H O W W E D O I T

Use of Warfarin in the

Patient With Cancer
Joanna Maudlin Pangilinan, PharmD, BCOP, Percival H. Pangilinan Jr, MD, and Francis P. Worden, MD

Case Vignette: The Interplay Between Warfarin and Cancer

AJ is a 53-year-old woman with stage IV colon At that time, her warfarin dose was stable with a Dr. J. M. Pangilinan is
cancer (T4N2M1), liver metastasis, and proximal deep therapeutic INR. Prior to the chemotherapy infusion, a Pharmacist and Dr.
vein thrombosis of the left leg who returned to the she received granisetron (Kytril), dexamethasone, and Worden is a Clinical
Assistant Professor,
physician’s office for follow-up after completing a 3- lorazepam for the intermediate emetogenic potential University of Michigan
month course of enoxaparin (Lovenox). Laboratory FOLFIRI regimen. Post infusion, she reported tolerable Comprehensive Cancer
evaluations demonstrated that alanine aminotrans- nausea and vomiting once daily, which were effectively Center, Ann Arbor.
ferase (ALT) and aspartate aminotransferase (AST) treated with prochlorperazine. Two episodes of diar- Dr. P. H. Pangilinan
levels were approximately twice the normal limit, and rhea daily were effectively treated with loperamide. A is Clinical Instructor,
the alkaline phosphatase level was slightly elevated. complete blood count revealed that the platelet count University of Michigan
Health System,
The total bilirubin level was within normal limits, and was 175,000/mm3, and the hemoglobin value was 10.1
Ann Arbor.
the albumin level was 3.2 g/dL. The international nor- g/dL. A repeat liver function test revealed stable hepat-
malized ratio ((INR) was 1.2, and the prothrombin time ic function, and cardiovascular evaluation was within
was 12.7 seconds. Hemoglobin and leukocyte values normal limits.
were within normal limits. Long-term anticoagula- After reporting bone pain, AJ was started on hy-
tion options were considered, including continued drocodone/acetaminophen (5 mg/ 325 mg) She sub-
low-molecular-weight heparin (LMWH) or initiation sequently reported taking the maximum dose for 3
of warfarin. Due to an estimated creatinine clearance days and was asked to have her INR checked.
(CrCl) of 40 mL/min and concern for worsening renal AJ asked about “calcium pills,” danshen for her
function, she was started on 3 mg of warfarin once heart, and St. John’s wort for her mood. It was deter-
daily (INR target, 2.5). Enoxaparin was discontinued mined that 0.04 mg of phytonadione (vitamin K) was
after the INR was greater than 2.0 for 2 days. contained in the calcium product. She was instructed
After one month, AJ was due for a cycle of FOLFIRI (in- to take the calcium supplement consistently and
fusional fluorouracil, leucovorin, irinotecan [Camptosar]). avoid the herbal products.

W
arfarin remains the foundation for oral ing number of factors, including genetic polymor-
anticoagulation, and due to a narrow phism, dietary intake, and drug and food interac-
therapeutic window, serious complica- tions, warfarin may be difficult to dose, even in
tions can occur with its use. Adverse reactions the seemingly uncomplicated patient.
with warfarin have been associated with hospital Warfarin has been found to be safe and effec-
admissions,1 and inpatient medication errors are tive in cancer patients,3 but patients with advanced
common with warfarin.2 Because of an astonish- cancer have an increased risk of a supratherapeutic
international normalized ratio (INR).4 Active can-
Manuscript submitted August 22, 2006; cer is a predictor of a lengthened time for a supra-
accepted October 25, 2006. therapeutic INR to decrease to target levels.5 Ad-
Conflicts of interest: Drs. J. M. Pangilinan and P. H. Pangilinan ditionally, maintaining an INR between 2 and 3 is
Jr, have nothing to disclose. Dr. Worden is on the speaker’s more difficult in cancer patients than in patients
bureau for ImClone Systems Incorporated. without cancer.3,6 Hutten and colleagues studied
Correspondence to: Joanna Maudlin Pangilinan, PharmD, venous thromboembolism (VTE) recurrence and
BCOP, University of Michigan Comprehensive Cancer Center,
bleeding and found that cancer patients had a six-
1500 East Medical Center Drive, Room B1-180, Ann Arbor,
MI 48109; telephone: (734) 647-8919; fax: (734) 647-8920; fold higher incidence of bleeding than did patients
e-mail: jamaudli@med.umich.edu without malignancy.6
J Support Oncol 2007;5:131–136 © 2007 Elsevier Inc. All rights reserved. Through the presentation of a brief case study

VOLUME 5, NUMBER 3 ■ MARCH 2007 www.SupportiveOncology.net 131

Use of Warfarin in the Patient With Cancer

Table 1 Table 2
Pharmacokinetics of Warfarin Factors That May Increase Response to
Warfarin in the Oncology Patient4,7,15–19
Absorption
Rapid and complete Patient characteristics
~ 100% bioavailable Elderly age
Peak up to 4 hours Debilitation
Half-life: R-warfarin ~29 hours, S-warfarin ~45 hours Low body weight
Distribution Patient adherence, cooperationa
Extensively bound to plasma albumin Acute conditions
Volume of distribution similar between enantiomers Diarrhea
Metabolism Fever
Extensively metabolized via cytochrome P450 system Infection
R-warfarin: 1A2, 3A4, 2C19 Nausea, vomiting
S-warfarin: 2C9 (major), 3A4 (minor) Steatorrhea
Elimination Dietary status
Metabolites excreted in urine Inconsistency of oral intake
Adapted from Wittkowsky9 Low albumin levels
Malabsorption
Undernourishment
(see boxed item), the authors address the numerous factors to Vitamin-K deficiency
consider when using warfarin in patients with cancer, explor- Comorbidities
ing such topics as venous thromboembolism, dosing guidelines Advanced malignancy
for warfarin, INR monitoring, concomitant use of other medi- Coagulopathy
cations, gastrointestinal toxicity, risks related to chemothera- Collagen vascular disease
py-induced thrombocytopenia and/or anemia, and the effects Congestive heart failure
of nutritional supplements and/or herbal preparations. Hepatic disorder or metastases
Hyperthyroidismb
Questions Medication regimen/anticancer regimen
Concurrent interacting medicationsa
WHY WAS WARFARIN CHOSEN FOR LONG- a
May increase or decrease response
TERM ANTICOAGULATION IN THE CASE STUDY, b
Hypothyroidism may increase warfarin requirements.
AND WHAT GUIDELINES FOR MANAGING VTE
IN CANCER PATIENTS ARE AVAILABLE?
The pivotal Comparison of Low-Molecular-Weight Hepa-
Warfarin is a vitamin K antagonist indicated for the prophy- rin Versus Oral Anticoagulation Therapy (CLOT) trial stud-
laxis and treatment of VTE. Warfarin inhibits the synthesis of ied 6 months of the LMWH dalteparin (Fragmin) versus 5 to
the vitamin K-dependent clotting factors II, VII, IX, X, and an- 7 days of dalteparin with 6 months of a coumarin in cancer pa-
ticoagulant proteins C and S. It is a racemic mixture in which tients with acute VTE. Patients receiving 6 months of daltepa-
the S-isomer is five-fold more active than the R-isomer.7 The rin had less probability of VTE recurrence than the coumarin
major risk with warfarin use is hemorrhage, and uncommon side group (9% vs 17%). No differences in bleeding, major bleed-
effects include necrosis and purple-toe syndrome.8 An overview ing, or mortality were found.11 The ACCP recommends that
of the pharmacokinetics of warfarin is found in Table 1.9 cancer patients receive 3 to 6 months of LMWH initially for
The antithrombotic effect of warfarin occurs when pro- long-term anticoagulation of DVT followed by anticoagulant
thrombin (factor II; half-life, ~60–70 hours) has been de- therapy indefinitely or until resolution of cancer.12
pleted.7 However, upon initiation of warfarin, a potential pro- Long-term warfarin was chosen for our patient due to concern
coagulant state exists, primarily due to decreasing protein C for unstable renal function. Lim and colleagues studied LMWH
(half-life, ~6 hours).10 Therefore, initial warfarin dosing, as use in non-dialysis patients with severe renal insufficiency (de-
in our case study, requires the co-administration of an im- fined as a creatinine clearance [CrCl] of 30 mL/min or less).
mediate-acting anticoagulant (low-molecular weight heparin This meta-analysis revealed that patients with severe renal in-
[LMWH] or unfractionated heparin concomitantly with war- sufficiency who received fixed-dose enoxaparin (Lovenox) had
farin) until the INR has been at least 2.0 for 48 hours. Bridg- higher anti-Xa levels and an increased risk for bleeding.14
ing allows time for the warfarin dose to reach its antithrom-
botic effect.11 (VTE treatment guidelines are available from WHAT CRITERIA DETERMINE INITIAL WARFARIN DOSING,
AND WHEN SHOULD THE INR BE MONITORED?
the American College of Chest Physicians [ACCP]12 and the
National Comprehensive Cancer Network.13) Initiating warfarin with a 5- or 10-mg dose is a topic of de-

132 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGY

 Pangilinan, Pangilinan Jr, and Worden

Table 3 Table 4
Proposed Mechanisms of Warfarin Drug Interactions Potential Warfarin/Anticancer Drug Interactions
↑↓ Clotting factor synthesis Increase INR
↑↓ Clotting factor catabolism Adrenal steroid inhibitor
↑↓ Metabolism of R-warfarin, S-warfarin Aminoglutethimide20
↓ Warfarin absorption Alkylating agent
↓ Production of vitamin K by gut flora Cyclophosphamidea,18
Additive anticoagulant effect Antimetabolite
Capecitabine21,22
Increased bleeding risk
Fluorouracil23,24
Adapted from Wittkowsky9 Gemcitabine25
Antimicrotubule agent
Paclitaxel26
bate.10 The ACCP recommends that an initial warfarin dose
Hormone/hormone modifier
of up to 5 mg be administered in elderly patients and patients Androgen9 (17-alkylated androgen)
who are malnourished, debilitated, or have liver disease or Antiandrogen
congestive heart failure.12 Table 2 lists factors to consider when Bicalutamide27
Flutamide28
initiating warfarin in the oncology patient.4,7,15–19 These factors
Nilutamide29
are numerous and include patient characteristics, acute con- Antiestrogen
ditions, dietary status, comorbidities, and concomitant medi- Tamoxifen30
cations. Clinicians may decide to start the oncology patient on Toremifene31
Progestin32
a substantially lower dose than 5 mg. Due to decreased dietary
Targeted therapy
intake, low albumin levels, and liver involvement, our patient Epidermal growth factor receptor inhibitor
was started on 3 mg. Erlotinib33
To our knowledge, no specific INR monitoring guidelines Gefitinib34
for the oncology patient have been published; however, moni- Monoclonal antibody
Trastuzumab35
toring suggestions for the general population exist. During Multikinase inhibitor
warfarin initiation, Jaffer and Bragg recommend monitoring Sorafenib36
the INR daily or every other day until it is therapeutic for 48 Protein tyrosine kinase inhibitor
hours; the INR should then be monitored every 3 to 5 days Imatinib9
Miscellaneous
until it is stable for 1 week, at which time it can be monitored
Interferon37
weekly.15 The ACCP recommends that no more than four Levamisole38
weeks should elapse between INR evaluations.7 Clinicians Regimens
should monitor INR values frequently due to the tenuous Etoposide/carboplatin39
state of the patient with cancer. Fluorouracil-containing regimens
Cyclophosphamide/methotrexate/fluorouracil (CMF)16
HOW WILL THE ADDITION OF A CHEMOTHERAPY Fluorouracil/folinic acid/oxaliplatin (FOLFOX)40
Fluorouracil/levamisole41
REGIMEN AFFECT THE INR? Ifosfamide/mesna42
Table 3 lists mechanisms by which warfarin can interact Paclitaxel/carboplatin26
with other medications.9 Pharmacokinetic drug interactions Decrease INR
Alkylating agent
may affect the absorption, distribution, metabolism, or elimi-
Cyclophosphamidea, 43
nation of warfarin. The most significant drug interactions are Antimetabolite
seen with medications that inhibit or induce the hepatic mi- Mercaptopurine44
crosomal enzymes. Enzyme inhibitors increase the INR by de- Hormone
creasing the metabolism of warfarin, whereas enzyme inducers Estrogens9
decrease the INR by increasing the metabolism of warfarin. Abbreviation: INR = international normalized ratio
Induction or inhibition of the 2C9 pathway is of particular a
May increase or decrease INR

concern due to interference with the more active S isomer.9

Pharmacodynamic drug interactions occur when medi- Table 4 lists chemotherapeutic agents that may interact with
cations affecting clotting factor synthesis or catabolism or warfarin.9,16,18,20–44 However, the majority of data on drug inter-
medications affecting hemostasis via alternative mechanisms actions are from case reports, retrospective reviews, and manu-
are added to a warfarin regimen.7 For example, concomitant facturers’ information. In addition, the list is likely to increase
use of aspirin may increase the bleeding risk of warfarin due due to the development of new chemotherapeutic agents.
to its antiplatelet effect; the additive effect cannot be moni- Before adding a drug that might interact with warfarin,
tored via the INR.16 clinicians should consider therapeutic alternatives to either

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Use of Warfarin in the Patient With Cancer

drug. Sometimes, however, alternatives do not exist, as in our occur during or immediately after infusion of irinotecan. Late
case study. Clinicians should then try to predict ensuing drug diarrhea occurs 24 hours or more after infusion of irinotecan
interactions. For example, the antimetabolites capecitabine and may be life-threatening.49 A clinical trial (Andre et al)
(Xeloda)21,22 and fluorouracil23,24 are known to increase the evaluating FOLFIRI in patients with advanced colorectal can-
INR in patients on warfarin. cer found that 12% had grade 3 or 4 diarrhea, 15% had grade
Kolesar and colleagues retrospectively reviewed the records 3 nausea or vomiting, and no patients experienced grade 3 or
of five patients who received fluorouracil while on chronic 4 mucositis.50 Patients should be instructed to notify health-
warfarin therapy.23 All patients developed an elevated INR care personnel if nausea, vomiting, or diarrhea becomes more
(range, 3.66–23.7) requiring reduction in the warfarin dose frequent or severe. Clinicians can then assess whether INR
(mean 44% decrease). In our patient, FOLFIRI (infusional monitoring is required.
fluorouracil, leucovorin, irinotecan [Camptosar]) would likely
increase her INR. Patients on chronic warfarin therapy should WHAT ARE THE INCREASED RISKS OF USING WARFARIN
IN THROMBOCYTOPENIC AND/OR ANEMIC PATIENTS?
be monitored weekly during capecitabine or fluorouracil
treatment.21,23 Closer monitoring enables clinicians to adjust Andre and colleagues noted that 33% of patients receiving
warfarin dosing before the INR becomes supratherapeutic. FOLFIRI had grade 1 or 2 thrombocytopenia and 24% had
Conversely, closer monitoring may help to identify a subthera- grade 1 or 2 anemia.50 Clinicians should consider the bleeding
peutic INR after the chemotherapy cycle has ended. risk when prescribing chemotherapeutics that cause marked
Though its effectiveness is controversial, some clinicians thrombocytopenia and/or anemia and take precautions if pos-
prescribe minidose warfarin (1 mg daily) to oncology patients sible. Thrombocytopenia could increase the risk for bleeding
to prevent catheter-associated thrombosis.45 Minidose warfa- in a patient taking warfarin, and anemia could mask a bleeding
rin given concomitantly with FOLFOX (infusional fluoroura- episode. Patients should minimize activities with high risk of
cil, leucovorin, oxaliplatin [Eloxatin]) regimens has resulted trauma, such as contact sports, and alert their physician about
in supratherapeutic INRs.40,46 Cunningham and colleagues45 any unusual bleeding episodes, deep cuts, or major falls.
recommend that the INR be monitored routinely and titrated
to ≤ 1.5 in patients with cancer on minidose warfarin. How- HOW MIGHT END-ORGAN DAMAGE DUE TO
DISEASE OR DRUG TOXICITY AFFECT THE INR?
ever, minidose warfarin is not recommended practice.
An inducing drug can take 1 or more weeks to decrease Major organ damage due to chemotherapeutic agents could
plasma levels of the affected drug. The time line is determined, alter the requirements of warfarin. Many chemotherapeutics
in part, by the half-life of the inducing drug.32 Therefore, cli- are cardiotoxic. For example, the anthracyclines may cause
nicians should monitor the INR frequently for several weeks cardiotoxicity, leading to congestive heart failure,51 a risk for
after addition, dose adjustment, or discontinuation of an in- increased response to warfarin.17 Further, many chemothera-
ducing drug.15 In general, increased INR monitoring should py agents are hepatotoxic.52 Hepatic damage could alter the
be performed during the 2 weeks after any new drug is added pharmacokinetics of warfarin and the production of clotting
or discontinued from a regimen containing warfarin.16 In the factor. For our patient, cardiotoxicity and hepatotoxicity were
future, warfarin management may be guided by pharmacoge- not major side effects in the FOLFIRI clinical trial.50 However,
netic studies.47 changes in her liver function due to metastatic disease needed
to be monitored. Clinicians should monitor changes in organ
WHY AND HOW SHOULD CHEMOTHERAPY-INDUCED function routinely in patients with organ damage due to dis-
GASTROINTESTINAL TOXICITY BE MANAGED?
ease or drug toxicity.
Gastrointestinal (GI) toxicity can manifest as nausea, vom-
iting, mucositis, diarrhea, or constipation. Such toxicity may HOW DOES CONCOMITANT USE OF PAIN
MEDICATION AND WARFARIN AFFECT THE INR?
affect dietary intake of vitamin K. In addition, GI toxicity
could alter the absorption of warfarin and dietary vitamin K. Because the oncology population frequently requires pain
Therefore, clinicians should consider the emetogenic poten- control, clinicians often prescribe an acetaminophen-contain-
tial and GI side effects of chemotherapy regimens that are to ing product. Acetaminophen is commonly prescribed to pa-
be given to a patient receiving warfarin. Maximal prophylactic tients on warfarin due to its lack of antiplatelet activity. How-
and breakthrough antiemetics should be prescribed. Clinicians ever, acetaminophen can increase the INR.
should note, however, that aprepitant (Emend), approved Hylek and colleagues4 found that patients taking at least
for moderate or highly emetogenic potential chemotherapy, 9,100 mg weekly (~1,300 mg/d) of acetaminophen had a ten-
should be used with caution in patients on warfarin, as it could fold greater risk of their INR values exceeding 6.0 than did
decrease the effectiveness of warfarin.48 patients not taking acetaminophen. Although the mechanism
Maximal measures to ease and reduce mucositis, diarrhea, of this interaction is not completely understood, Thijssen et al
or constipation should also be prescribed. Certainly, this was reported that the toxic metabolite of acetaminophen, N-ace-
the case in our patient; she received irinotecan, which can tyl-para-benzoquinone-imine (NAPQI), interacts with war-
cause serious early- or late-onset diarrhea. Early diarrhea can farin by interfering with vitamin K-dependent clotting factor

134 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGY

 Pangilinan, Pangilinan Jr, and Worden

synthesis.53 Patients should be monitored if they ingest more

than 2 g of acetaminophen daily54 or more than 1.3 g daily for Table 5
more than 2 weeks.55 Patients should be advised to avoid other Reasons for Warfarin Patients to Alert Their Physician
acetaminophen-containing products such as over-the-coun-
ter (OTC) cold medicine while taking acetaminophen-based Signs and symptoms of unusual bruising or bleeding
pain medication. Significant nausea, vomiting, and/or diarrhea
The alternatives for pain management may have implica- Significant change in oral intake
tions if given with warfarin. Non-steroidal anti-inflammatory New medication added to regimen (prescription, over the counter,
complementary, or alternative)
agents can increase the risk of bleeding when given with warfa-
Increased use of pain medication
rin because of their antiplatelet effect and potential for gastric
Signs and symptoms of infection
mucosal injury. Cyclooxygenase-2 inhibitors increase the risk
for GI hemorrhage when taken concomitantly with warfarin.56
High-dose salicylates may interfere with the production of clot- CAM therapies were herbal preparations. Vitamins and me-
ting factor, thereby increasing bleeding times.57 Opiates, on the dicinal teas were among other CAM therapies used.59 Ramsay
other hand, are not believed to interact with warfarin.16,18 and colleagues surveyed patients initiating warfarin therapy
on their use of CAM; they found that almost 27% were taking
HOW DO NUTRITIONAL SUPPLEMENTS TAKEN CAM and that 58% of those patients were taking a product
CONCOMITANTLY WITH WARFARIN AFFECT THE INR?
that could potentially interact with warfarin.60
Oncology patients often take vitamins, minerals, and Approval from the US Food and Drug Administration
nutritional supplements to improve their nutritional status. (FDA) is not required for dietary supplements, including
Some of these products contain phytonadione (vitamin K), herbal products, prior to marketing. Thus, these products are
which could counteract the mechanism of action of warfarin not regulated for safety and efficacy.61 Many reports of interac-
if taken in large doses. For example, certain calcium supple- tions between warfarin and herbal preparations exist. Herbal
ments also contain vitamins D and K. Whether the amount products may contain coumarins, salicylates, or vitamin K de-
of vitamin K could affect the efficacy of warfarin is unclear. rivatives or may have antiplatelet, anticoagulant, procoagu-
However, it is feasible that if such a calcium supplement lant, or fibrinolytic properties.9
were taken in conjunction with other vitamin K-containing Danshen and St. John’s wort are two Chinese herbs that
multivitamins and/or nutritional supplements, an interac- have been reported to interact with warfarin. Danshen, used
tion could occur. The combination of vitamin K with the to prevent cardiovascular and cerebrovascular atherosclero-
dietary vitamin K could act as a warfarin antagonist and ren- sis, has been reported to potentiate the anticoagulant effect
der warfarin less effective. Patients on warfarin should eat of warfarin.62 St. John’s wort, used for depression, has been
a diet consistent in the vegetables high in dietary vitamin reported to decrease the effectiveness of warfarin.63 Therefore,
K, namely the leafy-green vegetables (eg, spinach, kale, col- patients using warfarin should avoid herbal preparations16 and
lard greens).58 Patients should be instructed to review the should always consult with their physician before taking CAM.
contents of their multivitamins and nutritional supplements Additionally, clinicians should ask their patients specifically
with healthcare professionals to determine the content of about the use of CAM.
vitamin K. Patients should take these products consistently
and contact their physician if they take any additional prod- Conclusion
ucts. The INR should be monitored closely until the poten- The use of warfarin in the oncology patient is complex. As
tial for interaction has lapsed. this population may require long-term or indefinite antico-
agulation, warfarin complications could occur due to patient-
SHOULD CLINICIANS BE CONCERNED ABOUT specific factors, drug interactions, chemotherapeutic toxicity,
COMPLEMENTARY AND ALTERNATIVE MEDICATION
or disease state. Clinicians should educate patients about the
USE WITH WARFARIN?
proper use of warfarin, precautions to take while on warfarin
The use of complementary and alternative medicines therapy, and when to alert healthcare professionals (Table 5).
(CAM) is common in the oncology population. A survey Frequent INR monitoring and patient education may poten-
completed by patients with colorectal cancer found that 32% tially decrease complications in this medically complicated
started CAM after diagnosis of cancer. Almost half of the patient population.

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