Over the next few years, numerous similar chemicals (specifically 4-hydroxycoumarins with a large aromatic substituent at the 3 position) were found to have the same anticoagulant properties. The first drug in the class to be widely commercialized was dicoumarol itself, patented in 1941 and later used as a pharmaceutical. Karl Link continued working on developing more potent coumarin-based anticoagulants for use as rodent poisons, resulting in warfarin in 1948. The name "warfarin" stems from the acronym WARF, for Wisconsin Alumni Research Foundation + the ending "-arin" indicating its link with coumarin. Warfarin was first registered for use as a rodenticide in the US in 1948, and was immediately popular. Although warfarin was developed by Link, the Wisconsin Alumni Research Foundation financially supported the research and was assigned the patent.After an incident in 1951, in which an army inductee attempted suicide with multiple doses of warfarin in rodenticide, but recovered fully after presenting to a naval hospital and being treated with vitamin K (by then known as a specific antidote), studies began in the use of warfarin as a therapeutic anticoagulant. It was found to be generally superior to dicoumarol, and in 1954, was approved for medical use in humans.
Polymorphisms in two genes (VKORC1 and CYP2C9) play a particularly large role in response to warfarin. VKORC1 polymorphisms explain 30% of the dose variation between patients: particular mutations make VKORC1 less susceptible to suppression by warfarin. There are two main haplotypes that explain 25% of variation: low-dose haplotype group (A) and a high-dose haplotype group (B). VKORC1 polymorphisms explain why African Americans are on average relatively resistant to warfarin (higher proportion of group B haplotypes), while Asian Americans are generally more sensitive (higher proportion of group A haplotypes). Group A VKORC1 polymorphisms lead to a more rapid achievement of a therapeutic INR, but also a shorter time to reach an INR over 4, which is associated with bleeding.CYP2C9 polymorphisms explain 10% of the dose variation between patients, mainly among Caucasian patients as these variants are rare in African American and most Asian populations. These CYP2C9 polymorphisms do not influence time to effective INR as opposed toVKORC1, but does shorten the time to INR >4.Despite the promise of pharmacogenomic testing in warfarin dosing, its use in clinical practice is controversial. In August 2009, the Centers for Medicare and Medicaid Services concluded, "the available evidence does not demonstrate that pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness improves health outcomes in Medicare beneficiaries." A 2014 meta-analysis showed that using genotype-based dosing did not confer benefit in terms of time within therapeutic range, excessive anticoagulation (as defined by INR greater than 4), or a reduction in either major bleeding or thromboembolic events.