What did we learn from new oral anticoagulant treatment?

Abstract

Orally active direct inhibitors of thrombin and factor Xa have now been approved for treatment or prevention of deep vein thrombosis, and stroke associated with atrial fibrillation. The factor Xa inhibitor, rivaroxaban, has shown promising results in the treatment of acute coronary syndrome but is not yet approved for that indication. These agents share a rapid onset and are cleared with half lives of approximately 10 hours. At present there is no approved antidote for either class of anticoagulant, making the treatment of life-threatening bleeding episodes problematic. These agents have fewer drug interactions than warfarin, have a predictable clearance, and hence do not require monitoring. Patients with renal insufficiency have delayed clearance and hence may have elevated levels of the drug leading to increased risk of bleeding.Keywords direct thrombin inhibitor; direct factor Xa inhibitor; stroke; heart attack; deep vein thrombosis; atrial fibrillation A long term goal in anticoagulant management has been to obtain orally active anticoagulants with predictable pharmacodynamics (thereby avoiding the need for monitoring) whose function was minimally perturbed by diet, antibiotics or common drugs frequently used by the elderly. The advent of the new orally active anticoagulants appears to have addressed many of these issues with comparable or improved safety and efficacy. Areas where these drugs show comparable or superior efficacy and/or safety to warfarin or heparin are in the prevention of deep vein thrombosis following knee or hip replacement and in the prevention of stroke associated with non valvular atrial fibrillation. Areas currently under investigation are the potential use of these agents to prevent stroke and myocardial infarction in patients with acute coronary syndromes. For purposes of this brief review, rivaroxaban (Xarelto ® ), a factor Xa inhibitor, and dabigatran (Pradaxa ® ), a thrombin inhibitor, will be discussed and compared because these two drugs have the most available clinical data (Figure 1). ¶ This work is a summary of a plenary lecture presented at the XXII International Congress on Thrombosis held in Nice, France, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHMI Author Manuscript HHMI Author Manuscript HHMI Author ManuscriptAs the population ages, the need for anticoagulant treatment increases. For chronic treatment with orally active agents, the only available agent has been warfarin or closely related vitamin K antagonists. As the understanding of the structure and function of the coagulation enzymes increased and with the im...

Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor‐induced hypercoagulability in vitro and in vivo

“…It was suggested recently that, owing to the massive release of FV when platelets are involved and the subsequent formation of the prothrombinase complex, there may be too much thrombin produced to be inhibited by a thrombin inhibitor. In contrast, a direct FXa inhibitor inhibits prothrombinase activity and thereby reduces the amount of thrombin . Furthermore, a recent analysis of markers of inflammation using blood samples from a phase II study of the first oral DTI ximelagatran (Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage [ESTEEM]) showed that long‐term treatment with ximelagatran increased the levels of several markers of inflammation .…”

Latent opportunities for the prevention of ischemic stroke in patients with atherosclerosis-related diseases: additional analysis of randomized trials on rivaroxaban

“…Активность такого комплекса уменьшается за счет действия прямых ингибиторов Ха фактора, но на нее не влияют ингибиторы тромбина. За счет эффектов протромбиназы тромбоцитов может образовываться слишком много тромбина, и его концентрация не может существенно изменяться за счет действия ингибиторов тромбина [29,30]. Следовательно, активация тромбоцитов и образование начального протромбиназного комплекса играют важную роль на ранних стадиях образования артериального тромбоза.…”