CASE 11-5, QUESTION 6: What possible adverse effects from oral anticoagulation therapy should be
considered in A.W. and how should they be monitored?
Bleeding is the most common adverse effect associated with anticoagulation. A
summary of experimental and observational inception cohort studies determined that
the average annual frequency of fatal, major, and all (major or minor) bleeding in
patients treated with warfarin was 0.6%, 3%, and 9.6%, respectively.
wide variation in bleeding frequencies has been reported, likely due to differences in
patient characteristics, treatment protocols, and the definition and assessment of
The most common sites for anticoagulation-related bleeding are the nose, oral
pharynx, and soft tissues, followed by the GI and urinary tracts. Hemarthrosis
(bleeding into joint spaces) and retroperitoneal and intraocular bleeding represent
less common hemorrhagic complications of anticoagulation therapy.
and urinary tract bleeding in anticoagulated patients is often caused by previously
undiagnosed lesions. Menstrual blood flow may also be increased and prolonged in
women taking anticoagulants. This problem may be clinically significant if there is an
underlying pathologic condition (ovarian cysts, uterine fibroids, or polyps) resulting
For VTE treatment, the DOACs rivaroxaban and apixaban both showed
significantly lower rates for major bleeding in clinical trials compared to warfarin,
whereas edoxaban and dabigatran showed comparable rates. A recent meta-analysis
demonstrated no statistically significant differences for efficacy and safety associated
with most treatment strategies used to treat acute VTE compared with the
88 However, it showed that the UFH/VKA combination is
associated with a higher rate of recurrent VTE and that rivaroxaban and apixaban
demonstrated a lower risk for major bleeding.
Although it is uncommon, intracranial bleeding resulting in hemorrhagic stroke
represents the most common cause of fatal bleeding associated with warfarin therapy.
Rates of intracranial hemorrhage associated with anticoagulants have been estimated
to range from 0.3% to 2%, and up to 60% are fatal.
6 The DOACs have been shown to
be as effective as warfarin for stroke prevention in patients with atrial fibrillation
and are associated with lower rates of intracranial hemorrhage and reduced all-cause
mortality. However, all of the DOACs, except for apixaban, are associated with a
25% increased risk of gastrointestinal bleeding.
Many factors influence the risk of hemorrhagic complications associated with
warfarin. The frequency of bleeding is higher in the first 3 months of therapy than
90 Unlike heparin, the intensity of anticoagulation with
warfarin directly influences the risk of bleeding, including intracranial hemorrhage.
Other patient-specific variables that influence the risk of warfarin-associated
bleeding include a history of GI bleeding, serious comorbid disease (including
Several bleeding risk scores are available, including HAS-BLED (Hypertension,
Abnormal renal or liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs and
alcohol) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), which
may identify patients at higher risk of bleeding; however, how best to use these tools
92–94 None of these bleeding risk scores have been very effective
at predicting risk for major or fatal bleeding in the first 3 months of anticoagulation
for VTE, and none have performed well in the elderly in predicting major bleeding in
the first 90 days of anticoagulation for VTE.
Bleeding complications in A.W. can be minimized by careful attention to the signs
and symptoms of bleeding by the patient and her caregivers, maintenance of the INR
within the therapeutic range, avoidance of therapy with concomitant drugs known to
increase the risk of bleeding or to increase the INR, and routine outpatient follow-up
for INR monitoring and clinical assessment.
Warfarin-induced skin necrosis is a rare but serious adverse effect of oral
anticoagulation, occurring in approximately 0.01% to 0.1% of patients treated with
98 Patients present within 3 to 6 days of the initiation of warfarin therapy
with painful discoloration of the breast, buttocks, thigh, or penis. The lesions
progress to frank necrosis with blackening and eschar. Skin necrosis appears to be
the result of extensive microvascular thrombosis within subcutaneous fat and has
been associated with hypercoagulable conditions, including protein C or protein S
deficiency. In these patients, rapid depletion of protein C before depletion of vitamin
K-dependent clotting factors during early warfarin therapy can result in an imbalance
between procoagulant and anticoagulant activity, leading to initial hypercoagulability
and thrombosis. Adequate use of injectable UFH, LMWH, or fondaparinux during
initiation of warfarin can prevent the development of early hypercoagulability.
Warfarin therapy should be discontinued in patients who develop skin necrosis.
However, subsequent warfarin therapy is not necessarily contraindicated if it is
required for treatment or prevention of thromboembolic disease. In patients with
protein C or protein S deficiency and a history of skin necrosis, warfarin therapy can
be restarted at low dosages if given with UFH/LMWH/fondaparinux. Therapy is
maintained until the INR has been within the therapeutic range for 72 hours.
Supplementation of protein C through administration of fresh frozen plasma also may
Purple toe syndrome is a rarely reported adverse effect that typically occurs 3 to 8
weeks after the initiation of warfarin therapy and is unrelated to intensity of
99 Patients initially present with painful discoloration of the toes that
blanches with pressure and fades with elevation. The pathophysiology of this
syndrome has been related to cholesterol microembolization from atherosclerotic
plaques, leading to arterial obstruction. Because cholesterol microembolization has
been associated with renal failure and death, warfarin therapy should be discontinued
in patients who develop purple toe syndrome.
QUESTION 1: E.N. is a 42-year-old man newly diagnosed with unprovoked DVT. He will be treated as an
One of the keys to successful oral anticoagulant therapy is appropriate outpatient
management. In comparison with routine medical care, management of warfarin
clinics is associated with significant reductions in bleeding and thromboembolic
complications, with reductions in the rates of warfarin-related hospital admissions
and ED visits, and with outcome-based cost savings for healthcare organizations.
Pharmacist-managed anticoagulation clinics offer many benefits for the management
of anticoagulation therapy, including improved dosing regulation, continuous patient
education, early identification of risk factors for adverse events, and timely
intervention to avoid or minimize complications.
and to improve his clinical outcomes.
The availability of portable INR self-testing devices also allows the option of
anticoagulation monitoring in the home setting. Patient self-testing of INRs has been
shown to result in comparable outcomes to high-quality anticoagulation delivered via
6 For patients that may prefer this monitoring method, a
structured education and follow-up program should be designed and integrated with
the patient’s provider or the anticoagulation management service.
provider to ensure the safety and efficacy of warfarin therapy?
Successful warfarin therapy depends on the active participation of knowledgeable
6 The anticoagulant effect of warfarin is influenced by various factors, and
fluctuations in the intensity of the anticoagulant effect of warfarin can increase the
risk of both hemorrhagic complications and recurrent thromboembolism. Pharmacists
and other providers can improve adherence to the medication schedule, as well as
ensure the safety and efficacy of warfarin therapy, by providing appropriate
education to patients treated with this agent.
Key elements that form the basis of a thorough patient education program for
anticoagulation therapy are listed in Table 11-20. This information may be conveyed
through written teaching materials, recorded instruction, individual or group
discussion, or a combination of these approaches. Many useful educational tools are
available from the manufacturers of the oral anticoagulants and from other
E.N. should receive extensive education about warfarin therapy in an individual
teaching session or an organized education program. A wallet card, medical bracelet,
or alternative method of identifying him as a patient treated with warfarin should be
provided. The healthcare provider who assumes responsibility for his outpatient
warfarin therapy will need to provide continuing reinforcement of the essential
elements of medication information at each follow-up visit.
Factors that Influence Warfarin Dosing
INR is 1.7. What factors might account for this change in the intensity of anticoagulation?
Patients should always be questioned about their understanding of the prescribed
dose and their adherence to the prescribed regimen. Questions might include, “What
dose of the medication have you been taking?” “What time of the day do you take
your medication?” and “How many times in the last week did you miss a dose of your
medication?” If there is no evidence of misunderstanding of the correct dose or of
noncompliance, numerous other factors should be considered that are known to
influence warfarin dosing requirements in individual patients during both initiation
and maintenance phases of therapy. Changes in dietary vitamin K intake, underlying
disease states and clinical condition, alcohol ingestion, genetic factors, and
concurrent medications can significantly change the intensity of therapy, resulting in
the need for dosing adjustments to maintain the INR within the therapeutic range. In a
dosing cohort of 1,015 patients on warfarin therapy, body surface area, age, target
INR, amiodarone use, smoker status, race, current thrombosis, VKORC1
polymorphism 1639/3673 G.A, CYP2C9(*)3, and CYP2C9(*)2 were all independent
predictors of warfarin therapeutic dose.
Key Elements of Patient Education Regarding Oral Anticoagulation
Identification of generic and brand names
Visual recognition of drug and tablet strength
What to do if a dose is missed
Recognition of signs and symptoms of bleeding
Recognition of signs and symptoms of thromboembolism
What to do if bleeding or thromboembolism occurs
anticoagulation provider when invasive procedures are being scheduled
When, where, and with whom follow-up will be provided
Dabigatran only:swallow whole, keep in original container, caution about potential for GI upset
Rivaroxaban only: take with food (evening meal)
Warfarin only: importance of INR monitoring and expected frequency, consistency of vitamin K
INR, international normalized ratio.
The two primary sources of vitamin K in humans are the biosynthesis of vitamin K2
(menaquinone) by intestinal bacteria and dietary intake of vitamin K1
The US-recommended daily allowance for vitamin K is 70 to 140 mcg/day, and the
typical Western diet provides approximately 300 to 500 mcg/day.
found in high concentrations in certain foods, including green leafy vegetables
(asparagus, broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, endive,
kale, lettuce, parsley, spinach, and turnip greens), soy milk, certain oils, certain
nutritional supplements, and multiple vitamin products.
Variations in vitamin K intake have been linked to INR fluctuations in patients
In addition, diets high in vitamin K content have been
associated with acquired warfarin resistance, defined as excessive warfarin dosing
requirements to reach a therapeutic INR range.
106 Numerous cases have also been
reported in which patients previously stabilized with warfarin experienced
elevations in INR with or without hemorrhagic complications when dietary sources
of vitamin K were eliminated. Conversely, reductions in INR with or without
thromboembolic complications have been reported in patients in whom dietary
sources of vitamin K have been added.
Warfarin Interactions with Disease States and Clinical Conditions
Clinical Condition Effect on Warfarin Therapy
Advanced age Increased sensitivity to warfarin due to reduced vitamin K stores and/or lower
plasma concentrations of vitamin K-dependent clotting factors
Pregnancy Teratogenic; avoid exposure during pregnancy
Lactation Not excreted in breast milk; can be used postpartum by nursing mothers
Alcohol use Acute ingestion: inhibits warfarin metabolism, with acute elevation in INR
Chronic ingestion: induces warfarin metabolism, with higher dose
Liver disease May induce coagulopathy by decreased production of clotting factors, with
May reduce clearance of warfarin
Kidney disease Reduced activity of CYP2C9, with lower warfarin dose requirements
Heart failure Reduced warfarin metabolism due to hepatic congestion
Nutritionalstatus Changes in dietary vitamin K alter response to warfarin
Tube feedings Decreased sensitivity to warfarin, possibly caused by changes in absorption or
vitamin K content of nutritionalsupplements
Smoking and tobacco use Smoking: may induce CYP1A2, increasing warfarin dosing requirements.
Chewing tobacco: may contain vitamin K, increasing warfarin dosing
Fever Increased catabolism of clotting factors, causing acute increase in INR
Diarrhea Reduction in secretion of vitamin K by gut flora, causing acute increase in
Acute infection/inflammation Increased sensitivity to warfarin
INR, international normalized ratio.
This data illustrate the potential clinical significance of dietary changes in patients
taking warfarin. To minimize these potential effects, E.N. should be counseled to
maintain a consistent intake of dietary vitamin K.
107 His final warfarin maintenance
dose will be partially influenced by his typical diet. However, restriction of dietary
vitamin K intake is unnecessary, except in cases of significant resistance to the
anticoagulant effect of warfarin. E.N. should be aware of the types of foods and
supplements that contain large quantities of vitamin K, and should be counseled to
maintain a consistent diet, to avoid bingeing with foods high in vitamin K content,
and to report significant dietary changes to his healthcare provider. Appropriate
assessment and follow-up are essential to prevent hemorrhagic or thromboembolic
complications that may arise from changes in INR resulting from dietary alterations.
Underlying Disease States and Clinical Conditions
The presence or exacerbation of various medical conditions can also influence
(Table 11-21). Diarrhea-associated alterations in intestinal
flora can reduce vitamin K absorption, resulting in elevations in INR. Fever enhances
the catabolism of clotting factors and can increase INR. Heart failure, hepatic
congestion, and liver disease can also cause significant elevations in INR because of
a reduction in warfarin metabolism. End-stage renal disease is associated with
decreased CYP2C9 activity, resulting in lower warfarin dose requirements.
The impact of changes in thyroid function on warfarin dose requirements is
It has been suggested that levothyroxine initiation accelerates
clotting factor catabolism, enhancing warfarin’s anticoagulation effect; however,
there is conflicting evidence in whether a warfarin–levothyroxine interaction has an
109,110 A recent retrospective review did not show a difference in
the mean warfarin dose/INR ratios before and after levothyroxine initiation,
suggesting that no clinical interaction exists, and additional monitoring may not be
Acute physical or psychologic stress has been reported to increase INR. Increased
physical activity has also been reported to increase the warfarin dosing requirement.
Smoking can induce CYP1A2, which may increase warfarin metabolism in certain
patients, resulting in increased dose requirements.
content, chewing smokeless tobacco can suppress the INR response.
Thorough education of patients taking warfarin should include detailed attention to
recognizing the signs and symptoms of changes in underlying disease states and
clinical conditions that can influence warfarin dosing requirements. They should be
instructed to contact their anticoagulation management program whenever changes
occur that might influence INR and warfarin dose requirement.
Chronic alcohol ingestion has been associated with induction of the hepatic enzyme
systems that metabolize warfarin. Therefore, warfarin dosing requirements are
sometimes higher in alcoholic patients. Conversely, acute ingestion of large amounts
of alcohol can slow warfarin metabolism through competitive inhibition of
metabolizing enzymes, leading to elevations in INR and an increased risk of bleeding
6,107 Despite some reports linking low amounts of alcohol to an
in general it is believed that moderate intake of alcoholic beverages
is not associated with alterations in the metabolism or the therapeutic effect of
warfarin as measured by INR. Patients taking warfarin should be educated to limit
their alcohol consumption to less than one to two alcoholic beverages per day.
Chronic drinkers should be counseled to limit their drinking and maintain a regular
pattern to avoid fluctuations in INR.
107 E.N. does not need to abstain from drinking
alcoholic beverages in moderation, but he should be counseled to avoid the sporadic
ingestion of large amounts of alcohol.
Conversely, alcoholic liver disease (i.e., cirrhosis) can alter multiple hemostatic
mechanisms and reduces production of hepatic
clotting factors. Decreased production and clearance of vitamin K-dependent
clotting factors accounts for the prolonged PT and INR often seen in these patients.
Therefore, an increased response to warfarin would be expected in patients with
liver impairment. Worsening liver function is also a predictor for bleeding
complications and patients with end-stage liver disease are at increased risk of
bleeding. Before instituting warfarin therapy in these patients, the risks of bleeding
associated with both the underlying liver disease and warfarin therapy must be
weighed against the benefit of preventing thromboembolic events. If warfarin is
indicated, the best approach would be to use a cautious initiation and dose titration
approach by starting with lower doses and titrating up slowly to goal. Small
increases in dosage should be made, if indicated, recognizing that the full effect of
any dose adjustment may be delayed in patients with severe liver dysfunction.
Monitoring for bleeding complications is essential, even at goal INR ranges, when
warfarin is used in patients with liver dysfunction.
The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1
(VKORC1) genotypes have been associated with warfarin dose requirements, and
dosing algorithms incorporating genetic and clinical information have been shown to
be predictive of stable warfarin dose.
115 However, dosing algorithms that incorporate
CYP2C9 genotype and vitamin K epoxide reductase complex 1 (VKORC1)
haplotype along with other patient characteristics to predict warfarin maintenance
doses showed mixed results in randomized, prospective clinical trials, questioning
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