Review of Anticoagulants in Patients with Cancer:
A Focus on Oral Anticoagulants
Christina Davis, PharmD
PGY2 Oncology Pharmacy Resident
University of Colorado Anschutz Medical Campus
Aurora, CO
Cancer-associated venous thromboembolism (VTE) accounts for a significant degree of morbidity and mortality. Patients with cancer are at a several-fold increased risk for VTE compared to their counterparts without cancer, with an overall incidence of VTE between 4% and 20%.1 High-risk factors for developing VTE in this population include primary site of malignancy (e.g., lungs, pancreas, brain, gastrointestinal system, women’s reproductive organs, kidneys, blood and lymphatic systems), time since diagnosis (risk is higher within the first 3–6 months), advanced stage of disease development, type and intensity of chemotherapy (e.g., hormonal therapy, use of antiangiogenesis agents, high-dose dexamethasone), exposure to radiation therapy, ethnicity (risk is higher among African Americans), and the presence of comorbidities.1,2 This clinical picture of hypercoagulability is further complicated by the fact that patients with cancer also experience a higher rate of bleeding than the general population. It is reported that thrombocytopenia occurs in approximately 10% of cancer patients.3 This is most commonly a result of bone marrow or blood vessel infiltration by the tumor and abnormalities in platelet function or coagulation factors, which can be a result of liver dysfunction, chemotherapy, or radiation.3
Despite this increased risk of VTE in patients with cancer, there are little data to support routine thromboprophylaxis in the outpatient setting. Certain high-risk patients, such as those with multiple myeloma receiving lenalidomide or thalidomide in combination with dexamethasone or chemotherapy, are the exception, and for them prophylaxis with either a low-molecular-weight heparin (LMWH) or low-dose aspirin is recommended. Guidelines agree that most hospitalized patients with active cancer and those undergoing major cancer surgery require VTE prophylaxis in the absence of a contraindication to anticoagulation (Table 1 - see PDF).1,2
LMWH is the agent of choice for the initial 5–10 days of treatment of established deep vein thrombosis (DVT) or pulmonary embolism (PE) and for long-term secondary prophylaxis for at least 3–6 months.1 This recommendation was established based on the results of the Clots in Legs or sTockings (CLOT) trial, during which patients with active cancer and newly diagnosed symptomatic DVT/PE were randomized to receive either dalteparin 200 units/kg daily for 1 month followed by 100 units/kg daily for a total of 6 months or warfarin with a target international normalized ratio (INR) of 2–3. The results showed a statistically significant reduction in the primary outcome of recurrent VTE in patients who received dalteparin, with no significant difference in bleeding risk or overall survival at 6 months.4 Although no trials have directly compared the efficacy of other LMWH products, such as enoxaparin, to warfarin, many clinicians feel that this advantage can be extrapolated to other LMWH agents. Potential advantages of LMWHs that may contribute to their superior efficacy over vitamin K antagonists (VKA) include a more predictable dose-response curve, lack of need for routine therapeutic monitoring, and minimal dependence on genetic and environmental factors.5 Despite these advantages, aspects such as cost and unwillingness or inability to self-administer injections may make many patients hesitant about initiating therapy with LMWH.
A meta-analysis from 2011 compared the efficacy and safety of unfractionated heparin (UFH), LMWH, and fondaparinux for the initial treatment of VTE in patients with cancer. Results from this study showed a statistically significant reduction in mortality at 3 months follow-up with LMWH compared to UFH but did not show a difference in VTE recurrence. There was no difference in mortality, VTE recurrence, or major or minor bleeding with UFH compared to fondaparinux.6 On the basis of this information and the lack of routine monitoring needed, LMWHs are considered first-line treatments for the acute management of VTE in cancer patients (see Table 1).
Because of the lack of clinical experience regarding safety and efficacy in cancer patients, direct oral anticoagulants are not recommended in current guidelines for acute or chronic management of VTE (see Table 1). In the landmark trials that evaluated these agents for the treatment of VTE, the percentage of patients with active cancer was very small, ranging from 2.5% to 6% (Table 2 - see PDF). However, direct oral anticoagulants (DOACs) have many potential advantages that make their use attractive to providers. These include their wide therapeutic window, rapid onset and offset, lack of routine monitoring, predictable pharmacokinetics, and relatively few drug and diet interactions when compared to warfarin.7 A meta-analysis published in Chest in 2015 compared DOACs to conventional anticoagulants (heparin followed by VKA) for the treatment of cancer-associated VTE.8 Six studies were included in the analysis: two with dabigatran, two with rivaroxaban, one with apixaban, and one with edoxaban (Table 2 - see PDF). VTE recurrence and major bleeding rates in patients with cancer were reported to be 3.9% and 3.2% in the DOAC group versus 6% and 4.2% in the conventional anticoagulation group. This demonstrated a nonsignificant but favorable trend in reduction of recurrent VTE and no apparent increased risk of bleeding with the use of DOACs. This reduction was consistent across all of the studies used in the analysis.8 However, no clinical trials are currently available comparing these agents to LMWHs, which are the preferred first-line treatment for VTE in patients with cancer.
Several clinical factors must be considered when choosing the most appropriate anticoagulant for a patient. These include absolute contraindications to anticoagulant therapy, overall bleeding risk, renal function, cost, and burden of treatment (e.g., self-injecting, frequency of monitoring). It is also important to recognize potential drug-drug interactions between DOACs, chemotherapy, and common supportive-care medications. All of the DOACs are substrates of P-glycoprotein (P-gp) and both rivaroxaban and apixaban are major substrates of CY3A4, making avoidance of strong CYP 3A4 inhibitors/inducers imperative. Certain chemotherapy and targeted agents (e.g., dasatanib, ibrutinib, bevacizumab) also can put a patient at higher risk of bleeding and must be considered when assessing risk versus benefit of anticoagulation. One major clinical consideration is the availability of a reversal agent in the event of a life-threatening bleed or emergency surgery. Protamine is the agent of choice for reversal of UFH or LMWH (Table 3 - see PDF) and must be administered by slow intravenous infusion (no faster than 5 mg/min) because of the risk of anaphylaxis.2 Reversal strategies for warfarin are stratified according to the patient’s INR and the presence of bleeding or need for emergent surgery. In regard to DOACs, dabigatran is the only agent with a specific antidote with a cost of $4,200 per 5-gram dose of idarucizumab. Antidote availability, quality of evidence, and patient-specific factors should be considered when assessing the risk versus benefit of anticoagulation in patients with cancer.
References
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2. Streiff MB, Holmstrom B, Ashrani A, et al. NCCN clinical practice guidelines in oncology: Cancer-Associated Venous Thromboembolic Disease, Version 1.2016. J Natl Compr Canc Netw. 2016 July. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf
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