Primary prevention with the direct oral anticoagulant (DOAC) rivaroxaban reduced venous thromboembolism (VTE) and VTE-related mortality in patients with cancer, according to results from the placebo-controlled, randomized CASSINI trial, which were presented as a late-breaking abstract at the 2018 ASH Annual Meeting. The benefit was seen without an increase in major or clinically relevant bleeding events, lead investigator Alok A. Khorana, MD, from Cleveland Clinic in Ohio, noted.
“In 2018, most of our cancer treatment takes place in the outpatient setting, so most of the clots occur in the outpatient setting,” Dr. Khorana explained. “From a public health perspective, that is important because most of our [previous] efforts at preventing blood clots have focused on the inpatient setting.”
The CASSINI trial is the first to assess the use of DOACs – which can be taken as a daily pill at home – in patients who are actively receiving systemic chemotherapy.
Investigators enrolled 1,080 adult ambulatory patients with various cancers who were initiating a new systemic regimen and who had an increased risk for VTE (defined as a score ≥2 on the Khorana scale, which assigns risk for VTE based on cancer type, hemoglobin level, and pre-chemotherapy platelet and leukocyte counts). Patients were screened for deep-vein thrombosis (DVT) prior to randomization.
A total of 841 enrolled participants were randomized 1:1 to receive rivaroxaban 10 mg once daily or placebo for up to 180 days.
During the study period, patients were screened with lower-extremity ultrasounds every eight weeks on study to test for symptomatic or asymptomatic lower-extremity proximal DVT. The primary efficacy endpoint was a composite of DVT, pulmonary embolism, and VTE-related death during the six-month observation period. As a secondary, pre-specified endpoint, the investigators reviewed thrombotic risk during the on-treatment period to account for patients with cancer who changed therapeutic regimens or stopped anticoagulation.
The trial did not meet its primary efficacy endpoint for thrombotic prevention in the entire intent-to-treat population (which included all randomized patients): The composite outcome occurred in 25 of 420 rivaroxaban-treated patients (5.95%) and 37 of 421 placebo-treated patients (8.79%), for a hazard ratio (HR) of 0.66 (95% CI 0.40-1.09; p=0.10) and a number needed to treat (NNT) of 35.
Of all patients with VTE, 38.7 percent of events occurred after patients discontinued study drug, which “was [expected], because we know that patients not taking the drug won’t experience thrombotic prevention,” Dr. Khorana said. This finding also confirmed that a Khorana score ≥2 identified a “truly high-risk” population, given the thrombotic rate of 17 percent.
However, when the analyses were restricted to the “on-treatment” period, which was an average of 4.5 months for all participants, the primary endpoint occurred in significantly fewer rivaroxaban-treated patients (n=11/420; 2.62%), compared with placebo-treated patients (n=27/421; 6.41%). These data suggest that rivaroxaban treatment was associated with a 60-percent lower risk of thrombotic events (HR=0.4; 95% CI 0.20-0.80; p=0.007). The NNT to prevent thrombotic risk dropped even further in this analysis, from a historical NNT of 50 to 26.
In a prespecified analysis of all-cause mortality and composite primary outcome, the researchers also noted a “substantial 6.4-percent absolute risk reduction” with rivaroxaban, compared with placebo. “This adds to the potential clinical benefit observed [with] this primary prevention approach,” Dr. Khorana observed.
“With any primary prevention approach, safety is key, and thankfully we did not observe abnormal safety signals,” Dr. Khorana reported. Incidence of the primary safety endpoint of major bleeding and clinically relevant non-major bleeding among any patients treated with a study drug was “quite low” in each arm:
- major bleeding: 1.98% for rivaroxaban vs. 0.99% for placebo (HR=1.96; 95% CI 0.59-6.49; p=0.265)
- clinically relevant non-major bleeding: 2.72% vs. 1.98% (HR=1.34; 95% CI 0.54-3.32; p=0.532)
One patient in the rivaroxaban arm experienced a fatal bleeding event.
The study was limited by the failure to achieve the primary efficacy endpoint, but Dr. Khorana noted that this was largely because patients remained at high thrombotic risk after stopping the study drug. “Future recommendations regarding primary prevention of thrombotic events in cancer should be informed by the findings of this study,” he concluded.
The authors report financial relationships with Bayer and Janssen, which provided support for the study.
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). Abstract #LBA-1. Presented at the 2018 ASH Annual Meeting, December 4, 2018; San Diego, CA.