Using anticoagulants to treat chemotherapy-related VTE
Using anticoagulants to treat chemotherapy-related VTE
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Venous thromboembolism (VTE) increases morbidity and mortality in oncology patients. The incidence of VTE is 5-fold higher in patients with cancer compared with other patients, and the condition is the second leading cause of death in oncology patients.1-2 The risk of VTE in oncology patients is 0.5% per year and increases 6.5-fold for patients receiving chemotherapy.3 The risk of recurrence is also higher in oncology patients (20.7% of cancer patients compared with 6.8% of patients without cancer).4
Types of venous thromboembolism include superficial venous thrombosis (SVT), deep-venous thrombosis (DVT), and pulmonary embolism (PE). SVT and DVT occur when a blood clot forms in the superficial or deep veins, respectively. The signs and symptoms of a DVT typically include unilateral limb redness, swelling, or pain. PE occurs when blood clots travel to the lungs and obstruct the pulmonary arteries. Symptoms of PE include shortness of breath, tachypnea, pleuritic chest pain, hypoxia, hemoptysis, tachycardia, or syncope.5 The discussion of VTE in this article is confined to deep venous thrombosis and pulmonary embolism, as SVT is not typically treated via anticoagulation.
THROMBOSIS AND ANTICOAGULATION THERAPY
Cancer-associated mechanisms that can promote VTE include the release of prothrombotic factors, inflammation, local necrosis, and vascular stasis;3 patient-related factors include age, comorbidities, or previous VTE (Table 1). The risk of VTE or VTE recurrence is higher for patients with advanced stage cancer; who are undergoing surgery; or who are receiving cytotoxic, hormonal, or antiangiogenic chemotherapy agents.5-7
The coagulation cascade is a series of reactions that produces a fibrin-containing clot. When the coagulation cascade is activated, tissue factor binds to cofactors to activate factor X. The activated factor X, referred to as Xa, interacts with other factors to convert prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, which forms the clot. Other factors that interact with this cascade include the vitamin K-dependent factors II, VII, and IX (factor X is also vitamin K-dependent). Some coagulation factors work to inhibit clot formation; these include antithrombin and the vitamin K-dependent proteins C and S.3,7-9
Patients who develop VTE are often treated with anticoagulants such as low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux (Arixtra, generic), or warfarin (Coumadin, Jantoven, generics), a derivative of coumarin. UFH enhances the action of antithrombin, inactivating thrombin and preventing the conversion of fibrinogen to fibrin.10 UFH may be administered subcutaneously for VTE prophylaxis, and intravenously as initial treatment of VTE in hospitalized patients. LMWH (enoxaparin [Lovenox, generics] and dalteparin [Fragmin]) also bind antithrombin to inhibit factor Xa and thrombin activity.11,12 Although the LMWH products have not been compared in clinical studies, they are considered equivalent.13 Fondaparinux inhibits factor Xa; the drug is used to treat VTE as well as prophylaxis in patients undergoing surgery.14 Warfarin is an oral anticoagulant that inhibits synthesis of vitamin K-dependent coagulation factors and the anticoagulant proteins C and S.15 Prophylaxis options include the anticoagulants discussed above as well as mechanical methods such as compression stockings, intermittent pneumatic calf compression, or mechanical foot pumps.5,6 Oral direct thrombin inhibitors such as dabigatran (Pradaxa), are not recommended for prophylaxis or treatment in patients with cancer due to a lack of clinical data in these populations.16
In addition, some patients should not receive anticoagulants for treatment or prophylaxis of VTE. Contraindications to anticoagulation therapy include:
• Recent central nervous system (CNS) bleeding or intra-cranial or spinal lesions with a high risk of bleed;
• Active bleeding (acute or chronic)
• Thrombocytopenia with platelets less than 50,000/µL;
• Severe platelet dysfunction from uremia, medications, or dysplastic hematopoiesis;
• Recent major surgery with high risk for bleed;
• Underlying coagulopathy such as clotting factor abnormality (eg, factor VIII deficiency);
• Recent spinal anesthesia/lumbar puncture;
• High risk of falls or head trauma.6
Mechanical methods should be used for VTE prophylaxis in patients who meet any of these criteria. Patients with VTE for whom anticoagulant therapy is contraindicated or who have recurrent VTE despite optimal coagulation may be candidates for a vena cava filter to prevent emboli from traveling to the lungs.5-6
ANTICOAGULATION AS PROPHYLAXIS
Guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend VTE prophylaxis with anticoagulation therapy for hospitalized oncology patients, unless contraindicated (Table 2),5-6 and it should be continued throughout the hospitalization. Patients undergoing major surgery (duration more than 30 minutes) for malignant disease should also receive VTE prophylaxis.
Ideally, anticoagulation therapy is initiated prior to surgery or as soon after surgery as possible.5 VTE prophylaxis should be continued for at least 7 to 10 days after surgery, and may be extended up to 4 weeks in high-risk situations (eg, major abdominal or pelvic surgery with residual disease after surgery, obesity, prior VTE, older than 60 years, advanced cancer, surgery lasting more than 2 hours, or patient is bed bound for more than 3 days).5-6 In patients who underwent major abdominal surgery, VTE rates were lower in those who received prolonged prophylaxis (4 weeks) with dalteparin compared with 1 week of prophylaxis (16.3% vs 7.3%, P = 0.012).17
The guidelines also recommend using mechanical methods in addition to pharmacologic agents, especially in high-risk surgical patients. However, mechanical methods should not be used alone unless anticoagulation is contraindicated.5-6 VTE prophylaxis is not recommended for most ambulatory oncology patients, but it is recommended in ambulatory patients with multiple myeloma who are receiving thalidomide (Thalomid) or lenalidomide (Revlimid) in combination with chemotherapy or dexamethasone (Ciprodex, generics) due to the high risk of thrombosis in these patients.5-6