaecologic and urologic surgery but mass index) [20]. However, the bleeding rates de- there is less bleeding with LMWH [28]. creased when the dose of dalteparin was reduced Patients operated on for malignant conditions to 120 Xa units/kg q 12h. Similarly, one study in- have been shown to have a higher incidence of ve- dicated that the volume of distribution and clear- nous thromboembolism when compared with pa- ance of dalteparin did not differ significantly from tients operated on for non-malignant conditions. these values in patients of normal weight, suggest- Bergqvist et al. compared the use of dalteparin ing that doses of dalteparin in obese patients 5,000 Xa units daily with UFH 5,000 units twice April 30, 2004 EUROPEAN JOURNAL OF MEDICAL RESEARCH 217 daily in 1,040 patients undergoing abdominal sur- 2,500 units was given two hours before surgery gery of whom 637 patients had malignant disease and a second dose of 2,500 units was given on the [29].