Acute DVT or PE in Cancer Patients: Apixaban Reasonable to Use?

Study Title: Apixaban for the Treatment of Venous Thromboembolism in Patients With Cancer: A Prospective Randomized Open Blinded End-Point (Probe) Study (CARAVAGGIO)

ClinicalTrials.gov Identifier:NCT03045406

Participating Centers: Multicenter, international study under the leadership of Dr. G. Agnelli, of the University of Padova in Italy

Accrual Goal: 1,168. As of May 21, 2019, 1,135 patients have been randomized worldwide.

Study Design: This is an open-label randomized treatment trial. Individuals on the experimental arm receive oral apixaban, 10 mg twice daily for seven days, after which they are transitioned to 5 mg twice daily (total treatment period, 6 months). Subjects on the active comparator arm receive dalteparin, 200 IU/kg subcutaneously once daily for one month, and thereafter, 150 IU/kg once daily for five months. The primary outcome is recurrent venous thromboembolism (VTE) during six months on the trial. Patients are eligible if they have 1) newly diagnosed, objectively confirmed symptomatic or unsuspected proximal lower-limb deep vein thrombosis (DVT) or symptomatic pulmonary embolism (PE), or unsuspected PE in a segmental or more proximal pulmonary artery, and 2) any type of cancer (other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumor or intracerebral metastasis, and acute leukemia). Exclusion criteria include poor Eastern Cooperative Oncology Group (ECOG) Performance Status (grade 3 or 4); life expectancy of less than six months; active bleeding or a high risk of bleeding that contraindicates anticoagulation; and thrombectomy, vena cava filter insertion, or thrombolysis used to manage the index episode. Sponsors include the Fadoi Foundation (Federation of the Associations of Internist Hospital Managers, www.fadoi.org/en), an Italian internal medicine society, and the University of Perugia, Italy.

Rationale: Based on somewhat dated society guidelines from 2015 to 2016,^1-3  low-molecular-weight heparin (LMWH) is still the gold-standard treatment for patients with cancer who have VTE. A new American Society of Clinical Oncology cancer guideline is expected to be published soon, and based on recent clinical trial data of the studies listed in the table, it may well list edoxaban and rivaroxaban together with LMWH as treatment options preferred over vitamin K antagonist therapy in patients with cancer and acute VTE. Given the inconvenience of subcutaneous injections and the cost of LMWH, the question that many oncologists have is whether direct oral anticoagulants (DOACs) — any of them or just selected ones — can be used instead of LMWHs. Is there sufficient evidence of DOAC efficacy and safety when compared to LMWH to support their use in patients with cancer and acute DVT or PE?

Three prospective clinical trials that compared the performance of three different DOACs with the LMWH dalteparin (Table) have been completed and published in the past 1 ½ years. The large HOKUSAI trial (n=1,046) showed that edoxaban was noninferior to dalteparin with respect to the composite endpoint of recurrent VTE or major bleeding⁴ ; while the rate of recurrent VTE was lower, the rate of major bleeding was higher with edoxaban than with dalteparin. Given the noninferiority of edoxaban, the clinician practicing evidence-based medicine can, with confidence, use edoxaban instead of LMWH in patients with cancer and acute DVT or PE. However, in the U.S. edoxaban is not a widely used DOAC. Therefore, the question is whether the two DOACS mostly used in the U.S. — apixaban and rivaroxaban — can be used instead of LMWH.

The SELECT-D (n=406) trial was set up as a pilot trial to compare rivaroxaban with dalteparin; it found, similar to the HOKUSAI trial, a lower risk of recurrent VTE with rivaroxaban, but at the cost of more clinically relevant nonmajor bleeding.⁵  The results provide evidence that rivaroxaban is also an effective alternative to LMWH for the treatment of VTE in patients with cancer. The ADAM trial (n=300, published so far only as an abstract), designed to investigate the safety of apixaban compared to dalteparin, found that apixaban was associated with a low rate of bleeding and significantly lower VTE recurrence than LMWH, suggesting the clinical utility of apixaban for the acute treatment of VTE in patients with cancer.⁶  However, given the relatively small size of the trial, the confidence in the findings and generalizability to all cancer patients are limited.

Therefore, a larger, more definitive study of a size similar to the HOKUSAI study is needed to ensure clinicians that apixaban is noninferior to the current gold standard LMWH in the treatment of acute VTE in patients with cancer.

Comment: The CARAVAGGIO Study started enrollment in April 2017, with a target enrollment number of 1,168. As of May 21, 2019, 1,135 patients have been randomized worldwide. Enrollment is expected to finish at the end of May 2019, and follow-up of the last patient enrolled will end six months later, around late November 2019. This study, like the HOKUSAI trial, is well designed and of sufficient size to provide solid data on the efficacy and safety of apixaban in patients with cancer who have acute VTE. While numerous oncologists have already switched from using LMHW to rivaroxaban or apixaban, this switch has occurred with only limited data to support the use of apixaban in this setting. The CARAVAGGIO trial will provide the appropriate evidence so that we know whether apixaban can, indeed, be safely and effectively used in patients with cancer and acute DVT or PE.