medwireNews: The results of the randomized CASSINI and AVERT trials support the prophylactic use of the direct oral anticoagulants (DOACs) rivaroxaban and apixaban in cancer patients undergoing chemotherapy who are at risk for venous thromboembolism (VTE) events.
Both trials recruited ambulatory patients who were initiating systemic treatment for a range of solid tumors or lymphoma and who had a Khorana score of 2 or higher, indicative of an increased VTE risk, and both were placebo controlled.
In CASSINI, 5.95% of the 420 participants given rivaroxaban 10 mg/day for up to 180 days experienced the primary efficacy endpoint, which was a composite of symptomatic or asymptomatic lower-limb proximal deep vein thrombosis (DVT), symptomatic upper- or lower-limb distal DVT, symptomatic or incidental pulmonary embolism, and death due to a VTE, during the observation period of 180 days.
The rate of the primary endpoint in the placebo group was numerically higher, at 8.79%, but this difference did not reach statistical significance.
Alok Khorana (Cleveland Clinic, Ohio, USA) – who presented the findings at the 60th American Society of Hematology Annual Meeting in San Diego, California, USA – said that the lack of statistical significance could be because over a third (39%) of the events occurred in participants who had discontinued the study medication.
And he pointed out that an analysis focusing on the on-treatment period was statistically significant in favor of rivaroxaban, with a rate of 2.62% versus 6.41% for placebo, and a hazard ratio (HR) of 0.40.
Treatment with the DOAC did not significantly increase the incidence of major bleeding or clinically relevant non-major bleeding relative to placebo, with rates of 1.98% versus 0.99%, and 2.72% versus 1.98%, respectively.
The findings of the Canadian AVERT trial were reported in The New England Journal of Medicine by Philip Wells (University of Ottawa, Ontario, Canada) and colleagues.
They evaluated the incidence of major VTE – defined as any symptomatic or incidentally detected proximal DVT of the lower or upper extremities, any nonfatal symptomatic or incidental pulmonary embolism, and pulmonary embolism-related death – among patients given either apixaban 2.5 mg twice daily or placebo.
The primary endpoint occurred in 4.2% of the 288 apixaban-treated patients and 10.2% of the 275 given placebo, and equated to a significant 59% reduction in the risk for major VTE with the DOAC.
The efficacy of apixaban in preventing a major VTE event appeared even greater when just the on-treatment period was considered, with corresponding rates of 1.0% and 7.3%, and a significant 86% decrease in major VTE risk.
However, patients in the apixaban group were twice as likely as those in the placebo group to experience a major bleed, with rates of 3.5% versus 1.8% over the 180-day follow-up, a significant difference.
But the rates were comparable during the on-treatment period, as was the incidence of major bleeding episodes categorized as severe, and “[t]here were no cases of fatal bleeding or bleeding into critical organs,” remark Wells et al.
Speaking to medwireNews, Alok Khorana commented that “these two studies together provide firm evidence for benefit of primary prevention in high-risk patients as defined.”
He continued: “[W]e may be moving the landscape from a ‘reactive’ stance of managing events when they occur to a ‘proactive’ stance of preventing events in the first place.”
With regard to the ostensible differences between the CASSINI and AVERT results, Khorana believes that these are “essentially due to the differences in study design.”
He explained that unlike CASSINI, the AVERT trial used a modified intention-to-treat analysis, including only those participants who received at least one dose of the study drug. Additionally, the CASSINI trial required participants to undergo a baseline screening ultrasound to select out any individuals with existing thrombosis. “Together, these two design differences reduced the power of the primary CASSINI analysis,” Khorana said.
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