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COUMADIN^®

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WARFARIN

Clinical Pharmacology.

1. Warfarin is a coumarin that possesses the ability to interfere with the action of vitamin K₁. Specifically, warfarin inhibits the regeneration of reduced vitamin K₁ in the liver from the epoxide form of vitamin K. (1)
2. By blocking vitamin K generation, glutamate residues on coagulation factors II, VII, IX and X are not adequately carboxylated, rendering these coagulation proteins nonfunctional. (2) (38)
3. Thus, warfarin does not directly inhibit active coagulation, it simply lowers the plasma level of 4 functional coagulation proteins, making effective coagulation more difficult.
4. Other vitamin K dependent proteins inhibited by warfarin include proteins C and protein S, proteins that are involved in the fibrinolytic system.
5. The effect of warfarin on blood coagulation is measured using an in-vitro coagulation test, either the prothrombin time (PT) or the better standardized international normalized ration (INR).
6. Mathematically, the INR= (PR)^ISI, where the PR is the prothrombin ratio (prothrombin time divided by the laboratory control prothrombin time) and the ISI is the international sensitivity index of the thromboplastin reagent. Use of the INR eliminates variation in PT results between laboratories caused by differences in the sensitivity thromboplastin reagents. (39)
7. Factors that affect the PT/INR are: a) pharmacokinetic factors, such as changes in the serum level of warfarin or sudden changes in protein binding, b) pharmacodynamic factors, particularly the amount of vitamin K₁ available in the liver, and c) laboratory variation in the measurement of the PT/INR.

Dosing Warfarin.

1. Because the half-life of warfarin is very long (mean t_1/2 = 35-40 hours):
   a) once a day dosing is sufficient, and
   b) the time required to achieve steady-state warfarin levels while taking a daily maintenance dose is 6-7 days.
2. There is very wide variation between patients in the maintenance dose required to achieve a specific PT/INR, e.g. an INR between 2.0-3.0. The average dose to achieve this effect is approximately 4.5 mg/day, but the dose ranges from 1.0 mg/day to over 20 mg/day. One cannot reliably predict the maintenance dose based on clinical or demographic parameters alone.
3. The drug is highly protein bound (97-99% when albumin levels are > 3.2 mg/100ml) and only the "free" drug exerts a biological effect. When the albumin level is low, for example in post-operative patients or in very sick patients, the level of amount of free warfarin increases. Hence, sick patients generally require less warfarin. As the albumin level rises, the maintenance dose rises as well.
4. After giving a loading dose of warfarin, development of the biologic effect requires degradation of functional clotting factors as well as synthesis of nonfunctioning factors. The factor with the shortest half-life is factor VII (t_1/2 ~ 6 hours) and the factor with the longest half-life is factor II (t _1/2 ~ 60 hours). Thus, although low levels functional factor VII may be reached after just 1-2 days, evidenced by a "therapeutic" anticoagulant response (PT/INR), reduction of all of the vitamin K dependent clotting factors (antithrombotic effect) requires many days, hence the need to overlap heparin and warfarin for at least 5 days. (40,41)
5. A large number of commonly used drugs interact with warfarin in such a manner as to cause either an appreciable rise in the PT/INR or fall in the PT/INR. These drugs are listed in Table 5. (42)

Indications for Warfarin.

Specific indications for warfarin therapy, together with the level of scientific evidence in support of the use of warfarin are shown in Table 6. (1,43)
 

Initiation of Warfarin Therapy.

No foolproof dosing regimen can be recommended. Dosing must be individualized!

1. Giving a large loading dose of warfarin, e.g. 50 mg, does not hasten establishment of anticoagulation compared to using a small loading dose, but it dramatically increases the likelihood of excessive anticoagulation. (44,45) Giving a small loading dose, e.g. 10 mg a day for the first 1-2 days does not speed up the time required to achieve a steady state response in most patients, but prolongation of the PT/INR to dangerous levels occurs in 20% of cases. (46)
2. Older age, low albumin levels and significant comorbid disease, particularly congestive heart failure and liver disease increase the likelihood that an excessive anticoagulant will occur after giving 10 mg for two days. In these individuals, selecting 2.5 to 5.0 mg doses for the first two days is wise.
3. Accurate dosing of warfarin during the first few days of treatment requires either a great deal of clinical experience or, better, the help of computer-assisted dosing using a software program [e.g. Drugcalc^R, Therapeutic Technologies, Tallahassee, Fl] that can be kept on a computer in the pharmacy. (22) (47) A nomogram has been published for dosing warfarin on day 2 and day 3, but the timing of warfarin administration and the measurement of the PT/INR response has to match the nomogram, and the accuracy of the nomogram has not been duplicated. (48)
4. A very common dosing error is to give a 10 mg dose late in the evening, draw a PT/INR early the next morning (before factor VII levels have had a chance to fall), note a near normal PT/INR, give another 10 mg of warfarin that night and discover and very high PT/INR the following morning. Optimally, 20-30 hours should elapse between the initial dose of warfarin and measurement of the PT/INR response that you will use to select the second dose of warfarin. For example, if the first dose is given in the evening, a stat PT/INR should be measured late in the afternoon the next day, several hours before the next dose is given.
5. The INR 20 hours after the first dose = 1.3 in an average patient who will require 4.5 mg of warfarin each day. A higher INR suggests greater sensitivity to warfarin, necessitating a lower dose.
6. If the INR 20 hours after the first dose is greater than 1.8, the second dose should be held or a very small dose, e.g. 1 mg, given. If the INR remains in the range from 1.0-1.1 after 24 hours, a second dose of 10 mg can be given. For intermediate INR values between 1.2-1.8 a second dose between 9.0 mg and 1.0 mg, respectively, should be selected.
7. If the INR remains low after two doses of 10 mg, a higher third dose (15 or 20 mg) can be given. At this point computer-assisted dosing is recommended. Suffice to say in some individuals the slow rise in the INR reflects resistance to warfarin (maintenance dose is over 12 mg/day) whereas in other individuals the slow INR rise reflects modest resistance combined with slow degradation of clotting factors (maintenance dose is between 7-10 mg/day).

Maintenance of Warfarin Therapy.

1. The PT/INR must be monitored frequently during the initial few weeks of anticoagulation therapy! (49) (43)
2. Patients are often recovering from a significant illness or surgery, and warfarin requirements change as health improves.
3. Drug interactions are also common as new drugs are often started.
4. Optimally, the warfarin dose should be constant each day. For example, if the dose is approximately 6 mg/day, either a 6 mg tablet or 3 two-mg tablets should be given each day. If alternate day dosing is selected, the difference between the daily doses should be kept to a minimum, e.g. 7.5 mg alternating with 5 mg/day. This minimizes peaks and troughs in the PT/INR response.
5. If a pattern of a stable INR is established, the monitoring interval can be extended for as long as every month or 6 weeks, but it will require 6 months of more frequent monitoring to become confident in the longer interval between testing.
6. Repeat PT/INR measurements should be made if a new drug is started or if the patient's INR is labile

Mini-Dose Warfarin.

1. Several studies have evaluated mini-dose warfarin, e.g. a fixed dose of 1 mg/day, for prevention of thromboembolism. One study suggested that this dose may be effective in preventing upper extremity DVT in patients with central catheters, (50) however a more recent study suggests that it has only marginal efficacy.
2. Mini-dose warfarin is clearly ineffective following high-risk orthopaedic surgery. Recent data have also shown that mini-dose warfarin is ineffective (together with aspirin)in high risk patients with atrial fibrillation. (51)
3. Mini dose warfarin may be modestly effective in breast cancer patients being given chemotherapy. (52) However, there are no widely accepted indications for mini-dose warfarin! Standard dosing (target INR= 2.5) should be your strategy.

Perioperative Prophylaxis.

1. The efficacy of warfarin in preventing post-operative deep vein thrombosis has been most rigorously studied in high-risk orthopaedic patients undergoing total hip replacement and total knee replacement. (53,54,55,56)
2. Warfarin is given the evening before surgery (10 mg or 5 mg) and either no warfarin or 5 mg is given the evening after surgery. In randomized controlled trials, warfarin appears to be as effective as standard dose heparin or LMWH in preventing proximal deep vein thrombosis following total hip replacement. (54) Warfarin may be somewhat less effective in preventing calf-vein thrombosis following total knee replacement. (35)
3. Use of warfarin is associated with a comparable or lower rate of major bleeding and a somewhat higher incidence of calf-vein thrombosis compared to low molecular weight heparins. (this is no surprise since its effect takes 2-4 days to begin.)

Perioperative Management of Warfarin Therapy.

Patients on chronic warfarin occasionally require major surgery. (57)

1. If the risk of hemorrhagic complications of the procedure/surgery is low:
2. 
   a) Dental procedures such as simple restorations, subgingival scaling, simple extractions and local and regional injections of anesthesia. Multiple extractions or extensive oral surgery poses a higher risk of bleeding - see below. (74,75)
   b) Eye surgery such as cataract surgery, vitreoretinal surgery or trabeculectomy. Orbital surgery or complex lid or lacrimal surgery poses a higher risk of bleeding - see below. (76,77)

1. If the risk of hemorrhagic complication is high and the risk of thrombosis is low (e.g. remote hx of DVT, atrial fibrillation without multiple risk factors for stroke) warfarin can be discontinued 90-115 hours (skip 3 or 4 doses) before surgery. (40,58,59,60)
2. If the risk of hemorrhagic complication is high and the risk of thrombosis is high (e.g. mechanical valve, early stages of treating DVT) the effect of warfarin can be safely reversed by:
3. 
   Regimen #1
   1. stop warfarin 2 days before procedure,
   2. administer a small dose of vitamin K, 1-2 mg PO or SC, admitting the patient to the hospital and starting intravenous heparin 6 ?10 hours later,
   3. continue heparin for 24?36 hours,

1. discontinue the heparin 3?6 hours prior to surgery,
2. check INR morning of surgery and proceed with surgery if INR <1.5
3. restart heparin (consider LMWH, given subcutaneously) postoperatively as soon as the risk of hemorrhage is felt to be low, and then
4. reinitiate warfarin therapy, hopefully as an outpatient, stop heparin once INR therapeutic.

Regimen #2

1. discontinue warfarin either 4 days (for INR close to 2.0) or 5 days (for INR close to 3.0) before surgery and start LMWH (therapeutic dose, such as enoxaparin 1 mg/kg q 12) the following day,
2. give last dose of the LMWH 24 hr. before surgery
3. restart heparin (especially LMWH, given subcutaneously) postoperatively as soon as the risk of hemorrhage is felt to be low, and then
4. reinitiate warfarin therapy as an outpatient, stop heparin once INR therapeutic.

These time and resource consuming regimes are probably not needed are they cost effective in most patients. Nevertheless, the standard of practice is to employ one of these regimens if the patient is deemed to be at high risk for thrombosis.
 

Risk Factors for Bleeding During Warfarin Therapy.

1. Age - Most studies have demonstrated an increased risk of bleeding in older patients. A review published in 1995 found seven studies, enrolling a total of 14,388 patients, that showed that elderly patients are twice as likely to have bleeding complications as younger patients.(30) The review also noted seven other studies enrolling 2940 patients in which the elderly did not have an increased risk for bleeding. The discrepancy of these findings likely results from differences in the patient population in these studies. A 1996 report that examined 2376 patients attending anticoagulation clinics concluded that elderly patients up to age 80 were not at increased risk for bleeding. (84) Those patients over age 80 had a increased risk (relative risk 4.6) of bleeding compared to younger patients. Although old age alone should not be considered an absolute contraindication for anticoagulation, these data suggest that age should clearly be considered when judging the overall risks and benefits of anticoagulation in the individual.
2. Intensity of anticoagulation - Several controlled and observational studies have noted that the intensity of anticoagulation is associated with the risk of hemorrhage, with bleeding approximately three times as common in patients treated more intensively (INR 3.0 to 4.5) compared to less intensively (INR 2.0 to 3.0).(83) Studies from Europe of patients with mechanical heart valves indicate that the risk of bleeding does not increase significantly until the INR rises above 5.0.(86) The discrepancy between these findings in Europe and ;the United States is unclear, but may relate to the definition of significant bleeding.
3. Variability of anticoagulation - Variability or fluctuation of the INR has also shown to be a predictor of bleeding. Patients who required more than four dosage adjustment per year bled in one study 25% more than patients who had fewer adjustments.(80) This variability may be secondary to patient noncompliance, dietary influences in vitamin K intake, medication changes, or fluctuations in the patient's coexisting illnesses.
4. Patient characteristics
   1. History of cerebrovascular disease - Most studies have found that a history of cerebrovascular disease is an independent risk factor for intracranial hemorrhage while anticoagulated. (81) A recent case-control analysis found that a history of stroke was associated with a three-fold increase for intracranial hemorrhage. Another study found a history of stroke is associated with a relative risk of 6.6 for intracranial hemorrhage.
   2. History of gastrointestinal bleeding - Past gastrointestinal bleeding, not peptic ulcer disease alone, has been associated with an approximate three fold increased risk of anticoagulant-related bleeding. Previous gastrointestinal bleeding during warfarin therapy is a major risk factor for bleeding.(85)
   3. Hypertension - Patients with treated hypertension are probably not at higher risk. Studies that have controlled for age and history of stroke have not found hypertension to be an independent predictor for hemorrhage.
   4. Cancer - Although most older series report an increase association of bleeding in patients with cancer, a more recent report has shown no increase risk. This recent study did, however, note that therapeutic INR's were more difficult to sustain.
   5. Hepatic disease - Liver disease has not been shown to increase the risk of bleeding, although, this may be due to the reluctance of physicians to start anticoagulants in patient with severe hepatic dysfunction.
   6. Alcoholism - It is also difficult to demonstrate an association with alcoholism and anticoagulant-related bleeding because the diagnosis of alcoholism is often inaccurate and when diagnosed correctly, physicians are reluctant to start an alcoholic on warfarin.

Evaluation of the Anticoagulated Patient who has a GI or GU Bleed.

Approximately 5% of anticoagulated patients without a history of prior bleeding may have gastrointestinal (GI) hemorrhage and 3% of patients may have genitourinary (GU) hemorrhage. Should the anticoagulated patient who has either GI or GU bleeding be evaluated for the specific cause of bleeding? Several studies have attempted to answer this question.

1. GI bleeding - diagnostic evaluations using upper and lower endoscopy uncovered the source of bleeding between 40 and 80% in these studies. Upper tract sources were usually from peptic ulcer disease and lower tract from diverticular disease or polyps. GI malignancies were discovered between 4 and 6% of the patients in each of the studies. When the three studies were combined, 143 patients had 7 malignancies; one esophageal, two gastric, and four colorectal cancers.
2. GU bleeding - there was also a high success rate in finding abnormalities among anticoagulated patients with hematuria. (82) Of 32 patients with two episodes of GU bleeding (the criteria for starting a work-up in this study), abnormalities were found in 27. Sixteen had infections and 2 had malignancies. Other causes included renal cyst (n=6), nephrolithiasis (n=2), and papillary necrosis (n=1). In another study, 6 of 18 patients were found to have an abnormality explaining their hematuria, one patient had a malignancy.
3. Work-up - The decision to initiate diagnostic testing should be individualized for the specific patient. Anticoagulated patients, particularly young patients, who have no risk factors for malignancies may have extensive testing deferred if the bleeding is felt to be likely self-limited or easily treated (as in bleeding from hemorrhoids or a urinary tract infection). However, in most instances it will be necessary to rule out potentially remediable lesions. In GI bleeding, patients may initially have either an upper or lower endoscopy. Alternatively, patients may have an upper GI or barium enema radiographs. Which tract to initially evaluate should be based on the patient's history. If either the upper or lower tract evaluation reveals an abnormality, there is generally no need to evaluate the other tract. In patients with hematuria and pyuria, a urine culture should be performed to exclude a urinary tract infection. If the urine is sterile, a renal ultrasound or an intravenous pyelogram should be performed. If this is normal, a cystoscopy may reveal the source.

Emergent Reduction of the PT/INR.

There are conflicting guidelines for administration of vitamin K in patients with an elevated PT/INR.

1. If the PT/INR is between 6.0- 10.0 and you think the patient's INR reflects a steady state response (that is, not an overdose, not an acute drug interactions, not acute hepatitis or CHF, etc.) and if there is no evidence of bleeding, warfarin can simply be discontinued. (61)
2. Assuming the patient is at steady-state, the INR begins to fall approximately 30 hours after the last dose of warfarin. The half-life of the INR varies from 0.5-1.2 days, with older individuals having a longer half-life. Thus, for most high INRs (7-10 range), the value will fall to ~ 3.0 an average of 72 hours after the last dose of warfarin. Example: INR= 9.0 and warfarin is stopped. Thirty hours later the INR will be ~9.0, 54 hours after discontinuation it will be 5.0, 78 hours after discontinuation it will be ~ 3.0, and 102 hours after discontinuation it will be ~2.0. (40)
3. If the INR is high (7-10) and the patient is at high risk for bleeding or if you think the INR is possibly rising because of a drug interaction or coexisting disease, or error in warfarin dosing, vitamin K, 0.5 or 1.0 mg should be given intravenously over 20 minutes. Twenty?four hours after administration the INR should fall to a value near INR = 3.0 assuming the INR reflected a steady state (and not, for example, an overdose of super warfarin, acute liver failure etc.). Once the INR begins to fall, an adjusted lower dose of warfarin can be given to the patients who need ongoing anticoagulation. (62)
4. If the patient is actively bleeding, intravenous vitamin K (any dose) should be given slowly together with 3 units (jumbo pack) of fresh frozen plasma, which may need to be repeated after 12-15 hours if the INR remains elevated.

Use of Warfarin During Pregnancy.

Because warfarin is teratogenic, all women of childbearing potential who are treated with warfarin should be informed of its risk and be offered contraception. (9) If a patient becomes pregnant, subcutaneously administered heparin should be substituted for the remainder of the pregnancy. (63,64) Warfarin can be safely given to women who breast feed their children.
 

Adverse Effects of Warfarin.

1. Hemorrhage is the major complication associated with warfarin therapy. (30) Rates of life threatening bleeding are on the order of 0.5-1.0 events/ 100 patient-years and bleeding that requires medical attention occurs at a rate of ~7-10 events/100 patient years. Because one risk factor for bleeding is an excessively high PT/INR, vigilance following the PT/INR is required.
2. Warfarin induced skin necrosis is a very rare complication seen in patients started on warfarin without heparin; many of these patients have an underlying procoagulant disorder such as protein C deficiency. Because warfarin reduces protein C levels, it exacerbates this deficiency in the fibrinolytic system and predisposes to thrombosis, which is manifest in small vessels in adipose tissue. Rational treatment is fresh frozen plasma (providing protein C), initiation of intravenous heparin and, at least temporary discontinuation of warfarin.
3. Some patients with protein C & S deficiency have been successfully started on warfarin (gradually increasing the dose) while on heparin therapy. (65)
4. Other uncommon complications include persisting diarrhea and alopecia. Use of a different coumarin preparation (e.g. dicumerol) may be beneficial.

Recurrent Thromboembolism During Warfarin Therapy.

1. Although recurrent venous thromboembolism is a major problem, recurrence during adequate warfarin therapy is rare. (66)
2. When a patient who is adequately anticoagulated develops symptoms of recurrent DVT, the clinician should suspect either post-phlebitic swelling or recurrent thrombosis despite adequate warfarin.
3. A useful test to exclude active thrombosis is to measure the plasma level of D-dimer (using an ELISA test), which is elevated in over 95% of patients with venous thromboembolism. A high level of D-dimer although not specific, raises the possibility that the patient has a procoagulant disorder leading to the thrombosis during warfarin therapy, particularly an underlying adenocarcinoma. (67,68,69)
4. Repeat venography or ventilation-perfusion lung scanning may document recurrent thrombosis if a baseline test was done.
5. Serial real-time ultrasound testing is less reliable in detecting recurrent ipsilateral clot since neither the exact extent of thrombosis or clotting in collateral vessels are usually reported.
6. A common cause of active thrombosis during adequate warfarin therapy is the presence of an underlying malignancy (especially adenocarcinoma of pancreas, GI tract, prostate, ovary, stomach and breast). If a malignancy is documented, heparin should be substituted for warfarin since the latter is usually ineffective. (70)
7. In patients with thrombosis and the Lupus-anticoagulant, a higher intensity of anticoagulation may be required, i.e. INR= 3.0-4.0.(79) Serial D-dimer testing may be useful to document effectiveness of warfarin in these patients. (71,72)

TABLE 1. HEPARIN DOSING NOMOGRAMS
 
 

* BOLUS 80 U/KG 
^** BOLUS 40 U/KG 
⁺ 1,240 U/HR. IF AT HIGH RISK FOR BLEED
^$ BOLUS 5,000 U
^# HOLD 30 MIN
^## HOLD 60 MIN

____________________________________________________________________________

¹ Ann Int Med. 1993; 119:874-872. ² Arch Int Med. 1992; 152:1589-1595.
³ Arch Int Med. 1991; 151:333-337.
 
 

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