Newer Oral Anticoagulants

Abstract

Anticoagulant medications are beneficial for a range of conditions and indications including prevention of stroke and peripheral arterial embolism in patients with atrial fibrillation, prevention of complications from thrombosis of mechanical heart valves, prevention of venous thromboembolism (VTE) in postoperative and immobilized medically ill patients, for individuals with acute coronary syndrome (ACS) and for the treatment of VTE. The first oral anticoagulant medication was approved by the US Food and Drug Administration (FDA) in 1954 and had remained the only available and approved oral agent until October of 2010. Over the decades warfarin has prevented an immeasurable number of potential devastating fatal and nonfatal thrombotic and embolic events with an overall good safety profile. While complications occur, most importantly hemorrhagic, for the vast majority of patients this is a rare occurrence. Despite excellent efficacy and safety, for a number of reasons there has been significant interest in development of new, safe alternatives, which until recently was an elusive goal. The most important drawbacks of warfarin include a delayed onset of action, the need for frequent monitoring with dose adjustments, a plethora of drug–drug and drug–food interactions, and its reputation for being thought of as a “rat poison.” The new oral anticoagulants have the benefit of more predictable pharmacokinetics, a rapid onset of action, no need for routine laboratory monitoring, fixed dosing regimens, and fewer drug–drug and drug–food interactions. By the same token, there may be times when monitoring anticoagulant activity is necessary, which creates a challenge as the new anticoagulants do not all have the same effect on routine laboratory assays most physicians are familiar with. Additionally, there may be circumstances in which rapid reversal of anticoagulant activity is needed, presenting another more significant challenge in the setting of life-threatening bleeding or need for emergent surgery. Three new drugs, Dabigatran, Rivaroxaban, and Apixaban, have been approved by the US FDA for multiple indications beginning in 2010 to the present and there are others in development. They work through direct reversible or irreversible inhibition of either factor IIa or factor X. Their onset of action is rapid, within 1–3 h because they do not rely on inhibiting future coagulation factor production as seen with warfarin. Furthermore, they have relatively short elimination half-lives, ranging from 4 to 17 h in patients with normal renal function, relative to warfarin with an elimination half-life of 20–60 h. These features have both positive and potentially negative implications. On the positive side, the rapid onset of action and the short elimination half-life mean the need for complicated bridging instructions with parental anticoagulants may no longer be necessary. On the negative side, this means that unlike warfarin even a single missed dose can result in subtherapeutic anticoagulant levels with the potential for subsequent thromboembolic complications. Metabolism and elimination are more dependent on renal clearance for the new oral anticoagulants (although apixaban is less dependent on renal mechanisms relative to dabigatran and rivaroxaban) compared with 100 % liver metabolism seen with warfarin (Poulsen et al. Drugs 72:1739–1753, 2012). This underscores the importance of checking renal function prior to prescribing these medications and monitoring for changes in renal function. While there are some notable drug–drug interactions, they are far less when compared to warfarin and there are no drug–food interactions. Table 16.1 summarizes the key features of the newer oral anticoagulants discussed in this chapter.