Cancer and clots: All cases of venous thromboembolism are not treated the same

MANAGING VTE IN PATIENTS WITH KNOWN CANCER

Managing VTE is far more complex in cancer patients than in patients without cancer. Also, cancer patients with VTE have lower rates of survival than cancer patients without VTE and are at greater risk of adverse outcomes such as anticoagulant-associated bleeding and recurrent venous thrombotic events.^15–17

Up to 21.5% of patients with VTE have another event within 5 years,¹⁸ but the risk is two to three times higher if they also have cancer.^16,18 The risk of recurrence may be linked to the location of the thrombus and to the extent of the malignancy.

In one study, the 3-month rate of recurrence was up to 5.1% if the clot was in the popliteal vein, 5.3% if in the femoral vein, and 11.8% if in the iliac vein.¹⁹

Prandoni et al¹⁶ found that the risks of VTE recurrence and bleeding were higher in patients with extensive cancer than in those with less-extensive cancer. In this study, major bleeding was documented in 12.4% of patients with cancer vs 4.9% of patients without cancer. Compared with patients without cancer, the hazard ratio for a major bleeding event was 4.8 in patients with extensive cancer and 0.5 in patients with less-extensive cancer.

In addition, not all patients with bleeding had excessive levels of anticoagulation, and not all patients with recurrent events had subtherapeutic levels.^16,17 Therefore, treatment of venous thrombosis in cancer patients requires a careful, individualized risk-to-benefit decision analysis.

ACUTE THERAPY FOR VTE: PARENTERAL AGENTS

Treatment in the first several hours or days after a thromboembolic event is with short-acting parenteral agents: unfractionated heparin; one of the low-molecular-weight heparins (LMWHs), ie, dalteparin (Fragmin), enoxaparin (Lovenox), or tinzaparin (Innohep); or fondaparinux (Arixtra).

Before starting anticoagulation, consider:

• Does the patient have severe chronic kidney disease (ie, a creatinine clearance < 30 mL/min)? If so, unfractionated heparin may be better than an LMWH or fondaparinux, which are cleared by the kidney.
• Does he or she need inpatient care? If not, LMWH therapy at home may be appropriate.
• Are there concerns about the ease of anticoagulation administration (ie, whether the patient can give the injections or have a family member do it), the cost of the drugs, or the ability to reverse the anticoagulant effect, if necessary? If so, unfractionated heparin may be more appropriate.

For acute treatment, the 2008 guidelines of the American College of Chest Physicians²⁰ (ACCP) recommend using an LMWH in a weight-based dose; unfractionated heparin given intravenously; unfractionated heparin given subcutaneously with monitoring and dosing adjustments; unfractionated heparin given subcutaneously at a fixed dose; or fondaparinux (grade 1A recommendation). The 2007 National Comprehensive Cancer Network (NCCN) guidelines²¹ recommend an LMWH, fondaparinux, or unfractionated heparin. Treatment should start promptly after the diagnosis of VTE is confirmed. However, if VTE is strongly suspected and a delay in diagnostic testing is anticipated, therapy should be started while awaiting the test results.

LONG-TERM THERAPY: LMWH OR WARFARIN

The ACCP and the NCCN guidelines recommend LMWH monotherapy for extended treatment of VTE in patients with active malignancy, when appropriate.^20,21 However, if long-term LMWH is not appropriate, then oral anticoagulation with a vitamin K antagonist, such as the coumarin derivative warfarin (Coumadin), is an alternative and should be started on the same day as the heparin. The heparin and the warfarin therapy must overlap for a minimum of 4 or 5 days and until a stable, therapeutic level of anticoagulation is achieved, ie, an international normalized ratio (INR) of 2 to 3 for 2 consecutive days.²⁰

The duration of anticoagulant therapy depends on comorbidities and the patient’s underlying predisposition for VTE. In patients with limited disease, the guidelines recommend continuing anticoagulation for a minimum of 3 to 6 months for deep venous thrombosis and pulmonary embolism.^20–21 Patients with active malignancy, ongoing treatment for the cancer, or continued risk factors may need indefinite treatment. In some circumstances, such as catheter-associated deep venous thrombosis, anticoagulation should continue for as long as the catheter is in place and for 1 to 3 months after its removal.²¹

WARFARIN CAN BE DIFFICULT TO USE

In 1954, the US Food and Drug Administration (FDA) approved the vitamin K antagonist warfarin for medical use in humans. Experience has shown it to be effective in preventing and treating VTE. However, it can be somewhat difficult to use, for several reasons:

• A narrow therapeutic window
• Genetic polymorphisms and variability in dose response
• Drug interactions and dietary considerations
• The need for laboratory monitoring and dose adjustment
• Patient noncompliance or miscommunication between the patient and physician.²²

In cancer patients, the response to warfarin may be unpredictable because of poor nutrition, interactions with chemotherapy and antibiotics, and comorbid conditions.²² Furthermore, its onset of action can be delayed and its clearance may be prolonged, further increasing the risk of complications, especially in patients prone to developing chemotherapy-related anemia or thrombocytopenia.²² Bleeding risk is the highest in the first 3 months of therapy. In addition, the risk of bleeding is higher in older patients, women, and patients with a history of gastrointestinal bleeding, stroke, recent myocardial infarction, diabetes, renal insufficiency, malignancy, or anemia.^23,24