Clinical Reviews
| Risk Management in Long Term Care: Consultative Services on Warfarin Therapy by Pharmacists | Charles H. Brown |
Objectives: To review risk management concepts as they may apply to consultant pharmacists performing drug regimen reviews on long-term care facility (LTCF) residents receiving warfarin therapy and to describe a systematic approach for pharmacists to initially dose, adjust, monitor, and assess warfarin therapy.
Setting: LTCF or ambulatory care facility within a hospital.
Data Sources: Clinical literature on anticoagulant therapy, monitoring, and risk management.
Data Synthesis: In an increasingly litigious society, consultant pharmacists in long-term care facilities can perform an invaluable service that enhances patient care and reduces risk. Periodic review of therapeutic regimens that include drugs with narrow therapeutic indices, such as warfarin, allows early identification of adverse reactions or toxicity. The dosage of warfarin must be titrated and patients must be monitored to ensure optimal therapeutic outcome and to reduce or avoid potentially life-threatening adverse events.
Conclusion: A well-documented drug-review protocol will reduce the risks associated with warfarin therapy, as well as demonstrate diligent and appropriate care in case an untoward event does occur.
Key Words: Anticoagulant therapeutic drug monitoring; Consultant pharmacists; Drug-drug interactions; International normalized ratio; Low- and high-intensity warfarin therapy, Pharmacokinetics and pharmacodynamics; Prothrombin time; Thromboembolic disorders; Vitamin K; Vitamin K content of foods; Risk management.
Abbreviations Used: aPTT=Activated partial thromboplastin time, AMI=Acute myocardial infarction, ACCP=American College of Chest Physicians, CYP=Cytochrome P450, INR= International normalized ratio, ISI=International sensitivity index, I.V. = intravenous; PT=Prothrombin time, LTCF = Long-term care facility; PTR=Prothrombin time ratio, QAAC=Quality assessment and assurance committee, SGPT=Serum glutamic pyruvic transaminase (ALT=Alanine aminotransferase), SGOT=Serum glutamic oxaloacetic transaminase (AST=Aspartate aminotransferase), TQA=Total quality assurance, WHO=World Health Organization.
Consult Pharm 1996; 11: 390-408.
The term risk management involves managing and controlling risks associated with providing a service or product to the consumer. It may be associated with the risk of medical malpractice or professional liability. In the health care environment, risk management refers to the practice of detecting, evaluating, and reducing the risk of financial loss associated with accidents or other untoward events that may occur while providing patient care. Risk management involves developing proactive programs designed to: identify and correct deficient practices of a health care facility's staff that could lead to malpractice claims, avoid or decrease factors contributing to a crisis or loss, and reduce the operational and financial effects of unavoidable losses to their lowest practical cost.
Because of the commonality of their goals, risk management procedures in some institutions may be combined with other quality assurance measures such as those associated with the Quality Assessment and Assurance Committee (QAAC) in long-term care facilities (LTCFs) or total quality assurance (TQA) procedures in hospitals. The overall purposes of this combination are to: (1) improve coordination of the efforts of all staff involved, (2) minimize risks, and (3) ensure the provision of high quality patient care.1
Potential medication-related problems resulting from the use of oral anticoagulant drugs can subject institutionalized patients in hospitals and LTCFs to substantial risk. An illustration of this potential risk is the recent case of Thompson v. Nason Hospital,2 in which an automobile accident victim was transported by ambulance from the accident scene to a local hospital emergency room, where she was admitted with head and leg injuries and placed on continuous intravenous (I.V.) heparin infusion along with previous medication taken at home. From an admission interview medication history, hospital personnel determined that the patient had been taking oral crystalline warfarin sodium (Coumadin, Du Pont Pharma, Wilmington, DE 1988). On the patient's third day in the hospital, one of the hospital physicians noted that the patient had gross hematuria and bleeding in the right eye secondary to anticoagulant therapy. Another hospital physician agreed with this observation and decided to withhold warfarin but to continue the use of I.V. heparin. The next day, the patient experienced paralysis of the left side of her body and was transferred to another facility secondary to progressive neurologic problems. Later diagnostic tests revealed a large intracerebral hematoma in the right frontal, temporal, and parietal lobes of the brain. About two weeks later, the patient was discharged from the hospital without having regained motor function on her left side.
Following litigation of this case, the Supreme Court found that "a hospital is liable for negligence if a patient is injured as a result of a failure of the hospital's staff to report changes in a patient's condition or to question a physician's order that is not in accord with standard medical practice."2 The Court recognized that a hospital staff member (e.g., physician, nurse, or pharmacist) has the duty to report abnormalities in the treatment and condition of a patient. In addition, the Court stated that if the attending physician fails to act after being informed of such abnormalities, it is incumbent on hospital staff to advise the hospital authorities so that appropriate action may be taken.
In a comparable situation, the consultant pharmacist for a LTCF reviews each patient's drug therapy monthly and makes appropriate recommendations to physicians about needed changes in a patient's drug regimen. If the consultant pharmacist detects drug therapy problems and fails to make appropriate recommendations to physicians, he or she may be at risk of liability. In addition, if a facility's administrative staff allows these recommendations to be ignored by physicians, the facility and its administrative staff as well as the physicians may be liable.
This article examines relevant information about warfarin and
the indications for warfarin pharmacotherapy to enable consultant
pharmacists to improve their assessment and monitoring of anticoagulant
therapy of patients in LTCFs. It also explores warfarin therapy-monitoring
guidelines and reviews risk-management concepts as they may apply
to consultant pharmacists for LTCFs. By being more knowledgeable
about thromboembolic disorders and anticoagulant therapy, consultant
pharmacists will be more effective at performing drug-regimen
reviews; assisting physicians in the achievement of optimal therapeutic
outcomes; decreasing risk associated with anticoagulant therapy;
and producing positive patient outcomes.
Warfarin Information
The oral anticoagulants, or vitamin K antagonists, are coumarin
derivatives and have been used extensively for more than 50 years.
Coumarin compounds as a group generally produce fewer nonhemorrhagic
complications than do other oral anticoagulants and are now used
exclusively. Of these compounds, warfarin (4-hydroxycoumarin)
is the most widely used in the United States. For these reasons,
the content of this article focuses primarily on the use of oral
Coumadin Tablets (Warfarin Sodium Tablets, USP) Crystalline.
Pharmacology
Warfarin inhibits the synthesis of vitamin K-dependent clotting factors: Factors II, VII, IX, and X, and anticoagulant proteins C and S. The drug specifically inhibits vitamin K epoxide reductase and vitamin K quinone reductase, the enzymes essential for cyclic interconversion of the oxidized form of vitamin K to its active reduced form, vitamin KH2 (Figure 1).3 In this manner, synthesis of only vitamin K-dependent clotting factors is prevented, which leads to an anticoagulant effect. Since warfarin inhibits the cyclic conversion of vitamin K and depletes vitamin KH2, hepatic production of coagulant proteins is impaired. Ultimately, the liver secretes partially carboxylated and decarb- oxylated proteins, which are dysfunctional and cannot contribute to the body's coagulation process.4-7
Figure 1 Not Available
Because warfarin does not affect the catabolism of blood coagulation factors that were formed before initiation of warfarin therapy, depletion of circulating vitamin K-dependent clotting factors must occur before peak effects of warfarin become apparent. The rate of depletion of functional coagulation Factors II, VII, IX, and X depends on their individual rates of degradation. Following initiation of warfarin therapy, sequential depression of blood concentrations of functional coagulation Factor VII (plasma half-life 4 to 6 hours) occurs first, followed by Factors IX (plasma half-life of 24 hours) and X (plasma half-life of 48 to 72 hours), and finally Factor II (plasma half-life of about 60 hours) activities. The half-lives of proteins C and S are approximately 8 and 30 hours, respectively.8,9
An initial anticoagulant effect occurs within 24 hours after warfarin administration. However, the peak anticoagulant effect may be delayed for 72 to 96 hours. The therapeutic duration of action of a single dose of warfarin is two to five days. The anticoagulant effect of warfarin becomes more pronounced as the effects of daily warfarin maintenance doses overlap. Warfarin therapy inhibits thrombus formation when stasis is induced and may prevent extension of existing thrombi. However, warfarin apparently has no direct effect on the physiologic process that initiates thrombi formation and appears to have little, if any, effect on the pathogenesis of arterial thrombi that result from the interaction of platelets with an abnormal vessel wall.8 Because the drug affects the synthesis of blood coagulation factors that are involved in both the extrinsic and intrinsic coagulation cascade system, it prolongs both the prothrombin time (PT), which measures the extrinsic coagulation pathway, and the activated partial thromboplastin time (aPTT), which measures the intrinsic coagulation pathway (Figure 2).5
Figure 2 Not Available
When warfarin therapy is discontinued or when vitamin K (phytonadione) is administered, blood concentrations of functional vitamin K-dependent clotting factors begin returning to pretreatment levels. Antithrombogenic effects of warfarin generally occur only after concentrations of functional coagulation Factors IX and X are significantly diminished, which may not occur until two to seven days following initiation of warfarin therapy.8
Because of variable interpatient and intra-patient dose-response
relationships, each patient's anticoagulant therapy must be individualized,
and the dosage and patient response must be monitored very closely.
The dose response to warfarin is influenced by both pharmacokinetic
factors (differences in absorption and metabolic clearance of
warfarin) and pharmacodynamic factors (differences in the hemostatic
response to given concentrations of warfarin). Technical factors
that can contribute to apparent variability in dose response include
inaccuracies in laboratory testing and reporting, poor patient
compliance, and unsatisfactory patient- physician communication.
At times, the variable dose response within individuals remains
unexplained.10,11
Pharmacokinetics and Pharmacodynamics
Warfarin is the most widely used oral anticoagulant because of the predictability of its onset and duration and its excellent bioavailability.12 Intravenous administration of warfarin should provide the patient with the same blood concentration as an equivalent oral tablet dose, but the maximum plasma concentration will be reached earlier. The full anticoagulant effect of an oral tablet or I.V. dose produces similar biological effects in about the same amount of time. The injectable form of warfarin may be used when patients cannot take medications orally.8 At this time, there are no available data to show efficacy of administering injectable warfarin solution either orally or through a nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tube. However, oral tablets can be crushed and administered through feeding tubes or crushed and mixed with food (e.g., applesauce or pudding) and administered by mouth.
Warfarin is a racemic mixture of approximately equal proportions of two optically active stereoisomers (enantiomers), the rectus (r) and sinister (s) forms. The s-warfarin form is two to five times more potent as a vitamin K antagonist than is the R-warfarin form.12-14
Following oral administration of warfarin tablets, the drug is rapidly absorbed from the gastrointestinal tract and reaches peak blood concentrations within four hours. About 99% of the drug is stereoselectively bound to plasma proteins (primarily albumin) with less than 1% circulating as unbound, active free drug.8,10,11
Warfarin R- and S-isomers are eliminated almost entirely by hepatic metabolism but by different mechanisms. The R-warfarin form is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route), and the S-warfarin form is metabolized by reductases to reduced metabolites (warfarin alcohols), which have minimal anticoagulant activity. Warfarin metabolites are excreted principally into the urine, and to a lesser degree, into the bile. A number of cytochrome P-450 (CYP) isoenzymes are involved with the metabolism of warfarin (e.g., 2C9, 2C19, 2C8, 2C18, 1A2 and 3A4), and the CYP2C9 isoenzyme is primarily responsible for modulating the anticoagulant activity of warfarin.8,12-14 In addition to inactive metabolites of warfarin being excreted in the urine, less than 1% of warfarin is excreted unchanged in the urine. The effective half-life of warfarin after a single dose ranges from 20 to 60 hours with a mean half-life of about 40 hours. The half-life of the R-warfarin form ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours.8,9
It is generally reported that there are no significant age-related
differences in the pharmacokinetics of racemic warfarin.8
There is little if any difference in the clearance of S-warfarin
(the most potent warfarin isomer) in elderly versus younger subjects.
However, there appears to be a slight decrease in the clearance
of R-warfarin in the elderly compared to younger subjects. In
addition, older patients (60 years or older) appear to have an
increased responsiveness to the anticoagulant effects of warfarin.
The precise mechanism of the increased responsiveness to warfarin
is not known.8,9,15 Overall, renal clearance is considered
to be a minor determinant of an anticoagulant response to warfarin.
Therefore, no warfarin dosage adjustment is considered necessary
for patients with renal failure.8 Hepatic dysfunction
can potentiate the anticoagulant response to warfarin through
impaired synthesis of vitamin K clotting factors and decreased
metabolism of warfarin.8
Warfarin Drug Interactions
Concomitant drug therapy can influence the pharmacokinetics of
warfarin (e.g., reducing its absorption or altering its clearance)
or its pharmacodynamics (e.g., inhibiting the synthesis, increasing
the metabolic clearance of vitamin K-dependent coagulation factors,
or interfering with other pathways of hemostasis). Some drugs
also influence the anticoagulation effect of warfarin through
unknown mechanisms.8,16,17
Table 1. Selected Drugs That Potentiate the Anticoagulant
Effects of Warfarin and Their Mechanisms of Action.
Alcohol (chronic use, especially with liver disease)a
Amiodaronea
Anabolic steroidsb
Antibiotics/Antibacterials
a Inhibits metabolic clearance of warfarin.
b Unknown mechanisms .
c Antiplatelet aggregation effects.
d Inhibits vitamin K synthesis.
e Inhibits synthesis of vitamin K-dependent clotting
factors and inhibits vitamin K synthesis.
f Decreases platelet counts.
g Inhibits thrombin and other serine protease coagulation
enzymes.
h Decreases vitamin K absorption.
i Potentiates metabolism of vitamin K-dependent clotting
factors.
Drugs That Potentiate the Anticoagulant Effects of Warfarin. The mechanism of action for drugs interacting with warfarin can include a variety of known mechanisms and some as-yet unknown mechanisms. When administered together, the drugs listed in Table 1 have a high capability and probability for causing clinically important potentiation of the anticoagulant effects of warfarin8,16-18 regardless of their effect on plasma warfarin concentrations. Concurrent use of these drugs with warfarin should be avoided, but if their use together is a medical necessity, the dosage of warfarin should be titrated cautiously with frequent monitoring of therapy with appropriate laboratory tests, and the patient should be monitored very closely for hemorrhagic complications.5,6,8,16-20
Drugs such as aspirin (ASA), dipyridamole, sulfinpyrazone, nonsteroidal anti-inflammatory drugs (NSAIDs), and ticlopidine inhibit platelet aggregation function by blocking platelet production of thromboxane A2 or interfere with platelet membrane function by inhibiting ADP-induced platelet fibrinogen binding and can either increase the risk of bleeding or prolong bleeding time.19-25 By interfering with other hemostatic pathways, concomitant use of these drugs should be avoided because they can increase the risk of warfarin-associated bleeding. Factors such as the unsupervised use of these drugs, their prolonged effect on hemostasis, and the damage they can cause to the gastric mucosa (possibly producing upper gastrointestinal bleeding) also contribute to the concern generated over the concomitant use of aspirin and warfarin. Daily dosages of ASA in excess of 1 gram per day combined with high-intensity warfarin therapy have caused serious bleeding episodes.21,22,24 In contrast, low daily doses of ASA (e.g., 81 mg or less per day) are associated with minimal gastric side effects, inhibit platelet aggregation, maintain antithrombotic efficacy, and can be used in combination with lower-intensity warfarin. This combination of supervised use of ASA and warfarin has a better safety profile than previously used combination regimens.8,21-25
Drugs that Diminish the Anticoagulant Effects of Warfarin. Many of the drug-drug interactions with warfarin diminish the anticoagulant effect that occurs when the pharmacokinetics of warfarin metabolism are potentiated. In some patients, these interactions have the potential for causing life-threatening thromboembolic complications. When administered together, the drugs listed in Table 2 have a high risk for decreasing the anticoagulant effects of warfarin. Concurrent use of these drugs with warfarin should be avoided, but if their use together is a medical necessity, the dose of warfarin may need to be increased, and the patient should be monitored very closely for hemostatic complication.5,6,8,16-20
Table 2. Selected Drugs That Diminish the Anticoagulant
Effect of Warfarin and Their Mechanisms of Action
Alcohol (acute use)a
Antacidsd
Barbituratesa
Carbamazepinea
Celestipold
Chlordiazepoxidea
Cholestyramined
Griseofulvinb
Rifampina
Smokinga
Sucralfated
Vitamin K (from foods high in vitamin K and parenteral and enteral
nutritional products)c
a Increases metabolic clearance of warfarin.
b Mechanism of action unknown.
c Stimulates production of vitamin K clotting factors.
d Decreases absorption of warfarin.
Diseases and Foods that Alter the Anticoagulant Effects of Warfarin.
The pharmacodynamics of warfarin can be affected by dietary and disease-related factors that ultimately change its anticoagulant efficacy. Dietary considerations can become a major factor in warfarin therapy when the daily amount of vitamin K fluctuates significantly. The content of vitamin K is particularly high in certain green leafy vegetables containing phylloquinone (Table 3).8,9,18,26-29 Patients do not necessarily have to avoid these vegetables entirely, but diets rich in these foods can increase the daily intake of vitamin K enough to reduce the anticoagulant effects of warfarin. Conversely, the administration of broad-spectrum antibiotics along with poor vitamin K intake can lead to potentiation of the anticoagulant effects of warfarin.
Table 3. Selected Foods With High Vitamin K Content
Avocados
Broccoli
Brussels sprouts
Cabbage
Collard greens
Cucumber peel
Green scallion
Kale
Lettuce
Mustard greens
Parsley
Spinach
Turnip greens
Watercress
Certain disease, including fat-malabsorption syndromes, hepatic dysfunction, and hypermetabolic states, also influence the anticoagulant effects of warfarin. In particular, hepatic dysfunction and hypermetabolic states, such as high fever or hyperthyroidism, potentiate the response to warfarin through impaired synthesis and increased catabolism of coagulation factors, respectively.8,9,30 Conversely, fat malabsorption impairs warfarin absorption, thereby diminishing the anticoagulant effects of warfarin.
Adverse Drug Reactions
Bleeding from the gastrointestinal and urinary tracts is the most common complication of warfarin therapy. The incidence of any bleeding is 6-39% of patients during long-term anticoagulant therapy. Life-threatening bleeding episodes occur in about 2-8% of patients receiving long-term warfarin therapy. The higher the intensity of warfarin therapy, the greater the risk of bleeding.31,32
Skin necrosis is an uncommon adverse effect of warfarin that usually occurs within the first 10 days of beginning warfarin therapy. The cause of skin necrosis is reported to be secondary to the rapid depletion of protein C when warfarin therapy is started. The risk of protein C-related skin necrosis may be increased with large loading doses of warfarin or the presence of a protein C deficiency. If skin necrosis occurs, warfarin should be discontinued and heparin therapy should be initiated.33,34
"Purple toes syndrome" is a rare complication of warfarin therapy, characterized as bilateral, painful, purplish discoloration of the toes and other areas of the feet.35 This syndrome may be related to cholesterol microembolization from ruptured atherosclerotic plaques and may cause renal failure, stroke, and death. If this complication is suspected, warfarin should be discontinued.36
Contraindications
Warfarin is contraindicated in pregnant women or in women who are planning to become pregnant. Warfarin crosses the placental barrier and may cause fetal hemorrhage and/or birth defects. Warfarin should be avoided throughout pregnancy. If anticoagulant therapy is required, heparin therapy should be used.6,37
Warfarin is contradicted in patients with8:
Warfarin Therapy
Before initiating warfarin therapy, a clinician will usually obtain several laboratory tests to establish a patient's baseline or pretreatment status: blood coagulation status (International Normalized Ratio or INR and prothrombin time or PT), complete blood cell (CBC) count, platelet count, kidney function, liver function, and presence of heme in the urine and stools.
Because there are no rigid guidelines for dosing warfarin, high interpatient and intrapatient variability, and the complexity of warfarin's pharmacokinetics, establishing dosage requirements of warfarin in specific patients is subject to a high degree of variability. As a result, initial dosing of warfarin is often empiric. Two general methods of dosing warfarin are frequently used in medical practice.
Rapid warfarin induction is used to initiate warfarin therapy in patients whose antithrombotic requirements are considered urgent and who have no important factors present that would increase the risk of bleeding is called rapid warfarin induction. In these patients, anticoagulant therapy can be initiated with a loading dose of warfarin 10 mg orally per day (about twice the expected maintenance dosage) for two or three days of therapy. The warfarin dosage is then lowered to daily maintenance doses of approximately 5 mg per day. When loading doses of warfarin are given in this manner, they have been shown to produce a rapid and sometimes excessive reduction in the activity of clotting Factor VII, which can predispose patients to a higher risk of hemorrhage in the early stages of therapy. However, studies suggest that administering daily loading doses of warfarin in this manner does not produce a correspondingly rapid decline in the other vitamin K-dependent coagulation Factors II, IX, and X. With this method, a steady-state anticoagulation effect will be achieved in five to seven days.5,6,30,38 The clinician should remember that in the early stages of warfarin therapy there is a two- to three-day lag time before major effects on the PT and INR are manifested. For example, the laboratory values reported this morning are the result of the warfarin doses given two to three days ago. The following warfarin dosing plan illustrates how a typical patient would be dosed using this dosing method.
Example of Rapid Warfarin Induction
When two PTs and INRs run on successive days or intervals and the results obtained are in the therapeutic range without a dosage change, the frequency of monitoring the PT and INR can be reduced to once weekly. If the patient remains stable (no dosage changes or only minor dosage changes) and the INRs are therapeutic, PT and INR monitoring can be reduced to every two weeks, and, if the stability continues, monitoring can be reduced to once monthly. At any time when INRs fall outside the targeted range and the warfarin dosage has to be changed, the cycle of daily, weekly, or other intervals for PTs and INRs should be repeated until desired INRs and therapy stability are regained. A CBC should be obtained on most patients every three to six months or more often if signs and symptoms of blood loss are present.
Slow warfarin induction is generally for patients whose antithrombotic need is not considered urgent or who have some factors that would increase the risk of bleeding. In these patients, antithrombotic therapy is initiated with warfarin doses of 5 mg orally per day. When using this method, a steady-state anticoagulation effect will usually be achieved in about five to seven days. Since a steady-state anticoagulation effect is achieved by both dosing methods in comparable time periods, the major advantage of this second method is that it is less likely to subject a patient to bleeding episodes early in therapy.5,30,38 The following warfarin dosing plan illustrates how a typical patient would be dosed using this second, slower method.
Example of Slow Warfarin Induction
Because elderly patients tend to be more sensitive to the anticoagulant effects of warfarin and because of the increased risk of bleeding associated with bolus doses, this dosing method may subject older patients to increased risk of bleeding. For this reason, a warfarin dose of 3-4 mg may be a more appropriate starting dose.5,6,8,9
Warfarin has both a slow onset and a slow decline of pharmacologic activity. A single-strength 5-mg tablet is often prescribed for patients because fractions or multiples of the tablet can be conveniently given when different doses or alternating dosages are needed. When a patient's blood coagulation laboratory test results are unacceptable (i.e., either low or high test results) and a warfarin dosage adjustment is needed, the new daily dosage should be based on the total weekly dosage (measured in milligrams of warfarin). Except in some situations where it may be necessary to withhold the daily dose of warfarin for one or more days, an increase or decrease of 10-20% in the total weekly dosage is generally sufficient to manage most changes in warfarin dosage (Table 4).5,38
Table 4. Daily Warfarin Dosage Schedule Using a Proposed Daily Reduction Schedule
| Daily Doses (mg/day) | Total Weekly Dosage Reduction | |||||||
| Mon | Tues | Wed | Thur | Fri | Sat | Sun | Dose (mg/wk) | % Dose Decrease |
|---|---|---|---|---|---|---|---|---|
| 5 | 5 | 5 | 5 | 5 | 5 | 5 | 35.0 | ... |
| 5 | 5 | 5 | 5 | 5 | 5 | 2.5 | 32.5 | 2.5 ( 7.1) |
| 2.5 | 5 | 5 | 2.5 | 5 | 5 | 5 | 30.0 | 5.0 (14.3) |
| 2.5 | 5 | 2.5 | 5 | 2.5 | 5 | 5 | 27.5 | 7.5 (21.4) |
Because of warfarin's long half-life and its ability to substantially increase the risk of bleeding, patients taking warfarin should advise each of their physicians, dentists, and dental hygienists of this fact before surgical or dental procedures are performed.
When a life-threatening event (e.g., pulmonary embolism) requires more urgent antithrombotic effect, an I.V. bolus of heparin followed by continuous infusion of heparin is generally administered along with oral maintenance doses of warfarin. When I.V. heparin is administered in this manner, therapeutic anticoagulant effects can be produced within 24 hours. Oral warfarin can be added to the patient's regimen on day two of heparin therapy. As warfarin effects become evident by an increase in the INR from baseline, warfarin will potentiate the heparin effects, increasing the aPTT. After a steady-state anticoagulant therapeutic effect is achieved with warfarin and maintained for at least two consecutive days, heparin therapy may be discontinued and the patient maintained on oral warfarin tablets.5,30,38
Monitoring Anticoagulant Therapy
About one million people a year in the United States receive warfarin for the treatment of various thromboembolic disorders. Because of interpatient and intrapatient variability, and unpredictable pharmacokinetic and pharmacodynamics of warfarin, close therapeutic monitoring of anticoagulant therapy employing clinical laboratory tests is necessary to ensure desired therapeutic outcomes and to help avoid toxicity and adverse drug effects.5 In most medical practices, the PT and the INR are commonly used to monitor and evaluate the anticoagulant effects of warfarin therapy.
Prothrombin Time. The prothrombin time (PT) is a clinical laboratory test that measures the time in seconds it takes for clotting to occur in a patient's blood specimen. It has been used almost exclusively to monitor oral warfarin anticoagulant therapy in the United States for the past 50 years. For interpretative purposes, a patient's PT is compared with a "patient control reference range" (e.g., 11.2 to 13.1 seconds) and a "mean reference control" (e.g., 12.3 seconds), which are specific control values for the clinical laboratory.
A patient's PT increases from baseline or pretreatment level in response to depression of vitamin K-dependent procoagulant clotting factors (Factors II, VII, IX, and X). At the initiation of anticoagulant therapy, the PT primarily reflects the depression of Factor VII, since this factor has the shortest half-life (five hours) of the vitamin K-dependent factors. During maintenance therapy with warfarin, the test also reflects changes in Factor II (prothrombin) and Factor X levels.5 Some clinicians consider anticoagulant therapy with warfarin therapeutic if the PT value is 1.5 to 2 times the mean reference control for the laboratory. This ratio of the patient's PT to the mean reference control for the laboratory is termed the prothrombin time ratio (PTR).5,6,26
The PT laboratory assay is performed by adding a mixture of calcium and thromboplastin reagent to citrated plasma. The thromboplastin reagent is a phospholipid-protein extract of tissue that contains both tissue factor and the phospholipid necessary to promote the activation of Factor X by Factor VII. Because there can be marked differences between the sensitivity of thromboplastin reagents from different commercial sources,38-40 PTs determined using reagents with different sensitivity ratings may not be directly comparable. Thromboplastin reagents used in the United States vary markedly in their sensitivity or responsiveness, depending on tissue origin and methods of preparation. Further, thromboplastin reagents used in Europe are more reactive than the ones used in the United States, making standardized reporting of PT values between clinical laboratories difficult.27
International Normalized Ratio. Attempts to standardize the PT laboratory test led to the development of a mathematical comparison based on the linear relationship between the logarithm of the PTR obtained with the use of laboratory reference and test thromboplastins. The PTR is determined by dividing the patient's PT by the laboratory's PT mean reference control. This International Normalized Ratio (INR) model 39-44 acts to "calibrate" each thromboplastin reagent with an International Sensitivity Index (ISI), which measures the ability of a given thromboplastin to detect a reduction in the vitamin K-dependent coagulation factors. The lower the thromboplastin's ISI, the more responsive the reagent and the closer the derived INR will be to the observed PTR. The World Health Organization5 (WHO) reference thromboplastin reagent has an ISI value of 1.0. A patient's INR is calculated as follows:
INR = [PT (patient)/PT (mean patient control)]ISIThe INR determination was adopted by WHO in 19825 as the world standard for monitoring warfarin therapy and the organization encouraged physicians to discontinue using the PT test and replace it with the INR.
The major advantage of the INR is that it can be used to standardize the reporting of PTs by converting the PTR determined with any thromboplastin reagent into an INR. Disadvantages of using the INR include:
These disadvantages can be overcome by having better educated laboratory personnel and by using sensitive thromboplastins with ISI values close to 1.0.45
Once an appropriate daily warfarin dosage is established and PTs and INRs are therapeutic and stable, many institutionalized patients receiving long-term warfarin therapy maintain a reasonably stable response. When unexpected INR and PT test fluctuations occur, warfarin dosage requirements may be altered because of changes in the patient's diet; concomitant medication use (especially new prescription or non-prescription drugs, or discontinued medication), illness, patient noncompliance, intermittent smoking or alcohol consumption, major changes in dietary intake of vitamin K (including entural and parenterical nutritional supplements), or laboratory error. If none of these possible causes is determined to be responsible for the variation, laboratory personnel should be questioned to determine whether a new or different throm-boplastin reagent, with a different ISI value, may have been used to perform the PT test.
Therapeutic Range of INRs for Warfarin Therapy. Based on clinical studies, optimal therapeutic ranges for laboratory evaluation of oral warfarin therapy using INRs were established by a panel of national medical experts. Guidelines on the intensity of anticoagulation therapy for many medical indications were adopted by the American College of Chest Physicians (ACCP) in 19896 and revised in 1992 and 1995 (Table 5).5,6,26 Currently, the ACCP recommends two levels of intensity of warfarin therapy for thromboembolic disorders: a less intense warfarin therapy, corresponding to an INR of 2.0 to 3.0; and a more intense warfarin therapy, corresponding to an INR of 2.5 to 3.5. These ACCP recommendations were based on studies showing that, when low-dose anticoagulant therapy achieved the desired level of intensity, therapy was as effective as that achieved with higher doses, and patients had a significantly lower incidence of bleeding.
Table 5. Guidelines For Therapeutic Range of INRs for Warfarin Therapy26
| Indication for Warfarin | Suggested INRa |
| Dilated cardiomyopathy | 2.0-3.0 |
| Prophylaxis of venous thrombosis (high-risk surgery) | 2.0-3.0 |
| Treatment of venous thrombosis | 2.0-3.0 |
| Treatment of pulmonary embolism | 2.0-3.0 |
| Prevention of systemic embolism | 2.0-3.0 |
| Tissue heart valves |   |
| Mechanical prosthetic heart valves | |
| Acute myocardial infarction (to prevent systemic embolism) | |
| Valvular heart disease | |
| Atrial fibrillation | |
| Mechanical prosthetic valves (high risk) | 2.5-3.5 |
a INR indicates International Normalized Ratio.
Reversing the Warfarin Effects
The anticoagulant effect of warfarin can be reduced or reversed by lowering the dose, withholding or discontinuing treatment, administering vitamin K, or replacing the defective vitamin K-dependent coagulation factors with fresh frozen plasma or plasma concentrates (Table 6).6,8 Generally, reducing or withholding warfarin therapy lowers the INR slowly over about 24-48 hours, depending on the level of the INR and the dose of warfarin. The INR will not return to baseline within this time frame. This lag time reflects the replacement of warfarin-impaired coagulation factors with newly synthesized, fully carboxylated proteins as the plasma warfarin levels are decreased.
1. If the INR is above the therapeutic range but below 6.0, the patient is not bleeding, and rapid reversal is not indicated, then the next few warfarin doses can be omitted and warfarin commenced at a lower dose when the INR or PT returns to the therapeutic range. Bleeding with INRs in this range is usually caused by something other than the elevated INR.
2. If the INR is above 6.0 but below 10.0 and the patient is not bleeding, or more rapid reversal is required for elective surgery, then vitamin K 1-2 mg subcutaneously can be given with the expectation that demonstrable reduction of the INR will occur at 8 hours; many patients will be in the therapeutic range of 2.0 to 3.0 in 24 hours. If the INR is still too high, the dose of 0.5 mg can be repeated every 12 hours. Warfarin treatment may resume at a lower dose when the INR is in therapeutic range.
If a dose of vitamin K (1-2 mg) is to be given intravenously, dilute and infuse the solution over 10-20 minutes. If a 10-mg I.V. dose of vitamin K is to be given, dilute and infuse the solution over 20-30 minutes.
3. If the INR is above 10 but below 20 and the patient is not bleeding, a higher dose of vitamin K of 3 to 5 mg S.C. or I.V. should be given with the expectation that demonstrable reduction of the INR will occur at 6 hours. The INR should be checked every 6-12 hours; vitamin K can then be repeated every 12 hours if necessary. It should be noted that some clinical laboratories may not report INRs if they exceed an INR value of 10.
4. If a rapid reversal of anticoagulant effect is required because of serious bleeding or major warfarin overdose (INR > 20), a vitamin K dose of 10 mg should be given by subcutaneous injection and check the INR every 6 hours. Vitamin K may be repeated every 12 hours and supplemented with 1-2 units of fresh frozen plasma transfusion or factor concentrate depending on the urgency of the situation.
5. In case of life-threatening bleeding or serious warfarin overdose, replacement with prothrombin complex concentrate is indicated, supplemented with 10 mg of intravenous vitamin K, to be repeated as necessary depending on the INR. It is not usually necessary to give vitamin K for the immediate reversal if prothrombin complex concentrates containing factor VII are used.
6. If continued warfarin therapy is indicated after high doses of vitamin K administration, then heparin can be given until the effects of vitamin K have been reversed, and the patient becomes responsive to warfarin. The use of smaller doses of vitamin K has the advantage of reversing the activity but not interfering with the total effects of warfarin.
a Guidelines for reversing or lowering the anticoagulant
activity of warfarin have recently been published in reference
1. These recommendations are based on recent findings (see reference
6) that lower doses of vitamin K may be used to lower the INR
or PT without producing a state of warfarin resistance.
If a more rapid reversal is required, low-dose vitamin K may be administered by the oral route, intramuscular, I.V., or by subcutaneous (S.C.) injection. Of these, the S.C. route of administration is preferred. Intravenous infusion of vitamin K should be done only when a person is in shock or when a bleeding episode is considered life-threatening. When indicated, I.V. vitamin K should be administered by slow infusion over 20-30 minutes (not to exceed 1 mg per minute) to minimize the risk of serious anaphylactic reaction. Low S.C. doses of vitamin K (0.5-1.0 mg) are recommended if moderate lowering of the INR and partial reversal of anticoagulant effects of warfarin are required. For example, repeated doses of 10 mg or more of vitamin K may render the patient resistant to warfarin's anticoagulant effects for up to seven days. With parenteral vitamin K administration, a partial reversal of the anticoagulant effect of warfarin is evident within six hours, with peak effects in about 12 hours.5,6,8 In the case of warfarin overdose, vitamin K administration may have to be repeated because the vitamin is cleared from the circulation more rapidly than warfarin. If complete reversal of the anticoagulant effect and inhibition of vitamin K clotting factors are considered urgent because of serious warfarin overdose or life-threatening bleeding, high-dose vitamin K (e.g., 10 mg S.C. or I.V. repeated about every 12-24 hours as necessary) should be supplemented with fresh frozen plasma or plasma concentrates containing the vitamin K-dependent clotting factors. In these situations, very close monitoring of the patient for hemorrhagic or hemostatic complications is essential and a neurologic assessment should be performed every four hours.
Indications for Warfarin Therapy
Warfarin therapy is indicated for the treatment of a variety of thromboembolic disorders.5,6,26,30,46-58 Oral anticoagulants have been proven effective in the prevention of systemic arterial embolism in patients with atrial fibrillation or dilated cardiomyopathy, and in patients who have received prosthetic heart valves. They are also used to prevent recurrent infarction and death in patients after an acute myocardial infarction (AMI), an AMI from occurring in patients with peripheral arterial disease, venous thromboembolism, and stroke. Target INRs for these thromboembolic disorders range from 2.0 to 3.5 (Table 5).
When warfarin therapy is not continued for a period of time following the initial treatment of an acute thromboembolic disorder, patients are predisposed to recurrent venous thromboembolism. The optimal duration of anticoagulant therapy for venous thromboembolism is a controversial issue. Most clinicians recommend four to eight weeks of oral anticoagulant therapy for patients with calf vein thrombosis, and 12 to 24 weeks of treatment for patients with proximal vein thrombosis or pulmonary embolism. Warfarin therapy should be continued for more than three months in patients with recurrent venous thrombosis and/or pulmonary embolism, antithrombin III deficiency, protein C deficiency, or protein S deficiency. Warfarin should be given indefinitely in patients with documented thrombosis who have one of the three inherited molecular abnormalities (deficiency of antithrombin III, protein C, or protein S) and those who have a lupus anticoagulant or anticardiolipin antibodies. Patients with two documented episodes of recurrent venous thrombosis or pulmonary embolism and patients with uncontrolled cancer should be treated with warfarin indefinitely.59
The antiplatelet aggregation effect of low-dose ASA therapy is
also reported to be effective in reducing the risk of thromboembolic
events, although it is considered less effective than warfarin.
Thus, ASA may be considered as a possible alternative therapy
for warfarin in these patients needing anticoagulant therapy for
whom warfarin may be contraindicated. For patients who are either
allergic to ASA or who cannot tolerate aspirin therapy, the drug
ticlopidine should be considered as a possible alternative for
ASA therapy.
Suggested Guidelines for Monitoring Warfarin Pharmacotherapy
Consultant pharmacists in LTCFs perform an indispensable function in the overall process of risk management by reviewing and monitoring the drug therapy of their residents. Pharmacists focus on assessing the appropriateness of drug therapy and making recommendations to physicians on a variety of patient-related and drug-therapy-related matters, including identifying adverse drug reactions or toxicity, detecting and evaluating the importance of potentially life-threatening drug-drug interactions, reducing or increasing drug dosages, withholding or discontinuing drugs, replacing drugs with more appropriate therapeutic agents, and obtaining laboratory tests. Over the past few years, physicians have increasingly relied on and valued the input of consultant pharmacists on these matters, and their acceptance of pharmacists' drug therapy recommendations is reportedly as high as 80-90%.60,61
Pharmacists working closely with physicians use drug protocols in some patient-care environments to provide unique anticoagulation services, such as initiating and titrating warfarin and/or heparin therapy to achieve a patient's targeted INR, PT, and aPTT laboratory test results without first contacting the physician; ordering related laboratory tests; evaluating laboratory test results; and assessing patient response to therapy for institutionalized and ambulatory patients. This type of practice has been fostered in part by an expanding number of indications for the use of warfarin, the complexity and variability of patient response to warfarin therapy, an increasing number of patients requiring long-term anticoagulant therapy, and the need for close therapeutic drug monitoring for warfarin. For patient safety and to assure therapeutic effects, patients taking anticoagulants require comprehensive follow-up and therapeutic monitoring. Warfarin is the most commonly used oral anticoagulant. It has a very narrow therapeutic index, and a number of factors influence its pharmacologic effects.
Monitoring Warfarin In Long-term Care Patients
Establishing a proactive medication review process that protects
patients from adverse drug reactions, whether caused by drug interactions
or changes in disease state, is the consultant pharmacist's major
role in risk management. Documenting the process is the second
necessary step in limiting financial exposure in the event that
an adverse event occurs. When performing a drug regimen review
of a patient who receives warfarin, the pharmacist must review
and evaluate a number of patient-,drug-, and disease-related factors.
The following suggested systematic approach to drug-regimen review62
provides the pharmacist with a comprehensive listing of factors
that must be evaluated in patients for whom warfarin is prescribed
for the first time as well as those who have been taking it for
some time. By working through the following step-wise approach,
relevant patient, drug, and disease considerations will be reviewed.
As patient data are collected, this information should be maintained
on a written patient record or stored on a computerized patient
profile for documentation and future reference. This suggested
comprehensive step-wise approach to patient, drug therapy, and
disease management helps ensure that consistent patient care is
provided and helps reduce the risk of adverse patient and drug
therapy outcomes.
Step 1: Patient Data Collection
The pharmacist should begin the process of managing the patient, drug therapy, and disease by collecting general patient data such as age, gender, vital signs (temperature, heart rate, respiration rate, and blood pressure), height and weight (actual and ideal body weight), history of cigarette smoking (pack-years), history of alcohol use (extent and amount), and known drug allergies or sensitivities. The pharmacist can obtain this information from a patient interview or extract it from the physician's and nurses' admission history and physical examination, physician progress notes, nursing progress notes, or graphics sections in the patient's medical record.
Formulate a Patient Problem List. The pharmacist should determine whether the patient has any acute or chronic thromboembolic disorders or other medical conditions, as well as detect the presence of any acute or chronic physical signs or symptoms of these disorders. The effects of acute or chronic diseases on warfarin therapy may reduce or exacerbate its anticoagulant effects. The pharmacist can obtain this information from the admission history, physical examination, physician progress notes, and nursing notes sections of the patient's medical record.
Determine Current and Past Medication Histories. The pharmacist should formulate a current listing of routine and "as needed" medications, their start dates, dosages, dosage intervals, and dates of discontinuation. These medications should be reviewed and evaluated to help avoid any serious drug-drug interactions with warfarin or subjecting the patient to a higher risk of bleeding. Each medication should also be thoroughly reviewed to determine its appropriate role in the treatment of at least one of the patient's medical conditions. Any medication deemed not needed for the treatment of a specific diagnosis or medical problem should be considered an unnecessary drug and presented to the medical staff for discontinuation. The pharmacist can obtain this information from the physician's orders and medication administration record of the patient's medical record. For further background information, the pharmacist can review the information on drug-drug interactions with warfarin and the pharmacokinetic and pharmacodynamic effects of warfarin that may either potentiate or diminish its anticoagulation effects (Tables 1 and 2).5,6
Determine Laboratory Test Results. The pharmacist should obtain and evaluate the results of all laboratory tests as possible indicators of adverse drug reactions and to determine whether the patient's disorder is or is not controlled with the current anticoagulant therapy. Pertinent laboratory test results include INR, PT, urinalysis, heme test of stools, hemoglobin, hematocrit, platelet count, kidney function (e.g., serum creatinine, estimated creatinine clearance, and blood urea nitrogen [BUN]), liver function (e.g., SGOT [AST], SGPT [ALT]), alkaline phosphatase, and total bilirubin), and serum albumin level. Ideally all of these laboratory tests are helpful in performing an in-depth review, but some tests may not always be available on a regular basis. Periodic PT, INR, CBC tests are essential. The pharmacist can obtain this information from the laboratory test section of the patient's medical chart. In some institutions, the INR and PT test results and current warfarin dosage will be recorded on an anticoagulation flow sheet often located near the front portion of the medical chart.
Determine Dietary Status. The pharmacist should determine the patient's current diet, its content of protein and vitamin K (e.g., green leafy vegetables), and caloric needs. The facility's clinical dietitian can be very helpful in providing this information. The pharmacist can locate these data in the physician's orders and dietitian's assessment and progress notes within the patient's medical chart. For further information, the pharmacist should be familiar with the vitamin K content of selected foods (Table 3).
Step 2: Patient Assessment and Evaluation
Determine Appropriateness of Warfarin Therapy Intensity for
the Thromboembolic Diagnosis. The pharmacist should locate
the primary indication for warfarin therapy in the patient's chart,
along with the physician's plan for its use and the expected duration
of therapy and be knowledgeable of the signs and symptoms of the
thromboembolic disorder being treated. The pharmacist should also
determine that the use of warfarin conforms to ACCP guidelines
for appropriate use of warfarin therapy for thromboembolic disorders
(Table 5).26 For some thromboembolic disorders such
as transient ischemic attacks (TIAs) or cerebrovascular accidents
(CVAs), an antiplatelet aggregation drug may be safer and more
appropriate.
STEP 3: Suggested Guidelines For Initiating, Adjusting, and Monitoring Warfarin Therapy
Determine Appropriateness of Initial Warfarin Dosage Regimen. In most instances, patients will be anticoagulated using one of the two warfarin dosage regimens previously discussed; the pharmacist must determine its appropriateness. One method is to give loading doses of warfarin 10 mg orally per day for two to three days followed by maintenance doses of approximately 5 mg per day. This is a typical warfarin regimen for many patients, but it may be inappropriate for elderly patients. The second method is to give maintenance doses of warfarin 5 mg orally per day. This regimen is probably more appropriate for elderly patients. Because of a reported exaggerated anticoagulant response associated with advancing age, the elderly may require lower maintenance doses of warfarin than younger patients. Using patient data, especially risk factors for warfarin therapy along with drug and disease monitoring parameters, the pharmacist must review the appropriateness of the patient's warfarin dosage regimen.63
Titrate Warfarin Dosages. Depending on individual patients and their response to warfarin therapy (e.g., INR and PT test results), a patient's total weekly dosage of warfarin may need to increase or decrease by 10-20%. If adjusting the current warfarin dosage is necessary, divide the weekly total milligrams being taken by seven to obtain the adjusted daily dose (Table 4). The pharmacist should make appropriate recommendations to adjust the patient's warfarin doses to achieve desired INR and PT values and meet ACCP guidelines. The pharmacist should be aware that once warfarin therapy is stabilized, frequent changes in the warfarin dosage may indicate poor patient compliance, undesirable dietary changes or drug-drug interactions, which can lead to abnormal coagulation test values. Before adjusting the warfarin dosage, the cause of the abnormal values should be determined.
Assess Appropriateness of Time Periods Between Dosage Changes and Obtaining INR and PT Tests. If a patient has had a recent change in warfarin dosage, it will take five to seven days or longer before INRs and PTs reach the new steady-state values. The pharmacist should compare the dates of dosage changes with the dates when INR and PT tests were run to determine if they were run before or after a new steady state level of coagulation factors was achieved.
Monitor Warfarin Therapy. Patients taking warfarin who are stable and for whom treatment is therapeutic should have coagulation laboratory tests (INR and PT) run at least monthly. Initially, coagulation laboratory tests on unstable patients should be run daily to detect expected increases in the PT and INR as well as detection of excessive anticoagulant activity. When patients are stable and the warfarin therapy is therapeutic (INR is in appropriate range for the diagnosis), run tests two to three times weekly for two weeks, then once monthly. A CBC or hemogram should be checked at least every three to six months to help detect any blood loss and to monitor platelet counts.
Bleeding is the most common adverse effect of warfarin and signs of bleeding will often appear first as excessive bruising of the skin or in the urine or stools. A patient's urine and stools should be periodically checked for occult blood. Other signs or symptoms of bleeding include hypotension resulting in falling episodes and mental confusion. When a 2 g/dL drop in the hemoglobin value from baseline has been documented without obvious bleeding signs or symptoms, the patient may be bleeding into a body cavity or space.
Reverse Warfarin Anticoagulant Effects with Vitamin K. The use of oral, subcutaneous, or intravenous vitamin K can be very helpful in emergency situations, but may not be needed for patients with only mildly elevated INRs and PTs (Table 6). Small doses of vitamin K plus withholding the dose of warfarin for a short time period will usually return the INR and PT to desired levels. Administering frequent high doses of vitamin K may completely inhibit synthesis of vitamin K-dependent clotting factors and render the patient resistant to the anticoagulant effects of warfarin for several days. If this situation occurs, the patient can be at high risk for a thromboembolic event. If the patient is not bleeding, withholding the drug for a few days will usually resolve many situations. For further information, the pharmacist should review additional information on ACCP guidelines for reversing the anticoagulant effects of warfarin (Table 6).
Document Drug-Regimen Review Findings. Documentation of a patient's drug-regimen review findings by the consultant pharmacist must be included in the patient's medical chart and communicated to the patient's physician, the director of nursing, and the facility's administration. Adequate documentation improves overall patient care, helps decrease the risk of liability for consultant pharmacists, physicians, and LTCF administrative staff.
Conclusion
Therapeutic management of anticoagulation therapy in long-term care patients is a major responsibility and presents a unique opportunity for appropriately trained consultant pharmacists to provide pharmaceutical care to institutional and ambulatory patients. Pharmacists' activities for patients should:
By functioning as members of the health care team and essential partners in the process of risk management, consultant pharmacists help improve overall drug therapy, which results in better patient care and reduces the risk of liability.
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Charles H. Brown, M.S. Pharm., is Associate Professor of Clinical Pharmacy, Purdue University, School of Pharmacy and Pharmacal Sciences, West Lafayette, and Clinical Pharmacist, Critical Care, Lafayette Home Hospital, Lafayette, Indiana.
Address for reprints: Charles H. Brown, Purdue University School of Pharmacy and Pharmacal Sciences, Robert Heine Pharmacy Building, West Lafayette, IN 47907
Acknowledgment: To Marta Brooks, Pharm.D., for her helpful critique of this manuscript.
Copyright © 1996, American Society of Consultant
Pharmacists, Inc. All rights reserved.