Dalteparin Sodium in the Management of Thromboembolic Disorders

DRUG PROFILE

Dalteparin sodium in the management of thromboembolic disorders

Agnes YY Lee Low molecular weight heparins have largely replaced unfractionated heparin for the McMaster University, Hamilton Health Sciences, prevention and treatment of venous and arterial thromboembolic disease since they are Henderson Hospital, efficacious, safe and more convenient. Dalteparin sodium (Fragmin®, Pfizer Inc.) is a low 711 Concession Street, molecular weight heparin produced by controlled nitrous acid depolymerization of Hamilton, Ontario, L8V 1C3, Canada unfractionated heparin. Although specific indications and usage vary across countries, Tel.: +1 905 527 4322; dalteparin has received regulatory approval for use in preventing venous ext. 42484 thromboembolism following major abdominal and orthopedic surgery, treating acute Fax: +1 905 574 7625 [email protected] deep vein thrombosis, and preventing recurrent venous thromboembolism in cancer patients. It is also used for the treatment of unstable coronary arterial disease and prevention of clotting of the extracorporeal system during hemodialysis. More recent research efforts have examined the potential role of dalteparin as an antineoplastic agent. Dalteparin has significantly improved and simplified the management of venous thromboembolism and will remain a very useful anticoagulant of choice, particularly in the oncology population.

Anticoagulants are the mainstay therapy for the Fondaparinux (Arixtra®, GlaxoSmithKline) prevention and treatment of acute arterial and is a parental synthetic pentasaccharide with venous thrombotic disorders. Unfractionated and potent inhibitory activity against Xa [2]. It has low molecular weight heparins (LMWHs) are the been shown to reduce the risk of deep vein standard agents for acute treatment or short-term thrombosis (DVT) by 50% compared with the prophylaxis, while vitamin K antagonists, such as LMWH enoxaparin (Lovenox®, Clexane®, warfarin, are used almost exclusively for long- Sanofi Aventis) in major arthroplasty surgery term therapy. Although these agents are highly [3]. It is marketed for this indication but its use efficacious and have reasonable safety profiles, is not widespread because of a concern over a LMWHs are superior due to ease of use and min- higher risk of bleeding compared with imal adverse effects. Consequently, this class of LMWH. This drug is comparable to enoxa- drugs has largely replaced unfractionated heparin parin for the initial treatment of DVT and to (UFH) in most clinical settings and has recently intravenous UFH for initial treatment of pul- been recommended as the first-line therapy over monary embolism (PE) [4,5]. The major advan- warfarin for long-term prevention of recurrent tage of fondaparinux over heparins is that it venous thromboembolism (VTE) in patients does not cause drug-related thrombocytopenia. with cancer. A long-acting derivative, idraparinux, is currently being investigated for long-term use [6]. Overview of the market The advantage offered by idraparinux is once- Although LMWHs are effective and safe, their weekly subcutaneous injection but it lacks a pharmacological and clinical limitations have specific antidote for rapidly reversing its prompted the ongoing search for the ideal anti- anticoagulant activity. coagulant. In contrast to traditional anticoagu- Ximelagatran (Exanta®, AstraZeneca) is an lants that are relatively nonspecific, novel agents oral direct thrombin inhibitor that had received Keywords: dalteparin, low molecular weight heparin, are being developed to specifically target critical approval in some countries for short-term proph- thromboprophylaxis, venous steps in the coagulation cascade (Figure 1) [1]. This ylaxis in orthopedic surgery [7]. It was extensively thromboembolism approach is based on the hypothesis that specific investigated for extended use in atrial fibrillation or selective agents will reduce the risk of bleeding [8] and for treatment of DVT [9,10]. These trials while preserving antithrombotic efficacy. Drugs found an unexpected increased risk of hepatotox- that inhibit activated factor X (Xa) or thrombin icity with prolonged exposure to ximelagatran. Future Drugs Ltd have the most advanced clinical data. The drug has now been withdrawn from the

Figure 1. Sample of new antithrombotic agents in development.

Steps in coagulation Coagulation cascade Drug

NAPc2 Initiation TF/VIIa FVIIai

X IX TTP 889

Protein C α IXa Drotrecogin (act)- sTM VIIIa Va Fondaparinux Xa Propagation Idraparinux DX9065a Razaxaban II BAY 59-7939 LY 517717 BMS-562247 DU-176B

Ximelagatran IIa Dabigatran

Thrombin activity Fibrinogen Fibrin

TF: Tissue factor; Xa: Activated factor X.

market worldwide by the manufacturer [11]. • Ability to release various mediators from the Other promising oral direct thrombin inhibitors vascular endothelium are in Phase II/III development. • Degree of neutralization by protamine sulfate However, whether these differences are impor- Introduction to the compound tant clinically remains debated and large clinical Dalteparin sodium is one of several LMWHs that trials that would be needed to compare the effi- are commercially available worldwide (Figure 2). cacy and safety of these agents directly are not Similar to all LMWHs, dalteparin is a potent anti- feasible [15]. Regulatory agencies do not consider coagulant that acts through indirect inhibition of these agents to be interchangeable and country- thrombin, the key procoagulant that converts specific indications differ for the various fibrinogen to fibrin [12]. Each commercially availa- LMWH preparations. ble LMWH is prepared from unique chemical or enzymatic depolymerization of porcine or bovine Chemistry & pharmacology mucosal heparin and these manufacturing meth- Dalteparin sodium is a fractionated derivative of ods are considered proprietary (Table 1). Conse- UFH prepared by controlled nitrous acid depo- quently, these agents are biologically distinct. lymerization of sodium heparin from porcine They differ in their oligosaccharide composition intestinal mucosal [16,17]. While UFH is a hetero- and they vary considerably in their molecular geneous mixture of large glycosaminoglycan mol- weight distribution and degree of sulfation [13,14]. ecules with a mean molecular weight of 15,000 Such biological differences result in physiologic Da (with a range of 3000–30,000 Da), dalteparin variability among LMWHs in their: is composed of strongly acidic sulfated polysac- • Affinity to bind to antithrombin, heparin charide chains with an average molecular weight cofactor II, and platelet factor 4, as well as of 5000 Da. Approximately 90% of the material, other plasma proteins however, ranges in weight from 2000 to 9000 Da.

462 Therapy (2006) 3(4) Dalteparin sodium – DRUG PROFILE

Figure 2. Dalteparin sodium.

R 2 CH OR R2 CH OR R 2 2 3 R3 O O CH OH O O 2

O O O OH HO OR OR NHR 1 HO OR Therapy

The glycoaminoglycan structure is composed of LMWHs also inhibit Xa activity indirectly alternating polymers of D-glucosamine and either through the induction of tissue-factor pathway gluconic or iduronic acid. The sulfur content is inhibitor (TFPI) release from endothelial cells approximately 11% with approximately 2% [13]. TFPI is an endogenous modulator of the tis- sulfation/disaccharide unit [17]. sue factor-VIIa complex that also binds and inac- Similar to UFH, dalteparin exerts its anticoagu- tivates Xa. The degree of TFPI release varies lant activity by accelerating the inhibition of acti- among the different LMWHs but whether this vated coagulation factors by antithrombin, the contributes to differences in the antithrombotic major physiological anticoagulant in plasma. By potency of these agents is unknown. binding to antithrombin via a unique, high affinity In addition to stimulating the release of pentasaccharide sequence that is found randomly TFPI, dalteparin also enhances the release of distributed along approximately 20% of the prostacyclin, tissue plasminogen activator, and polysaccharide chains, dalteparin induces a confor- von Willebrand factor from vascular endothe- mational change in antithrombin that accelerates lium [13]. Dalteparin does not appear to have an its inactivation of Xa and thrombin (factor IIa) [12]. effect on the fibrinolytic system and it has less However, since inactivation of thrombin by anti- lipolytic activity than UFH. It does not affect thrombin requires a heparin chain of at least 18 plasma antithrombin levels and release of saccharide units long to form a ternary complex platelet factor (PF)4. between the heparin molecule, antithrombin and The pharmacologic properties of dalteparin thrombin, dalteparin has a lower inhibitory activ- are more specific in comparison with those of ity against thrombin compared with UFH because UFH and are attributable to the lower affinity of of its shorter chain length (Figure 3). Consequently, dalteparin to bind to endogenous plasma pro- dalteparin (like other LMWHs) predominantly teins, endothelial cells, and macrophages. inhibits Xa over thrombin. This differential inhibi- Dalteparin also binds less avidly to PF4, high- tion of Xa and thrombin is expressed as the anti- molecular-weight multimers of von Willebrand Xa:anti-IIa ratio, which is defined as 1:1 for UFH. factor and osteoclasts. These differences in non- The anticoagulant potency of LMWHs is also specific binding also lead to the lower risk of described in international anti-Xa units (IU) refer- heparin-induced thrombocytopenia (HIT) and enced against a WHO standard [18]. This standard osteoporosis for dalteparin compared with UFH. is currently used only for pharmaceutical purposes to assign an international unit of potency to each Pharmacokinetics, pharmacodynamics & batch of LMWH; its clinical usefulness and corre- metabolism lation with pharmacologic activity remain uncer- As for all LMWHs, the pharmacokinetic and tain. The specific activity of dalteparin on Xa is pharmacodynamics parameters of dalteparin are 130 IU/µg and its specific activity on thrombin is conventionally expressed as the inhibitory activ- 58 IU/µg. This produces an anti-Xa:anti-IIa ratio ity on exogenous Xa rather than by the actual of 2.2:1 for dalteparin (Table 1) [17]. The relative concentration of dalteparin in blood or target importance of inhibition of Xa and inhibition of tissues. The pharmacodynamics of dalteparin thrombin in mediating the antithrombotic effect is can also be measured as the inhibition of factor unclear, but clinical studies show that specific IIa or TFPI, or the prolongation of the clotting inhibitors of Xa are comparable in efficacy to UFH time as determined by the Heptest. These vari- and LMWH. ous activities have been shown to correlate with

www.future-drugs.com 463 DRUG PROFILE – Lee

Table 1. Commercially available low molecular weight heparins.

‡ Product Company Preparation Molecular T½ (h)* Anti-Xa:Anti- Bioavailability weight (Da) IIa ratio‡ (%)§ mean Ardeparin Wyeth-Ayerst Peroxidase 6000 3.3 1.9 92 (Normiflo) cleavage Certoparin Novartis Isoamyl nitrate depolymerization Dalteparin Pfizer Nitrous acid 5000 3–5 2.2 87 (Fragmin) digestion, chromatographic purification Enoxaparin Sanofi-Aventis Benzylation and 4200 4.5 3.9 91 (Lovenox) alkaline hydrolysis Nadroparin Sanofi-Aventis Optimized nitrous 4500 3.3 3.5 98 (Fraxiparin) acid depolymerization Reviparin Knoll AG Nitrous acid 4000 3.0 3.5 (Clivarin) digestion, chromatographic purification Tinzaparin Leo Pharma Heparinase 4500 3.3 1.5 90 (Innohep) digestion using Flavobacterium heparinicum Heparin Leo Pharma 11,400 1 1.0 30 (range 10–40) *Apparent elimination half-life subcutaneously; ‡Amidolytic; §Based on anti-Xa activity

blood concentrations of LMWHs and anti-Xa approximately 40–60 l/kg and a steady-state activity has become the accepted standard for plasma level is reached after two to four doses, measuring the anticoagulant activity of all based on twice-daily subcutaneous administra- LMWHs. It is important to emphasize, however, tion (100 IU/kg every 12 h). Approximately that this activity reflects only one of the many 70% is cleared by renal mechanisms via a first- different physiological effects of dalteparin and order process, and the remainder is cleared by other LMWHs. Consequently, true bioequiva- the liver [16]. Consequently, dalteparin may lence is not achieved even when the same anti-Xa accumulate in patients with renal insufficiency. activity is obtained with different LMWHs. In contrast to UFH, the prothrombin time (PT), Clinical efficacy activated partial thromboplastin time (APTT) General surgery and thrombin time (TT) are not affected by Dalteparin has been extensively investigated for therapeutic doses of dalteparin and are therefore prevention of VTE in major elective abdominal not useful for monitoring. surgery. Compared with placebo, dalteparin According to anti-Xa activity, dalteparin pro- 2500 IU once-daily significantly reduces the risk duces a predictable anticoagulant response when of DVT by 74% (4.2 vs 15.9%; p = 0.008) [19]. it is given via subcutaneous administration. This Compared with UFH 5000 IU given two or reflects its bioavailability, half-life, and dose- three times a day, dalteparin 2500–5000 IU independent clearance via non-saturable mecha- given once daily appears equally efficacious and nisms. After subcutaneous administration, the safe [20]. Both heparins were usually given 1–2 h bioavailability of dalteparin is approximately prior to surgery and continued for 5–10 days 87%, compared with 20–30% for UFH [16]. The after surgery. With either agent, the incidence of plasma half-life of dalteparin is 2 h after intrave- DVT is approximately 4% and that of major nous injection and 3–4 h after subcutaneous bleeding is 3%. Most trials included patients injection. The volume of distribution is with malignancy but few reported the results

464 Therapy (2006) 3(4) Dalteparin sodium – DRUG PROFILE

Figure 3. Differential binding of LMWH and UFH to antithrombin and its effect on inhibition of activated factor Xa and thrombin.

Pentasaccharide sequence Factor Xa

Unfractionated heparin

Thrombin

Pentasaccharide sequence

Low-molecular weight heparin Factor Xa

LMWH: Low molecular weight heparin; UFH: Unfractionated heparin.

separately for these patients [19,21–23]. The lim- malignancy [25]. Following routine prophylaxis ited data suggest that dalteparin, particularly with dalteparin 5000 IU given once-daily for the 5000 IU once-daily, is effective in reducing first week while in hospital, patients were rand- venous thrombotic events in this high-risk popu- omized to continue with dalteparin or no further lation without increasing the risk of bleeding. In prophylaxis. Venography was performed at these trials, the incidence of VTE was higher in 28 days after surgery. The trial was conducted in patients with cancer than those without. an open-label fashion but the venograms were Two studies have evaluated two different dos- reviewed by radiologists masked to treatment ing regimens of dalteparin [22,24]. Both studies assignment. Preliminary results showed that pro- showed that dalteparin 5000 IU (given once- longing prophylaxis with dalteparin significantly daily or in two equal doses) was more effective in reduced the incidence of overall DVT from 19.6 preventing DVT than 2500 IU daily. There was to 8.8% (p = 0.03) and proximal DVT from a trend for a dose response in bleeding in 10.4 to 2.2% (p = 0.02). patients without malignancy but there was no In summary, randomized clinical trials have increase in bleeding in patients with cancer. demonstrated that in patients undergoing major One single study has evaluated the use of elective abdominal surgery, dalteparin given in dalteparin beyond discharge from hospital fol- single daily doses of 2500–5000 IU is superior to lowing major surgery for an abdominal or pelvic placebo and comparable to UFH 5000 IU two www.future-drugs.com 465 DRUG PROFILE – Lee

or three times a day. Further studies are needed these patients may develop thrombotic complica- to evaluate the efficacy and safety of extended tions after surgery [36]. Two randomized trials have prophylaxis in patients with malignancy. studied dalteparin: one comparing once-daily dalteparin with UFH 5000 IU three times a day Orthopedic surgery and the another dalteparin with pneumatic com- Dalteparin has been evaluated in randomized, pression [37,38]. In both studies, dalteparin controlled trials in patients undergoing major hip 2500 IU was given 1–2 h before surgery and was surgery. Similar to the regimen in major abdomi- repeated at 12 h afterwards. Patients then contin- nal surgery, dalteparin is initiated either 2 h or the ued to receive dalteparin 5000 IU once-daily. evening before surgery and then given within Both studies were small and there were very few 4–8 h after surgery and then once-daily thereafter. cases of symptomatic thrombotic events. Overall, The pre-operative and same-day dose is 2500 IU, no difference in efficacy or bleeding complications while 5000 IU is recommended post-operatively. was observed between treatments. Double-blind, placebo-controlled studies have shown that dalteparin reduces the incidence of Other prophylaxis settings DVT by approximately 50% in patients who have A large, randomized controlled trial has demon- undergone fractured hip repair [26] or elective hip strated that patients hospitalized for medical rea- arthroplasty [27]. It has been reported to be more sons benefit from dalteparin for routine efficacious than adjusted-dose warfarin (target thromboprophylaxis. Using symptomatic VTE internal normalized ratio [INR]: 2.5) but the and DVT detected by ultrasonography as the pri- transfusion requirement was also greater in the mary outcome, the PRospective EValuation of dalteparin group [28]. A large, double-blind trial dalteparin Efficacy for prevention of VTE in comparing warfarin with pre- and postoperative immobilized patieNts Trial (PREVENT) showed regimens of dalteparin also found that dalteparin that once-daily dalteparin 5000 IU for 14 days was more efficacious than warfarin in reducing significantly reduced the incidence of proximal overall and proximal DVT (11.9 vs 24%; DVT by 45% (5.0 vs 2.8%; p = 0.002) [39]. p < 0.001) but there was no significant difference There was a low risk of bleeding (0.49%) with in efficacy between pre- and post-operative start of dalteparin. A small trial comparing dalteparin dalteparin [29]. Major bleeding was significantly with UFH had suggested that the two agents are higher for the preoperative dalteparin group com- comparable [40]. Dalteparin has received regula- pared with warfarin (8.9 vs 4.5%; p = 0.01) but tory approval in various countries for use in there was no difference in bleeding between the medical inpatients for primary prophylaxis. postoperative dalteparin and warfarin groups. Dalteparin has also been investigated in Also, two trials have shown no difference between patients with acute ischemic stroke. In a small, dalteparin and adjusted-dose UFH in efficacy or double-blind placebo controlled randomized bleeding [30,31]. Based on these studies, dalteparin trial, dalteparin 2500 IU twice-daily for 14 days is approved by the FDA for prevention of DVT in significantly reduced the risk of DVT (20 vs hip replacement surgery and is widely used in 50%; p = 0.05) without increasing bleeding [41]. Canada and Europe for prophylaxis after other Finally, dalteparin has been evaluated for pre- types of major orthopedic surgery as well. vention of central venous catheter-related Dalteparin has also been investigated for pre- thrombosis in patients with cancer. Although an vention of VTE following discharge from hospital earlier study had suggested that dalteparin after total hip replacement. In double-blind, pla- 2500 IU once-daily was effective in reducing cebo-controlled randomized trials, dalteparin catheter-related thrombosis [42], a more recent 5000 IU once daily was found to reduce the inci- and larger study has failed to show any difference dence of DVT by 40–60% [32–34]. Although in the incidence of symptomatic catheter-related extended prophylaxis after major hip surgery is thrombosis between patients who received recommended by the American College of Clinical dalteparin 5000 IU and those who received pla- Pharmacy (ACCP) guidelines, regulatory approval cebo [43]. A placebo-controlled study evaluating has not be obtained for this indication [35]. the efficacy of enoxaparin 40 µg once-daily also failed to show any reduction in catheter-related Gynecological oncology surgery thrombosis in the same patient population [44], The use of LMWH has also been evaluated in suggesting that standard prophylactic doses of women undergoing surgery for gynecological LMWHs do not provide protection against cath- malignancies in the pelvis because up to 38% of eter-related thrombosis in cancer patients.

466 Therapy (2006) 3(4) Dalteparin sodium – DRUG PROFILE

Consequently, the ACCP now recommends that their clinical efficacy and safety [15]. Dalteparin low-dose LMWH should not be used for routine does not have US FDA approval for the treat- prophylaxis in this setting [35]. ment of acute VTE, although it is approved and used widely in Canada and Europe for this Initial treatment of acute venous indication. thromboembolism A number of randomized, controlled trials have Long-term treatment of venous compared the relative efficacy and safety of thromboembolism subcutaneous dalteparin with intravenous Although coumarin derivatives are the mainstay UFH for treatment of acute DVT. Most of the of long-term treatment in preventing recurrent studies were small and used improvements in VTE, some patients tolerate warfarin poorly. the venographic Marder score as the primary They include patients with malignancy, malab- outcome measure. These studies consistently sorption syndromes and those with a high risk of showed that dalteparin, given as bleeding. Consequently, LMWH has been inves- 100–120 IU/kg twice-daily or 200 IU/kg tigated as an alternative to vitamin K antagonists once-daily, was comparable to APTT-adjusted for long-term therapy. UFH infusion in preventing recurrent throm- Three randomized trials have evaluated bosis [45–48]. Early studies also showed no sig- dalteparin for long-term therapy. The first was a nificant differences in Marder score values small, open-label study that included patients between patients given 100 IU/kg twice-daily who were unable to tolerate warfarin [56]. and those given a daily dosage adjusted to Patients were randomized to twice-daily injec- maintain the plasma anti-Xa activity at tions of either dalteparin 5000 IU or UFH 0.5–1.0 IU/ml [49], as well as between patients 10,000 U. Only 3.3% of patients presented with who received 100 IU/kg twice-daily and those recurrent VTE during 3 months of follow-up who received 200 IU/kg once-daily [50]. Conse- and no difference was observed between the two quently, the recommended treatment dose is groups. The second trial primarily included 200 IU/kg subcutaneously once-daily. The patients without cancer and found no difference expected anti-Xa levels achieved is more than in efficacy or safety between dalteparin 5000 IU 0.3 IU/ml before injection and less than once-daily and warfarin adjusted to an INR of 1.7 IU/ml 3–4 h after injection. Monitoring, 2.0–3.0 [57]. The third study is the largest trial however, is not required for routine treatment investigating the use of LMWH for long-term but it is recommended in pregnant women, therapy in cancer patients. The Comparison of patients with renal insufficiency, and children Low-molecular-weight heparin versus Oral anti- because relatively little pharmacological and coagulant Therapy for the prevention of recur- clinical data are available in these populations. rent venous thromboembolism (CLOT) trial was Dalteparin has been shown to be efficacious a multicenter, randomized, open-label study in and safe when given on an outpatient basis for which 676 cancer patients with proximal DVT, treatment of acute DVT in several studies [51,52]. PE or both were randomized to usual treatment Although dalteparin is more expensive than with dalteparin initially followed by coumarin UFH, the overall cost for treating DVT is less therapy or dalteparin therapy alone for 6 months with dalteparin because of the reduction in hos- [58]. In the dalteparin group, patients received pitalization and the elimination of APTT therapeutic doses at 200 U/kg once-daily for the monitoring [53,54]. first month and then 75–80% of the full dose for A single small randomized pilot study has the next 5 months. Over the 6-month treatment evaluated dalteparin 120 U/kg twice-daily period, dalteparin significantly reduced the inci- against intravenous UFH for the initial treat- dence of recurrent VTE from 17 to 9% (risk ment of submassive PE [55]. During the 10-day reduction 52%; p = 0.002). There were no dif- treatment period, there were no symptomatic ferences in bleeding and overall mortality recurrent events or new perfusion defects on between the groups. lung scans in either treatment group. To date, smaller studies have evaluated the use Adequate studies directly comparing the of other LMWHs in the oncology population efficacy and safety of various LMWHs for ini- but none have provided results in favor of the tial treatment are lacking. The limited data LMWH [59–61]. Similarly, studies in primarily that compare each LMWH with UFH do sug- patients without cancer also have not shown any gest that LMWHs do not differ significantly in difference between the LMWH and warfarin for www.future-drugs.com 467 DRUG PROFILE – Lee

recurrent thrombosis or bleeding evaluating. placebo or dalteparin 120 IU/kg twice-daily for Meta-analyses of these studies suggest that 6 days followed by 7500 IU once-daily for LMWH is comparable to warfarin in patients 35–45 days [72]. All patients also received aspi- without cancer [62,63]. rin 75 µg daily. The primary outcome was the incidence of death or new MI during the first 6 Antineoplastic effects of dalteparin days. Lower rates of death and new MI were Experimental studies have suggested that seen in the dalteparin group than in the placebo LMWHs may have anticancer effects. The mech- group at day 6 (1.8 vs 4.7%; p < 0.001), prima- anisms being explored include inhibition of ang- rily due to a reduction in MI. Dalteparin also iogenesis, interference with tumor cell adhesion significantly reduced the need for revasculariza- and inhibition of tumor invasion and metastasis tion procedures and intravenous heparin. Dif- [64,65]. Clinical data have shown that LMWHs can ferences between groups were maintained at improve survival, particularly in patients with lim- 40 days but were no longer significant at ited disease, but whether this benefit arises from 4–5 months after the end of treatment. anticoagulant or antitumour mechanisms, or both Dalteparin was then compared with UFH in remain uncertain. It is clear, however, that activa- patients with unstable angina or non-Q-wave tion of coagulation is criticially involved in tumor MI in the FRagmin In Unstable Coronary artery growth and progression [66–68]. disease (FRIC) Study [73]. Patients were rand- The Fragmin Advanced Malignancy OUt- omized to receive either intravenous UFH (dose come Study (FAMOUS) is the first randomized, adjusted to maintain APTT 1.5 × control) and placebo-controlled trial to investigate the effect aspirin or dalteparin (120 IU/kg twice-daily) of dalteparin 5000 IU once-daily on overall sur- and aspirin for 6 days. They were then subse- vival in patients with advanced solid tumors [69]. quently randomized to treatment with placebo Therapy was continued for 1 year or until death, or dalteparin 7500 IU daily. The primary end if earlier. A trend for survival benefit was point was the composite of death, MI or recur- observed but it was not statistically significant rent angina at the end of the acute 6-day period. (p = 0.29). In contrast, a small study in patients A significant difference was not observed with newly diagnosed small cell lung cancer has between dalteparin and UFH. In the prolonged shown a survival benefit with low-dose phase, there was also no difference between dalteparin [70]. In this study, patients were rand- dalteparin and placebo, suggesting that omized to standard chemotherapy with or with- dalteparin did not confer additional benefit over out dalteparin 5000 IU once-daily. Significant aspirin alone. differences were seen in overall, median and The Fragmin and/or Early Revascularization progression-free survival, favoring the dalteparin During Instability in Coronary Artery Disease group. The mechanisms for the antineoplastic (FRISC II) study also evaluated dalteparin effects of dalteparin are unknown, but preclini- against placebo in a double-blind design [74]. All cal studies have suggested that dalteparin may patients were treated with dalteparin 120 IU/kg have antiangiogenic properties. Another twice-daily and aspirin 75–320 µg/day for at LMWH, nadroparin, has also reported survival least 5 days and then were randomized to pla- benefits in patients with noncurative solid cebo or dalteparin 5000–7500 IU twice-daily for tumors [71], suggesting that antineoplastic effects 90 days. The primary end point was a composite may be a property of this class of anticoagulants. of death and MI during the double-blind 90-day Further research is needed to confirm these pre- treatment period. No significant difference was liminary findings and investigate the observed at 90 days but bleeding was increased. mechanisms of action. Overall, the evidence from these trials suggest that dalteparin is effective and comparable to Acute coronary syndromes UFH in reducing ischemic outcomes in patients Dalteparin was first introduced as an alternative with unstable angina or non-Q-wave MI, but to UFH in the late 1990s to reduce the risk of that it does not provide any added efficacy over recurrent ischemic events in patients presenting aspirin alone beyond the first week of treatment. with acute coronary syndrome. The FRagmin These results are similar to those seen in rand- during InStability in Coronary artery disease omized trials comparing enoxaparin and UFH (FRISC) trial randomized patients with unsta- [75], although differences in study design pre- ble angina or non-Q-wave myocardial infarc- cludes valid comparisons about the relative tion (MI) in a double-blind fashion to receive efficacy and safety of these agents.

468 Therapy (2006) 3(4) Dalteparin sodium – DRUG PROFILE

Hemodialysis & hemofiltration and must be avoided within 2 h of insertion or Dalteparin is used for prevention of fibrin depo- manipulation of an indwelling epidural catheter. sition and clotting of blood in the extracorporeal Heparin-induced thrombocytopenia (HIT) is circulation of patients undergoing hemodialysis caused by the formation of antibodies directed and hemofiltration. It appears to be comparable against complexes of heparin and PF4 that form to UFH for this indication [76,77]. Various regi- on the surface of platelets and activate their Fc mens of dalteparin have been tested. The most receptors [85]. The true incidence of HIT associ- common regimen for chronic renal failure is an ated with dalteparin and other LMWHs is not intravenous bolus of 30–40 IU/kg followed by known but the incidence is much lower than an infusion of 10–15 IU/kg/h. This normally that with UFH [86]. Patients with a history of produces plasma levels of 0.5–1.0 IU/ml. HIT should not receive dalteparin. Osteoporosis has been reported with pro- Use of dalteparin in pregnancy longed LMWH use but the incidence is uncer- Dalteparin is frequently used in pregnant tain. Similar to HIT, osteoporosis with LMWH women for prevention and treatment of VTE, as use is much lower compared with UFH use. [87] well as for improving live birth rates in women The mechanisms of action on bone turnover with antiphospholipid antibody syndrome and between LMWHs and UFH are different and recurrent pregnancy losses [78–80]. Large rand- favor less bone loss with LMWHs [88,89]. omized trials, however, are lacking to identify the Dalteparin has been used successfully in preg- optimal regimen in these settings. Pharmacoki- nant women for prevention and treatment of VTE, netic studies also have provided conflicting history of recurrent fetal loss, as well as an alterna- information on how dalteparin is metabolized tive to warfarin in women with mechanical heart during various pregnancy-related thrombosis set- valves [87]. However, the experience is based largely tings but suggest that laboratory monitoring of on observational studies and very small rand- the anti-Xa effect is essential in order to maintain omized trials. LMWHs do not cross the placenta therapeutic levels [81–83]. Laboratory studies also but there have been reports of congenital anomalies suggest various LMWHs differ in their pharma- in infants born to women who received LMWHs codynamic and hemostatic profiles in pregnancy during pregnancy, including cerebral anomalies, but whether such variation translate to limb anomalies, hypospadias, peripheral vascular differences in efficacy and safety is unknown [84]. malformation, fibrotic dysplasia and cardiac defects Given the sensitive and difficult population, and [17]. There is, however, no evidence that demon- the lack of large randomized trials in pregnancy set- strates an increased incidence of congenital anoma- tings, none of the LMWHs have regulatory lies compared to the general population or a causal approval for use in pregnancy. relationship with LMWH exposure. Of note, the multidose vial preparation of dalteparin Safety & tolerability (25,000 IU/ml) contains benzyl alcohol Dalteparin has few serious adverse effects. (14 µg/ml) as a preservative, which has been associ- Besides the risk of major hemorrhage that can ated with a potentially fatal ‘gasping syndrome’ in result from the use of any anticoagulant, neonates. This can manifest as metabolic acidosis, dalteparin has been associated with HIT, oste- respiratory distress, convulsions and intracranial oporosis, and rarely hypersensitivity. The risk of hemorrhages. Due to the fact that benzyl alcohol major bleeding reported with dalteparin is less may cross the placenta, this formulation of than 5% in the postoperative setting and 5–10% dalteparin should not be used in pregnancy when used in therapeutic doses. Its use is con- women. It is not known whether dalteparin is traindicated when there is active bleeding, severe excreted in human milk. thrombocytopenia (platelet count < 50 × 109/l) Like other LMWHs, the efficacy and safety of and it must be used with extreme caution in con- dalteparin has not been well established in chil- ditions that predispose to serious bleeding. The dren although it is used in this population for use of dalteparin in patients with renal impair- treatment of thrombotic disorders [90]. ment is not well studied and must be monitored carefully. Prolongation of the anticoagulant Expert commentary & outlook effect in such patients may lead to an increased Dalteparin is a LMWH with a 20-year history in risk of bleeding even at reduced doses. the management of thrombotic disorders. It is at Dalteparin should be used with caution in least as efficacious as UFH in these settings, and patients receiving spinal or epidural anesthesia may be safer and more cost effective. It has a solid, www.future-drugs.com 469 DRUG PROFILE – Lee

safety profile over extended periods of use and it is or bleeding while on dalteparin therapy or other convenient and safe to administer on an outpatient anticoagulants. According to the CLOT trial, 9% basis. Its major limitation remains its parenteral of patients with cancer and VTE will experience administration and cost. It may have a future role recurrent VTE while on dalteparin and the as an antineoplastic agent but further studies are management of such patients has not been studied. needed to explore this possibility. Finally, an oral agent that does not require labora- The other area of clinical and research interest is tory monitoring and has few drug interactions and the extended treatment of VTE in patients with low toxicity will definitely challenge all the available cancer. Unlike other indications in which it has sig- anticoagulants and is one that would be highly wel- nificant market competition, dalteparin is the only comed by physicians and patients. Many novel anti- LMWH with strong evidence in this setting. How- coagulants with these putative advantages are in late ever, it remains unknown whether the regimen Phase II/early Phase III development. Whether any identified in the CLOT trial is the optimal of these agents are going to provide clinicians with approach, or whether a shorter duration of more options in antithrombotic management will dalteparin administration or a higher long-term remain unanswered until Phase III trials demon- dose would provide similar or even better results. strate evidence of superiority, or at least comparabil- Related to this, research is clearly needed to stratify ity, over traditional anticoagulants in efficacy, patients with respect to the risk of recurrent VTE safety, cost and convenience.

Highlights

• Dalteparin binds to antithrombin and accelerates the inhibition of activated factor X (Xa) and thrombin. • Its induction of tissue-factor pathway inhibitor (TFPI) release from endothelium may contribute to the antithrombotic effect. • Dalteparin given subcutaneously has a bioavailability of 87% and achieves a peak plasma level in 2–3 h. • Half-life is approximately 4 h and is cleared by the kidneys via a first-order dose-independent process. • Monitoring of its anticoagulant effect can be done using anti-Xa levels taken at 3 h after a subcutaneous injection. • It does not alter the prothrombin time (PT) or activated partial thromboplastin time (APTT) when administered in prophylactic or therapeutic doses. • Dalteparin is an efficacious anticoagulant for the prevention and treatment of venous and arterial thromboembolic disorders. • It is approved for prophylaxis after major surgery, hip replacement surgery, and medical inpatients. • It is also approved for treatment of acute VTE and long-term treatment to prevent recurrent VTE in patients with cancer. • It is used commonly for preventing clotting of extracorporeal circulation of patients undergoing hemodialysis and hemofiltration. • Dalteparin has a good safety profile with few side effects. • It is associated with a low risk of bleeding when used in the appropriate clinical situations. • It should be used in caution in patients with renal insufficiency, pregnant women and in children because of limited data in these populations. • Prophylaxis in general surgery: dalteparin 2500 IU is given 1–2 h before the operation and no sooner than 4 h after surgery, followed by 5000 IU subcutaneously once-daily for 5–7 days starting on the day after surgery. Alternatively, dalteparin 5000 IU is given the evening before surgery and then 5000 IU the following evenings for 5–7 days. • Prophylaxis in elective hip surgery: dalteparin 2500 IU is given 1–2 h before the operation and no sooner than 4 h after surgery, followed by 5000 IU subcutaneously once-daily for 5–7 days starting on the day after surgery. Alternatively, dalteparin 5000 IU is given the evening before the operation and then 5000 IU the following evenings for 5–7 days. • Prophylaxis in medical inpatients: dalteparin 5000 IU once-daily for 14 days. • Treatment of acute deep vein thrombosis: dalteparin 200 IU/kg subcutaneously once-daily or 100 IU/kg subcutaneously twice- daily for a minimum of 5 days. Dose should be individualized in patients with renal insufficiency, pregnant women, and children. • Unstable coronary artery disease: dalteparin 120 IU/kg twice-daily for up to 6 days. • Extended treatment for prevention of recurrent VTE in patients with cancer: dalteparin 200 IU/kg once-daily for 30 days then approximately 150 IU/kg for subsequent 5 months. • Hemodialysis and hemofiltration: For chronic renal failure, 30–40 IU/kg intravenous bolus injection followed by intravenous infusion of 10–15 IU/kg/h.

Bibliography 2. Koopman MM, Buller HR. Short- and 4 randomized double- blind studies. Arch. 1. Weitz JI, Hirsh J, Samama MM. New long-acting synthetic pentasaccharides. J. Intern. Med. 162(16), 1833–1840 (2002). anticoagulant drugs. the Seventh ACCP Intern. Med. 254(4), 335–342 (2003). 4. Buller HR, Davidson BL, Decousus H et al. Conference on Antithrombotic and 3. Turpie AG, Bauer KA, Eriksson BI, Lassen Subcutaneous fondaparinux versus Thrombolytic Therapy. Chest 126(Suppl. 3), MR. Fondaparinux vs enoxaparin for the intravenous unfractionated heparin in the S 265– S 286 (2004). prevention of venous thromboembolism in initial treatment of pulmonary embolism. major orthopedic surgery. A meta-analysis of

470 Therapy (2006) 3(4) Dalteparin sodium – DRUG PROFILE

N. Engl. J. Med. 349(18), 1695–1702 thromboembolic disorders. Drugs 52(2), fracture surgery. A placebo-controlled study. (2003). 276–305 (1996). Clin. Orthop. 278, 95–100 (1992). 5. Buller HR, Davidson BL, Decousus H et al. 17. Fragmin dalteparin sodium. In: 27. Torholm C, Broeng L, Jorgensen PS et al. Fondaparinux or enoxaparin for the initial Compendium of Pharmaceuticals and Thromboprophylaxis by low-molecular- treatment of symptomatic deep venous Specialties. Repchinsky C (Ed.). Canadian weight heparin in elective hip surgery. A thrombosis. a randomized trial. Ann. Intern. Pharmacists Association; Webcom Ltd, placebo controlled study. J. Bone Joint Surg. Med. 140(11), 867–873 (2004). Ontario, Canada 845–848 (2005). Br. 73(3), 434–438 (1991). 6. Walenga JM, Jeske WP, Fareed J. Short- and 18. Barrowcliffe TW, Curtis AD, Johnson EA, 28. Francis CW, Pellegrini VD, Jr., Totterman S long-acting synthetic pentasaccharides as Thomas DP. An international standard for et al. Prevention of deep-vein thrombosis antithrombotic agents. Expert Opin. Investig. low molecular weight heparin. Thromb. after total hip arthroplasty. Comparison of Drugs. 14(7), 847–858 (2005). Haemost. 60(1), 1–7 (1988). warfarin and dalteparin. J. Bone Joint Surg. 7. Eriksson B. Ximelagatran in orthopaedic 19. Ockelford PA, Patterson J, Johns AS. A Am. 79(9), 1365–1372 (1997). surgery. Pathophysiol. Haemos.t Thromb. double-blind randomized placebo controlled 29. Hull RD, Pineo GF, Francis C et al. Low- 34(Suppl. 1), 10–17 (2005). trial of thromboprophylaxis in major molecular-weight heparin prophylaxis using 8. Albers GW, Diener HC, Frison L et al. elective general surgery using once daily dalteparin in close proximity to surgery vs Ximelagatran vs warfarin for stroke injections of a low molecular weight heparin warfarin in hip arthroplasty patients: a prevention in patients with nonvalvular fragment (Fragmin). Thromb. Haemost. double- blind, randomized comparison. The atrial fibrillation. a randomized trial. JAMA 62(4), 1046–1049 (1989). North American Fragmin Trial 293(6), 690–698 (2005). 20. Mismetti P, Laporte S, Darmon JY, Investigators. Arch. Intern. Med. 160(14), 9. Fiessinger JN, Huisman MV, Davidson BL Buchmuller A, Decousus H. Meta-analysis 2199–2207 (2000). et al. Ximelagatran vs low-molecular-weight of low molecular weight heparin in the 30. Eriksson BI, Kalebo P, Anthymyr BA, heparin and warfarin for the treatment of prevention of venous thromboembolism in Wadenvik H, Tengborn L, Risberg B. deep vein thrombosis. a randomized trial. general surgery. Br. J. Surg. 88(7), 913–930 Prevention of deep-vein thrombosis and JAMA 293(6), 681–689 (2005). (2001). pulmonary embolism after total hip 10. Schulman S, Wahlander K, Lundstrom T, 21. Bergqvist D, Burmark US, Frisell J et al. replacement. Comparison of low-molecular- Clason SB, Eriksson H. Secondary Thromboprophylactic effect of low weight heparin and unfractionated heparin. prevention of venous thromboembolism molecular weight heparin started in the J. Bone Joint Surg. Am. 73(4), 484–493 with the oral direct thrombin inhibitor evening before elective general abdominal (1991). ximelagatran. N. Engl. J. Med. 349(18), surgery: a comparison with low-dose 31. Dechavanne M, Ville D, Berruyer M et al. 1713–1721 (2003). heparin. Semin. Thromb. Hemost. Randomized trial of a low-molecular-weight 11. Mohapatra R, Tran M, Gore JM, Spencer 169(Suppl.), 19–24 (1990). heparin (Kabi 2165) versus adjusted-dose FA. A review of the oral direct thrombin 22. Bergqvist D, Burmark US, Flordal PA et al. subcutaneous standard heparin in the inhibitor ximelagatran. not yet the end of Low molecular weight heparin started before prophylaxis of deep- vein thrombosis after the warfarin era. Am. Heart J. 150(1), 19–26 surgery as prophylaxis against deep vein elective hip surgery. Haemostasis 19(1), 5–12 (2005). thrombosis: 2500 versus 5000 XaI units in (1989). 12. Weitz JI. Low-molecular-weight heparins. 2070 patients. Br. J. Surg. 82(4), 496–501 32. Hull RD, Pineo GF, Francis C et al. Low- N. Engl. J. Med. 337(10), 688–698 (1997). (1995). molecular-weight heparin prophylaxis using Published erratum appears in:N. Engl. J. 23. Kakkar VV, Cohen AT, Edmonson RA, dalteparin extended out- of-hospital vs in- Med.337(21), 1567 (1997). Phillips MJ, Cooper DJ, Das SK et al. Low hospital warfarin/out-of-hospital placebo in 13. Fareed J, Hoppensteadt D, Schultz C et al. molecular weight versus standard heparin hip arthroplasty patients: a double-blind, Biochemical and pharmacologic for prevention of venous thromboembolism randomized comparison. North American heterogeneity in low molecular weight after major abdominal surgery. The Fragmin Trial Investigators. Arch. Intern. heparins. Impact on the therapeutic profile. Thromboprophylaxis Collaborative Group Med. 160(14), 2208–2215 (2000). Curr. Pharm. Des. 10(9), 983–999 (2004). [seecomments]. Lancet 341(8840), 259–265 33. Lassen MR, Borris LC, Anderson BS et al. 14. Fareed J, Walenga JM, Hoppensteadt D, (1993). Efficacy and safety of prolonged Racanelli A, Coyne E. Chemical and 24. Kakkar VV, Kakkar S, Sanderson RM, thromboprophylaxis with a low molecular biological heterogeneity in low molecular Peers CE. Efficacy and safety of two weight heparin (dalteparin) after total hip weight heparins: implications for clinical use regimens of low molecular weight heparin arthroplasty--the Danish Prolonged and standardization. Semin. Thromb. fragment (Fragmin) in preventing Prophylaxis (DaPP) Study. Thromb. Res. Hemost. 15(4), 440–463 (1989). postoperative venous thrombolism. 89(6), 281–287 (1998). 15. Wells PS, Anderson DR, Rodger MA et al. A Haemostasis 16(Suppl. 2), 19–24 (1986). 34. Dahl OE, Andreassen G, Aspelin T et al. randomized trial comparing 2 low- 25. Rasmussen MS, Wille-Jorgensen P, Prolonged thromboprophylaxis following molecular-weight heparins for the Jorgensen LN et al. Prolonged hip replacement surgery--results of a double- outpatient treatment of deep vein thromboprophylaxsis with low molecular blind, prospective, randomised, placebo- thrombosis and pulmonary embolism. Arch. weight heparin (dalteparin) following major controlled study with dalteparin (Fragmin) Intern. Med. 165(7), 733–738 (2005). abdominial surgery for malignancy. Blood [seecomments]. Thromb. Haemost. 77(1), 16. Dunn CJ, Sorkin EM. Dalteparin sodium. 102(11), 56a (186) (2004). 26–31 (1997). A review of its pharmacology and clinical 26. Jorgensen PS, Knudsen JB, Broeng L et al. 35. Geerts WH, Pineo GF, Heit JA et al. use in the prevention and treatment of The thromboprophylactic effect of a low- Prevention of venous thromboembolism: molecular-weight heparin (Fragmin) in hip the Seventh ACCP Conference on www.future-drugs.com 471 DRUG PROFILE – Lee

Antithrombotic and Thrombolytic Therapy. Two daily subcutaneous injections of venous thrombosis. Support Care Cancer Chest 126(Suppl. 3), 338S–400S (2004). fragmin as compared with intravenous 12(7), 531–536 (2004). 36. Crandon AJ, Koutts J. Incidence of post- standard heparin in the treatment of deep 54. Lindmarker P, Holmstrom M. Use of low operative deep vein thrombosis in venous thrombosis (DVT). Thromb. molecular weight heparin (dalteparin), once gynaecological oncology. Aust. N. Z. J. Haemost. 64(4), 506–510 (1990). daily, for the treatment of deep vein Obstet. Gynaecol. 23(4), 216–219 (1983). 46. Fiessinger JN, Lopez-Fernandez M, Gatterer thrombosis. A feasibility and health 37. Fricker JP, Vergnes Y, Schach R et al. Low E et al. Once-daily subcutaneous dalteparin, economic study in an outpatient setting. dose heparin versus low molecular weight a low molecular weight heparin, for the Swedish Venous Thrombosis Dalteparin heparin (Kabi 2165, Fragmin) in the initial treatment of acute deep vein Tr i a l Gr ou p. J. Intern. Med. 240(6), prophylaxis of thromboembolic thrombosis. Thromb. Haemost. 76(2), 395–401 (1996). complications of abdominal oncological 195–199 (1996). 55. Meyer G, Brenot F, Pacouret G et al. surgery. Eur. J. Clin. Invest. 18(6), 561–567 47. Lindmarker P, Holmstrom M, Granqvist S, Subcutaneous low-molecular-weight heparin (1988). Johnsson H, Lockner D. Comparison of fragmin versus intravenous unfractionated 38. Maxwell GL, Synan I, Dodge R, Carroll B, once-daily subcutaneous Fragmin with heparin in the treatment of acute non Clarke-Pearson DL. Pneumatic compression continuous intravenous unfractionated massive pulmonary embolism: an open versus low molecular weight heparin in heparin in the treatment of deep vein randomized pilot study. Thromb. Haemost. gynecologic oncology surgery: a randomized thrombosis. Thromb. Haemost. 72(2), 74(6), 1432–1435 (1995). trial. Obstet. Gynecol. 98(6), 989–995 186–190 (1994). 56. Monreal M, Lafoz E, Olive A, del Rio L, (2001). 48. Luomanmaki K, Grankvist S, Hallert C Vedia C. Comparison of subcutaneous 39. Leizorovicz A, Cohen AT, Turpie AG, et al. A multicentre comparison of once- unfractionated heparin with a low molecular Olsson CG, Vaitkus PT, Goldhaber SZ. daily subcutaneous dalteparin (low weight heparin (Fragmin) in patients with Randomized, placebo-controlled trial of molecular weight heparin) and continuous venous thromboembolism and dalteparin for the prevention of venous intravenous heparin in the treatment of deep contraindications to coumarin. Thromb. thromboembolism in acutely ill medical vein thrombosis. J. Intern. Med. 240(2), Haemost. 71(1), 7–11 (1994). patients. Circulation 110(7), 874–879 85–92 (1996). 57. Das SK, Cohen AT, Edmondson RA, (2004). 49. Alhenc-Gelas M, Jestin-Le Guernic C, Melissari E, Kakkar VV. Low-molecular- 40. Poniewierski M, Barthels M, Kuhn M, Vitoux JF, Kher A, Aiach M, Fiessinger JN. weight heparin versus warfarin for Poliwoda H. Effectiveness of low molecular Adjusted versus fixed doses of the low- prevention of recurrent venous weight heparin (Fragmin) in the prevention molecular-weight heparin fragmin in the thromboembolism: a randomized trial. of thromboembolism in internal medicine treatment of deep vein thrombosis. World J. Surg. 20(5), 521–526 (1996). patients. A randomized double-blind study Fragmin-Study Group. Thromb. Haemost. 58. Lee AY, Levine MN, Baker RI, Bowden C, [German]. Med. Klin. (Munich) 83(7), 71(6), 698–702 (1994). Kakkar AK, Prins M et al. Low-molecular- 241–245, 278 (1988). 50. Holmostrom M, Berglund MC, Granquist weight heparin versus a coumarin for the 41. Prins MH, Gelsema R, Sing AK, van Heerde S, Bratt G, Tornebohm E, Lockner D. prevention of recurrent venous LR, den Ottolander GJ. Prophylaxis of deep Fragmin once or twice daily subcutaneously thromboembolism in patients with cancer. venous thrombosis with a low-molecular- in the treatment of deep venous thrombosis N. Engl. J. Med. 349(2), 146–153 (2003). weight heparin (Kabi 2165/Fragmin) in of the leg. Thromb. Res. 67(1), 49–55 59. Deitcher SR, Kessler CM, Merli G, Rigas J, stroke patients. Haemostasis 19(5), 245–250 (1992). Lyons RM, Cort S. Secondary prevention of (1989). 51. Harrison L, McGinnis J, Crowther M, venous thromboembolic events (VTE) in 42. Monreal M, Alastrue A, Rull M et al. Upper Ginsberg J, Hirsh J. Assessment of patients with active malignancy. a extremity deep venous thrombosis in cancer outpatient treatment of deep-vein randomized study of enoxaparin sodium patients with venous access devices-- thrombosis with low- molecular-weight alone vs. initial enoxaparin sodium followed prophylaxis with a low molecular weight heparin [seecomments]. Arch. Intern. Med. by warfarin for a 180-day period. J. Thromb. heparin (Fragmin). Thromb. Haemost. 75(2), 158(18), 2001–2003 (1998). Haemost. 1(Suppl. 1), OC194 (2003). 251–253 (1996). 52. Wells PS, Kovacs MJ, Bormanis J, Forgie 60. Hull R, Pineo GF, Mah AF, Brant RF, for 43. Karthaus M, Kretzschmar A, Kroning H MA, Goudie D, Morrow B et al. Expanding the LITE Investigators. A randomized trial et al. Dalteparin for prevention of catheter- eligibility for outpatient treatment of deep evaluating long-term low-molecular-weight related complications in cancer patients with venous thrombosis and pulmonary heparin therapy for three months vs. central venous catheters: final results of a embolism with low-molecular-weight intravenous heparin followed by warfarin double-blind, placebo-controlled phase III heparin: a comparison of patient self- sodium in patients with current cancer. J. trial. Ann. Oncol. 17(2), 289–296 (2006). injection with homecare injection Thromb. Haemost. 1(Suppl. 1), P1373 44. Verso M, Agnelli G, Bertoglio S et al. [seecomments]. Arch. Intern. Med. 158(16), (2003). Enoxaparin for the prevention of venous 1809–1812 (1998). 61. Meyer G, Marjanovic Z, Valcke J et al. thromboembolism associated with central 53. Avritscher EB, Cantor SB, Shih YC, Comparison of low-molecular-weight vein catheter: a double-blind, placebo- Escalante CP, Rivera E, Elting LS. Cost- heparin and warfarin for the secondary controlled, randomized study in cancer minimization analysis of low-molecular- prevention of venous thromboembolism in patients. J. Clin. Oncol. 23(18), 4057–4062 weight heparin (dalteparin) compared to patients with cancer: a randomized (2005). unfractionated heparin for inpatient controlled study. Arch. Intern. Med. 45. Bratt G, Aberg W, Johansson M, treatment of cancer patients with deep 162(15), 1729–1735 (2002). Tornebohm E, Granqvist S, Lockner D.

472 Therapy (2006) 3(4) Dalteparin sodium – DRUG PROFILE

62. Iorio A, Guercini F, Pini M. Low-molecular- heparin with unfractionated heparin acutely pregnancy to maintain therapeutic levels of weight heparin for the long-term treatment and with placebo for 6 weeks in the anticoagulation. Am. J. Obstet. Gynecol. of symptomatic venous thromboembolism: management of unstable coronary artery 191(3), 1024–1029 (2004). meta-analysis of the randomized disease. Fragmin in unstable coronary artery 83. Ensom MH, Stephenson MD. comparisons with oral anticoagulants. J. disease study (FRIC) Circulation 96(1), Pharmacokinetics of low molecular weight Thromb. Haemost. 1(9), 1906–1913 (2003). 61–68 (1997); Erratum: Circulation 97(4) heparin and unfractionated heparin in 63. van der Heijden JF, Hutten BA, Buller HR, 413 (1998). pregnancy. J. Soc. Gynecol. Investig. 11(6), Prins MH. Vitamin K antagonists or low- 74. FRagmin and Fast Revascularisation during 377–383 (2004). molecular-weight heparin for the long term InStability in Coronary artery disease 84. Ellison J, Thomson AJ, Conkie JA, McCall treatment of symptomatic venous investigators. Long-term low-molecular- F, Walker D, Greer A. Thromboprophylaxis thromboembolism. Cochrane Database Syst. mass heparin in unstable coronary-artery following caesarean section--a comparison of Rev. (1), CD002001 (2003). disease. FRISC II prospective randomised the antithrombotic properties of three low 64. Cosgrove RH, Zacharski LR, Racine E, multicentre study. Lancet 354(9180), molecular weight heparins--dalteparin, Andersen JC. Improved cancer mortality 701–707 (1999). enoxaparin and tinzaparin. Thromb. with low-molecular-weight heparin 75. Antman EM, Cohen M, Radley D et al. Haemost. 86(6), 1374–1378 (2001). treatment: a review of the evidence. Semin. Assessment of the treatment effect of 85. Warkentin TE, Greinacher A. Heparin- Thromb. Hemost. 28(1), 79–87 (2002). enoxaparin for unstable angina/non-Q-wave induced thrombocytopenia: recognition, 65. Smorenburg SM, van Noorden CJ. The myocardial infarction. TIMI 11B- treatment, and prevention: the Seventh complex effects of heparins on cancer ESSENCE meta-analysis. Circulation ACCP Conference on Antithrombotic and progression and metastasis in experimental 100(15), 1602–1608 (1999). Thrombolytic Therapy. Chest 126(Suppl. 3), studies. Pharmacol. Rev. 53(1), 93–105 76. Schrader J, Stibbe W, Armstrong VW et al. 311S–337S (2004). (2001). Comparison of low molecular weight 86. Walenga JM, Prechel M, Jeske WP, Bakhos 66. Nash GF, Walsh DC, Kakkar AK. The role heparin to standard heparin in M. Unfractionated heparin compared with of the coagulation system in tumour hemodialysis/hemofiltration. Kidney Int. low-molecular-weight heparin as related to angiogenesis. Lancet Oncology 2, 608–613 33(4), 890–896 (1988). heparin-induced thrombocytopenia. Curr. (2001). 77. Suzuki T, Ota K, Naganuma S et al. Clinical Opin. Pulm. Med. 11(5), 385–391 (2005). 67. Rickles FR. Relationship of blood clotting application of Fragmin (FR-860) in 87. Sanson BJ, Lensing AW, Prins MH et al. and tumor angiogenesis. Haemostasis hemodialysis: multicenter cooperative study Safety of low-molecular-weight heparin in 31(Suppl. 1), 16–20 (2001). in Japan. Semin. Thromb. Hemost. 16 pregnancy: a systematic review. Thromb. 68. Wojtukiewicz MZ, Sierko E, Klement P, (Suppl.), 46–54 (1990). Haemost. 81(5), 668–672 (1999). Rak J. The hemostatic system and 78. Jacobsen AF, Qvigstad E, Sandset PM. Low 88. Bhandari M, Hirsh J, Weitz JI, Young E, angiogenesis in malignancy. Neoplasia 3(5), molecular weight heparin (dalteparin) for Venner TJ, Shaughnessy SG. The effects of 371–384 (2001). the treatment of venous thromboembolism standard and low molecular weight heparin 69. Kakkar AK, Levine MN, Kadziola Z et al. in pregnancy. BJOG 110(2), 139–144 on bone nodule formation in vitro. Thromb. Low Molecular Weight Heparin Therapy (2003). Haemost. 80(3), 413–417 (1998). With Dalteparin and Survival in Advanced 79. Stephenson MD, Ballem PJ, Tsang P et al. 89. Shaughnessy SG, Young E, Deschamps P, Cancer: The Fragmin Advanced Malignancy Treatment of antiphospholipid antibody Hirsh J. The effects of low molecular weight Outcome Study (FAMOUS). J. Clin. Oncol. syndrome (APS) in pregnancy: a and standard heparin on calcium loss from 22(10), 1944–1948 (2004). randomized pilot trial comparing low fetal rat calvaria. Blood 86(4), 1368–1373 70. Altinbas M, Coskun HS, Er O A et al. A molecular weight heparin to unfractionated (1995). randomized clinical trial of combination heparin. J. Obstet. Gynaecol. Can. 26(8), 90. Monagle P, Chan A, Massicotte P, Chalmers chemotherapy with and without low- 729–734 (2004). E, Michelson AD. Antithrombotic therapy molecular-weight heparin in small cell lung 80. Hunt BJ, Gattens M, Khamashta M, in children: the Seventh ACCP Conference cancer. J. Thromb. Haemost. 2(8), Nelson-Piercy C, Almeida A. on Antithrombotic and Thrombolytic 1266–1271 (2004). Thromboprophylaxis with unmonitored Therapy. Chest 126(Suppl.), S 645– S 687 71. Klerk CP, Smorenburg SM, Otten HM et al. intermediate-dose low molecular weight (2004). The effect of low molecular weight heparin heparin in pregnancies with a previous on survival in patients with advanced arterial or venous thrombotic event. Blood Affiliation malignancy. J. Clin. Oncol. 23(10), Coagul Fibrinolysis 14(8), 735–739 (2003). Agnes YY Lee, MD, MSc, FRCP(C), 2130–2135 (2005). 81. Sephton V, Farquharson RG, Topping J Associate Professor, McMaster University, 72. Fragmin during Instability in Coronary et al. A longitudinal study of maternal dose Hamilton Health Sciences, Artery Disease (FRISC) study group. Low- response to low molecular weight heparin in Henderson Hospital, 711 Concession Street, molecular-weight heparin during instability pregnancy. Obstet. Gynecol. 101(6), Hamilton, Ontario, in coronary artery disease. Lancet 1307–1311 (2003). L8V 1C3, Canada 347(9001), 561–568 (1996). 82. Barbour LA, Oja JL, Schultz LK. A Tel.: +1 905 527 4322; ext. 42484 73. Klein W, Buchwald A, Hillis SE et al. prospective trial that demonstrates that Fax: +1 905 574 7625 Comparison of low-molecular-weight dalteparin requirements increase in [email protected]