Development of New Anticoagulants: Present and Future

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

REFERENCES

• 1 Beller F K, Mammen E. Studies on a third plasma factor in thromboplastin formation.  Klin Wochenschr. 1955;  33 155-156
• 2 Nieth H, Mammen E, Gross R. Heparinization of blood in extracorporeal hemodialysis.  Klin Wochenschr. 1958;  36 372-376
• 3 Troy S, Fruncillo R, Ozawa T, Mammen E, Holloway S, Chiang S. The dose proportionality of the pharmacokinetics of ardeparin, a low molecular weight heparin, in healthy volunteers.  J Clin Pharmacol. 1995;  35 1194-1199
• 4 Mammen E F. Why low molecular weight heparin?.  Semin Thromb Hemost. 1990;  16(Suppl) 1-4
• 5 Mammen E F, Arcelus J, Messmore H, Altman R, Nurmohamed M, Eldor A. Clinical differentiation of low molecular weight heparins.  Semin Thromb Hemost. 1999;  25(Suppl 3) 135-144
• 6 Harenberg J, Casu B. Glycosaminoglycans I.  Semin Thromb Hemost. 1994;  20 133-222
• 7 Harenberg J, Casu B. Glycosaminoglycans: anticoagulant and nonanticoagulant actions.  Semin Thromb Hemost. 2002;  28 325-402
• 8 Harenberg J, Casu B. New anticoagulants.  Semin Thromb Hemost. 2007;  33 449-562
• 9 Mammen E F. Preface. Glycosaminoglycans: anticoagulant and nonanticoagulant actions.  Semin Thromb Hemost. 2002;  28 323-324
• 10 Bates S M, Weitz J I. The status of new anticoagulants.  Br J Haematol. 2006;  134 3-19
• 11 Hirsh J, O'Donnell M, Eikelboom J W. Beyond unfractionated heparin and warfarin: current and future advances.  Circulation. 2007;  116 552-560
• 12 Eikelboom J W, Weitz J I. A replacement for warfarin. The search continues.  Circulation. 2007;  116 131-133
• 13 Saiah E, Soares C. Small molecule coagulation cascade inhibitors in the clinic.  Curr Top Med Chem. 2005;  5 1677-1695
• 14 Bauer K A. New anticoagulants.  Hematology (Am Soc Hematol Educ Program). 2006;  450-456
• 15 Turpie A GG. Oral, direct factor Xa Inhibitors in development for the prevention and treatment of thromboembolic diseases.  Arterioscler Thromb Vasc Biol. 2007;  27 1238-1247
• 16 Ma Q, Fareed J. Idraparinux sodium. Sanofi-Aventis.  IDrugs. 2004;  7 1028-1034
• 17 Herbert J M, Herault J P, Bernat A et al.. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting pentasaccharide.  Blood. 1998;  91 4197-4205
• 18 Bijsterveld N R, Vink R, Van Arken B E et al.. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers.  Br J Haematol. 2004;  124 653-658
• 19 The van Gogh Investigators . Idraparinux versus standard therapy for venous thromboembolic disease.  N Engl J Med. 2007;  357 1094-1104
• 20 The van Gogh Investigators . Extended prophylaxis of venous thromboembolism with idraparinux.  N Engl J Med. 2007;  357 1105-1112
• 21 Bousser M G, Bouthier J, Bü;ller H R Amadeus Investigators et al.. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial.  Lancet. 2008;  371 315-321
• 22 Harenberg J, Joerg I, Vukojevic Y, Weiss C, Mikus G. Anticoagulant effects of idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials.  Eur J Clin Pharmacol. 2008;  64 555-563
• 23 Harenberg J, Weiss C, Mikus G, Joerg I, Vukojevic Y. Long elimination half life of idraparinux after termination of therapy explains bleeding in the van Gogh trials.  J Thromb Haemost. 2008;  6 890-892
• 24 Savi P, Herault J P, Duchaussoy P et al.. Reversible biotinylated oligosaccharides, a new approch for a better management of the anticoagulant therapy.  J Thromb Haemost. 2008;  6 1697-1706
• 25 Lassen M R, Dahl O E, Mismetti P, Destrèe D. AV5026, a new anticoagulant for prevention of venous thromboembolism in total knee replacement surgery – TREK: a dose ranging study.  Blood. 2007;  110 , Abstract 311
• 26 Paccaly A, Frick A, Rohatagi S et al.. Pharmacokinetics of otamixaban, a direct factor Xa inhibitor, in healthy male subjects: pharmacokinetic model development for phase 2/3 simulation of exposure.  J Clin Pharmacol. 2006;  46 37-44
• 27 Cohen M, Deepak L, Bhatt D L on behalf of the SEPIA-PCI Trial Investigators et al. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI Trial.  Circulation. 2007;  115 2642-2651
• 28 Rezaie A R. DX-9065a inhibition of factor Xa and the prothrombinase complex: mechanism of inhibition and comparison with therapeutic heparins.  Thromb Haemost. 2003;  89 112-121
• 29 Alexander J H, Yang H, Becker R C on behalf of the XANADU-ACS Investigators et al. First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XANADU-ACS trial.  J Thromb Haemost. 2005;  3 439-447
• 30 Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases.  Expert Opin Investig Drugs. 2006;  15 843-855
• 31 Eriksson B I, Lars C, Borris L C for the ODIXa-HIP Study Investigators et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59–7939), for thromboprophylaxis after total hip replacement.  Circulation. 2006;  114 2374-2381
• 32 Lassen M R, Ageno W, Borris L C et al. for the RECORDS 3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.  N Engl J Med. 2008;  358 2276-2286
• 33 Kakkar A K, Brenner B, Dahl O E et al.. Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with enoxaparin after total hip arthroplasty: the RECORD2.  Blood. 2007;  110 , Abstract 307
• 34 Eriksson B I, Borris L C, Friedman R J et al.. for the RECORD 1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after total hip arthroplasty: The RECORD1.  N Engl J Med. 2008;  358 2765-2775
• 35 Mueck W, Agnelli G, Buller H. Rivaroxaban has predictable pharmacokinetics (PK) and pharmacodynamics (PD) when given once or twice daily for the treatment of acute, proximal deep vein thrombosis (DVT).  Blood. 2007;  110 Abstract 1880
• 36 Agnelli G, Gallus A, Goldhaber S Z for the ODIXa-DVT Study Investigators et al. Treatment of proximal deep-vein thrombosis with the oral direct Factor Xa inhibitor rivaroxaban (BAY 59–7939) The ODIXa-DVT Study.  Circulation. 2007;  116 180-187
• 37 Buller H R, Lensing A W, Prins M H et al.. Einstein-DVT Dose-Ranging Study investigators. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.  Blood. 2008;  112 2242-2247
• 38 Pinto D J, Orwat M J, Koch S et al.. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.  J Med Chem. 2007;  50 5339-5356
• 39 Lassen M R, Davidson B L, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.  J Thromb Haemost. 2007;  5 2368-2375
• 40 Buller H, Deitchman D, Prins M, Segers A. Botticelli Investigators . Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.  J Thromb Haemost. 2008;  6 1313-1318
• 41 Iwatsuki Y, Shigenaga T, Moritani Y et al.. Biochemical and pharmacological profiles of YM150, an oral direct factor Xa inhibitor.  Blood. 2006;  108 , Abstract 911
• 42 Eriksson B I, Turpie A GG, Lassen M L on behalf of The Onyx Study Group et al. A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery.  J Thromb Haemost. 2007;  5 1660-1665
• 43 Eriksson B I, Turpie A GG, Lassen M R et al.. Once daily YM150, an oral direct factor Xa inhibitor, for prevention of venous thromboembolism in patients undergoing elective primary hip relpacement.  Blood. 2007;  110 , Abstract 309
• 44 Eriksson B I, Quinlan D J. Oral anticoagulants in development: focus on thromboprophylaxis in patients undergoing orthopaedic surgery.  Drugs. 2006;  66 1411-1429
• 45 Agnelli G, Haas S K, Krueger K A. et al. A phase II study of the safety and efficacy of a novel oral FXa inhibitor (LY517717) for the prevention of venous thromboembolism following TKR or THR.  J Thromb Haemost. 2007;  5 746-753
• 46 Abe K, Siu G, Edwards S et al.. Animal models of thrombosis help predict the human therapeutic concentration of PRT54021, a potent oral factor Xa inhibitor.  Blood. 2006;  108 , Abstract 901
• 47 Linkins L A, Weitz J I. Pharmacology and clinical potential of direct thrombin inhibitors.  Curr Pharm Des. 2005;  11 3877-3884
• 48 Weitz J I. Factor Xa or thrombin: is thrombin a better target?.  J Thromb Haemost. 2007;  5(Suppl 1) 65-67
• 49 Weitz J I, Buller H R. Direct thrombin inhibitors in acute coronary syndromes: present and future.  Circulation. 2002;  105 1004-1011
• 50 Gustafsson D, Nystrom J, Carlsson S et al.. The direct thrombin inhibitor melagatran and its oral prodrug H376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.  Thromb Res. 2001;  101 171-181
• 51 Harenberg J, Jörg I, Weiss C. Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran.  Eur J Clin Pharmacol. 2006;  62 173-177
• 52 Gurewich V. Ximelagatran—promises and concerns.  JAMA. 2005;  293 736-739
• 53 Harenberg J, Jörg I, Weiss C. Observations of alanine aminotransferase and aspartate aminotransferase in THRIVE studies treated orally with ximelagatran.  Int J Toxicol. 2006;  25 165-169
• 54 Lee W M, Larrey D, Olsson R et al.. Hepatic findings in long-term clinical trials of ximelagatran.  Drug Saf. 2005;  28 351-370
• 55 Stangier J, Rathgen K, Staehle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects.  Br J Clin Pharmacol. 2007;  64 292-303
• 56 Eriksson B I, Dahl O E, Buller H R et al.. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.  J Thromb Haemost. 2005;  3 103-111
• 57 Ezekowitz M D, Reilly P A, Nehmiz G et al.. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study).  Am J Cardiol. 2007;  100 1419-1426