The old and new: PCCs, VIIa, and long-lasting clotting factors for hemophilia and other bleeding disorders.

What is the correct use of established clotting factors, prothrombin complex concentrates (PCCs), and activated factor VII in bleeding complications of trauma, surgery, and old and new oral anticoagulants? How will new clotting factors, specifically the long-acting factors, change the hemostatic management of coagulation deficiency disorders? From bench to bedside, comparative coagulation studies and clinical trials of modified clotting factors are providing insights to help guide hemostatic management of congenital and acquired bleeding disorders. Comparative thrombin-generation studies and preclinical and clinical trials suggest that PCCs and fresh-frozen plasma are effective in reversing the anticoagulant effects of warfarin, yet there are few data to guide reversal of the new oral anticoagulants dabigatran and rivaroxaban. Although coagulation studies support the use of PCCs to reverse new oral anticoagulants, correlation with clinical response is variable and clinical trials in bleeding patients are needed. For congenital bleeding disorders, exciting new technologies are emerging from the bench. Data from clinical trials of molecularly modified coagulation factors with extended half-lives suggest the possibility of fewer infusions, reduced bleeds, and better quality of life in persons with hemophilia. Preclinical studies of other novel prohemostatic approaches for hemophilia and other congenital coagulation disorders include RNA interference silencing of antithrombin, monoclonal anti-tissue factor pathway inhibitor (anti-antibody, anti-tissue factor pathway inhibitor) aptamer, bispecific anti-IXa/X antibody, and fucoidans. Understanding the comparative coagulation studies of established prohemostatic agents, the pharmacokinetics of new long-acting clotting factors, and their correlation with bleeding outcomes will provide opportunities to optimize the hemostatic management of both congenital and acquired hemostatic disorders.

The new oral anticoagulants: a challenge for hospital formularies.

Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.

Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban.

INTRODUCTION: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF. AREAS COVERED: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug. EXPERT OPINION: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.