The aim of the prospective randomized open-label Caravaggio trial was to assess whether oral apixaban was noninferior to subcutaneous dalteparin with respect to the prevention of recurrence of venous thromboembolism (VTE) in patients with cancer. 1170 consecutive patients with cancer and symptomatic or incidental acute proximal deep vein thrombosis or pulmonary embolism (PE) were randomized in a 1:1 fashion to receive either 10 mg of apixaban twice daily for 7 days, followed by 5 mg of apixaban twice daily, or to receive 200 IU per kilogram of dalteparin once daily for one month, followed by 150 IU per kilogram of dalteparin once daily (treatment period 6 months). The primary outcome was objectively confirmed recurrent VTE and the principal safety outcome was major bleeding occurring during the 6-month trial period. All outcome events and deaths were reviewed by a central adjudication committee in a blinded manner.
Recurrent VTE occurred in 5.6% of apixaban patients and in 7.9% of dalteparin patients (HR 0.63, 95% CI 0.37-1.07, p<0.001 for noninferiority, p=0.09 for superiority). As shown in the supplementary appendix, apixaban was more effective than dalteparin in the prevention of recurrent VTE in patients younger than 65 years.
Major bleeding was observed in 3.8% of apixaban patients and in 4.0% of dalteparin patients (HR 0.82, 95% CI 0.40-1.69, p=0.60), major gastrointestinal bleeding occurred in 1.9% of apixaban patients and in 1.7% of dalteparin patients. In the apixaban group no fatal bleeding events occurred, while 2 fatal bleedings occurred in the dalteprain group. The rate of the combined cumulative incidence of recurrent TVE or major bleeding was 8.9% in the apixaban group and 11.4% in the dalteparin group (HR 0.70, 95% CI 0.45-1.07). Death from any cause occurred in 23.4% of apixaban-patients and in 26.4% of dalteparin-patients. 85.2% of deaths in the apixaban group and 88.2% of deaths in the dalteparin-group were related to cancer.
This multinational, investigator-initiated randomized-controlled trial on the use of apixaban in cancer patients with VTE supports the previously published, smaller ADAM-VTE study. As discusses by Agnes Y.Y. Lee in an accompanying editorial, the relatively low mortality of the ADAM-VTE study suggested patients selection. The results of Caravaggio, however, are in line with those of previous edoxaban and rivaroxaban trials in patients with cancer and VTE. In contrast to previous studies on other non-vitamin K antagonist in patients with cancer and VTE, the frequencies of major bleeding (including major gastrointestinal bleeding) were similar between the apixaban and the dalteparin group. Nonmajor bleedings (mostly genitourinary system and upper airways), however, were more frequent in the apixaban group.
Referring to the above mentioned editorial, Agnes Y.Y. Lee highlights the need for a careful differentiation between patients with different cancer types, bleeding risks, concomitant medications and patient's experience (e.g. patients with brain tumors, known intracerebral metastases, or acute leukemia were excluded from Caravaggio). Nevertheless, the Caravaggio study will further advance the spectrum of treatment options for patients with cancer and VTE.