Skip to main content
Top
Published in: Journal of Thrombosis and Thrombolysis 1/2008

01-02-2008

New oral Xa and IIa inhibitors: updates on clinical trial results

Author: Sylvia Haas

Published in: Journal of Thrombosis and Thrombolysis | Issue 1/2008

Login to get access

Abstract

Heparins and VKAs have been the cornerstones of anticoagulation therapy for several decades and these agents have become most important drugs in the primary and secondary prevention of venous and arterial thromboembolic disease. Although effective, their use has been hampered by numerous limitations. In the search for new agents matching the ‘ideal’ anticoagulant profile, a number of different steps in the coagulation cascade have been targeted, including direct thrombin inhibition, and direct inhibition of Factor Xa. There are currently a host of promising new agents at various stages of development and clinical evaluation. With potential benefits including predictable efficacy, rapid onset of action, ability to bind clot-bound coagulation factors and no requirement for therapeutic monitoring, these new agents are set to improve the management of thromboembolic disorders.
Literature
1.
go back to reference Geerts WH, Pineo GF, Heit JA et al (2004) Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):338S–400SPubMedCrossRef Geerts WH, Pineo GF, Heit JA et al (2004) Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):338S–400SPubMedCrossRef
2.
go back to reference Buller HR, Agnelli G, Hull RD et al (2004) Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):401S–428SPubMedCrossRef Buller HR, Agnelli G, Hull RD et al (2004) Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):401S–428SPubMedCrossRef
3.
go back to reference Ansell J, Hirsh J, Dalen J et al (2001) Managing oral anticoagulant therapy. Chest 119(1 Suppl):22S–38SPubMedCrossRef Ansell J, Hirsh J, Dalen J et al (2001) Managing oral anticoagulant therapy. Chest 119(1 Suppl):22S–38SPubMedCrossRef
4.
go back to reference Hart RG, Benavente O, McBride R et al (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 131(7):492–501PubMed Hart RG, Benavente O, McBride R et al (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 131(7):492–501PubMed
5.
go back to reference Haas S (2003) Medical indications and considerations for future clinical decision making. Thromb Res 109(Suppl 1):S31–S37PubMedCrossRef Haas S (2003) Medical indications and considerations for future clinical decision making. Thromb Res 109(Suppl 1):S31–S37PubMedCrossRef
6.
go back to reference Hirsh J, Raschke R (2004) Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):188S–203SPubMedCrossRef Hirsh J, Raschke R (2004) Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126(3 Suppl):188S–203SPubMedCrossRef
7.
go back to reference Weitz JI, Hudoba M, Massel D et al (1990) Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 86(2):385–391PubMedCrossRef Weitz JI, Hudoba M, Massel D et al (1990) Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 86(2):385–391PubMedCrossRef
8.
go back to reference Di Nisio M, Middeldorp S, Buller HR (2005) Direct thrombin inhibitors. N Engl J Med 353(10):1028–1040PubMedCrossRef Di Nisio M, Middeldorp S, Buller HR (2005) Direct thrombin inhibitors. N Engl J Med 353(10):1028–1040PubMedCrossRef
9.
go back to reference Stangier J, Rathgen K, Stahle H et al (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64(3):292–303PubMedCrossRef Stangier J, Rathgen K, Stahle H et al (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64(3):292–303PubMedCrossRef
10.
go back to reference Wienen W, Stassen JM, Priepke H et al (2007) Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis. J Thromb Haemost 5(6):1237–1242PubMedCrossRef Wienen W, Stassen JM, Priepke H et al (2007) Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis. J Thromb Haemost 5(6):1237–1242PubMedCrossRef
11.
go back to reference Eriksson BI, Dahl OE, Buller HR et al (2005) 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 3(1):103–111PubMedCrossRef Eriksson BI, Dahl OE, Buller HR et al (2005) 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 3(1):103–111PubMedCrossRef
12.
go back to reference Eriksson BI, Dahl OE, van Dijk CN et al (2006) A new oral anticoagulant, dabigatran etexilate, is effective and safe in preventing venous thromboembolism after total knee replacement surgery (The RE-MODEL Trial). Blood 108:Abstr. 573 Eriksson BI, Dahl OE, van Dijk CN et al (2006) A new oral anticoagulant, dabigatran etexilate, is effective and safe in preventing venous thromboembolism after total knee replacement surgery (The RE-MODEL Trial). Blood 108:Abstr. 573
13.
go back to reference Wallentin LC, Ezekowith M, Simmers TA et al (2005) Safety and efficacy of a new oral direct thrombin inhibitor dabigatran in atrial fibrillation—a dose finding trial with comparison to warfarin. Eur Soc Cardiol Cong (abstr):P2949 Wallentin LC, Ezekowith M, Simmers TA et al (2005) Safety and efficacy of a new oral direct thrombin inhibitor dabigatran in atrial fibrillation—a dose finding trial with comparison to warfarin. Eur Soc Cardiol Cong (abstr):P2949
14.
go back to reference Bauer KA (2006) New anticoagulants. Hematology/the Education Program of the American Society of Hematology. American Society of Hematology, pp 450–456 Bauer KA (2006) New anticoagulants. Hematology/the Education Program of the American Society of Hematology. American Society of Hematology, pp 450–456
15.
go back to reference Alexander JH, Yang H, Becker RC et al (2005) 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 3(3):439–447PubMedCrossRef Alexander JH, Yang H, Becker RC et al (2005) 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 3(3):439–447PubMedCrossRef
16.
go back to reference Paccaly A, Frick A, Rohatagi S et al (2006) 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 46(1):37–44PubMedCrossRef Paccaly A, Frick A, Rohatagi S et al (2006) 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 46(1):37–44PubMedCrossRef
17.
go back to reference Paccaly A, Ozoux ML, Chu V et al (2005) Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor. Thromb Haemost 94(6):1156–1163PubMed Paccaly A, Ozoux ML, Chu V et al (2005) Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor. Thromb Haemost 94(6):1156–1163PubMed
18.
go back to reference Hinder M, Paccaly A, Frick A et al (2005) Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, with tirofiban in healthy volunteers. Thromb Haemost 93(4):794–795PubMed Hinder M, Paccaly A, Frick A et al (2005) Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, with tirofiban in healthy volunteers. Thromb Haemost 93(4):794–795PubMed
19.
go back to reference Hinder M, Frick A, Rosenburg R et al (2006) Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid. Thromb Haemost 95(2):224–228PubMed Hinder M, Frick A, Rosenburg R et al (2006) Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid. Thromb Haemost 95(2):224–228PubMed
20.
go back to reference Perzborn E, Strassburger J, Wilmen A et al (2005) In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 3(3):514–521PubMedCrossRef Perzborn E, Strassburger J, Wilmen A et al (2005) In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 3(3):514–521PubMedCrossRef
21.
go back to reference Kubitza D, Becka M, Wensing G et al (2005) Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 61(12):873–880PubMedCrossRef Kubitza D, Becka M, Wensing G et al (2005) Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 61(12):873–880PubMedCrossRef
22.
go back to reference Kubitza D, Haas S (2006) Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs 15(8):843–855PubMedCrossRef Kubitza D, Haas S (2006) Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs 15(8):843–855PubMedCrossRef
23.
go back to reference Eriksson BI, Borris L, Dahl OE et al (2006) Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 4(1):121–128PubMedCrossRef Eriksson BI, Borris L, Dahl OE et al (2006) Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 4(1):121–128PubMedCrossRef
24.
go back to reference Turpie AG, Fisher WD, Bauer KA et al (2005) BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 3(11):2479–2486PubMedCrossRef Turpie AG, Fisher WD, Bauer KA et al (2005) BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 3(11):2479–2486PubMedCrossRef
25.
go back to reference Eriksson BI, Borris LC, Dahl OE et al (2006) A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 114(22):2374–2381PubMedCrossRef Eriksson BI, Borris LC, Dahl OE et al (2006) A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 114(22):2374–2381PubMedCrossRef
26.
go back to reference Fisher WD, Eriksson BI, Bauer KA et al (2007) Rivaroxaban for thromboprophylaxis after orthopedic surgery: pooled analysis of two studies. Thromb Haemost 97(6):931–937PubMed Fisher WD, Eriksson BI, Bauer KA et al (2007) Rivaroxaban for thromboprophylaxis after orthopedic surgery: pooled analysis of two studies. Thromb Haemost 97(6):931–937PubMed
27.
go back to reference Weitz JI (2006) Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 96(3):274–284PubMed Weitz JI (2006) Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 96(3):274–284PubMed
28.
go back to reference Lassen MR, Davidson BL, Gallus A et al (2006) A phase II randomized, double-blind, eight-arm, parallel-group, dose–response study of Apixaban, a new oral factor Xa inhibitor for the prevention of deep vein thrombosis in knee replacement surgery—on behalf of the Apixaban Investigators. Blood 108:Abst. 574 Lassen MR, Davidson BL, Gallus A et al (2006) A phase II randomized, double-blind, eight-arm, parallel-group, dose–response study of Apixaban, a new oral factor Xa inhibitor for the prevention of deep vein thrombosis in knee replacement surgery—on behalf of the Apixaban Investigators. Blood 108:Abst. 574
29.
go back to reference Agnelli G, Haas S, Ginsberg JS et al (2007) A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 5(4):746–753PubMedCrossRef Agnelli G, Haas S, Ginsberg JS et al (2007) A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J Thromb Haemost 5(4):746–753PubMedCrossRef
30.
go back to reference Eriksson BI, Turpie AG, Lassen MR et al (2005) YM150, an oral direct factor Xa inhibitor, as prophylaxis for venous thromboembolism in patients with elective primary hip replacement surgery. A dose escalation study. Blood 106:Abstr. 1865 Eriksson BI, Turpie AG, Lassen MR et al (2005) YM150, an oral direct factor Xa inhibitor, as prophylaxis for venous thromboembolism in patients with elective primary hip replacement surgery. A dose escalation study. Blood 106:Abstr. 1865
31.
go back to reference Morishima Y, Furugohri T, Isobe K et al (2004) In vitro characteristics, anticoagulant effects and in vivo antithrombotic efficacy of a novel, potent and orally active direct factor Xa inhibitor, DU-176b. Blood 104(11):Abstr. 1862 Morishima Y, Furugohri T, Isobe K et al (2004) In vitro characteristics, anticoagulant effects and in vivo antithrombotic efficacy of a novel, potent and orally active direct factor Xa inhibitor, DU-176b. Blood 104(11):Abstr. 1862
32.
go back to reference Zafar MU, Gaztanga J, Velez M et al (2006) A phase-I study to assess the antithrombotic properties of Du-176b: an orally active direct factor-Xa inhibitor. J Am Coll Cardiol 47:Abstr. 288A Zafar MU, Gaztanga J, Velez M et al (2006) A phase-I study to assess the antithrombotic properties of Du-176b: an orally active direct factor-Xa inhibitor. J Am Coll Cardiol 47:Abstr. 288A
Metadata
Title
New oral Xa and IIa inhibitors: updates on clinical trial results
Author
Sylvia Haas
Publication date
01-02-2008
Publisher
Springer US
Published in
Journal of Thrombosis and Thrombolysis / Issue 1/2008
Print ISSN: 0929-5305
Electronic ISSN: 1573-742X
DOI
https://doi.org/10.1007/s11239-007-0108-7

Other articles of this Issue 1/2008

Journal of Thrombosis and Thrombolysis 1/2008 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.