Apixaban in Atrial Fibrillation

It is hard to imagine a poorer candidate drug than warfarin. It has a narrow therapeutic window, multiple interactions with other drugs, and a multitude of dietary interactions. It has unpredictable dose–response characteristics mandating trial-and-error dose adjustment and requires frequent blood monitoring to achieve therapeutic levels and avoid toxicity. Consequently, many patients are unable or unwilling to be treated with warfarin. Further, those patients that can be treated with warfarin spend just over half the time actually within the therapeutic target range of the drug.1 And yet, for more than 50 years, warfarin and the other vitamin K antagonist derivatives (VKAs) have been the only available oral anticoagulants. Were it not for the extraordinary efficacy of these medications at preventing stroke and other thromboembolic events, such drugs could not possibly have survived in clinical use so long. The discovery of the VKAs has its roots in the environmental degradation of the midwestern United States in the 1920s.2 During the so-called “Dust Bowl” years, depletion of soil nutrients due to poor farming practices led to dramatic changes in local ecosystems. It was soon found that sweet clover could survive in the barren soil, and coincident with the spread of sweet clover came a hemorrhagic disease in cattle. Two veterinarians, Drs Schofield and Roderick, determined that the hemorrhagic disease was due to consumption of moldy sweet clover and that the disease was associated with a reduction in prothrombin activity. The (possibly apocryphal) story of the discovery of the VKAs themselves occurred in 1933, when a farmer in Wisconsin, upset by this hemorrhagic disease killing his cattle, brought a pail of unclotted blood to Dr Karl Link at the University of Wisconsin in Madison. 2 Over the next 8 years, Dr Link was able to isolate and identify the causative agent in sweet clover, and dicumarol, the first VKA, was synthesized and given its name by early 1941. Within several months, investigators at the Mayo Clinic had given dicumarol to 6 patients and published their preliminary results. Probably never again will a compound move from the “bench to bedside” with such speed! Decades later, advances in pharmacogenetics finally identified part of the problem with VKAs. Common variants in genes involved in the metabolism of these drugs dramatically influence an individual’s dose requirement. Despite this important observation, clinical trials have yet to demonstrate that genetic-based dosing algorithms improve time in the therapeutic range or clinical outcomes, and there is substantial doubt as to whether such an approach could be cost-effective.3 Meanwhile, it has taken approximately 70 years for the next generation of oral anticoagulants to emerge from clinical development. However, finally, these new oral anticoagulants are indeed emerging. Within just the past 5 years, several large Phase III trials of new oral anticoagulants in patients with atrial fibrillation have either been completed or are nearing completion, and other agents are in early clinical development. These agents include the oral direct thrombin inhibitor dabigatran (the first agent to achieve regulatory approval in the United States) and the oral factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. The oral direct thrombin inhibitor ximelagatran showed efficacy similar to warfarin in 2 large trials but was abandoned due to liver toxicity. 4,5 The development pathway of these drugs has