Results from the Phase 3 CASSINI study contributes new data on the use of oral anticoagulant rivaroxaban (brand name Xarelto, Johnson & Johnson) in the management and prevention of venous thromboembolism (VTE) in high-risk patients with cancer.
The composite primary endpoint of VTE occurrence did not reach statistical significance during the full study period. However, use of the anticoagulant resulted in a clinically meaningful and nominally significant 60% reduction of VTE events compared to placebo during the time patients were actively receiving treatment. Bleeding rates were low, though higher with rivaroxaban. The results were presented in a late-breaking trials session at the 60th American Society of Hematology (ASH; 1–4 December) Annual Meeting in San Diego.
“We want patients to focus on treating their cancer and getting better, without the concern and burden of blood clots,” said Alok Khorana (Cleveland Clinic, Cleveland, USA) lead investigator on the trial. “Building on prior research supporting the use of rivaroxaban for the treatment of VTE in patients with cancer, this new CASSINI data signal the role of rivaroxaban in preventing blood clots.” Khorana was compensated by Janssen for his role as chair of the CALLISTO advisory council and co-chair of the CASSINI steering committee.
In the intent to treat (ITT) population, the primary efficacy composite endpoint (symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper-extremity or distal lower-extremity DVT, symptomatic or incidental PE, and VTE-related death) occurred during the study period in 8.79% of patients in the placebo group and in 5.95% of patients treated with rivaroxaban 10mg once daily; however, this result was not statistically significant (HR=0.66; 95% CI, 0.40–1.09; p=0.101). Approximately 62.4% of patients completed the double-blind trial period from randomisation through the end of the study’s 180-day observation period, regardless of whether they discontinued the study medication. Withdrawal of consent and death were the primary reasons for discontinuation.
Researchers also examined the primary efficacy composite endpoint in all randomised patients, during the time they were actively taking treatment, known as the ‘on-treatment’ period. For this pre-specified analysis, rivaroxaban was associated with a statistically significant 60% reduction in VTE events compared to placebo (2.62% vs. 6.41%; HR=0.40; 95% CI, 0.20–0.80; p=0.007). The primary safety outcome, ISTH major bleeding, during the on-treatment period was low across both treatment arms and occurred in 4/404 (0.99%) patients treated with placebo and 8/405 (1.98%) patients treated with rivaroxaban; this result was not statistically significant, though the study was not powered to detect a significant difference. (HR=1.96; 95% CI, 0.59–6.49; p=0.265).
- Of the total VTE events that occurred, approximately 39% were experienced by patients who had prematurely discontinued treatment.
- All-cause mortality, a secondary efficacy endpoint, was similar between both groups at the end of the 180-day observation period (20% for rivaroxaban vs. 23.8% for placebo; HR=0.83; 95% CI, 0.62–1.11). Many patients died as a result of their cancer, with a small number of VTE-related deaths.
- Efficacy and safety outcomes were consistent across all prespecified subgroups.
Despite being largely preventable, blood clots remain the second leading cause of death in patients with cancer. The risk of VTE, which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is five times greater in people with cancer, and that risk is magnified in those receiving certain types of chemotherapy. VTE risk is also highest in the newly diagnosed and in those with more advanced, metastatic disease. Recent guidelines issued by the International Society on Thrombosis and Haemostasis (ISTH) and National Comprehensive Cancer Network (NCCN) recommend rivaroxaban as an option for the treatment of cancer-associated VTE. Currently, no medical therapy is approved for the primary prevention of VTE in high-risk, ambulatory cancer patients, due to limited clinical data.