Venous thromboembolism (VTE) is a major cause of morbidity and mortality worldwide. In the United States alone, it is estimated to be responsible for up to 100,000 deaths each year. While there are several known risk factors for VTE, cancer and related treatments may confer the greatest risk. Indeed, thrombosis is a leading cause of death in cancer patients. The presence of VTE in cancer patients can disrupt planned cancer treatment, increase hospitalizations, and reduce quality of life, among other adverse effects.
Given the high prevalence in cancer patients, there is great interest in identifying treatments that can reduce thrombosis incidence in this patient population. “Although treatment of thrombosis has traditionally been done with daily injections of heparin, new oral agents have recently been shown to be at least as effective albeit with an increased risk of bleeding in some patients. Current clinical practice guidelines do not recommend routine anticoagulation for prevention of thrombosis in cancer outpatients due to the variable risk of thrombosis among patients as well as the inconvenience and bleeding risk associated with anticoagulation,” said Dr. Gary Lyman, member in the Public Health Sciences and Clinical Research Divisions. Additionally, data from randomized clinical trials on thromboprophylaxis in patients at elevated risk for VTE have been limited. Dr. Lyman and colleagues recently published a paper in the New England Journal of Medicine in which they report the results from a phase 3b clinical trial (CASSINI trial) on the efficacy and safety of rivaroxaban, an oral blood thinning agent, in ambulatory cancer patients at an elevated risk for VTE.
The CASSINI trial was designed to specifically assess thromboprophylaxis in high-risk patients, as more focused treatment may reduce the number of patients that would need to be treated to prevent a VTE event. “Our research group developed and validated a clinical risk score for thrombosis in ambulatory patients receiving cancer chemotherapy”, described Dr. Lyman. In research published in the journal Blood and led by collaborators Drs. Alok Khorana and Nicole Kuderer, the Khorana score, as it is commonly referred to, is based on cancer site, hemoglobin, platelet and white cell counts, and body mass index; higher scores indicate greater risk. In CASSINI, ambulatory cancer patients without pre-existing deep-vein thrombosis (DVT) but with a Khorana score of 2 or higher and who were starting a new cancer treatment regimen were eligible to enroll. Patients were randomized to receive either rivaroxaban (420 patients) or placebo (421 patients) for 180 days. All participants underwent compression ultrasonography of both legs at 8 weeks, 16 weeks, and 180 days or at the end of treatment for subjects who ended trial participation early.
Image provided by Dr. Gary Lyman
The study used a composite primary efficacy endpoint of VTE (composite included symptomatic or asymptomatic proximal DVT in a lower limb, symptomatic DVT in an upper limb or distal DVT in a lower limb, symptomatic or incidental pulmonary embolism, and death from venous thromboembolism). The primary safety endpoint was major bleeding during the treatment period, defined as the time of first dose through the last dose plus 2 days.
In the primary analysis, the composite endpoint was assessed up to day 180 of the intervention period for all subjects, including those who discontinued the treatment early. Events of the composite endpoint occurred in 6.0% of the rivaroxaban group and 8.8% of the placebo group (see figure, left panel). Although this was a 34% reduction in risk in the rivaroxaban group, the difference was not statistically significant. In this primary analysis, 39% of all events occurred after patients had discontinued the study treatment. In a prespecified secondary analysis, the authors then assessed the composite endpoint in the intervention period only, defined as the time from first dose of trial agent to last dose plus two days. This per-protocol analysis revealed a significant reduction in event occurrence in the rivaroxaban group as compared to the placebo group, 2.6% versus 6.4% (see figure, right panel). Major bleeding events were reported in 2.0% of patients in the rivaroxaban group and 1.0% in the placebo group, but this difference was not significantly different. There was also no significant difference in clinically significant nonmajor bleeding events between the two groups.
Results from a separate randomized clinical trial on thromboprophylaxis in high-risk cancer patients were published in the same recent issue of the New England Journal of Medicine as the CASSINI trial. “Despite some differences in study design and outcome measures, taken together these trials demonstrate that these agents reduce the risk of thrombosis compared to placebo with a small increase in bleeding” said Dr. Lyman, and “help to fill a gap in on the efficacy of thromboprophylaxis in this patient population and may impact clinical practice guidelines.” Dr. Lyman elaborated, “The efficacy and safety results from these trials are currently being reviewed by guideline panels that are anticipated to provide formal clinical practice recommendations in the coming months. These recommendations will strongly encourage physician assessment of the patients’ risk of thrombosis and a discussion of the potential benefits and harms associated with the treatment options available.”
This work was supported by the National Heart, Lung, and Blood Institute, Janssen, and Bayer.
Fred Hutch/UW Cancer Consortium members Drs. Gary Lyman and David Garcia contributed to this research.
Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH. 2019. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. New England Journal of Medicine. doi: 10.1056/NEJMoa1814630.