For over a half a century, the vitamin K antagonists coumarin and warfarin have been the only anticoagulants available to prevent clot formation in a variety of cardiovascular clinical settings. They are now about to be replaced with direct thrombin and factor Xa inhibitors. Vitamin K antagonists have not only dominated anticoagulant therapy, they have created an entire industry within the cardiovascular domain for the monitoring and control of its dose administration.
The story began in 1933 when Karl Paul Link, Ph.D., working in a laboratory at the University of Wisconsin School of Agriculture, was asked to examine the blood of cows dying of hemorrhage thought to be due to the ingestion of spoiled sweet clover. After years of research, Link was able to isolate an anticoagulant from the clover feed, called dicumarol, and he initially patented it in 1941 as rat poison. The marketed drug was called warfarin, after the Wisconsin Agricultural Research Foundation (WARF). Based on that patent, billions of dollars were generated for future research at the WARF.
Warfarin began to be used in the 1950s by a number of clinical investigators to prevent pulmonary embolism in the setting of an acute myocardial infarction (Lancet 1954;266:92-5). At that time, 1 month of complete bed rest was standard therapy for an AMI, and thrombophlebitis together with pulmonary and systemic embolism were the main causes of mortality. When early ambulation became acceptable for AMI patients, warfarin use tapered off. As clinicians became more focused on the prevention of intravascular thrombus formation after prosthetic valve surgery, and to prevent thromboembolism in patients with atrial fibrillation, warfarin therapy became more widely used, and the definition of the therapeutic dose of warfarin became important.
It soon became evident that vitamin K antagonists had a very narrow therapeutic window, framed by excessive bleeding at high doses and inefficacy at lower dose. As a result, the need for closer dose monitoring became important, and this led to the establishment of anticoagulant clinics. However, even with the establishment of these clinics, it became obvious that the clinical status of patients and dietary variability played major roles in dosing. The need for frequent blood sampling and the logistics of dose management were frustrations for both the patient and physician for decades.
As the need for better anticoagulant therapy became evident, drugs were developed that had a wider therapeutic range and that could be administered orally without the need of blood monitoring. The development of direct-acting thrombin and factor Xa inhibitors have led to major advances in anticoagulant therapy, resulting in safer oral fixed-dose drugs with therapeutic efficacy comparable to or better than vitamin K antagonists. In addition, they appear to be free from the effects of dietary variation. The factor Xa inhibitors apixaban and rivaroxaban have been approved by the Food and Drug Administration for the prevention of systemic emboli in patients with atrial fibrillation. Rivaroxaban is also indicated for preventing and treating deep vein thrombosis and pulmonary embolism. The direct thrombin inhibitor dabigatran has also been approved for the prevention of thromboembolism in patients with atrial fibrillation. The only settings for which the new anticoagulants have not been approved are acute coronary syndrome and prevention of thromboembolism with prosthetic valves.
The development of new anticoagulants provides an opportunity to improve therapy and witness the retirement of a ponderous and complicated dosing program that has been inconvenient to both patients and doctors. The retirement of warfarin and the death of the anticoagulant clinic will be appreciated by all.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.