A Review of the Anti-Blood Clot Medication: Warfarin

In the early 1920s, healthy cattle in the Northern Plains of America began dying of internal bleeding with no obvious cause [2]. Two veterinarians, Schofield and Roderick, identified a correlation, in the mid-to-late 1920s, between moldy sweet clover hay that the cattle were eating and the incidence of bleeding in the herds [2]. Schofield and Roderick discovered that the persistent internal bleeding could be reversed by removing the moldy hay or by giving the affected animals a blood transfusion with fresh blood [2]. Dr. Karl Link, a Professor at the University of Wisconsin, expanded on the veterinarians’ findings by isolating the compound from the moldy sweet clover hay responsible for the internal bleeding in the cattle – 3,3`-methylene-bis[4-hydroxycoumarin] – later named dicoumarol [2]. Dr. Link got the idea to use dicoumarol as a rodenticide, and began synthesizing various compounds from the naturally occurring molecule, until he synthesized a product from the naturally occurring dicoumarol that was active enough to be useful: warfarin (semi-synthetic) [2]. At the discovery and apparent marketability of warfarin as rat poison, The Wisconsin Alumni Research Foundation (organization funding Dr. Karl Link’s research) filed for multiple patents beginning in 1947 relating to the synthesis of warfarin and the molecule itself before it was sent to market in 1948 as rat poison [5, 6]. 

            Warfarin is a vitamin K antagonist (VKA) and anti-coagulant that is used to treat/prevent blood clots in the veins and/or arteries [3].  Warfarin works by inhibiting the subunit 1 of the multi-unit vitamin K epoxide reductase complex (VKORC1). Effectively causing the depletion of functional vitamin K (VK) reserves in the body. This is an effective target for blood clot treatment because the hepatic synthesis of coagulation factors II, VII, IX, X, and proteins C and S all require the presence of functional VK [3, 9]. Warfarin’s mechanism of action essentially halts the body’s ability to form blood clots via depleting a reagent (VK) necessary for the production of the above-named clotting factors, making it very effective as a means to reduce the formation of blood clots, which could otherwise cause heart attack or stroke.   

            Investigation into warfarin as a medication was not immediately investigated, but instead was looked as an option only after a farmer tried to commit suicide by over-dosing on warfarin in 1951 [7]. When the farmer was taken into the emergency room, they treated him with an excess of vitamin K and completely reversed the effects of the warfarin [7]. This made warfarin all-the-more valuable as a possible medication, which is why it was so serendipitous when it was discovered that it could be used as an effective means to treat stroke and other ailments caused by clotting. However, in the early development and usage of warfarin, there was not a reliable method available for dosage control. Laboratories were using commercial reference thromboplastins to control the dosages required for patients based on their prothrombin times (PTs), allowing them to express their results as a prothrombin ratio (PTR) [2]. However, PTR did not solve the dosing problem. If a less responsive commercial thromboplastin was used larger doses of warfarin would be administered to meet the target PTR. This would lead to over-dosages and bleeding in patients. This was something that desperately needed improvement. The researchers later determined that if PTR was obtained from a patient with two different commercial thromboplastin and plotted on a log-log plot against each other that the points would lay on a straight line. From this realization, WHO (World Health Organization) adopted a model to convert PTRs obtained with any commercial thromboplastin to an International Normalized Ratio (INR) [2]. This effectively halted the over-dosages that caused major bleeding in many patients. 

            Despite this critical improvement in the drug, warfarin still has many adverse reactions that need improvement. For example, major and fatal bleeding, even with the improvement of using INR as a means to monitor dosing, is still a major problem [3]. The risk of increased bleeding, and consequent mortality increases even more in patients with atrial fibrillation (AF), and in the elderly [1]. These problems in particular earned warfarin (specifically the brand-name warfarin, Coumadin) box warnings, making doctors, pharmacists, and patients a-like aware of the potential adverse effects of taking the drug [8]. Warfarin dosing requires frequent monitoring of INR during treatment, and has adverse interactions with many over-the-counter and prescribed medications [1,3]. Many of these issues have been improved in the new anti-coagulant drug, Apixaban. Apixaban, in general, was shown to be more effective than warfarin in reducing the rate of major bleeding and mortality across all age groups, and especially in patients with AF [4]. Apixaban was shown to require less coagulation monitoring, have fewer drug interactions, and allows for a lower dose (2.5mg vs 5mg) without losing effectiveness than warfarin [4]. In all, Warfarin is an essential drug for the treatment of blood clots, but it needed critical improvements, which have been satisfied in the new drug, Apixaban.

Commercialization Information 

            With Warfarin’s promising medicinal future, discovered in 1951, Endo Laboratories purchased the rights to manufacture the molecule from the Wisconsin Alumni Research Foundation and got it approved for medical use in 1954 [10]. Endo Laboratories hit the market with Warfarin, sold under the brand-name Coumadin, in 1956 [10]. Around this same time, Endo Laboratories was purchased by DuPont Pharmaceuticals [10]. DuPont lost patent protection in 1962, but despite this they held a virtual monopoly in the oral anticoagulant market with Coumadin for the next 35+ years [10]. Due to the virtual monopoly that DuPont held, they achieved sales exceeding $400-$500 million annually [10]. In the 1980s numerous pharmaceutical companies tried their hand at generic versions of warfarin, though they all failed and are now marked as discontinued in the FDA’s Orange Book[10]. In the 1990s a couple new studies came out of the New England Journal of Medicine indicating that warfarin was effective in preventing strokes in patients suffering from atrial fibrillation, and in reducing heart attack and stroke of those patients that had previously suffered a heart attack or stroke [10, 11]. These reports spurred renewed interest in the oral anticoagulants, which would ultimately draw the interest of Bristol-Myers-Squibb, the present holder of Coumadin. However, at this time of renewed interest three pharmaceutical companies filed with the FDA for generic versions of Warfarin/Coumadin and were approved, Barr (1997), Geneva (1998), and Taro Pharmaceuticals (1999) – and these companies are still producing generic warfarin today [10].

            In 2001, DuPont settled a $44.5m lawsuit over the monopoly that they held in the oral anticoagulant industry and the methods they went about to make that monopoly happen [12]. Specifically, they were sued over unlawful marketing and promotional practices, which claimed that the generic forms of Warfarin were not as effective or as pure as brand-name Coumadin [12]. After the settlement, DuPont Pharmaceuticals was purchased by Bristol-Myer-Squibb for $7.8 billion, who continue to manufacture and sell Coumadin today without any patent protection [13, 14]. 

References

[1] Hull R, et al. Warfarin and other VKAs: Dosing and adverse effects. https://www.uptodate.com/contents/warfarin-and-other-vkas-dosing-and-adverse-effects. Accessed Sep. 18, 2018.

[2] Wardrop D., Keeling D. (2008) The story of the discovery of

           heparin and warfarin. Br J Haematol; 141:757–763.

[3] Warfarin: Drug Information. https://www.uptodate.com/contents/warfarin-drug-information. Accessed Sep. 18, 2018.

[4] Sigrun Halvorsen et al; Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial, European Heart Journal, Volume 35, Issue 28, 21 July 2014, Pages 1864–1872. 

[5] US3077481A. https://patents.google.com/patent. Accessed Oct. 30, 2018.

[6] US2777859A. https://patents.google.com/patent. Accessed Oct. 30, 2018. 

[7] Jeff Guillory. The Story of Coumadin. Southeast Texas Medical Associates, LLP. http://www.setma.com/Your-Life-Your-Health/pdfs. Accessed Oct. 30, 2018.

[8] Coumadin Box Warnings. https://packageinserts.bms.com/medguide. Accessed Oct. 30, 2018. 

[9] Warfarin DB00682. https://www.drugbank.ca/drugs. Accessed Oct. 30, 2018.

[10] Coumadin Chain of Custody. http://www.cisg.law.pace.edu/cases/020510. Accessed Nov. 4, 2018.

[11] Warfarin FDA. https://www.accessdata.fda.gov/drugsatfda_docs. Accessed Oct. 30, 2018.

[12] DuPont Pharma Settles Lawsuit. https://www.icis.com/resources/news/2001/08/06. Accessed Nov. 4, 2018.

[13] Bristol-Myer-Squibb acquires DuPont. https://www.pharmaceuticalonline.com. Accessed Oct. 24, 2018.

[14] Coumadin. https://www.drugpatentwatch.com.Accessed Oct. 30, 2018.