WARFARIN: PAST, PRESENT, and FUTURE


ABSTRACT:
After being initially isolated from decomposing sweet clover hay in the early 1920s, warfarin compounds have become the most widely used anti-coagulation medication prescribed. By inhibiting the carboxylation of vitamin K-dependant protein in blood clotting mechanisms, warfarin can greatly down-regulate clotting factors in blood, allowing physicians to prevent a variety of chronic blood conditions in patients. Among these are arial fibrillation, valve replacements, and thrombosis. Dosing of warfarin depends on the regimen chosen by the physician, based on the patient’s age, weight, and specific condition, and is usually combined with an initial, small dosing of heparin to jumpstart the therapeutic process. Warfarin has very few life-threatening interactions, and the most common complications arising from warfarin use are incorrect self-dosing by outpatients. Because of the cost to develop and prove a drug’s efficacy, competition in the anticoagulant market has been nonexistent until recently. New drugs currently in development may eventually subvert warfarin as most common anticoagulant, but for now, warfarin remains a mainstay of clinical protocol.

INTRODUCTION:
Warfarin is an anticoagulant that inhibits the formation of coagulation factors in the blood that are dependant on vitamin K (1). It has been in clinical use since the mid-1950s, and has become the most prescribed anti-coagulant medication in the world. In the UK alone, it is estimated that 8% of the population over eighty are regularly taking warfarin (2). It’s widespread use is also partly responsible for emergency room visits resulting from incorrect self-administration, most commonly in elderly patients. Warfarin is commonly prescribed to manage maladies ranging from atrial fibrillation to controlling clots in patient’s with prosthetic heart valves. Although originally marketed as a rodent pesticide, the stability that made warfarin a good pesticide also readily allows for oral administration, without the latent period common with heparins or coumarins that are intravenously administered (2).

HISTORY AND DEVELOPMENT:
In the early 1920s, healthy cattle grazing on wet sweet clover hay in Canada and the northern United States began dying with no apparent cause. As livestock was a pivotal industry, and the Great Depression had economically stretched North America, two veterinary surgeons, Schofield and Roderick investigated, and concluded that 'sweet clover disease' was a coagulation disorder caused by plasma prothrombin defect, which was reversible if blood were transfused into the bleeding cattle (2). One exasperated Wisconsin farmer named Ed Carlson, brought his dying cow 200 miles through a blizzard to an agricultural experiment station, where he took a can of the dying animal's blood to Karl Link and Wilhelm Schoeffel, the resident researchers. Link and Schoeffel began isolating the active component responsible for sweet clover disease from the plant itself, as only the source of the disease was known at that time. Using an in vitro clotting assay and 6 years of work, 3,3′-methylene-bis[4-hyfroxycoumarin] was crystallized (2). Link and Schoeffel observed that, in the moldy hay, the coumarin was oxidized, causing the clotting disorder upon ingestion. The Wisconsin Alumni Research Foundation (WARF) provided funding for the work, resulting in large-scale isolation finally accomplished by Mark Stahmann. In 1945, Karl Link had the idea of using oxidized coumarin as rat poison, and the 42nd variant became known as warfarin, after the alumni foundation. Three years later, Link’s vision paid off and warfarin became commercially available as a pesticide.
The transition of warfarin from rodentcide to clinical applications was made under the name coumadin, and because it was administered orally, coumarin was a more viable option than heparin-based anti-coagulants. The most important difference between heparin and coumadin, however, was the ability to reverse coumarin's effects with vitamin K (2). Coumarin garnered considerable publicity when President Eisenhower suffered a heart attack, and coumarin was administered to treat the clotting. The success of its use prompted wider clinical usage. After it’s success treating the President, promoters claimed, “what was good for a war hero and the President of the United States must be good for all, despite being a rat poison” (2). As its popularity soared, dosage control of warfarin became a problem. The measure of clotting time, known as the prothrombin time, varied greatly depending on the sensitivity of the thrombroplasins used to measure the prothrombin time of warfarin (2). Different sensitivities in the UK and US versions prompted the World Health Organization to create an international standard for anticoagulant control. In 1960, the first randomized clinical trials for warfarin were performed on patients with pulmonary embolisms between heparin and a control, than heparin and acencoumorol (2). Heparin with acencoumorol resulted in none of the 60 patients extending their condition. No matter which combination was administered, patients who received the proper dosage within the first 24 hours saw an almost 10-fold decrease in recurrence rate (2). Differences in practice between the US and UK dosage practices resulted in controversy that was not resolved until the W.H.O. stepped in and standardized the procedure.

MECHANISM AND SYNTHESIS:
Vitamin_K_cycle.gif
Warfarin’s anticoagulant properties are a result of warfarin’s interference with the cyclic conversion of vitamin K and it’s epoxide. By interfering with the vitamin K conversion (shown at right), the coagulation factors remain partially decarboxylated, reducing the coagulant activity (7). When the coagulation factors are sufficiently carboxylated, they promote vitamin K-dependant proteins to bind to phospholipid surfaces, increasing coagulation (7). In order to be carboxylated, the vitamin K-dependant proteins require the reduced form of vitamin K, KH2. Warfarin inhibits the enzyme responsible for reducing vitamin K, creatively named vitamin K epoxide reductase (7).
Synthesis of wafarin begins with ethyl carbonate reacting with ortho-hydroxyacetophenone (1–2), as shown below. Following that, the cyclization of the compound is accomplished by the phenoxide attacking the ester group, and creating the coumarin form of the product. In order to become warfarin, an additional reaction is required between methyl styryl ketone and the anion of the coumarin product (12). The mechanism for the conversion from coumarin to warfarin is known as the Michael Addition. The Michael Addition is a conjugate addition of a nucleophilic carbanion with an unsaturated alpha, beta carbonyl compound with an R-group (16). For warfarin, the R-group is the phenyl group on the ketone added to the coumarin product.
external image 800px-Warfarin_Rx.png

CURRENT CLINICAL PRACTICES:
From 1998 to 2004, a 45% increase in Coumarin or generic warfarin prescribed to patients was observed (6). This corresponds to a jump from 21.1 million to over 30 million patients. Because of it’s stability and predictability in patients, prescriptions of warfarin can be administered by patients in their home, rather than intravenously under close supervision. Depending on the type of treatment required, either urgent or routine, different dosage algorithms have developed to treat patients.
The Kovacs regimen was designed to optimize the time it takes to bring a patient’s international normalized ratio (INR) for clotting into therapeutic ranges. The reasoning behind the optimization of Kovacs regimen was to reduce the cost of treating patients with heparins, as well as to shorten the period of time patients were required to take heparins, which must be administered under close supervision in a hospital setting. The Kovacs regimen also lowers the number of times a patient’s INR needs to be rechecked, as previous regimens required daily INR measurement to adjust the dosages. The Kovacs regimen begins with two days of 10 mg dosages of warfarin, followed by variable dosages on the third day, depending on the patient’s INR (20). Heparin is also administered for the first 5 days at 200 micrograms per kilogram of body weight (20). Five days following the start of treatment, 83% of patients on the Kovacs regimen had reached a therapeutic INR, compared against only 46% of patients who began their treatment on just 5 mg of warfarin (20).
For patients with no chronic risk factors, the Fennerty regimen treats patient for four weeks with low dosages of warfarin following an initial three-day dosage of heparins to initially control a patient’s venous thromboembolic disease (19). The heparin treatment stabilizes the patient’s INR within acceptable ranges, and the continued administration of warfarin is designed to regulate the INR until the patient’s natural anti-coagulation factors can resume their normal duties. Patient’s with a single recurrence are placed on warfarin for a period of three months, and patient’s who have a history of thromboembolic episodes may be prescribed warfarin for longer durations, potentially for the rest of the patient’s life (19).
In studies of elderly female patients with atrial fibrillation, it was observed that the patients required a smaller initiation dose of warfarin (18). To treat these patients especially, the Tait regimen was designed with an initial dosage of 5mg, rather than the 10 mg that is standard on both the Kovacs and Fennerty regimens (18). The Tait regimen was designed to optimize the thereaputic time for elderly patients treated on an outpatient basis, rather than a more costly and distressing inpatient treatment. In studies focusing on the first 21 days of treatment, patients treated on the Tait regimen experienced a lower maximum INR, with a more accurate prediction of the maintenance dosage (18). By lowering the initial dose, the Tait regimen offers several advantages for patients and physicians. First and foremost, on the Tait regimen, elderly patients with no other hospital-worthy conditions can be treated on an outpatient basis. The lower initiation dosages led to lower incidence of hemorrhagic complications associated with a high INR in elderly patients. For physicians, if elective procedures are necessary, the Tait regimen provides a less aggressive, and therefore safer, treatment of patients post-op.

ADVERSE REACTIONS:
When taken in the proper amounts, warfarin poses little to no danger to patients. However, it can still cause adverse reactions when taken in incorrect dosages, or coincidentally with certain drugs. According to a study of emergency room visits caused by adverse drug reactions, warfarin came second only to insulin as the cause of ER visits, and was responsible for all 23 anti-coagulant visits in a 13,004 visit sample (3). Of those 23 patients, one died of retroperitoneal hemorrhage; bleeding into the abdominal cavity near the kidneys (4). Like many drugs, when taken in too large a dose, warfarin ceases to be a therapeutic agent, and becomes toxic to the system, as the drug once did to rodents. Fatal bleeding from warfarin overdose is uncommon however, with an incidence rate ranging from 0-2.9% of all patient’s prescribed (6). In a different study, conducted by Wysowski et al., of 9,766 cases of warfarin-related bleeding in America from 1993 to July of 2006, only 999, or 10%, of bleeds were fatal. As a result of the Wysowski study, a warning about the bleeding risks of warfarin was added to the US boxes of the drug (6).
Warfarin, when taken with other drugs that have the potential to cause bleeding, becomes far more dangerous. Acetaminophen, commonly sold as Tylenol, is commonly prescribed for patients also taking warfarin, as the acetaminophen does not increase the incidence of gastrointestinal bleeding. In a study of 62 patients taking oral anti-coagulation medication, like warfarin, the patients were given 650mg of acetaminophen four times a day over the course of 4 weeks. The prothrombin time of 12 patients increased 5.3 seconds, corresponding to an international normalized ratio increase of 1-1.5 units (7). The other patients in the study had a prothombin time increase of 3.6 seconds. The study, conducted by Gebauer et al. concluded that, although there was a correlation, healthy volunteers showed that the combination of warfarin and acetaminophen under 2g/day is not significant (7). Acetaminophen dosages over 2g/day, however, when given to patients already receiving warfarin may cause excessive anticoagulant effects (7).
A second cause of adverse drug interactions occurs between warfarin and broad-spectrum antibiotics. Bacteria that naturally occur in our bowels produce a significant amount of vitamin K, a pro-clotting factor targeted by warfarin (22). Reducing the amount of bacteria through antibiotics also reduces the volume of pro-clotting factors. When given simultaneously, antibiotics significantly lower the amount of vitamin K in a patient, causing what would otherwise be a normal dose of warfarin to become more toxic to the patient (22).
One rare side effect of warfarin use is called Purple Toe Syndrome. Occurring within 3-8 weeks of the start of warfarin treatment, Purple Toe Syndrome is the result of cholesterol deposits entering the skin of the toes and feet, often causing pain (21). Depending on the severity of the symptoms, warfarin use may be stopped.

ALTERNATIVE TREATMENTS:
Although it is now considered less effective than warfarin, heparins have been used as anticoagulants since their discovery nearly a century ago (2). Originally synthesized by medical student Jay McLean while working under physiologist William H. Howell. McLean isolated phosphatides from compounds in dog livers that caused excessive bleeding in experimental animals. Two years following McLean’s discovery, Howell and another medical student, L. Emmet Holt Jr., isolated a different compound from dog liver, which Howell termed “heparin” from the Greek word for liver (2). Baltimore pharmaceutical company Hynson, Westcott, and Dunning were the first to commercially produce Howell’s heparin, but a Mayo Clinic study conducted by Edward Mason raised some concerns on the side-effects of the drug. Although the drug continued to be produced, Mason’s study concluded that the method used by Howell to isolate heparin was causing patient’s headaches, nausea and fever (2). In Canada, two teams of scientists, headed by D. W. G. Murray and Charles Best. Murray worked out of the Toronto General Hospital, where his team was the first to use a more pure isolation of heparin on a patient on April 16th, 1937, resulting in a much higher clotting time throughout a two hour infusion (2). Following World War II, Drs Peter Moloney and Edith Taylor published a cheaper and higher yield method of isolating heparin, that made the method developed by Murray and Best obsolete (2). Today, unfractioned heparins like those synthesized by Murray and Best have been supplanted by low-molecular weight heparins, which are used to treat patients with acute coronary symptoms (15). Low-molecular weight heparins are preferred because, in patients, LMW heparins have a higher potency, and take effect faster than unfractioned heparins (15).
Even after 60 years in clinical usage, warfarin’s efficacy has been unmatched by heparins, and therefore warfarin has become a mainstay of clinical practice. Unlike heparin and warfarin, which were both discovered as bi-products of naturally occurring secretions from dogs and plants long before the coagulation mechanism was understood, new anticoagulant drugs are rationally targeting different parts of the anticoagulation process (10). One of the first considerations made for these new drugs is their efficacy-to-safety ratio. Since the development of wafarin over half a century ago, randomized, controlled trials have become standard procedure for drug development, which is part of the reason why the market for anticoagulants has been a relatively stable environment. Pharmaceutical companies are required to prove the efficacy and safety first in rodents, then in non-rodent animals, and finally in humans. The other half of the challenge for pharmaceutical companies is the cost of demonstrating the ability of their new product, leading many companies to shrewdly invest their money into markets where there is no established competitor. Pradaxa is a Boehringer Ingelheim product that is the first to be approved by the FDA and, in trials of patients with moderate risk of stroke, Pradaxa proved just as effective as warfarin (8). What separated Pradaxa in the eyes of physicians, however, was the capability of Pradaxa to lower a patient’s risk of intracranial bleeding (8). Within the next year, Pradaxa could be on the market, and supplanting warfarin as the anticoagulant of choice for the nation’s physicians.

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