By Mike McEvoy
Generic Name: Warfarin (multiple manufacturers)
Common Brand Name: Coumadin (Bristol-Myers Squibb — U.S.)
Popularity: 22nd most commonly prescribed drug between 2002 — 2008 (U.S.)
Class: anticoagulant
Treatment Uses — Prevention and treatment of blood clots and thromboembolic events associated with atrial fibrillation, cardiac valve replacement, certain cancers, antiphospholipid syndrome, stroke, heart attack, coronary stent placement, advanced heart failure, indwelling venous catheter placement, and migraine headaches. Prevention and treatment of pulmonary embolism and venous thrombosis. Fully one-third of patients with atrial fibrillation do not get appropriate anticoagulant therapy even though it has been shown to decrease their incidence of stroke by 60 to 80 percent. Blood clots from atrial fibrillation cause nearly one-quarter of all strokes in the elderly. There are few, if any, reasons why a patient with atrial fibrillation should not be anticoagulated. Prehospital providers should encourage patients in atrial fibrillation who are not on warfarin to discuss anticoagulation with their health care provider.
Dosing and Administration — Orally, most patients are maintained on two to 10 mg of warfarin daily. Dosage is individualized for each patient, usually adjusted by measuring blood prothombin time (PT). Wide variations in laboratory controls prompted the World Health Organization in 1983 to develop a system of standardizing PT for oral anticoagulant therapy based upon determination of an International Normalized Ratio (INR).
An INR of 1.0 times the control indicates no depression of clotting factors, whereas 1.5 to 2.5 times control is considered therapeutic for most purposes. Certain heart valves with higher clotting risk require INR as high as 3.5. There is no therapeutic benefit to be gained for most patients and a markedly increased risk of bleeding when the INR is above four.
Warfarin takes several days to reach peak anticoagulant effect; patients requiring immediate anticoagulation are simultaneously treated with continuous infusion of an intravenous anticoagulant (such as heparin) while waiting for warfarin to achieve therapeutic INR. To temporarily discontinue warfarin before planned surgical or invasive procedures, warfarin is stopped approximately five days prior to the procedure and heparin is administered while waiting for warfarin to wear off.
The heparin is then stopped for the procedure, then restarted afterward until a therapeutic INR is regained with warfarin. Warfarin can be resumed 12 to 24 hours after surgery. Large loading doses (greater than 5 mg) do not offer any more rapid protection and increase the incidence of bleeding from over anticoagulation. Dosing for children and infants is extremely variable but typically ranges from 0.1 to 0.2 mg/kg/day. IV warfarin is available, and uses the same dosing as oral warfarin, but has little utility in today’s pharmaceutical armamentarium.
Recent studies have demonstrated genetic differences in response to the anticoagulant effects of warfarin. Combined with age, race (Asian patients often require lower warfarin dosing), height, body weight, interacting drugs, and target INR levels, there is significant risk of over anticoagulating many patients. It cannot be emphasized too strongly that warfarin dosing is a highly individualized matter and requires close monitoring to avoid adverse outcomes.
Dosage adjustments are necessary in patients with liver disease, advanced heart failure, the elderly, chronically malnourished, or in patients taking other medications that significantly enhance the effects of warfarin. Dose adjustments are not necessary in renal failure; warfarin is not removed by hemodialysis.
There are numerous reports of elevated INR levels and bleeding events in patients taking warfarin who consume large quantities of cranberry juice; it is prudent to caution patients against drinking large amounts of cranberry juice.
Warfarin acts by interfering with vitamin K dependent clotting factors. In overdoses or emergencies where reversing the effects of warfarin is necessary, oral or injectable vitamin K is the first line of therapy. Published literature is inconclusive on optimal dosing of vitamin K for reversal of warfarin anticoagulation, other than to caution that large doses of vitamin K can render patients refractory to warfarin for up to two weeks. This consideration must be carefully balanced with choosing vitamin K as a reversal agent. When ineffective, or when bleeding is life threatening, it may be necessary to correct clotting times with the administration of blood plasma products.
Pharmacology/Pharmacokinetics/Stability — Following oral administration, warfarin is absorbed rapidly from the gut with little individual variation. While peak plasma drug levels occur at one-half to four hours after administration, the anticoagulant effect occurs within 24 hours, peaks in 72 to 96 hours, and tapers off after five days. Reports of differences in the bioavailability of different brands of warfarin suggest that patients should be cautious when changing from one brand to another.
Warfarin is metabolized primarily in the liver. Nearly 92 percent is excreted as warfarin by products by the kidneys. Bile and breast milk also contain excreted warfarin. Warfarin rapidly crosses the placenta and is implicated in a variety of birth defects and complications, posing significant issues for women who require anticoagulation during pregnancy.
Warfarin works in the body by inhibiting the synthesis of vitamin K dependent clotting factors. Anticoagulants have no effect on already formed thrombus (clots) nor will they reverse ischemic tissue damage. Following thrombotic events, anticoagulation prevents further extension of formed clot(s) and prevents secondary thromboembolic complications.
Warfarin tablets are light sensitive and should be stored at room temperature (54-86 F). Tablets come in a variety of strengths from one to 10 mg and are single scored for further flexibility in dosing using half tablets.
Cautions and Warnings — People taking warfarin are at greater risk of bleeding. IM injections should be avoided or given only in the upper extremities where bleeding can be readily controlled by direct pressure. Spinal punctures and other diagnostic or therapeutic procedures with risks of uncontrolled bleeding should also be avoided. Some dental and surgical procedures may require interruption of warfarin therapy. Studies of trauma patients anticoagulated with warfarin range from no greater than normal to a fivefold higher risk of death compared to nonanticoagulated patients.
The risks of serious bleeding are greatest when initially starting warfarin, when INR is greater than 4.0, in patients aged 65 or older, and when INRs are highly variable. Patients with history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, and long-term warfarin therapy are also at higher risk for serious or fatal bleeding.
Important Side Effects and Interactions — Bleeding is the most common and significant warfarin side effect. Warfarin is considered a “narrow therapeutic range drug,” meaning that it is difficult to continuously maintain therapeutic levels. Two factors likely involved are the extremely long life of the drug and dietary intake of vitamin K. Leafy green vegetables, certain legumes (peas, beans), and vegetable oils contain high levels of vitamin K. Fluctuating dietary levels of vitamin K increase and decrease warfarin effects. A steady diet coupled with an awareness of vitamin K content is helpful to avoid swings in therapeutic warfarin levels.
Currently, there are 441 drugs reported to interact with warfarin. Of these, three are significant to prehospital and emergency medicine providers: amiodarone, acetaminophen, and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).
Amiodarone decreases warfarin metabolism within the first week of administration. A 25 percent reduction in warfarin dosing is recommended when amiodarone is started and the INR should be closely monitored. For reasons poorly understood and probably related to liver metabolism, acetaminophen is known to dramatically increase anticoagulant effects of warfarin. Patients are advised to take no more than 2 grams of acetaminophen per day for no more than three days without careful monitoring of INR.
Despite this limitation, acetaminophen remains the drug of choice for pain and fever in patients taking warfarin. NSAIDs comprise an ever-expanding class of medications including drugs such as ibuprofen. Nearly all NSAIDs interfere to some degree with platelet (clotting) function and require caution when used with warfarin. Aspirin poses less danger when used with warfarin; in several studies, patients who took both had no increased risk of bleeding.
Average Costs — U.S.
• 2 mg tablet/ 5 mg tablet (brand name Coumadin)
Patient cost: $0.76 each/ $0.83 each*
Large Hospital cost: $0.63 each/ $0.69 each
Generic warfarin is typically about one-half the cost of brand name drug.
*($4.00 generic available at Wal Mart® and Target for 1 month or $10.00 for 90 day supply)
References:
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed October, 2009).
2. Albany Medical Center Pharmacy, Albany, New York.
