Fondaparinux. Fondaparinux is an indirect factor Xa (FXa) inhibitor given subcutaneously. Advantages of fondaparinux include the lack of monitoring required and the ability to use it in patients with a history of heparin-induced thrombocytopenia. Fondaparinux is contraindicated in patients with a creatinine clearance <30 mL/minute. Van Doormaal et al42 found the rate of VTE recurrence was lower with fondaparinux than UFH in the treatment of PE. In another study conducted by Akl et al,46 the rate of VTE recurrence was higher with fondaparinux than LMWH in the treatment of DVT.
Warfarin. Warfarin is very problematic in cancer patients due to the need for frequent laboratory monitoring, numerous drug-drug and drug-nutrient interactions, slow onset of action, and long duration of action. Although it has shown inferiority in cancer patients when compared to LMWH, it may still be an option for long-term treatment, especially for patients with financial barriers, adversity to injections, or renal failure. Due to the slow onset of action of warfarin (steady state is not achieved for 5-7 days), it is important to bridge with a parenteral anticoagulant until therapeutic International normalized ratio is achieved.
Apixaban and Rivaroxaban. Both of these agents are direct FXa inhibitors and can be classified as new oral anticoagulants. Although initial evidence is promising and these agents may be attractive due to feasibility of oral administration without required monitoring, they are currently not recommended for initial therapy in cancer patients. Current published trials have included very few cancer patients, thus limiting the authors’ ability to extrapolate results to the cancer population. Also, these anticoagulants lack reliable agents for reversal in cases of life-threatening bleeding complications.
Thrombolytics. These agents promote rapid clot lysis, reduce venous outflow obstruction, and prevent venous valvular dysfunction, which may help to limit long-term complications such as postthrombotic syndrome. No significant differences in reduction of recurrent PE, death, or major bleeding were found in a recent meta-analysis comparing heparin and thrombolytic agents in patients with acute PE.47 However, thrombolytic therapy is recommended for massive PE (ie, defined as PE with a systolic blood pressure <90 mm Hg).48 There is also growing evidence to support the use of thrombolytics in certain populations for submassive or moderate PE.2,5,48 Alteplase 100 mg via IV infusion over 2 hours can be given for thrombolysis in these settings. Absolute contraindications to thrombolysis include, but are not limited to severe, uncontrolled hypertension; known intracranial (IC) neoplasm or aneurysm; internal bleeding; or recent IC surgery or trauma (Table 3).
Nonpharmacological Treatment
Inferior Vena Cava Filters. In patients with contraindication to therapeutic anticoagulation, an inferior vena cava (IVC) filter can be inserted for prevention of PE.49 Insertion of an IVC filter should be assessed on a case-by-case basis after evaluation of the risk-benefit ratio. If contraindications to anticoagulant therapy are no longer present, anticoagulant therapy should be initiated.
Other treatment strategies such as catheter-directed thrombolysis and surgical thrombectomy can be considered, especially in patients presenting with severe, gangrenous limbs due to obstructive VTE. Until recently, thrombolytics were delivered systemically through an IV catheter, the main disadvantage of which was increased likelihood of bleeding and reduced efficacy of the therapy. Catheter-directed delivery of thrombolytic agents directly into the clot has allowed more localized targeting of therapy and, in combination with mechanical thrombectomy, results in a significant higher rate of complete clot dissolution than systemic anticoagulation.50
Treatment Recommendation
Per the guidelines outlined above, the preferred therapy in cancer patients with VTE is LMWH. Depending on other factors such as risk of bleeding, renal function, anticipated procedures, and financial barriers, other anticoagulant options are available but treatment should be assessed on a case-by-case basis.
Challenging Cases
Incidental VTE. Several studies have suggested that approximately half of cancer-associated VTE events are detected incidentally on routine CT scans performed for diagnosis, staging, or follow-up.51 A meta-analysis of 12 studies including more than 10,000 patients, had a weighted mean incidental PE prevalence of 3.1% (95% CI, 2.2-4.1%).52 Incidental VTE found on routine CT scans should be treated similarly to patients with symptomatic VTE, as many have subtle clinical symptoms of active disease on further evaluation.