Development of New Anticoagulants: Present and Future Job Harenberg, M.D.1 ABSTRACT Anticoagulant drugs are the most frequently hospital-prescribed compounds in many countries and are used with the intention to prevent and treat venous and arterial thromboembolism. Because of side effects and the necessity of dose adjustment of unfractionated heparins and coumarins, low-molecular-weight heparins, heparinoids, and direct systemically applied thrombin inhibitors were developed. Because of limitations of these anticoagulants, synthetic indirect and direct factor Xa inhibitors and direct thrombin inhibitors were further developed with the aim to improve the benefit/risk ratio for anticoagulant therapy of patients using a simplified mode of action. This overview describes the results of some recent studies of these inhibitors of blood coagulation. KEYWORDS: Thromboembolism, heparin, low-molecular-weight heparin, factor Xa inhibitors, direct thrombin inhibitors, rivaroxaban, apixaban, idraparinux, ximelagatran, dabigatran The treatment of thromboembolic diseases is namics of LMWH.3 He identified the reduced incidence one of the main therapeutic areas in medicine, because of heparin-induced thrombocytopenia as one of the up to 50% of patients with acute deep vein thrombosis main advantages over conventional heparins. He wrote (DVT) will die without anticoagulant treatment within a in 1990: few days. Heparin historically reduced the mortality rate to less than 5%. Unfractionated heparin (UFH) became ‘‘the introduction of LMW heparins has opened the drug of choice in the mid–20th century for this new avenues for the management of patients with indication. Because of the necessity of laboratory mon- thromboembolic diseases. In contrast to regular heparin, itoring by the activated partial thromboplastin time, the mean molecular weights are smaller and represent which had to be prolonged 2 to 3 times the normal about half that of regular heparin. Yet, they are still value, low-molecular-weight heparins (LMWHs) have somewhat heterogeneous and seem to differ from pre- been developed. paration to preparation in some of their biologic proper- Eberhard Mammen identified in the mid–20th ties. No two LMW heparins are alike. In spite of these This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. century the inhibition of coagulation factor 3 through differences, certain commonalities do exist, which may 1 anticoagulants such as heparin. Soon thereafter, he represent an advantage over unfractionated heparin, described the benefit of anticoagulation of blood in especially in their use as a prophylactic antithrombotic 2 hemodialysis patients with heparin. At the beginning modality: 1. LMWHs are at least as effective, if not of the LMWH era, he investigated the pharmacody- more effective, as antithrombotic agents when com- 1Clinical Pharmacology, Faculty of Medicine Mannheim, Ruprecht- A Tribute to Eberhard F. Mammen, M.D. (1930–2008); Guest Editor, Karls University of Heidelberg, Mannheim, Germany. Emmanuel J. Favaloro, Ph.D., M.A.I.M.S. Address for correspondence and reprint requests: Job Harenberg, Semin Thromb Hemost 2008;34:779–793. Copyright # 2008 by M.D., Clinical Pharmacology, Faculty of Medicine Mannheim, Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY Ruprecht-Karls University of Heidelberg, Theodor Kutzer Ufer 1-3, 10001, USA. Tel: +1(212) 584-4662. D-68167 Mannheim, Germany (e-mail: job.harenberg@medma. DOI 10.1055/s-0029-1145260. ISSN 0094-6176. uni-heidelberg.de). 779 780 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 34, NUMBER 8 2008 pared with unfractionated heparin. 2. The rate of Later he focused on the relevance to differentiate absorption from the subcutaneous depots is more com- LMWHs.5 plete, leading to a longer efficacy in vivo. This translates He participated in 2002 in one of the Glycosa- to a once a day injection instead of the twice a day use of minoglycan Symposia held in the Villa Vigoni at unfractionated heparin. 3. There are suggestions that Menaggio situated at Lake Como in northern Italy their use is associated with less bleeding than unfractio- (Figs. 1 and 2). He invited the organizers of the symposia nated heparin, although the final outcome awaits com- to submit manuscripts of the participants for publication pletion of many ongoing clinical trials. LMW heparins in Seminars in Thrombosis and Hemostasis on the occasions are not free of bleeding complications, but hemorrhages of the 3rd, 10th, and 14th Glycosaminoglycan Symposia, seem to occur that are dose dependent. 4. The overall each of these symposia having selected manuscripts incidence of heparin-induced thrombocytopenia seems published 1 year later in 1994,6 2002,7 and 2007.8 to be markedly reduced with LMW heparins. It is still In the preface of the 2002 volume of Seminars in encountered in an occasional patient and may be related Thrombosis and Hemostasis, he described the anticoagulant to the preparation used. There is reason to believe that and non-anticoagulant actions of glycosaminoglycans heparin fractions free of heparin-induced thrombocyto- (GAGs) as topics of the 8th symposium. The most widely penia will be forthcoming. As LMW heparins are used known GAGs are heparins and LMWHs and they are therapeutically, new dosage schemes and new laboratory best known for their anticoagulant properties. Although tests will have to be developed to assure maximum safety the clinical usefulness of heparins cannot be disputed, for the patients’’.4 there are serious side effects associated with their use, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Figure 1 Eberhard Mammen at the 10th Glycosaminoglycan Symposium, September 20, 2002. DEVELOPMENT OF NEW ANTICOAGULANTS/HARENBERG 781 Figure 2 Eberhard Mammen (indicated by an arrow) in the group of participants of the 10th Glycosaminoglycan Symposium, September 20th, 2002. more with UFH than with LMWH. These problems IDRAPARINUX have spurred continuous efforts to develop modifications Idraparinux is a polymethylated derivative of fondapar- of UFH to make compounds safer without compromising inux that binds antithrombin with high affinity, which the desired anticoagulant activities.9 One of Eberhard results in increasing elimination half-life up to 60 days Mammen’s scientific and clinical interests was the im- after a 6-month treatment period. After the first injec- provement of anticoagulant therapy for patients with ven- tion, the elimination half-life was calculated as 1 week, ous and arterial thromboembolic diseases. In these fields, after 12 once-weekly injections as 25 days, and after 24 to he focused his research on laboratory determinations and 56 injections as 60 days. The steady state of idraparinux is early clinical development of new anticoagulants. obtained during chronic once-a-week subcutaneous ad- The unmet clinical need of conventional antico- ministration after 240 to 300 days.16 Idraparinux may not agulants should be overcome by novel synthetic anti- require routine monitoring of anticoagulant intensity coagulants inhibiting specifically only one activated except in patients with renal impairment, in children, or coagulation factor. The main characteristics are rapid in presence of bleeding complications.17 It does not onset and offset of action, lack of need for routine interact with protamine, the antidote for heparin. Thus, monitoring and dose adjustment, lack or infrequent if uncontrolled bleeding occurs, a procoagulant, such as food and drug interactions, and probably better efficacy recombinant factor VIIa, may be beneficial.18 Because of and safety compared with those of the conventional increased bleeding complications in the prolonged pro- anticoagulants. The rapid onset and offset of action phylaxis of venous thromboembolism (VTE) for may avoid switching off and on with subcutaneous 12 months compared with 6 months19,20 and during heparins as is required during anticoagulation with vita- prophylaxis of embolism in patients with atrial fibrilla- min K antagonists.10–12 tion,21 further clinical development of idraparinux was The development of new anticoagulants has stopped. therefore focused on synthetic small molecules to avoid Pharmacokinetic analysis by the S2222 chroma- the side effects or dose adjustment of the conventional genic anti-factor Xa assay and Heptest (Heptest This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. anticoagulants.13 Factor Xa inhibitors act more upstream Laboratories, Inc., St. Louis, MI) showed higher con- in the coagulation cascade compared with thrombin centrations of idraparinux after 12 months than after inhibitors. Small, indirect antithrombin dependent in- 6monthsoftherapy(p < 0.0001). Because of the long hibitors inhibit factor Xa (FXa) in plasma but not factor half-life, idraparinux takes 240 days to reach steady- Xa in the prothrombinase complex or bound to the fibrin state levels. This may explain the higher bleeding rate clot. Small, direct synthetic molecules directed toward during long-term treatment.22,23 FXa and FIIa can neutralize their respective targets whether or not the targets are free in plasma, clot or prothrombinase-bound, an advantage over the indirect BIOTINYLATED IDRAPARINUX inhibitors that require antithrombin to mediate their The elimination of the anticoagulant activity of effect.14,15 The advantage or disadvantage of this differ- the new biotinylated idraparinux by avidin