Abstract
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 …
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