According to data from the phase IIIb CASSINI trial presented at the 2018 ASH Annual Meeting, rivaroxaban could significantly reduce venous thromboembolism occurrence in patients currently receiving treatment with systemic therapy.
Alok A. Khorana, MD
According to data from the phase IIIb CASSINI trial presented at the 2018 ASH Annual Meeting, rivaroxaban (Xarelto) could significantly reduce venous thromboembolism (VTE) occurrence in patients currently receiving treatment with systemic therapy.
Although rivaroxaban failed to significantly reduce VTE events during the primary analysis period of 180 days, Alok A. Khorana, MD, professor of medicine, Cleveland Clinic Lerner College of Medicine, said this was due to the large number of patients who stopped treatment with the agent prior to the end of the 6-month period.
“The problem was that this is a cancer patient population getting chemotherapy, many of whom are switching chemotherapy drugs or progress on chemotherapy and switch to a different clinical drug,” he added. “So, about half of patientsin the entire study population—did not take the drug for the full 6 months.”
The international, multicenter, randomized, double-blind, placebo-controlled superiority study compared the efficacy and safety of rivaroxaban with placebo for thromboprophylaxis in 1080 ambulatory patients with cancer. The researchers aimed to assess the use of the direct oral anticoagulants (DOAC), administered as a daily pill, and to investigate the therapy’s use when restricted to patients at high risk for VTE, initiating a new systemic regimen to determine VTE risk (defined as Khorana score ≥2).
“About 10 years ago my research colleagues and I developed a score that helps predict patients who are at risk for getting a blood clot, and that is helpful because if we target prevention toward high-risk patients, then the benefit would be greater and so the clinical benefit to patients would be greater,” Khorana said. “So, that was really our hypothesis going in to this clinical trial.”
Forty-nine patients had deep vein thrombosis (DVT) at baseline and another 190 screen-failed for other reasons. In total, 841 patients were randomized 1:1 to receive either 10 mg rivaroxaban once daily (n = 420) or placebo (n = 421) up to day 180.
A composite of events-comprised of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, and symptomatic or incidental pulmonary embolism and VTE-related death-served as the primary endpoint; while ISTH-defined major bleeding as the primary safety endpoint.
A composite of events in the primary efficacy endpoint occurred in 25 patients (6%) in the rivaroxaban arm compared with 37 (8.8%) in the placebo arm (HR, 0.66; 95% CI, 0.40-1.09;P= .101). However, as Khorana had noted, this was not unexpected given that 38.7% of patients discontinued treatment with the DOAC during the 6-month period and went on to experience a clot event. “It’s not unexpected, because we know that if patients are not taking the drug, then you obviously won’t prevent a clot,” he added.
When the researchers compared efficacy outcomes using a pre-specified analysis of all randomized patients during the on-treatment period of patients actually taking the drug, events occurred in 11 (2.6%) patients in the treatment arm compared with 27 (6.4%) in the placebo arm (HR, 0.40; 95% CI, 0.20-0.80;P= .007).
As a secondary efficacy endpoint, the researchers conducted a pre-specified analysis of the composite of the primary endpoint with the addition of arterial and visceral thromboembolic events in the up-to-day 180 observation period. The rivaroxaban arm demonstrated significantly fewer events compared with the placebo arm (6.9% vs 10.7%; HR, 0.62; 95% CI, 0.39-0.99;P= .04).
During both time periods, the researchers also evaluated the number needed to treat (NNT), or “how many patients have to take the drug to prevent a blood clot for one of them not to have a blood clot,” Khorana explained. In the up-to-day 180 period, 35 patients would have had to have been treated to prevent 1 blood clot compared with 26 patients during the on-treatment period. “And then if you include some of these additional secondary endpoints (arterial plus visceral VTE), it is actually only 20,” he added. “So, the clinical benefits continue to improve when you include secondary endpoints and the (on-treatment) endpoint.”
All-cause mortality occurred in 20.0% of patients in the rivaroxaban group and 23.8% in the placebo group (HR, 0.83; 95% CI, 0.62-1.11;P= .213); while a pre-specified composite of the primary endpoint with all-cause mortality occurred in 23.1% and 29.5%, respectively (HR. 0.75; 95% CI, 0.57-0.97;P= .03).
Safety analyses were conducted for the on-treatment period only for patients who received at least one dose of study drug (n = 405) or placebo (n = 404). Major bleeding occurred in 8 (2%) and 4 patients (1%), respectively (HR, 1.96; 95% CI, 0.59-6.49;P= .265); while 11 (2.7%) and 8 (2%) patients, respectively, experienced clinically relevant non-major bleeding (HR, 1.34; 95% CI, 0.54-3.32;P= .53). Sites of major bleeding included gastrointestinal (n = 8), intraocular (n = 2), and intracranial (n = 2), while a fatal bleed occurred in the rivaroxaban arm. The researchers noted adverse events were comparable between groups.
Lastly, the Khorana risk score cut-off of ≥2 identified patients who were at risk for VTE events both at baseline (4.5%) and during the study (8.8%), as well as 1.7% arterial events in the placebo group.
“Because nearly one-third of these events were at baseline, before patients have even started on chemotherapy, we wonder if baseline screening should be considered in patients start treatment with systemic therapy,” Khorana said. “Regardless, we believe our findings should inform future recommendations regarding thromboprophylaxis for higher-risk ambulatory cancer patients.
Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban thromboprophylaxis in high-risk ambulatory cancer patients receiving systemic therapy: results of a randomized clinical trial (CASSINI). In: Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, California. Abstract LBA1.