Warfarin is an acronym derived from the name of the patent holder Wisconsin Alumni Research Foundation.  Following the report of hemorrhagic disorder in cattle, the cause was found to be spoiled sweet clover silage, and the hemorrhagic agent was identified in 1939.  In 1948 a more potent synthetic congener was synthetized and marketed as a very effective rodenticide. (Goodman & Gilman 11th edition 2006, p. 1475 hereafter G&G)

The list of drugs and other factors that may affect the action of warfarin and related anticoagulants is prodigious and expanding.  Warfarin acts as an antagonist of vitamin K. (G&G 1477) Bleeding is the major toxicity of oral anticoagulant drugs. Especially serious episodes involve sites where irreversible damage may result from compression of vital structures (e.g., intracranial, pericardial, verve sheath, or spinal cord).  Although the reported incidence of major bleeding episodes varies considerably, it is generally less than 5% per year in patients treated with a target INR of 2 to 3.  {Since the drug is given long-term the risk is 50% in ten years for just this side effect, and serious bleeding has been defined as need at least a transfusion of 2 pints of blood—jk}  The risk of intracranial hemorrhage increases dramatically with an INR greater than 3, especially in older patients. (G&G 1478)  

Oral anticoagulants are used to prevent the progression or recurrence of acute deep vein thrombosis or pulmonary embolism following an initial course of Heparin [Heparin is a glycosaminoglycan found in the secretory granules of mast cells.  Heparin increases the rate of the thrombin-antithrombin reaction at least a thousand fold.  It is used to initiate treatment of venous thrombosis and pulmonary embolism because of its rapid onset of action.  (G&G 1471-72) ,  A 2006 retrospective study of 14,564 Medicare recipients showed that warfarin use for more than one year was linked with a 60% increased risk of osteoporosis-related fracture in men; there was no association in women.   

Drug Interactions: Warfarin (COUMADIN)

     Worst Pills Best Pills Newsletter article December, 2007 http://www.worstpills.org/member/newsletter.cfm?n_id=565  
    

These days, prescription drugs often become popular after drug companies inundate health professionals and the public with advertising (especially on television).

But after the initial hype, some of these drugs are doomed to extinction due to toxicity – sometimes unanticipated, and sometimes known but hidden or downplayed by those with a vested interest. Other drugs languish over time, and still others are superseded by newer drugs that are more effective and/or less toxic.

But occasionally a drug has staying power and continues to be used over the decades. Warfarin (COUMADIN) is such a drug. It debuted on the U.S. market in 1954, and last year about 24 million prescriptions were filled in U.S. pharmacies for this important drug.

What is warfarin used for?
Warfarin has been used as an anticoagulant (“blood thinner”) to reduce the chances of blood clots in high-risk individuals. If blood clots form, they can break off from inside the blood vessel in which they formed and travel throughout the body, sometimes blocking blood flow within vital organs such as the lungs and brain.

Who uses warfarin?
The drug is commonly used in patients with a tendency to form blood clots in their legs (deep venous thrombosis). If these clots travel to the lungs, they can cause what is known as a pulmonary embolism, which is frequently fatal.

Warfarin is also used in patients with abnormal heart rhythms such as atrial fibrillation, which can cause clots to form in the heart and then travel to the brain, resulting in a stroke.

In addition, the drug is used to prevent second heart attacks in some patients who have already had one, to prevent clots in patients with artificial heart valves and to treat a number of other blood clotting problems.

What side effects does warfarin have?
Although warfarin has saved many lives, its one big drawback is that, by reducing blood clotting, it increases the risk of bleeding. Often the bleeding is easy to find, such as in the urine, stool or skin, and it serves as an early warning sign to the patient to have his or her blood checked for excessive “thinning.”

Sometimes, however, the bleeding is serious or life-threatening but can be difficult to detect, such as bleeding from the stomach or bleeding into the brain, especially when there is a smaller amount of bleeding that does not cause symptoms. Keep in mind that serious bleeding is uncommon, and as long as clotting has not been slowed too much, the benefit of warfarin for well-established indications often outweighs the risks.

How can the risk of bleeding be minimized?
Although the risk of bleeding in people taking warfarin cannot be completely reduced, even with optimal management, patients taking the drug are less likely to have bleeding problems if they follow dosage directions very carefully, and have their blood tested to measure the degree of clotting inhibition exactly as they have been advised.

Minimizing the risk of warfarin-induced bleeding, however, also requires that patients pay close attention to drug interactions because some of these can raise the International Normalized Ratio (INR; see Box) into a range that is too high, with an unnecessarily increased risk of bleeding. Other interactions may lower the INR below the desired range and thereby put the patient at risk of clotting.

The International Normalized Ratio (INR) is a test applied to a sample of a patient’s blood to determine how “thin” it is. The normal value in people not using warfarin ranges from 0.8 to 1.2. Higher numbers indicate thinner blood, so the number increases with warfarin use.

Therefore, the likelihood that dangerous clotting will occur, decreases with these higher numbers.

For most patients who use warfarin, the desired INR range is between 2 and 3. Their dose of the drug will be adjusted until their test result is somewhere in that range. An INR higher than that may increase the chance of bleeding, and a ratio lower than that may not protect patients from the clotting for which they are using the drug.

The first step in avoiding bad interactions between warfarin and other drugs is never to start, stop or change the dosage of any prescription, non-prescription or alternative medication without informing the health professional who is managing your warfarin treatment. Many patients are prescribed drugs by several different health care professionals: general physicians, specialists, dentists, nurse practitioners, physician assistants and others. The only way a patient can be sure that the person managing their warfarin therapy will know all of his or her medications (prescription or not) is if the patient provides an up-to-date list of all of these drugs and/or dietary supplements.

Is bleeding the only risk with warfarin drug interactions?
No. Some drugs interfere with the blood-thinning effects of warfarin, cause the INR to decrease and may actually increase the risk of having a clot. This can be just as dangerous as drug interactions that increase bleeding risk.

Can over-the-counter (OTC) medications interact with warfarin?
Absolutely. In fact, one of the most common serious warfarin drug interactions occurs when people on warfarin take common OTC painkillers such as aspirin, ibuprofen (ADVIL, MEDIPREN, MOTRIN, NUPRIN), or naproxen (ALEVE, ANAPROX, NAPROSYN). Combining warfarin with these painkillers increases the risk of serious stomach bleeding. While doctors sometimes use warfarin and aspirin together for additive blood thinning, it should only be done after careful consideration of the benefit versus risk balance, because the risk is clearly increased.

The take-home message is not to take any OTC medication – and especially any painkiller – without checking first with the person who is managing your warfarin therapy.

Can “alternative” medicines interact with warfarin?
Yes. Some complementary and alternative medications (CAMs) have been shown to interact with warfarin. For some dietary supplements (such as ginkgo) the risk of bleeding may be increased, while other dietary supplements (such as St. John’s Wart) may inhibit the blood thinning effect of warfarin and increase the risk of clotting. (See Table 1 for some dietary supplements that may interact with warfarin.)

Keep in mind that dietary supplements are generally not standardized, so different brands may interact differently because the amount of active ingredient (and in some cases “inactive” ingredients) may not be the same. Moreover, even different lots of the same brand may vary substantially as to content.

In short, patients on warfarin are rarely, if ever, justified in taking dietary supplements. (The same can be said for patients not taking warfarin, but that is a different story.)

Which prescription medications interact with warfarin?
Unfortunately, there is a very long list of prescription meds that interact with warfarin (See Tables 2 & 3). Part of the problem is that there are several ways that medications can interact with this drug. The most common is when another medication throws a monkey wrench into the body’s normal machinery for getting rid of warfarin from the body (see Table 2). Unless the blood is tested and the warfarin dose is adjusted accordingly, warfarin will accumulate, the blood will become too thin and bleeding may result. A good example is the commonly used antibiotic with the unwieldy name, trimethoprim and sulfamethoxazole (BACTRIM, COTRIM, SEPTRA); it can dramatically increase the blood-thinning effects of warfarin and increase bleeding risk.

Other medications can have the opposite effect from the monkey wrench, and ramp up the warfarin-gobbling machinery into “turbo” mode. This means that warfarin is being destroyed too fast so warfarin levels are reduced, the patient’s INR goes below the desired range, and the patient is more at risk of having a serious blood clot. Examples of drugs that can do this are found in Table 3.

Proper clotting involves both the production of chemicals called clotting factors (it is this process that warfarin inhibits) and the activity of small particles suspended in the blood called platelets. Some medications can interfere with the function of the blood’s platelets. Platelets normally help prevent bleeding by sticking together and plugging up leaks in blood vessels. When a patient’s blood has already been thinned by warfarin, the platelet’s job becomes even more important. A recent study confirmed that antiplatelet medications such as aspirin or NSAIDs caused a substantial increase in serious stomach bleeding in people taking warfarin.

Still other drugs can also affect the ability of the liver to manufacture these clotting factors. Thus these other drugs may join with warfarin to gang up on the liver to further suppress the production of these important clotting chemicals. If the blood becomes too thin, the patient may bleed. It is likely that thyroid replacement hormones act in this way. The thyroid-warfarin interaction is one of the most common of all drug interactions, and it is important to note that the risk of this interaction occurs primarily when thyroid medication is started, stopped or its dosage is adjusted. A person on stable doses of warfarin and thyroid replacement medication is not likely to have problems from the interaction.

What You Can Do  
Make sure the person managing your warfarin therapy is fully aware of all of the medications you are taking, including prescription and over-the-counter medications and dietary supplements.

Note that the drugs listed in Tables 1, 2 and 3 represent most of the established and important drug interactions involving warfarin. But due to the rapidly changing nature of medical knowledge, new warfarin drug interactions are regularly discovered. So be sure to consult with your health professional if you have any questions regarding interactions of warfarin with any other medications.

Table 1. Selected Dietary Supplements That May Interact With Warfarin

Table 2. Selected Prescription and Over-the Counter Medications That May Increase Risk of Bleeding with Warfarin

Table 3. Selected Prescription and Over-the-Counter Medications That May Increase Risk of Clotting with Warfarin

Below is another company funded study with market goals, in this case to get those.  Notice the failure to mention side effects, and the article source--jk.

New England Journal of Medicine:

http://content.nejm.org/cgi/content/short/360/8/753

Source: the International Warfarin Pharmacogenetics Consortium at 300 Pasteur Dr., Ln. 301, Mailstop 5120, Stanford, CA 94305,

Warfarin Dosing
The appropriate dose of warfarin is difficult to establish because it can vary by a factor of 10 among patients, and the consequences of receiving an incorrect dose can be catastrophic. Clinical factors, demographic variables, and variations in two genes — CYP2C9 (full name: cytochrome P450, subfamily 2, subfamily C, polypeptide 9) and VKORC1 (full name: vitamin K epoxide reductase complex, subunit 1) — contribute significantly to the variability among patients in dose requirements for warfarin. In 2007, the Food and Drug Administration added pharmacogenetic information to the warfarin product label but did not propose a specific method for using genetic information to predict the dose required for individual patients.*

ABSTRACT

Background Genetic variability among patients plays an important role in determining the dose of warfarin that should be used when oral anticoagulation is initiated, but practical methods of using genetic information have not been evaluated in a diverse and large population. We developed and used an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from a broad population base.

Methods Clinical and genetic data from 4043 patients were used to create a dose algorithm that was based on clinical variables only and an algorithm in which genetic information was added to the clinical variables. In a validation cohort of 1009 subjects, we evaluated the potential clinical value of each algorithm by calculating the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable therapeutic dose; we also evaluated other clinically relevant indicators.

Results In the validation cohort, the pharmacogenetic algorithm accurately identified larger proportions of patients who required 21 mg of warfarin or less per week and of those who required 49 mg or more per week to achieve the target international normalized ratio than did the clinical algorithm (49.4% vs. 33.3%, P<0.001, among patients requiring 21 mg per week; and 24.8% vs. 7.2%, P<0.001, among those requiring 49 mg per week).

Conclusions:  The use of a pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach. The greatest benefits were observed in the 46.2% of the population that required 21 mg or less of warfarin per week or 49 mg or more per week for therapeutic anticoagulation.

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