Venous Thromboembolism and Cancer: An Opportunity for Pharmacists to Optimize Care

The management of venous thromboembolism (VTE) disorders is well described in the literature,¹ and comprehensive guidelines are available from the American College of Chest Physicians.² In addition, guidelines are available that specifically address management of VTE for the individual with cancer.^3,4 Despite published guidelines, there are many challenges when providing care to those individuals with VTE and cancer. Unfortunately, not all clinical situations can be addressed in even the most comprehensive guidelines. Anticoagulation treatment is dynamic and should take into consideration the unique and often changing clinical aspects of the individual throughout the course of their disease and treatment(s). There is an important role for the pharmacist in anticoagulation therapy, and this role may be even more critical in the patient with cancer and VTE. Pharmacist collaboration with the health care team may better optimize care for the individual with cancer and VTE.

The individual with cancer receiving anticoagulation therapy requires initial and frequent education, counseling, and monitoring to assure that both coagulation and bleeding risks are minimized. Anticoagulation treatment may need to be modified based on the evolving clinical status of the patient, and the anticoagulation treatment plan should be adapted to best meet the treatment goals for the individual. The clinician must consider the cancer diagnosis, extent of disease, and planned treatment(s) for the malignancy as well as the potential impact of disease- and treatment-related complications.

Although the diagnosis of cancer has been associated with an increased risk of developing VTE, all cancers do not have the same risks of thrombosis.⁵ Similarly, the issues important in providing optimal anticoagulation therapy for a patient vary depending on both the type and extent of malignancy. This article will address some of the unique treatment considerations for the individual with cancer and VTE. Case examples will be used to highlight the role of the pharmacist in working with patients and patient families and/or caregivers as well as the health care team to provide safe and efficacious management of VTE.

PATHOPHYSIOLOGY OF CANCER-RELATED THROMBOSIS

The definition of VTE includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Unfortunately, VTE is common in individuals with cancer.⁵ In fact, in the absence of known risk factors in an individual with a new VTE, the presence of an underlying undiagnosed malignancy is often considered.⁶ The prevalence of VTE in the individual with cancer varies depending on the malignancy and treatment as well as patient-related factors.⁷

The pathophysiology of the cancer-related VTE is thought to be due in part to hypercoagulability associated with procoagulant factors produced from cancer cells. In addition, vascular injury and stasis of blood secondary to tumor compression on vessel walls contribute to the coagulation activation seen with thrombosis in malignancy.^7,8 Cancer treatment(s), including surgery, may increase the risk of VTE. Drug therapy for cancer treatment^9-11 and for management of the cancer- and treatment-related complications (eg, erythropoietin-stimulating agents for management of anemia¹²) may also increase the risk of VTE. The use of devices such as central venous catheters (CVC) also place some individuals with cancer at risk for thrombosis.^13,14 A model has been developed to help discriminate the risk of VTE in ambulatory patients with cancer receiving chemotherapy.¹⁵ Table 1 provides a list to help the pharmacist identify those individuals with cancer who are most at risk for VTE.^1,3

CASE: RISK FACTORS FOR VTE

Ms. Williams is a 56-year-old woman recently diagnosed with colon cancer. She has had resection of the cancer. She is scheduled to start adjuvant chemotherapy with oxaliplatin, fluorouracil, and leucovorin. Last week, a CVC was placed to facilitate the administration of the intravenous fluorouracil. She now reports some swelling in her arm on the same side as the CVC. She has read some of the literature she was given and is concerned about the risk of a blood clot.

Questions: What is/are risk factor(s) for VTE in Ms. Williams? What is appropriate counseling for the pharmacist?

Discussion:

Risk Factors

• Although it is difficult to identify all of the risk factors in Ms. Williams with such a brief history, one of the seemingly obvious risks includes the diagnosis of colon cancer. It is important to realize that she has received a curative surgery for the treatment of colon cancer, and does not have active disease at this time.

• Surgery also increases risk of thrombosis.

• She has a CVC.

• While she has not yet started chemotherapy, it will pose a risk once therapy is initiated.

Counseling

• Recommend that Ms. Williams seek medical advice immediately to have the situation evaluated with appropriate imaging. This is not a diagnosis that should be made based on clinical symptoms alone.

• Encourage the patient to contact her oncology team, as most oncology teams have on-call numbers available for this type of issue.

• Encourage the patient to seek medical evaluation immediately, and not to wait until her next appointment.

PREVENTION OF VTE IN THE INDIVIDUAL WITH CANCER

The role of prophylactic anticoagulation therapy for individuals with cancer is well defined in select situations. For those individuals with cancer undergoing a major surgery, prophylaxis with low molecular weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux is recommended.⁴ If there are known contraindications for pharmacologic prophylaxis in those individuals considered at high risk for thrombosis, mechanical methods such as pneumatic calf compression should be considered.¹⁶ A question remains concerning the duration for prophylaxis following surgery. The criterion often used is the mobility of patients, although there is evidence with some types of surgery (eg, abdominal surgery) that there is benefit for anticoagulation prophylaxis to continue postsurgery.¹⁷ This does not mean that anticoagulation prophylaxis is not needed in other patient populations postsurgery, but that the studies have not been done to demonstrate benefit. At a minimum, individuals should be counseled to use complementary nonpharmacologic techniques as appropriate (eg, mobility) after discussion with their health care team.

Prophylactic anticoagulation is also recommended for hospitalized cancer patients with a diagnosis of active cancer who do not have a contraindication to therapy aimed at lowering VTE incidence.³

STRATEGIES FOR MANAGEMENT OF VTE IN THE INDIVIDUAL WITH CANCER

Historically, the management of VTE includes the use of anticoagulation with UFH followed by a vitamin K antagonist such as warfarin. These treatment options remain an appropriate choice in the majority of individuals with VTE associated with cancer, but other options now exist. The appropriate treatment strategy is determined after evaluation and consideration of many patient and cancer treatment—related factors. Treatment strategies may include pharmacotherapy such as UFH, LMWH, warfarin, and fondaparinux. Importantly, if the patient has a history or evidence of heparin-induced thrombocytopenia (HIT), other drug therapies may be used and are reviewed more extensively in published guidelines.^2,3,18

When a patient develops a VTE, anticoagulation should be initiated as soon as possible. Anticoagulation therapy is initiated for management of VTE to prevent thrombus extension. Long-term treatment involves continuation of anticoagulation to both minimize the extension of thrombosis and reduce VTE recurrence. Anticoagulation therapy does not break down the thrombus; however, this is an area of confusion for many patients. It is helpful to patients and caregivers to review the intent of anticoagulation therapy. For example, an individual with a diagnosis of cancer and VTE may have multiple imaging scans to assess the management of cancer therapy. If the thrombus is still present after treatment, the patient may believe the anticoagulation therapy is not working. Conversely, if the thrombosis is resolved on subsequent imaging scans, the patient may feel it is not important to continue anticoagulation therapy. It is important to reinforce that the body is slowly dissolving the thrombus, and anticoagulation therapy is used to prevent extension and recurrence of thrombosis.

The risk of VTE recurrence is of major concern in an individual with active cancer because of the inherent thrombogenic risk associated with malignancy as described above. Patients with advanced disease or high tumor burden appear to have the highest risk of recurrence. The duration of anticoagulation for the individual with cancer is determined based on the type of VTE and the presence of active disease. For example, the patient with a diagnosis of VTE associated with malignancy may remain on anticoagulation therapy until they are considered disease free.³

CASE: DURATION OF ANTICOAGULATION THERAPY IN THE INDIVIDUAL WITH CANCER AND VTE

Mr. Jones is an elderly man with a long history of prostate cancer. Until recently, his prostate cancer was managed with antiandrogen therapy. There is evidence of disease progression, and he now has metastatic prostate cancer. The plan was to start chemotherapy. He was recently discharged from the hospital after it was discovered he had spinal cord compression, and he has severely limited mobility. Additionally, he was found to have a lower extremity DVT. His family has a number of questions about his medications, and is very concerned that he will be on a “blood thinner.” They have done some research, and their understanding is that he will continue on anticoagulation therapy for 3 months.

Question: What is the duration of therapy for anticoagulation in the patient with VTE and cancer?

Discussion: There is not one correct answer for this question. The duration of anticoagulation therapy is determined on an individual case basis. The decision will need to include consideration of risk versus benefit issues. At any time, if the risk of anticoagulation therapy outweighs its perceived benefit, the therapy should be discontinued. Therefore, in counseling Mr. Jones and his family, it is important to discuss that a definitive answer may not be appropriate. Some guiding points include:

• Patients with active disease, such as Mr. Jones, require anticoagulation therapy while they have evidence of cancer. Although Mr. Jones will be receiving chemotherapy, the intent of the therapy is to decrease disease progression and not to cure the cancer. It is likely that Mr. Jones will remain on anticoagulation therapy for the rest of his life, unless there is a change in status that makes the risk of anticoagulation outweigh the benefit.

• Patients with curable cancers may not require anticoagulation therapy longer than the time recommended for individuals without cancer. Unfortunately, this is not the situation with Mr. Jones.

• Patients with VTE associated with a CVC will require anticoagulation therapy for the duration of the time they have the device in place. Again, this is considered on an individual basis.

The role of mechanical devices such as inferior vena cava (IVC) filters in the individual with cancer is less clear in the literature, but is addressed in clinical guidelines.^3,19 IVC filters are percutaneously placed devices that prevent PE. However, the risk of DVT is increased in patients with permanent filters.²⁰ IVC filters may be used in patients where anticoagulation is not considered appropriate (eg, active bleeding, severe thrombocytopenia) or in patients with recurrent VTE despite “adequate” anticoagulation. In recent years, IVC filters that can be retrieved have been developed so that the filters may be left in place during the high-risk period, but subsequently removed when appropriate. For example, a patient with a history of VTE who is receiving myelosuppressive therapy associated with severe thrombocytopenia may benefit from placement of an IVC filter, and the filter can be removed when myelosuppressive therapy is complete and the risk of thrombocytopenia and associated bleeding resolves. Unfortunately, the filter itself is thrombogenic and associated with an increased risk of DVT and IVC thrombosis. Anticoagulation therapy is often used concurrently in individuals with an IVC filter if not contraindicated.

The decision to hold or discontinue anticoagulation therapy may be considered in a patient when the perceived risk of bleeding outweighs the perceived benefit. For example, the risk of significant bleeding, unmanageable thrombocytopenia, or platelet dysfunction may outweigh the risk of VTE. Table 2 gives examples of when the risk of anticoagulation therapy should be carefully considered. Contraindications to anticoagulation may be temporary, and should be reevaluated periodically to determine if initiation of anticoagulation therapy is appropriate.³

Low Molecular Weight Heparin

LMWH potentiates the inhibitory activity of antithrombin against factor Xa and thrombin. These agents are used for the acute management of VTE, chronic management of VTE in the individual with cancer, and as a strategy to convert patients from long-acting oral anticoagulants to shorter-acting anticoagulation prior to a planned procedure associated with a bleeding risk. Table 3 lists LMWH products and the standard doses used in the management of VTE. These doses are often individualized based on patient factors (eg, renal dysfunction) and less commonly on monitoring of anticoagulant effect discussed later.

The role of LMWH for acute management of VTE is well established. The rapid onset of action of these agents allows the initiation of effective anticoagulation to be done quickly. The availability of a product given subcutaneously allows for administration to be done by patients, caregivers, and the health care team in the ambulatory setting, including home. In the individual with cancer, VTE is not infrequently discovered incidentally on a routine imaging scan performed to evaluate disease. The individual is often asymptomatic. When dispensing LMWH to a patient for this initial dose, it is essential that the pharmacist ensures that the patient and/or caregiver has received and understands appropriate education. Counseling should include information on the proper storage, handling, and administration of the specific LMWH product. Pharmacists should also communicate risks and monitoring parameters associated with bleeding, signs and symptoms of VTE, and the impact that other prescription and OTC medications may have on anticoagulant therapy. For example, patients should be counseled to avoid use of aspirin and nonsteroidal anti-inflammatory agents for pain management due to the increased risk of bleeding while on anticoagulation therapy. The pharmacist may suggest the benefit of having a wallet card or identification bracelet that indicates the individual is on anticoagulation therapy. Although this type of counseling may be routine with oral anticoagulation such as warfarin, it may have been overlooked with LMWH when the first doses are given in the hospital or physician’s office.

There is clinical evidence that LMWH monotherapy is appropriate for the chronic management of patients with proximal DVT and/or PE to prevent recurrent VTE in individuals with advanced or metastatic cancer.²¹ One trial compared the LMWH dalteparin versus a coumarin anticoagulant for the prevention of recurrence of VTE in individuals with cancer. This study, often referred to as the CLOT trial, demonstrated that 6 months of dalteparin therapy was more effective than 6 months of therapy with an oral coumarin in reduction of recurrent VTE without increased risk of bleeding. Although the study evaluated the use of LMWH for only a 6-month treatment period, in practice, some patients may continue therapy beyond 6 months. Also, as LMWHs provide a relatively predictable anticoagulation response, routine laboratory monitoring to guide dosing is not required.

The use of LMWH for chronic therapy presents challenges. One potential problem is the patient’s willingness to continue subcutaneous therapy. Some patients are unable or unwilling to administer subcutaneous injections daily; this also must be assessed prior to initiation of therapy. At times, encouragement and education will help persuade a patient to consider this treatment option. The pharmacist can work with the patient, family, and/or caregiver to help alleviate fears. Demonstration of administration techniques and suggestions for strategies to minimize discomfort can be very helpful to optimize care.

Patients and/or their families may be resistant to chronic LMWH therapy due to costs associated with therapy. The out-of-pocket cost, even with insurance coverage, may be prohibitive for some patients. When verifying if an individual has insurance coverage for LMWH products, it is important to determine if there are limits on the duration of the coverage (eg, coverage limited for 7 days). Similar to other high-cost medications, LMWH may be covered by an individual’s insurance plan with a required copayment. Patients may be unable to afford or unwilling to pay the cost of such copayments. If an individual determines that the cost of therapy is prohibitive, then the pharmacist can facilitate discussion with the health care team to ensure that appropriate anticoagulation therapy is continued. In some cases, this may require initiation of another strategy of anticoagulation.

It is important that the health care team discuss the patient’s ability and willingness to continue LMWH when determining if this is the best chronic treatment option. Unfortunately, if this has not been assessed fully, the pharmacist may be the clinician faced with the patient’s reluctance to continue therapy.

As mentioned, the routine use of laboratory monitoring is not required for dosing of these agents. When required, measurement of antifactor Xa activity can be used to help monitor LMWH therapy. The clinical situations where this monitoring may be appropriate include patients with significant renal impairment (eg, creatinine clearance <30 mL/min), malnourished patients (eg, weight <50 kg), morbidly obese patients, and those patients who experience bleeding with standard dosing.³

CASE: ACUTE AND CHRONIC LMWH FOR VTE OF CANCER

Mr. Elliot is a 45-year-old man with history of non-Hodgkin’s lymphoma (NHL). He was initially treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with complete response. After 6 cycles, he had no evidence of cancer. Unfortunately, recent follow-up imaging scans show a recurrence of cancer and an incidental finding of a PE. The plan is to begin anticoagulation therapy as well as therapy for recurrent NHL. The oncologist has told Mr. Elliot he will receive 2 cycles of chemotherapy and then proceed with an autologous stem cell transplantation.

Question: What are appropriate options for management of this PE in Mr. Elliot?

Discussion:Acute Management—An incidental finding of PE requires treatment, and anticoagulation should be started immediately. Therapy could include UFH, but as this would require hospitalization, LMWH is probably a better option.

Chronic Management—Chronic therapy with LMWH offers many benefits, including the ability to easily hold anticoagulation for a short period of time when needed for procedures (eg, placement of CVC, bone marrow biopsy). Another beneficial effect of chronic therapy with LMWH is a lack of drug—drug interactions.

Fondaparinux

Fondaparinux is a factor Xa inhibitor that is approved for the prophylaxis and treatment of VTE. Fondaparinux is rapidly and completely absorbed following subcutaneous administration, and therefore may be used in the treatment of DVT and PE. This drug has the advantage of a long halflife (17—21 hours), and it allows for daily dosing. Although there are limited data specifically regarding use in the cancer population, it is a therapeutic option for patients that are unable to use heparin products (eg, patients with history of HIT). Unfortunately, the long half-life of the drug may be a problem in some patients, as the anticoagulation effect of fondaparinux persists for 2 to 4 days in patients with normal renal function. As the drug is primarily cleared via renal excretion, the effect may last longer in patients with renal dysfunction. In fact, the drug is not recommended in patients with renal failure. An example of where the prolonged effect is a problem is in the patient who requires frequent procedures that require reversal of anticoagulation.

Warfarin

Warfarin is the most commonly prescribed of the vitamin K antagonists, and has been extensively reviewed.²² Warfarin produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and vitamin K epoxide. This action inhibits the production of functional forms of vitamin K—dependent factors including the coagulation factors II, VII, IX, X, and the endogenous anticoagulation proteins C and S.

The impact of warfarin is dependent, in part, on the individual’s intake of vitamin K. Patients should be educated to maintain a consistent diet of vitamin K, and to notify their health care team if there is any change in diet. Many common foods include vitamin K, and patients should be reassured that they can eat foods with vitamin K. Appetite and nutrition are often a challenge for the individual receiving chemotherapy, and food choices should not be limited whenever possible. Foods high in vitamin K include green leafy vegetables and beef liver, but other sources of vitamin K in this population may include daily vitamins and nutritional supplements. As patients may have frequent changes in diet during the course of disease and/or cancer treatment, it is important to reassess diet routinely to help identify changes that may impact warfarin therapy. Directed questioning regarding diet and use of dietary supplements is an excellent method to help identify potential problems with diet and warfarin therapy.

Warfarin is highly water soluble and is rapidly absorbed from the gastrointestinal tract. The bioavailability is close to 100%. In those individuals with disruption of the gastrointestinal tract secondary to surgery or cancer, the absorption of warfarin may be affected. Additionally, cancer- or treatment-related emesis and/or diarrhea may impact warfarin absorption. It is important for the pharmacist to counsel patients taking warfarin on the necessity of communicating any onset or changes in diarrhea and emesis. This counseling should be reinforced regularly. For those patients receiving chemotherapy, the week following treatment is, at times, difficult due to nausea, vomiting, or taste changes. The pharmacist has an opportunity to help evaluate these symptoms to determine the potential impact on warfarin dosing, and to help manage symptoms with appropriate drug therapy.

Warfarin is highly bound to albumin and is extensively metabolized in the liver by enzymes of the cytochrome P450 (CYP) system. Commercially available warfarin is a racemic mixture of R and S isomers. The S isomer of warfarin is the more potent isomer and is metabolized predominantly by CYP2C9. The R isomer of warfarin is less potent and is metabolized via CYP1A2, CYP2C19, and CYP3A4. There is significant variation in the metabolism of warfarin between patients. As the impact of these individual variations is evaluated, the clinical question is, “How do we use this in practice?” The controversy has not been settled regarding the use of pharmacogenomic evaluation of the genetic variations in CYP2C9 isoenzymes and the vitamin K epoxide reductase to help determine warfarin dosing.^23,24

The half-life of warfarin is long and can range over 40 hours. The impact of the drug on the proteins it targets is dependent on the half-life of the protein. For example, the initial increase of the international normalized ratio (INR) is due predominantly to the impact of warfarin on factor VII, which has a relatively short half-life of 6 hours. The full impact of warfarin may not be seen for almost a week because of the long half-life of factor II. Similarly, it may take a few days until the full impact of a dose change may be seen. When the pharmacist evaluates the dose of warfarin, it is important to consider the dose(s) of drug taken over the last week of therapy at a minimum.

The relationship between the dose of warfarin and response is modified by both genetic and environmental factors that influence the pharmacokinetics and pharmacodynamics of the drug. Because warfarin has a narrow therapeutic window, its effect can be impacted by diet, drugs, and clinical issues such as diarrhea.²⁵ The dosing of warfarin can be challenging and is guided by assessment of patient-specific factors including diet, drug therapy, liver function, and by monitoring the patient’s INR. The INR is a method to determine the biologic activity of factors II, VII, and X and correlates to warfarin anticoagulation effect. The target or goal INR should be established prior to initiation of therapy, and a common target range is an INR of 2 to 3. The delayed impact of warfarin doses can present a challenge to the monitoring of INR and patient dosing as mentioned previously.

Some of the clinical challenges associated with the use of warfarin in the patient with cancer are highlighted in the following cases. As with any individual on warfarin, it is essential to continually monitor medication changes (eg, new medications, discontinuation of medications, dose modifications of medications) and evaluate the potential and actual effect on warfarin and its anticoagulation effect as measured by INR. During the time of treatment, patients with cancer often have frequent drug therapy changes based on clinical needs (eg, infection, nausea, pain). These changes may affect chronic medications. Additionally, medication changes occur during and between treatment cycles. As drug interactions with warfarin are common, all drug therapy changes must be routinely and frequently assessed. The pharmacist should be cautious in relying on only those published lists of drugs that interact with warfarin, as many agents used to treat cancer or manage cancer-related symptoms may not have been studied.

CASE: INITIATION OF THERAPY WITH WARFARIN

Mr. Glenn is a 35-year-old man with lung cancer. He was recently diagnosed with a thrombosis associated with his infusion port and was started on LMWH. He has limited insurance coverage at this time, and the plan is to start warfarin for chronic anticoagulation.

Question: What is the appropriate starting dose of warfarin for Mr. Glenn?

Discussion: It is important to continue therapy with LMWH as warfarin is initiated. As it will take a few days to a week to see anticoagulation effects from the warfarin, it is important to continue LMWH until the INR is within the targeted therapeutic range.

The clinical practice guidelines2 recommend the initiation of warfarin at doses between 5 and 10 mg for 1 to 2 days, and subsequent dosing is based on INR response. Lower doses are suggested for patients who are older, debilitated, malnourished, have liver disease and/or dysfunction, or are taking medications known to increase sensitivity to warfarin. Prior to recommending a dose for Mr. Glenn, it is important to assess the following:

• Nutritional status

• Concurrent dietary intake of vitamin K, including that provided in nutritional supplements, vitamins, and diet

• Concomitant drug therapy

• Liver function

As it is essential to monitor the INR to determine dose modification, it is important to assess when the patient will be able to have an INR monitored to determine “aggressiveness” of dosing.

CASE: MONITORING OF WARFARIN

Mr. Peterson is a 39-year-old man with head and neck cancer receiving radiation therapy. He has had extensive surgery, and his oral intake is limited to nutritional supplements. Other medical problems include history of DVT in his left leg, hypertension, and liver dysfunction secondary to chronic alcohol use. He has been managed with LMWH, but he has requested that he be changed to another therapy. He has continued on LMWH and was started on warfarin 2 mg po daily. Two days after initiation of warfarin, his INR is 2.9 with a target goal of 2 to 3.

Question: What is your recommendation for anticoagulation therapy?

Discussion:

• Anticoagulation therapy should include 4 to 5 days of overlap with both a LMWH and warfarin as well as a therapeutic INR before discontinuation of LMWH.

• It is concerning that the INR is 2.9 after only 2 days of warfarin, and the full effect of these doses has not been seen. It is likely that the INR will continue to rise, and that the dose of warfarin should be decreased even though his INR is in the goal range. It is important to closely monitor INR.

• There is an opportunity to talk with Mr. Peterson to determine what the impact of diet, concomitant drug therapy, and/or other modifiable factors have on the apparent low warfarin dose requirement.

- Assess amount of nutritional supplementation (and vitamin K content in supplementation)

- Obtain a complete medication history

- Evaluate alcohol use

CASE: WARFARIN AND DRUG INTERACTIONS

Ms. Green is a 63-year-old woman diagnosed with colon cancer. She has had surgical resection of the cancer and is now scheduled to start adjuvant chemotherapy with oral capecitabine (daily for 14 days every 21 days) and oxaliplatin (intravenous infusion every 21 days). She recently was found to have a DVT in her right lower extremity. She was initially managed with LMWH and bridged to warfarin therapy. She is taking 2.5 mg po daily with an INR of 2.8.

Question: Are there drug interactions with the chemotherapy and warfarin?

Discussion: There are drug interactions with warfarin and many chemotherapy agents. Some interactions are well described in the literature, but many are not. Additionally, the severity of interaction, onset, and mechanism of interaction are often not described. The pharmacist has the unique opportunity to identify when there is a change in medication for an individual and to monitor the impact of the interaction.

Individuals with cancer may obtain their medications from multiple pharmacies, including specialty pharmacies, community pharmacies, and physicians’ offices or clinics. It is important to educate the patient and family on the importance of keeping a complete list of all medications that the individual is taking, and sharing this with the pharmacist in addition to all health care providers.

In this case, capecitabine has been shown to increase the INR in patients taking warfarin.²⁶ The challenges of managing the interaction are identifying the onset, as the drug interaction may be delayed, and managing warfarin with the episodic dosing of capecitabine (eg, 14 of every 21 days). This requires careful monitoring of therapy or, in some patients, a change in therapy to LMWH.

CASE: WARFARIN AND INR FLUCTUATIONS

Mr. Botoni is a 57-year-old man with a history of a neuroendocrine tumor of the pancreas. He has been receiving monthly injections of octreotide with relatively good management of diarrhea. About 1 week ago, he noted new-onset shortness of breath and was found to have a PE. He was started on LMWH for initial treatment, but then bridged to warfarin therapy as he refused to subcutaneously self-administer any medication chronically. His INR has been erratic, and his dose of warfarin has been modified weekly. He is very upset that he is still having his blood work done once weekly.

Question: What questions should the pharmacist ask to help assess potential causes of this fluctuation in INR?

Discussion: A number of issues should be evaluated to determine potential changes in warfarin requirements:

• Dietary changes, including vitamin K containing vegetables, liver, nutritional supplement, etc.²⁵

• Changes in bowel function, especially in relation to monthly octreotide injections, as some patients will have an increase in diarrhea for the days to 1 week prior to scheduled dose of octreotide.

• Adherence to the dosing regimen prescribed.

• Alcohol use (eg, chronic alcohol use may increase warfarin requirements and episodic alcohol use may increase INR for individuals on warfarin).

• Use of OTC medications and complementary medications including acetaminophen and multivitamins.

• Any clinical changes, such as infection and fever.

CASE: MANAGEMENT OF SUPRATHERAPEUTIC INR FOR THE PATIENT ON WARFARIN

Ms. Keith is a 44-year-old woman with metastatic breast cancer who has a relatively recent history of DVT managed with warfarin 7.5 mg po daily. Her INRs have ranged from 1.9 to 2.3 over the last few weeks. She was doing well until recently when she experienced confusion and severe headaches. Subsequent evaluation demonstrated multiple brain lesions consistent with brain metastases. She is scheduled to start radiation therapy and was started on dexamethasone 4 mg po every 8 hours. Her INR today was 5.6 when she had blood work prior to radiation. The INR results were not reported until Ms. Keith left the physician’s office, and she is now at home.

Question: What is the best strategy to manage the supra-therapeutic INR in this patient?

Discussion:

• Reversal of anticoagulation from warfarin is based on the clinical presentation, INR, and the patient’s risk of bleeding. Table 4 provides some guidance.

• It is important to assess whether the INR is stable or is escalating secondary to recent changes in medications (eg, dexamethasone).

• Ms. Keith has not reported bleeding, but this should be evaluated. She is not currently receiving therapy that will cause thrombocytopenia and has no known risk for bleeding that we are aware of at this time. One possible consideration is the risk of gastric irritation with dexamethasone.

• The recent addition of dexamethasone may have a significant impact on INR for a patient on warfarin. As this medication is likely to be continued, and eventually tapered, it will be important to closely monitor INR with dexamethasone dose changes.

• Consideration of holding the dose of warfarin should be determined by both the clinical situation as well as the INR.

• The use of oral phytonadione 1 to 2.5 mg may be used in patients with high risk of bleeding. Although phytonadione has been given subcutaneously to manage elevated INRs, the absorption is erratic and delayed.

• The use of intravenous phytonadione, given slowly to avoid anaphylaxis, should be considered when there is serious bleeding.

SUMMARY

The role of the pharmacist in the management of VTE is well established. This role may be even more challenging when the pharmacist is working with the health care team to manage VTE in the individual with cancer. The goal of treatment remains the same: minimize the risks and complications of thrombosis as well as anticoagulation therapy. This review has focused on some of the unique challenges seen in the individual with cancer and provides some suggestions for opportunities for the pharmacist to work collaboratively with the health care team and patient to optimize care. The pharmacist is in a unique position to be a consistent resource for information and advice to the patient and patient family/caregiver. The health care team for the individual with cancer can be quite complex (eg, surgeons, oncologists, primary care providers), and there is always a risk of fragmentation of care and communication. The pharmacist is often one of the only consistent health care team members to routinely see the patient. The pharmacist may be one of the most effective health care professionals to ensure appropriate and effective management of VTE.