Warfarin introduced for clinical anticoagulation

Heparin, in clinical use since the 1930s, had to be injected, so it was impractical for long-term treatment of conditions like atrial fibrillation and deep vein thrombosis. Physicians needed a drug patients could take by mouth. The drug that filled that need began with a bleeding disease in cattle that ate spoiled sweet clover hay, first reported in North Dakota and Canada in 1921. In damp hay, mold turned the clover's natural coumarins into an anticoagulant.

Frank Schofield, a veterinary pathologist in Ontario, blamed damaged sweet clover in a 1924 report, and in 1931 Lee Roderick showed that the bleeding came from a lack of prothrombin. Karl Paul Link, a biochemist at the University of Wisconsin, extracted the toxic compound, dicumarol (bishydroxycoumarin), in 1939, and doctors at the Mayo Clinic reported clinical studies of it in 1941. Link's group then made more potent derivatives. The name warfarin joined the initials of the Wisconsin Alumni Research Foundation, which funded the work, to the suffix -arin from coumarin. Warfarin went on sale as a rat poison in 1948. It blocks the liver's vitamin K-dependent production of clotting factors, which made it lethal at high doses but controllable at low ones.

Warfarin was approved for human use in 1954. Doctors in the 1950s gave it after heart attacks, and it became widely known when President Dwight Eisenhower received it after his own in 1955. It was hard to use: the dose that prevented clots was close to the dose that caused bleeding. Drug interactions were extensive, spanning antibiotics, anti-inflammatory agents, and antifungals. Dietary vitamin K from leafy vegetables shifted the dose-response curve. Patients needed regular prothrombin time tests, reported as the INR after a 1983 World Health Organization recommendation, and frequent dose changes.

Warfarin still dominated oral anticoagulation for more than five decades. Trials supported its use in mechanical heart valves, non-valvular atrial fibrillation, and venous thromboembolism. No oral competitor with comparable evidence existed until the direct oral anticoagulants appeared. Dabigatran, a direct thrombin inhibitor, was approved in the United States in 2010; the factor Xa inhibitors rivaroxaban and apixaban followed within two years.

The newer agents offered fixed dosing, fewer drug interactions, and no need for routine monitoring. They displaced warfarin rapidly in atrial fibrillation and venous thromboembolism. Patients with mechanical heart valves are the main exception. A 2013 trial that gave such patients dabigatran or warfarin was stopped early, after 252 had enrolled, because of excess clots and bleeding in the dabigatran group, and warfarin is still their standard anticoagulant.