In patients with cancer-associated venous thromboembolism (VTE), treatment with oral apixaban was noninferior to subcutaneous dalteparin for the prevention of recurrent VTE, according to findings from the phase III CARAVAGGIO trial. The results of this trial may expand the proportion of cancer patients with VTE who are eligible for treatment with apixaban, including patients with gastrointestinal cancer, according to lead study author Giancarlo Agnelli, MD, of the University of Perugia in Italy.
Dr. Agnelli and colleagues recruited 1,155 adult patients with cancer and newly diagnosed symptomatic or incidental proximal lower-limb deep vein thrombosis (DVT) or pulmonary embolism (PE). Patients with basal cell or squamous cell carcinoma of the skin, primary brain tumor, known intracerebral metastases, or acute leukemia were ineligible.
The patients were randomly assigned (1:1) to either:
- oral apixaban (n=576)
- subcutaneous dalteparin (n=579)
Patients were treated at 119 centers across Europe, Israel, and the U.S. Oral apixaban was administered twice daily at 10 mg for the first 7 days and then twice daily at 5 mg thereafter. Subcutaneous dalteparin was administered once daily at 200 IU/kg for the first month and then once daily at 150 IU/kg thereafter. Treatment was administered for 6 months. The median duration of treatment was 178 days for apixaban and 175 days for dalteparin.
The primary outcome of the study was objectively confirmed recurrent VTE during the 6-month treatment period. Recurrent VTE included:
- proximal DVT of the lower limbs (symptomatic or incidental)
- symptomatic DVT of the upper limbs
- PE (symptomatic, incidental, or fatal)
Major bleeding comprised the principal safety outcome. This outcome was defined as acute clinically overt bleeding associated with:
- decrease in hemoglobin level of ≥2 g/dL
- transfusion of ≥2 units of red cells
- bleeding that occurred at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal)
- bleeding that required surgical intervention
- fatal bleeding
While gastrointestinal bleeding was not considered a prespecified study outcome, Dr. Agnelli and colleagues said they quickly understood that it was a relevant safety outcome based on emerging studies identifying this event with other direct oral anticoagulants (DOACs). Dr. Agnelli also commented that the sample size of the study was powered for recurrence of VTE, rather than to make definitive conclusions about bleeding.
Patients in both groups were balanced in terms of age, sex, weight, and platelet counts. The proportion of patients with a history of VTE prior to the index event was 7.8% in the apixaban arm versus 10.5% in the dalteparin group. Approximately 68% of patients in each arm had recurrent locally advanced or metastatic cancer.
By day 210, death from any cause was reported in 23.4% of patients treated with apixaban and 26.4% of patients treated with dalteparin. Mortality was attributed to cancer in 85.2% and 88.2% in the apixaban and dalteparin groups, respectively. In each treatment group, there were 4 deaths associated with VTE and 2 deaths associated with bleeding. In the apixaban group, the 2 bleeding-related deaths occurred >3 days following discontinuation of the drug.
A higher proportion of patients in the dalteparin arm experienced recurrent VTE during the 6-month treatment period compared with patients in the apixaban group (7.9% vs. 5.6%, respectively; hazard ratio [HR] = 0.63; p<0.001 for noninferiority). No difference was found between the apixaban and dalteparin groups in the rates of major bleeding (3.8% vs. 4.0%, respectively; HR=0.82; p=0.60).
Approximately 9% of patients treated with apixaban and 6% of patients treated with dalteparin experienced clinically relevant nonmajor bleeding. In addition, major or clinically relevant nonmajor bleeding was observed in 12.2% of patients treated with apixaban versus 9.7% of patients treated with dalteparin.
The oral administration route of apixaban represents a potential benefit of the therapy over subcutaneous injections of dalteparin, said Dr. Agnelli. “The results of the CARAVAGGIO study reinforce the use of DOACs in cancer-associated thrombosis, providing patients with the chance to improve their quality of life by using a DOAC instead of an injectable drug,” he explained. “The oral administration may facilitate the home management of patients with cancer-associated thrombosis, especially those at low risk of recurrence.” He also added that low-molecular weight heparin therapies like dalteparin tend to be more expensive.
A limitation of the study is the lack of generalizability to subgroups of patients who were excluded from enrollment for perceived safety reasons, including patients with brain tumors, cerebral metastases, or acute leukemia. Another limitation is the study’s open-label design, but this design was based on concerns about providing sham injections to patients with cancer.
Dr. Agnelli also noted that the ongoing APIxaban Cancer Associated Thrombosis (API-CAT) study is currently evaluating the efficacy and safety of apixaban after 6 months in this patient population, and the findings from this trial may add more information about the long-term effects of the therapy.
Study authors report relationships with Bristol-Myers Squibb and Pfizer, which sponsored this trial.
- Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382:1599-1607.
- ClinicalTrials.gov. API-CAT STUDY for APIxaban Cancer Associated Thrombosis (API-CAT). NCT03692065. Accessed June 10, 2020 from https://clinicaltrials.gov/ct2/show/NCT03692065.