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Anticoagulation in the Cancer Patient: Pharmacist Perspectives on the Management of Venous Thromboembolism

EPIDEMIOLOGY OF CANCER-RELATED VENOUS THROMBOEMBOLISM

Venous thromboembolism (VTE) is a significant concern for patients with cancer: they have been found to be 4 to 6.5 times more likely to develop a VTE than the general population.1 Further, patients with cancer who experience a VTE have a 2- to 6-fold increased risk of death, and VTE is the most common cause of 30-day post-operative mortality for these patients.2 VTE has been found in approximately 50% of autopsy reports for patients with cancer, which suggests that the current estimations of VTE incidence of 4% to 20% among cancer patients may be significantly lower than the actual occurrence.3 Additionally, the rate of VTE recurrence is 3 times higher for patients with cancer than for the general population.4

Mechanisms of thrombosis in patients with cancer

Several mechanisms are believed to play roles in VTE development in patients with cancer, and the classic components of Virchow’s triad (a description of 3 factors that contribute to thromboses) can be found in this patient population: periods of immobility (venous stasis), vessel wall damage from chemotherapy and/or surgery, and a hypercoagulable state from the malignancy itself.5 Hypercoagulability may be due to the presence of cancer procoagulant, which is produced by cancer cells.6 Additionally, the coagulation cascade activator, tissue factor, appears to be elevated in patients with cancer, which can lead to increased fibrin formation and, ultimately, thromboses.6 The type of malignancy may also influence the development of a hypercoagulable state. For example, patients with multiple myeloma have been found to have increased levels of von Willebrand factor and factor VIII and decreased levels of protein S.7 Inflammatory responses may also lead to the development of clots from increased levels of circulating proinflammatory cytokines or as a response to the cancer or chemotherapy treatment via formation of neutrophil extracellular traps, which have been shown to be prothrombotic.8 Finally, tumor cells may express plasminogen activator inhibitor-1, which is the major inhibitor of plasminogen activation and may lead to decreased clot breakdown.9

Patient case

CL is a 70-year-old male with metastatic gastric cancer, hypertension, and type 2 diabetes mellitus. The patient is 6’1” and weighs 102 kg. Current medications include amlodipine, lisinopril, metoprolol, metformin, insulin glargine, and insulin lispro. His oncologist plans to start treatment with chemotherapy consisting of cisplatin, fluorouracil, and leucovorin via a port (central venous catheter). What risk factors does CL have for the development of VTE?

Risk factors for VTE

Patient-related risk factors for VTE development in patients with cancer are often similar to risk factors for the general population. Several studies have reported that age older than 65 years and obesity increase VTE risk in patients with cancer.10 Also, a history of VTE and hypercoagulable states, such as pregnancy, increase a patient’s risk for recurrent VTE.6 Other general patient-related risk factors include prolonged immobilization due to hospitalization or surgery and poor performance status.6 Infection has also been identified as a risk factor for development of VTE. One study found that the incidence of VTE within the first 3 months after an infection was 3 times higher than that for patients who did not have an infection during the previous 12 months.11 Prechemotherapy platelet count greater than 350,000/mL, white blood cell count greater than 11,000/mL, and hemoglobin less than 10 g/dL are other patient-related factors that may increase VTE risk.6

Tumor-related factors, as well as the specific type of cancer, also impact VTE risk. Specifically, pancreatic and gastric cancers have been associated with the highest risk of VTE, followed by brain, gynecological, bladder, renal, lung, lymphoma, and bone malignancies. Patients with metastatic disease of any malignancy have a higher risk of VTE than those who have localized disease.6 Tumor histology also appears to impact risk: high-grade tumors double the risk of VTE compared to lower-grade tumors.12 Patients are at highest risk for VTE in the first 3 to 6 months after diagnosis due to the hypercoagulable state of the cancer itself.3

Treatment-related risk factors should also be considered when evaluating a patient’s risk of VTE development, since medications used to treat certain malignancies may increase the risk. For example, the immunomodulatory agents thalidomide, lenalidomide, and pomalidomide are known to cause VTE and their labels carry boxed warnings for VTE risk; thromboprophylaxis is recommended for patients receiving these therapies.13-15 Bevacizumab, a monoclonal antibody, and cisplatin, a platinum-based chemotherapy agent, have also been shown to increase the risk of VTE.16,17 Increased risk is not limited to traditional intravenous anti-cancer therapies, and oral hormonal agents may also increase the risk of VTE. These include not only hormone replacement therapy but also agents such as selective estrogen receptor modulators (tamoxifen and raloxifene) and oral contraceptives.6 Medications used for supportive care such as erythropoiesis-stimulating agents can increase a patient’s risk of VTE, as well.18 In addition to medications, the presence of a central venous catheter and receipt of blood transfusions are additional risk factors that affect many patients with cancer.18

Patient case, continued

Five months after initiating therapy for his metastatic gastric cancer, CL is diagnosed with a deep vein thrombosis (DVT) in his left leg. His oncologist inquires as to the most appropriate anticoagulant for CL at this time. What guidelines are available to direct therapy, and what anticoagulant should be recommended for CL?

GUIDELINE-RECOMMENDED THERAPY FOR VTE

Several national organizations, including the National Comprehensive Cancer Network (NCCN), the American College of Chest Physicians (CHEST), and the American Society of Clinical Oncology (ASCO), have published evidence-based guidelines for the management of VTE in patients with cancer. Of these guidelines, those produced by NCCN are the most up-to-date (2018), followed by CHEST (2016) and ASCO (2015). As a result of the gaps between publication of these guidelines, there are several new recommendations provided by NCCN that contrast those of CHEST and ASCO.

For patients with cancer-associated thrombosis (DVT or pulmonary embolism [PE]), the CHEST guidelines recommend treatment with low molecular weight heparin (LMWH) over other therapies such as warfarin or direct-acting oral anticoagulants (DOACs). The guidelines state that this recommendation was made for the following reasons: LMWH has been shown to be more effective than warfarin; maintaining a therapeutic range for warfarin in cancer patients is challenging; LMWH is tolerable for patients unable to swallow; and LMWH may easily be held for procedures or adverse effects. For patients unable to receive LMWH therapy, CHEST guidelines do not indicate a preference for warfarin or DOAC therapy due to the absence of direct and indirect comparisons. Lastly, CHEST recommends extending treatment duration beyond 3 months, if possible, regardless of bleeding risk.19

ASCO most recently updated its guidelines in 2015 and concluded that the guidelines from 2013 required no significant changes. Much like CHEST, ASCO recommends the use of LMWH over warfarin therapy for patients without severe renal impairment (i.e., creatinine clearance [CrCl] < 30 mL/min). For patients unable to tolerate LMWH, warfarin may be an alternative. In contrast to CHEST, ASCO does not recommend the use of DOAC therapy in this patient population. Additionally, ASCO guidelines direct that fondaparinux may be considered for patients with a history of heparin-induced thrombocytopenia (HIT); however, this regimen has not been well studied. ASCO recommends anticoagulation treatment for a minimum of 6 months and states that providers should consider extending therapy in high-risk patients.18

The NCCN guidelines for cancer-associated thromboembolic disease provide a more comprehensive review and more recommendations than ASCO and CHEST guidelines. Additionally, the writing committee provides several updated recommendations as a result of newer study data. Similar to ASCO and CHEST, NCCN recommends LMWH as the treatment of choice for cancer-associated VTE. However, dalteparin is preferred over other LMWHs, as its efficacy is supported by high-quality evidence and it is approved for this indication by the United States (U.S.) Food and Drug Administration. Additionally, the oral factor Xa inhibitor, edoxaban, has also been deemed a category 1 treatment option. For patients unable to tolerate LMWH or edoxaban, DOAC therapies or warfarin are recommended alternatives. For patients with active HIT or a history of HIT, fondaparinux should be considered. NCCN recommends treating patients for a minimum of 3 months. For patients with active cancer, those undergoing chemotherapy, or those with persistent risk factors, extension of therapy beyond 3 months is recommended. Lastly, for patients with catheter-associated thrombosis, treatment should continue until the catheter is removed and for a total duration of at least 3 months.6 

Anticoagulation therapy

Treatment of VTE centers on safe and effective anticoagulant therapy. In recent years, the armamentarium of anticoagulant medications has grown significantly. While agents such as LMWH, unfractionated heparin, and warfarin remain mainstays of therapy for many patients, DOAC therapy has gained significant momentum in non-cancer-related VTE. Additionally, CHEST guidelines currently recommend the use of DOAC therapy over warfarin for patients without cancer.19 Patients with cancer-associated VTE represent a unique population, and they have been shown to respond differently to anticoagulation therapy than patients without cancer.20 As a result, the anticoagulant options have become somewhat limited for patients with cancer. In contrast to non-cancer-related VTE, the use of DOAC therapy for patients with cancer-associated VTE is not as well established and remains somewhat novel. However, the use of these agents may gain popularity as a result of 2 recent randomized controlled trials.

LMWH

For patients with cancer-related VTE, all anticoagulation therapies are not created equal. This was made evident through randomized controlled trials comparing the effects of LMWH therapy and vitamin K antagonists such as warfarin in cancer patients with VTE. In the first of these trials, the CLOT trial (Randomized Comparison of Low-Molecular-Weight Heparin vs Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer), Lee and colleagues randomized patients with proximal DVT, PE, or both to dalteparin 200 units/kg once daily for 1 month followed by 150 units/kg once daily for 5 months or a coumarin derivative for 6 months (target international normalized ratio [INR], 2.5). After 6 months, more patients receiving warfarin experienced recurrent VTE than those receiving dalteparin (15.8% vs. 8%, p=0.002). No differences were observed in the rates of major bleeding or any bleeding. It is important to note that the INR time in therapeutic range for patients receiving warfarin was 46%, which could impact the efficacy results of warfarin compared to dalteparin. This factor could also be used to argue in favor of LMWH, since LMWH has no need for therapeutic drug monitoring.20

More recently, a second randomized controlled trial, the CATCH trial (Comparison of Acute Treatments in Cancer Haemostasis), was performed. This trial again evaluated the efficacy of LMWH therapy compared to vitamin K antagonist therapy in a population of patients with cancer-associated VTE. Lee and colleagues assessed the efficacy and safety of tinzaparin 175 units/kg and warfarin therapy (target INR, 2-3) for a period of 6 months for patients with VTE and active cancer. Unlike in the CLOT study, tinzaparin was not associated with a greater reduction in recurrent VTE than warfarin therapy (7.2% vs. 10.5%, p=0.07). There were no differences in major bleeding or mortality, but tinzaparin was associated with significantly less non-major bleeding. The INR time in therapeutic range for patients in the warfarin group was 47%. A consideration when comparing these studies is that a higher proportion of patients were receiving active cancer treatment in the CLOT trial than in the CATCH trial. While the results of CATCH contrast those of CLOT, it is worth noting that the CATCH study was underpowered as a result of a lower-than-expected rate of events in the warfarin group. Because of this limitation, the authors speculate that a significant difference may have been identified if the study was performed in a higher-risk population.21

As a result of these studies, current guidelines recommend LMWH therapy (specifically, dalteparin) as the treatment of choice for cancer-associated VTE. While the exact mechanism behind the potential superiority of LMWH therapy over warfarin is unknown, several theories have been postulated. First, maintaining a therapeutic INR in patients receiving cancer treatment can be challenging, since several chemotherapies have significant medication interactions with warfarin. As a result, subtherapeutic anticoagulation may lead to inferior outcomes compared to those achieved with LMWH. Additionally, adherence to warfarin therapy may prove challenging, since many patients may be unable to tolerate oral medications due to chemotherapy-related adverse effects (e.g., mucositis, dysphagia, emesis). Lastly, for patients undergoing surgical procedures, appropriate perioperative anticoagulation management can become complex in patients receiving warfarin therapy. Temporarily holding warfarin without appropriate perioperative bridging may place patients at an increased risk of recurrent VTE.19

When considering the use of LMWH for the treatment of cancer-related VTE, providers should be aware of disease states and patient characteristics that may require dose adjustments or result in contraindications. Of the currently available LMWH products in the U.S., both dalteparin and enoxaparin require dose adjustments and/or monitoring to ensure patients are not exposed to supratherapeutic concentrations. For patients with CrCl less than 30 mL/min, the manufacturers of dalteparin recommend monitoring anti-Xa levels to determine the appropriate dose (goal, 0.5-1.5 units/mL) (Table 1).22,23 In contrast, enoxaparin should be administered once daily instead of twice daily for patients with CrCl less than 30 mL/min.22 There are no additional manufacturer recommendations for patients with end-stage renal disease who are receiving dialysis. However, it is important to note that the safety of dalteparin and enoxaparin in this patient population have not been well established through high-quality studies.

Table 1. Anticoagulants for the Treatment of Venous Thromboembolism22,23,36-39,43
Medication Dose Renal Dose Adjustment* Significant Drug-Drug Interactions
Low molecular weight heparins
Dalteparin 200 units/kg subQ daily x 30 days, then 150 units/kg subQ daily (max dose: 18,000 units) CrCl < 30 mL/min: monitor anti-Xa levels to determine dose None
Enoxaparin 1 mg/kg/dose subQ every 12 hoursor1.5 mg/kg subQ daily CrCl < 30 mL/min: 1 mg/kg subQ daily None
Direct-acting oral anticoagulants
Edoxaban > 60 kg: 60 mg by mouth daily†£ 60 kg: 30 mg by mouth daily† CrCl 15-50 mL/min: 30 mg once daily‡CrCl < 15 mL/min: avoid use P-gp inhibitor§: 30 mg by mouth dailyP-gp inducer: avoid use
Rivaroxaban 15 mg by mouth twice daily x 21 days, then 20 mg by mouth daily CrCl < 30 mL/min: avoid use Dual P-gp and strong CYP3A4 inducers or inhibitors: avoid use
Dabigatran 150 mg by mouth twice daily† CrCl < 50 mL/min and concomitant P-gp inhibitor: avoid use‡ P-gp inhibitor and CrCl < 50 mL/min: avoid useP-gp inducer: avoid use
Apixaban 10 mg by mouth twice daily x 7 days, then 5 mg by mouth twice daily No dose adjustment necessary Dual P-gp and strong CYP3A4 inhibitors: reduce apixaban dose by 50%Dual P-gp and strong CYP3A4 inducers: avoid use
Factor Xa inhibitor
Fondaparinux < 50 kg: 5 mg subQ once daily50-100 kg: 7.5 mg subQ once daily> 100 kg: 10 mg subQ once daily CrCl 30-50 mL/min: use cautionCrCl < 30 mL/min: do not use None
CrCl, creatinine clearance; CYP, cytochrome P450; P-gp, P-glycoprotein; subQ, subcutaneously.
*CrCl calculated using Cockcroft-Gault formula with actual body weight for direct-acting oral anticoagulants.
†Parenteral therapy required for at least 5 days prior to initiation of oral medication.
‡Patients with CrCl < 30 mL/min at baseline were excluded from clinical trials.
Patients with creatinine > 2.5 mg/dL or CrCl < 25 mL/min were excluded from clinical trials.
§Specific P-gp inhibitors: verapamil, quinidine, short-term azithromycin, clarithromycin, erythromycin, oral itraconazole, and oral ketoconazole.

Obesity has become an epidemic in the U.S. and throughout the world: currently, nearly 40% of Americans are considered obese.24 Both dalteparin and enoxaparin are dosed according to body weight and dosing patients with morbid obesity can be challenging. Providers should be cautious with patients with extreme body weight, as these patients may be at an increased risk of medication accumulation and hemorrhagic events. For patients weighing 83 kg or more, the maximum dose of dalteparin should be 18,000 units.23 The maximum dose for enoxaparin in obese patients is unclear. Current literature demonstrates the safety of doses of 180 mg, but this dose may not be effective for patients weighing greater than 200 kg.25 Therefore, for patients with morbid obesity, alternative anticoagulant therapy, such as warfarin, should be considered.

Patients with cancer-related VTE often require cancer treatments that may result in significant thrombocytopenia. Therefore, many of these patients may be predisposed to bleeding while receiving LMWH. Because of this risk, the doses of both dalteparin and enoxaparin should be adjusted on the basis of platelet counts (Table 2).6,23 LMWH should be avoided in patients with a history of HIT. While receiving LMWH therapy, patients should be monitored for signs and symptoms of bleeding and their renal function should be assessed. Other pertinent laboratory monitoring parameters for evaluating anticoagulation include hemoglobin, platelet count, and serum creatinine.22,23

Table 2. Low Molecular Weight Heparin Dose Adjustments for Thrombocytopenia6,23
Medication Platelet Count Dose Adjustment
Dalteparin 50,000-100,000/mL Reduce dose to 2,500 units until platelets ≥ 100,000/mL
< 50,000/mL Hold until platelets > 50,000/mL
Enoxaparin 25,000-50,000/mL 0.5 mg/kg subQ every 12 hours
< 25,000/mL Hold until platelets > 25,000/mL
subQ, subcutaneously.

Patient case, continued

CL has been compliant with his LMWH injections for 2 months. He is curious about a television commercial he saw that mentioned an oral medication for blood clots that does not require monitoring like warfarin. He would like to know if this is an option for his VTE treatment. On the basis of currently available data, what would you recommend?

DOACs

While LMWH is considered the treatment of choice for cancer-related VTE, such therapy is not without limitations. One of the most significant drawbacks of using LMWH therapy is the route of administration. The subcutaneous injections can be challenging for many patients to manipulate and injection-site reactions such as bruising are common.22,23 When given the opportunity, patients prefer oral anticoagulation if it will provide the same level of efficacy as other routes.26 Additionally, although generic LMWH products are available, many insurance companies still require prior authorization for approval, as well as significant copays. As a result of these limitations, DOACs have become popular alternatives to LMWH therapy for the treatment of cancer-related VTE. Given the oral route of administration, minimal laboratory monitoring requirements, and growing insurance coverage, it is no surprise that DOAC use is on the rise.

However, a considerable limitation to DOAC therapy for patients with cancer is the lack of clinical efficacy compared to LMWH. The landmark clinical trials evaluating DOAC therapy versus warfarin in patients with VTE only included a small minority of patients with active cancer.27-31 Until recently, the efficacy and safety of DOAC therapy was only assessed in observational studies: while these provide valuable insight, they are not without inherent limitations.32 Fortunately, 2 recently published randomized controlled clinical trials have compared the efficacy and safety of DOAC therapy to LMWH. The first of these was the phase III Hokusai VTE Cancer trial, which compared edoxaban with dalteparin in patients with VTE and active cancer (excluding basal cell or squamous cell carcinomas) or a history of cancer diagnosis within the previous 2 years. Patients were randomized to receive edoxaban 60 mg orally once daily or dalteparin 200 units/kg subcutaneously daily for 30 days followed by 150 units/kg subcutaneously daily for a minimum of 6 months. Patients with CrCl of 30 to 50 mL/min, patients with body weight less than 60 kg, and patients receiving potent P-glycoprotein inhibitors received edoxaban 30 mg orally once daily. Prior to the initiation of edoxaban, all patients received 5 days of therapeutic LMWH. Following a median treatment duration of 211 days for edoxaban and 184 days for dalteparin, the investigators found edoxaban to be non-inferior to LMWH for the primary outcome of recurrent VTE or major bleeding at 12 months (12.8% vs. 13.5%, p=0.006 for non-inferiority). No statistical difference was found in the rates of recurrent VTE (7.9% vs. 11.3%, p=0.09). The rate of major bleeding was significantly higher in the edoxaban group (6.9% vs. 4%, p=0.04).30

The second and most recently published randomized clinical trial evaluating DOAC therapy for cancer-related VTE was the SELECT-D trial (Comparison of an Oral Factor Xa Inhibitor with Low Molecular Weight Heparin in Patients with Cancer with Venous Thromboembolism). Young and colleagues randomized patients with active cancer (defined as a diagnosis of cancer in the preceding 6 months [excluding basal cell and squamous cell carcinomas], treatment within the previous 6 months, metastatic disease, or a hematologic malignancy not in complete remission) to rivaroxaban 15 mg orally twice daily for 21 days followed by 20 mg orally once daily for 6 months or dalteparin 200 units/kg subcutaneously daily for 1 month followed by 150 units/kg subcutaneously daily for 5 months. Following a median treatment of 5.9 months in the rivaroxaban group and 5.8 months in the dalteparin group, the investigators found no differences in the rates of recurrent VTE or major bleeding (4% vs. 11%, 95% confidence interval [CI]: 2%-9%; 6% vs. 4%, 95% CI: 3%-11%, respectively). While these results are promising, it is important to note that this study was an open-label pilot trial that included significantly fewer patients than the Hokusai VTE Cancer trial. Additionally, due to challenges in patient recruitment, the sample size fell short of the initial estimate. However, the rates of recurrent VTE and bleeding were similar to previous studies, which assisted in validating the researchers’ findings.31

At this time, both apixaban and dabigatran have limited evidence supporting their efficacy and safety for the treatment of cancer-related VTE.33,34 While both agents have yielded promising results in observational studies, prospective trials are required to adequately evaluate these agents. Currently, only apixaban has an ongoing study evaluating its use in this patient population. The randomized controlled Caravaggio Study is currently underway to assess the efficacy of apixaban versus dalteparin for patients with cancer.35

Because of the high quality of the Hokusai VTE Cancer trial, edoxaban should be considered the DOAC of choice when anticoagulating cancer patients. This recommendation is echoed in the NCCN category 1 recommendation for edoxaban in this patient population. Given the efficacy of rivaroxaban demonstrated in the SELECT-D trial, it should be chosen as an initial alternative to edoxaban. For patients for whom edoxaban or rivaroxaban is not an option, providers can consider apixaban or dabigatran. However, clinicians should be aware that the efficacy and safety of these agents in cancer patients are not yet well established and future studies are warranted to confirm their efficacy relative to other DOACs.

There are several patient-related and medication-related characteristics that must be weighed when initiating DOAC therapy. Most notably, these include the requirement for initial parenteral therapy, renal function, body weight, medication interactions, and hemorrhagic risk. Unlike rivaroxaban and apixaban, both edoxaban and dabigatran require parenteral therapy for at least 5 days prior to initiation of therapy. Renal function is one of the biggest concerns related to DOAC therapy: since each agent is cleared by the kidneys (to varying degrees), failure to adjust the doses of these medications appropriately can lead to supratherapeutic drug concentrations and potentially fatal hemorrhagic events. Recommended dose adjustments based on renal function can be found in Table 1.36-39 It is important to note that the use of these agents for patients with CrCl less than 25 to 30 mL/min has not been evaluated in clinical trials.27-29 While there is a growing body of pharmacokinetic and observational data demonstrating the safety of these agents for patients with severe renal impairment and end-stage renal disease, the data are limited to patients receiving therapy for atrial fibrillation and not VTE.40 Therefore, the use of these agents for the treatment of cancer-related VTE in patients with severe renal impairment or end-stage renal disease should be discouraged at this time.

In obese patients, the efficacy and safety of DOAC therapy has not been established. As a result, the International Society of Thrombosis and Haemostasis recommends avoiding the use of DOACs in patients with body mass index (BMI) greater than 40 kg/m2 or body weight greater than 120 kg.41

While DOAC therapy is associated with significantly fewer medication interactions than warfarin, medication interactions do exist that warrant consideration. For patients receiving concomitant therapy that may inhibit or induce cytochrome P450, providers should ensure such interactions can be managed safely and discontinue DOAC therapy if use is not recommended.36-39 Also, a thorough bleeding risk assessment should be performed when considering DOAC therapy versus LMWH: both the Hokusai VTE Cancer trial and the SELECT-D trial demonstrated significantly higher rates of major bleeding with DOACs. It is important to note that both of these studies were limited to a 12-month follow-up period, and, as a result, the safety of these agents over longer periods of time may differ from what was observed in these studies. For patients with risk factors for major bleeding, such as a history of major bleed, concomitant antiplatelet therapy, liver disease, and renal impairment, providers should consider LMWH over treatment with a DOAC. When monitoring DOAC therapy, providers should periodically evaluate renal function, platelet count, hemoglobin, and the potential for medication interactions.

Vitamin K antagonist

Warfarin, a vitamin K antagonist, has long been established as a treatment option for patients without cancer who have been diagnosed with VTE.19 As discussed, warfarin was compared to LMWH in the CLOT and CATCH trials for treatment of VTE in patients with cancer. The guidelines continue to prefer LMWH over warfarin on the basis of the results of the these trials.6,18,19 Additionally, results of the CLOT trial showed increased recurrent VTE in patients receiving warfarin compared to those receiving dalteparin after 6 months (15.8% vs. 8%, p=0.002) but no differences in the rates of major bleeding or any bleeding.20 In the CATCH trial, the rates of recurrent VTE were not statistically different between patients receiving tinzaparin and those receiving warfarin (7.2% vs. 10.5%, p=0.07). Also, there were no differences in major bleeding or mortality, but tinzaparin was associated with significantly less non-major bleeding.21

Warfarin remains an option for chronic treatment of VTE for patients with HIT after platelet count recovery. As is standard with warfarin therapy, treatment should be overlapped with a direct thrombin inhibitor or fondaparinux until the goal INR of 2 to 3 is reached and maintained. Warfarin may be used for patients who are obese, and warfarin is also an option for patients with renal insufficiency, since it is not metabolized by the kidneys.6,18

Concerns with warfarin administration include the potential for significant drug-drug interactions and difficulty titrating to and maintaining a therapeutic INR. Warfarin remains an option for long-term treatment of VTE for patients with cancer according to current guidelines, but its use will likely decrease given the growth of the DOAC class of anticoagulants.6,18

Factor Xa inhibitor

The efficacy and safety of fondaparinux, a factor Xa inhibitor, for patients with cancer-related VTE have not been well established and current guidelines do not recommend its use as an initial treatment option. At this time, fondaparinux should primarily be considered for patients with a diagnosis or clinical suspicion of HIT. For most patients, treatment with fondaparinux will be limited to bridging to warfarin therapy for long-term treatment of HIT. However, for patients with a contraindication to warfarin, fondaparinux may be used as maintenance therapy.6 Currently, evidence supporting the use of fondaparinux for maintenance therapy is scarce. According to limited available evidence, treatment with fondaparinux has demonstrated similar rates of recurrent VTE and major bleeding compared to LMWH.42 When treating patients with fondaparinux, providers should monitor renal function closely, since accumulation and hemorrhagic complications can arise from inappropriate use. For patients with CrCl less than 30 mL/min, fondaparinux should be avoided. Additionally, providers should use caution in patients with moderate renal impairment and in elderly patients.43

THE PHARMACIST’S ROLE IN VTE MANAGEMENT

Pharmacists are well qualified to provide key assistance to providers when choosing appropriate anticoagulant therapy for patients with cancer. In this patient population, it is imperative to consider the ever-growing data that are available for reference. Guidelines are continually updated as research is completed and published, and pharmacists have the opportunity to be intimately involved in discussions with providers pertaining to the most recent VTE prophylaxis and treatment evidence. Because providers must consider a variety of risk factors, procedures, and treatments in a patient’s overall cancer treatment regimen, pharmacists can assist in optimizing potentially overlooked supportive care medications, especially anticoagulation. As such, pharmacists should remain up-to-date with published literature, as well as ongoing trials (Table 3),44 and be ready to offer guidance to providers.

Table 3. Ongoing Studies with Direct-Acting Oral Anticoagulants in Patients with Cancer44*
Study Title Medications Primary Outcome Secondary Outcomes
Direct oral anticoagulants (DOACs) versus LMWH +/- warfarin for VTE in cancer Rivaroxaban
Apixaban
Edoxaban
Dabigatran
Warfarin
Dalteparin
Enoxaparin
Fondaparinux		 Cumulative VTE recurrence (time frame: 6 months) Cumulative rates of major bleeding

Health-related quality of life via Optum SF-12v2 Health Survey Questionnaire

Burden of anticoagulation therapy reported by participants via the Anti-Clot Treatment Scale Questionnaire

Mortality
A phase 3b, prospective, randomized, open-label, blind evaluator (PROBE) study evaluating the efficacy and safety of (LMW) heparin/edoxaban versus dalteparin in venous thromboembolism associated with cancer Edoxaban
Enoxaparin		 Number of participants with recurrent VTE at end of study (time frame: 6 months) Number of participants with clinically relevant bleeding while on treatment
A prospective study of dabigatran etexilate as primary treatment of malignancy associated venous thromboembolism Dabigatran
Tinzaparin		 Number of patients with symptomatic VTE (time frame: up to 2 years) Mortality, number of participants with clinically relevant major and non-major bleeding
Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients - a randomized phase III study Rivaroxaban
Enoxaparin
Tinzaparin
Dalteparin		 Patient-reported treatment satisfaction with rivaroxaban in the treatment of acute VTE in cancer patients in comparison with the standard treatment with LMWH (time frame: from randomization to 4 weeks after treatment start) Rate of symptomatic VTE

Exploratory analysis for "time on treatment"

Subgroup analysis with regard to rate of PE, VTE recurrence and bleedings

Rate of myocardial infarction and ischemic stroke

Compliance of patients

Overall mortality at 3 and 6 months

Quality of life

Rate of clinically relevant bleeding within 3 months
Apixaban for the treatment of venous thromboembolism in patients with cancer: a prospective randomized open blinded end-point (PROBE) study Apixaban
Dalteparin		 Recurrent VTE (time frame: 6 months) ---
LMWH, low molecular weight heparin; PE, pulmonary embolism; VTE, venous thromboembolism.
*List is not all inclusive. More information can be found at https://clinicaltrials.gov.

In addition to VTE treatment, pharmacists can play a key role in VTE prophylaxis for patients with cancer in both the inpatient and ambulatory settings. Consideration of VTE prophylaxis should be based on a patient’s malignancy, clinical status, and renal function. The NCCN guidelines recommend LMWH, fondaparinux, or unfractionated heparin for inpatient prophylaxis.6 Generally, patients with cancer who are ambulatory will not require VTE prophylaxis, but patients with multiple myeloma and surgical oncology patients are exceptions to this rule.

Patients with multiple myeloma are known to be at an increased risk for VTE and, in the presence of other risk factors such as obesity (BMI ≥ 30 kg/m2), prior VTE, cardiac disease, chronic renal disease, diabetes, acute infection, or surgery, prophylaxis is warranted in these patients.6 The recommended prophylaxis regimen is aspirin 81 to 325 mg daily. Patients with multiple myeloma who are receiving therapy with an immunomodulatory agent in combination with a dexamethasone dose greater than 480 mg per month, doxorubicin, or multi-agent chemotherapy should receive prophylaxis with warfarin or LMWH. 6,45 Surgical oncology patients with a history of VTE should receive prophylaxis for 4 weeks following abdominal or pelvic surgery, anesthesia longer than 2 hours, bed rest for 4 or more days, or age greater than 60 years.6

Pharmacists should be well versed in the dosing regimens, dose adjustments, and monitoring parameters for each agent used for VTE treatment. Again, when choosing an anticoagulant for treatment of VTE, renal function, weight, concomitant medications, and bleeding risk should all be assessed prior to initiation of therapy. A pharmacist may find potential drug-drug interactions during medication review that were overlooked by a prescribing provider, and pharmacists may have insight into potential patient compliance barriers such as route of administration or appreciate the need for patient assistance programs due to high costs of some of these medications.

Incumbent on the pharmacy profession, patient counseling remains paramount to treatment success for patients who have been prescribed an anticoagulant. Often, patients may question the need for parenteral anticoagulation when they know of friends or family members who are using oral anticoagulants for treatment of VTE. A pharmacist remains one of the most readily accessible healthcare team members and has the knowledge and training to counsel patients about administration and side effects, as well as answer any medication-related questions they may have. For example, if a patient is started on LMWH and transitioned to edoxaban, a pharmacist should counsel him to start the edoxaban at the time the next dose of LMWH would have been due to decrease the risk for duplicate anticoagulant dosing during the transition.39 Additionally, patients receiving warfarin should be referred to an anticoagulation monitoring clinic, if available, for close monitoring and dose adjustments by an expert (who is often a pharmacist). Not only can pharmacists provide education and monitoring for these patients, they can also assist in perioperative anticoagulation management.

CONCLUSION

VTE remains a significant concern for patients with cancer. Several risk factors have been identified for the development of VTE and should be considered when initiating treatments in this patient population. When a patient is diagnosed with VTE, the treatment of choice is LMWH. DOACs, warfarin, and fondaparinux remain options for patients in specific circumstances. Pharmacists remain a vital part of the healthcare team and have opportunities for interventions when assessing for drug-drug interactions, recommending doses and dose modifications, and providing patient education.

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