A method to reduce the dosage of a DTI without compromising effectiveness.
- Lower DTI doses makes reversing much easier.
- Synergistic anticoagulation effects with combination of DTI and FXa inhibitor.
Direct Thrombin Inhibitors (DTIs) are used increasingly in cardiovascular interventions. The anticoagulant activity of DTIs is highly specific to thrombin - no other part of the coagulation pathway is affected.
To date there is no clinically available antidote to reverse DTIs in case of overdose or bleeding complications. Alternative methods to reduce the risk of overdose or bleeding are to combine other agents so that the dose of administered DTI can be decreased.
The inventors discovered the combination of factor Xa (FXa) inhibitor and contact pathway inhibitor augments bivalirudin (Angiomax) anticoagulant effects, thus the therapeutic concentration of the latter can be decreased. Therefore, when a FXa inhibitor, fondaparinux (Arixtra) is combined with bivalirudin, thrombin generation is suppressed better than bivalirudin alone.
Because bivalirudin only blocks thrombin, it requires very high therapeutic levels for coronary interventions and cardiopulmonary bypass. Combining FXa inhibitors and contact pathway inhibitors with any DTI allows complete blockade of thrombin generation cycle. A full anticoagulation comparable to heparin can be achieved without high plasma concentrations of bivalirudin which otherwise can result in profuse bleeding. These methods can be important when heparin anticoagulation is contraindicated or undesirable.
Fondaparinux - Unlike direct factor Xa inhibitors, it mediates its effects indirectly through antithrombin III, but unlike heparin, it is selective for factor Xa. Bivalirudin - Directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Contact pathway inhibitors - Currently none commercially available, but anti-IXa aptamer is in the phase II trials. Aptamers can be reversed with anti-aptamers.
Developmental Stage & Potential Market
- Two million patients treated each year in the US for venous thromboembolism (VTE), the primary end-users of DTIs; many of these patients will be exposed to heparing, which can be associated with heparin-induced thrombocytopenia and thrombosis in 0.3-0.5% of cases.
- All data acquired from human patient samples.