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©Ferrata Storti Foundation Thrombosis Perspectives on antithrombotic agents: from unfractionated heparin trends in hematology oncology to new antithrombotics haematologica 2002; 87:757-770 http://www.haematologica.ws/2002_07/757.htm GIANCARLO AGNELLI, FRANCESCO SONAGLIA Division of Internal and Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Italy Background and Objectives. Unfractionated heparin nfractionated heparin (UFH) has, for a long (UFH) has been the antithrombotic agent of choice time, been the anticoagulant agent of choice for the prevention and treatment of venous throm- Ufor the prevention and treatment of deep boembolism (VTE) for a long time. UFH is also wide- vein thrombosis (DVT) and pulmonary embolism ly used for the treatment of patients with acute coro- (PE). UFH has also been extensively evaluated in the nary syndromes. However, UFH has some limitations management of arterial thrombosis, in patients with such as the need for parenteral administration and acute myocardial infarction to speed-up thrombol- close monitoring of its anticoagulant effect. UFH is ysis or to prevent mural ventricular thrombosis, in also associated with bleeding, heparin-induced patients with unstable angina and in patients thrombocytopenia and osteoporosis. undergoing vascular surgery and percutaneous transluminal coronary angioplasty (PTCA) to pre- Evidence and Information Sources. Low molecular vent acute arterial thrombosis. UFH has some phar- weight heparins (LMWHs) are produced by the macological limitations mainly related to its non- depolymerization of UFH. LMWHs have pharmaco- specific binding to plasma proteins (fibrinogen, fac- logic advantages over UFH: a better bioavailability tor VIII, vitronectin and fibronectin), endothelial after subcutaneous administration, a longer plasma cells and macrophages. This binding complicates half-life and a more predictable anticoagulant effect. the clearance of UFH, reduces UFH bioavailability, These improved features allow once or twice daily and is responsible for the marked inter-individual subcutaneous injection of weight-adjusted doses of variation in the dose-anticoagulant response. UFH LMWHs without requiring laboratory monitoring in also has biophysical limitations due to the inabili- patients with VTE or unstable angina. ty of the heparin/antithrombin complex to inacti- vate factor Xa in the prothrombinase complex. Perspectives. A number of new antithrombotic Moreover, UFH is not able to inactivate thrombin agents are currently under development. These when this is bound to fibrin or to exposed suben- include direct antithrombins and factor Xa inhibitors. dothelial matrix. Subcutaneous injection of UFH at The results of the main clinical trials with LMWHs as low doses is associated with low bioavailability and well as those of the studies with the new antithrom- a short half-life. Moreover, UFH may cause heparin- botic agents will be reviewed in this article. induced thrombocytopenia (HIT), a disease that is ©2002, Ferrata Storti Foundation often complicated by arterial and/or venous throm- bosis (HITT) and has a severe prognosis. Key words: unfractionated heparin, low molecular Low molecular weight heparins (LMWHs) are weight heparins, venous thromboembolism, acute coronary syndromes, direct antithrombins, derivatives of UFH, produced by its depolymeriza- pentasaccharide. tion. LMWHs are composed of mixtures of saccha- ride chains with a mean molecular weight close to 5,000 Daltons. Approximately one third of the heparin chains contain the pentasaccharide sequence that constitutes the heparin-binding site to antithrombin. LMWHs bind less avidly to plasma proteins and endothelial cells than UFH. They have an almost complete bioavailability after subcuta- neous administration of low doses, a more linear Correspondence: Giancarlo Agnelli M.D. Division of Internal and Car- relationship between dose and anticoagulant effect diovascular Medicine, Department of Internal Medicine, University of and a longer plasma half-life than UFH. Finally, HIT Perugia, via Enrico dal Pozzo, 06126 Perugia, Italy. Phone: interna- tional +39.075.5783395. Fax: international +39.075.5722011 or is less commonly associated with the use of 5733642. E-mail: [email protected] LMWHs. haematologica vol. 87(7):july 2002 758 G. Agnelli et al. LMWHs in the prevention of post- 3,400 IU/day are associated with a lower incidence operative venous thromboembolism of bleeding than that associated with LDUFH. General surgery Cancer surgery Without prophylaxis, patients undergoing gener- The incidence of DVT diagnosed by bilateral al surgery have a 19% incidence of venographical- venography in patients undergoing surgery for can- ly-detected DVT. The incidence of proximal DVT (po- cer without prophylaxis is 29%. Patients treated pliteal or more proximal veins) is 6-7%; the inci- with LDUFH have a 13.7% incidence of DVT. Enoxa- dence of clinically overt PE and fatal PE is 1.6 and parin at a dose of 40 mg once daily was compared 0.9%, respectively.1 The most extensively investi- with LDUFH every 8 hours in patients undergoing gated anticoagulants are low doses of UFH (5,000 IU elective abdominal or pelvic surgery for cancer in every 8 or 12 hours) (LDUFH) and LMWHs. A pooled a large, randomized double-blind venography analysis of 29 trials including more than 8,000 study.9 The incidence of DVT was 14.7% in the patients randomized to LDUFH (started 2 hours enoxaparin group and 18.2% in the LDUFH group before surgery) or placebo showed that LDUFH (p=ns). No difference was observed in terms of reduces the incidence of DVT from 25 to 8%. Data bleeding episodes. The results of the ENOXACAN II from a meta-analysis2 and large clinical trials indi- study have been recently published.10 This was a cate that LDUFH also reduces the occurrence of fatal randomized, double-blind, venography study eval- PE.3 LMWHs were compared with LDUFH in a series uating the efficacy and safety of post-discharge of studies and several meta-analyses. Enoxaparin prophylaxis with enoxaparin in cancer surgery was investigated in five trials on the prevention of patients. After an open phase with in-hospital pro- VTE after general surgery. Samama et al. compared phylaxis of enoxaparin (40 mg once daily for a enoxaparin 20, 40 and 60 mg given once daily with week), patients were randomized to 3 weeks of LDUFH every 8 hours.4 DVT was diagnosed by a fib- prophylaxis with enoxaparin (40 mg once daily) or rinogen uptake test (FUT) confirmed by venography. to placebo. Patients underwent bilateral venogra- The incidence of DVT was 3.8, 2.8 and 2.9% in phy at the end of the double-blind period. Pro- patients receiving enoxaparin at doses of 20, 40 and longed prophylaxis with enoxaparin was associat- 60 mg and 7.8, 2.7 and 3.8% in LDUFH patients ed with a significant reduction in the incidence of (p=ns). Dalteparin given at a dose of 2,500 to 5,000 VTE. The incidence of DVT was 4.8% in patients anti-Xa IU once daily showed a similar efficacy and randomized to enoxaparin and 12% in placebo- safety to LDUFH, while the 7,500 anti-Xa IU dose of treated patients. Moreover, the incidence of prox- dalteparin was associated with an increased inci- imal DVT was 0.6 and 1.8%, respectively. No dence of bleeding. Three studies compared nadro- increase in major bleeding was associated with parin (2,850 anti-Xa IU) with LDUFH in the preven- prolonged enoxaparin prophylaxis. tion of VTE in general surgery.5-7 Two studies showed Major orthopedic surgery the superiority of nadroparin over LDUFH.5,6 DVT was Patients undergoing major orthopedic surgery assessed by FUT and confirmed by venography. In (elective total hip replacement, elective total knee the third study the incidence of DVT, assessed by replacement or surgery for hip fracture) have a par- Doppler ultrasound and plethysmography, confirmed ticularly high risk of post-operative VTE. by venography, was low in both treatment groups.7 Patients undergoing total hip replacement (THR) Nadroparin was not associated with an increase in have a high incidence of post-operative VTE despite bleeding. Reviparin sodium was investigated in a prophylaxis. Mechanical methods have a moder- large multicenter trial at a dose of 1,750 anti-Xa ate efficacy, making pharmacologic prophylaxis IU, and showed a similar efficacy to LDUFH every 12 necessary. The use of aspirin is associated with a hours but a lower incidence of bleeding.8 56% incidence of venographic DVT and is not rec- Therefore, LMWHs are at least as effective as ommended for the prevention of VTE in these LDUFH in the prevention of VTE in general surgery patients. LDUFH are not adequately effective in patients. The overall incidence of DVT with LMWHs preventing VTE in THR patients. The most effective is 6%. LMWHs have the advantage of their once anticoagulant regimens in the prevention of VTE daily administration. Bleeding complications are in these patients are adjusted dose UFH11 or oral related to the dose of LMWHs. Indeed, doses of anticoagulants12 and LMWHs. Adjusted dose UFH LMWHs higher than 3,400 anti-Xa IU/day are asso- or oral anticoagulants are both effective but ciated with a higher incidence of bleeding compli- require strict laboratory monitoring. Two meta- cations than LDUFH, whereas doses lower than analyses indicate that LMWHs are more effective haematologica vol. 87(7):july 2002 New perspectives on antithrombotic agents 759 than LDUFH in patients undergoing elective tion of venographic DVT associated with prolonged THR.13,14 Moreover, several randomized trials (3 weeks after discharge) out-of-hospital prophy- showed that LMWHs are at least as safe and effec- laxis with enoxaparin and dalteparin after elective tive as adjusted dose UFH or oral anticoagulants in THR. However, the clinical relevance of an asymp- the prevention of VTE in this setting.15-17 tomatic venographic DVT is not clear. Indeed, data The incidence of venographically-detected DVT in from recently reported overviews indicate that pro- patients undergoing elective total knee replacement longed prophylaxis with LMWHs or LDUFH is asso- (TKR) without prophylaxis is close to 60%; approx- ciated with a significant reduction of symptomatic imately 25% of these DVT are proximal.
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