Apixaban for VTE Associated with Malignancy

Mrs. Khan is a 67-year-old woman with a history of Stage III gastric adenocarcinoma for which she is currently receiving targeted immunotherapy. She presents to the emergency department with sudden-onset pleuritic chest pain and palpitations and is ultimately diagnosed with a segmental pulmonary embolism. You are asked to see her prior to discharge to make a recommendation for anticoagulation. The patient asks about alternatives to daily injection with low-molecular-weight heparin (LMWH).

The answer is not so straightforward. Outpatient management of venous thromboembolism (VTE) is typically limited to warfarin, LMWHs, and direct-acting oral anticoagulants (DOACs). The options are limited further when the VTE is associated with malignancy and requires the added objective of preventing recurrence. The seminal CLOT trial demonstrated that the LMWH dalteparin was more effective than warfarin at reducing VTE recurrence without increased risk of bleeding. However, the introduction of DOACs in 2008 compelled the assessment of these medications in various clinical scenarios because of their convenience of use. Edoxaban and rivaroxaban were the first to be tested in malignancy associated VTE and showed efficacy, but with the notable caveat of an increased risk of bleeding, especially in patients with gastrointestinal malignancies.

The Caravaggio trial is the largest study of a DOAC, in this case apixaban, for the treatment of malignancy associated VTE, and the results are encouraging, particularly for patients like Mrs. Khan. In the Caravaggio trial, apixaban was noninferior to dalteparin in preventing VTE recurrence (5.6% vs. 7.9%; hazard ratio, 0.63; 95% confidence interval, 0.37 to 1.07; P<0.001 for noninferiority). Notably, major bleeding events, including gastrointestinal bleeding, were similar in the two groups, distinguishing apixaban from the previously studied DOACs.

Choosing an appropriate anticoagulant in this clinical context requires consideration of multiple factors, including patient preference. The Caravaggio trial adds an important data point for physicians to consider when weighing treatment options in patients with malignancy associated VTE.

The following NEJM Journal Watch summary explains the study and results in more detail.

Brady L. Stein, MD, MHS reviewing Agnelli G et al. N Engl J Med 2020 Mar 29 Lee AYY. N Engl J Med 2020 Mar 29 

Recommended treatment of patients with cancer-associated thrombosis has evolved beyond warfarin and subcutaneous low-molecular-weight heparin (LMWH) to now include the direct oral anticoagulants (DOACs) edoxaban and rivaroxaban (NEJM JW Oncol Hematol Feb 2018; J Clin Oncol 2020; 38:496). However, studies of these DOACs have shown an increased risk for bleeding, particularly in patients with gastrointestinal (GI) malignancies (NEJM JW Oncol Hematol Oct 2018 and J Clin Oncol 2018; 36:2017; N Engl J Med 2018; 378:615).

Now, investigators have conducted an industry-funded, international, randomized, controlled, noninferiority study to compare rates of recurrent VTE in 1155 cancer patients with newly diagnosed incidental or symptomatic proximal deep vein thrombosis or pulmonary embolism who were treated with the DOAC apixaban or the LMWH dalteparin. Patients with acute leukemia or brain tumors were excluded.

Key findings were as follows:

• Rates of recurrent VTE were lower with apixaban than with dalteparin (5.6% vs. 7.9%; hazard ratio, 0.63; P<0.001 for noninferiority).

• Rates of major bleeding were similar with apixaban and dalteparin (3.8% and 4.0%, respectively), as were rates of major GI bleeding (1.9% and 1.7%).

• Rates of clinically relevant nonmajor bleeding (especially genitourinary and upper airway bleeding) were nonsignificantly higher with apixaban than with dalteparin (9% and 6%). 

COMMENT: These results support the inclusion of apixaban as an oral anticoagulant option for patients with cancer-associated thrombosis. An important finding was the similar rate of major GI bleeding with a DOAC or an LMWH in patients with GI malignancies. Still, patients will require careful selection for use of DOACs, based on tumor type (central nervous system tumors were excluded from this study, and genitourinary bleeding was of concern here), platelet count, and potential for drug interactions. Most patients with cancer-associated thrombosis require indefinite anticoagulation. This study reports outcomes at 6 months, so extended evaluations of safety will be important.

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Ahmad is a 2019-2020 editorial fellow at the New England Journal of Medicine. He is from Toronto, Canada where he is completing his training in pulmonary medicine at the University of Toronto.