Gary H. Lyman
Rivaroxaban led to substantially lower incidence of venous thromboembolism and death of VTE among ambulatory patients with cancer death during the treatment intervention, according to results of the phase 3b randomized trial CASSINI published in The New England Journal of Medicine.
However, rivaroxaban (Xarelto, Janssen) — an oral, highly selective direct inhibitor of factor Xa — did not significantly decrease incidence of VTE or death of VTE during the total 180-day trial period, results showed.
“After the cancer itself, blood clots are the second leading cause of death, along with infection, in real-world cancer outpatients receiving chemotherapy, and a major cause of morbidity, mortality and increased costs among patients hospitalized with a blood clot,” Gary H. Lyman, MD, MPH, senior lead for health care quality and policy at Fred Hutchinson Cancer Research Center, said in a press release. “The results of this study will help us understand how we should weigh the potential benefits of reducing blood clots with potential risks, and how to establish a standard for assessing which [patients with] cancer are at the highest risk [for] developing blood clots.”
Although ambulatory patients undergoing systemic cancer therapy are at risk for VTE, whether thromboprophylaxis benefits these patients is uncertain.
Researchers randomly assigned 841 ambulatory patients (median age, 63 years; range, 23-88; 50.9% men; 83% white) with cancer and without deep-vein thrombosis to receive 10 mg rivaroxaban (n = 420) or a placebo (n = 421) daily for up to 180 days. Screening took place every 8 weeks.
The most common cancer was pancreatic (n = 274), followed by gastric or gastrointestinal (n = 176) and lung (n = 134).
A composite of confirmed proximal DVT in a lower limb, pulmonary embolism, symptomatic DVT in an upper limb, distal DVT in a lower limb, or death from VTE, through day 180, served as the primary efficacy endpoint. Major bleeding served as the primary safety endpoint.
The mean intervention period was 4.3 months and ranged from the first dose to the last dose plus 2 days.
The primary endpoint occurred in 25 patients in the rivaroxaban group and 37 in the placebo group (6% vs. 8.8%; HR = 0.66; 95% CI, 0.4-1.09) up to day 180.
Death of any cause up to 180 days — a second efficacy endpoint — occurred among 84 patients in the rivaroxaban group and 100 in the placebo group (20% vs. 23.8%; HR = 0.83; 95% CI, 0.62-1.11).
Researchers also conducted a prespecified supportive analysis of the same endpoint during the intervention period. Results showed the primary endpoint occurred in 11 patients in the rivaroxaban group and in 27 in the placebo group (2.6% vs. 6.4%; HR = 0.4; 95% CI, 0.2-0.8) during the intervention period.
Eight patients in the rivaroxaban group and four in the placebo group experienced major bleeding (2% vs. 1%; HR = 1.96; 95% CI, 0.59-6.49).
About 47% of the patients in this study discontinued treatment prematurely, which served as a limitation. However, researchers wrote that this was expected because many of the patients had advanced disease.
Researchers next plan to conduct a cost utility analysis that incorporates impact on patients' quality of life. In addition, they are collaborating on a meta-analysis of this trial and the AVERT trial, an anticoagulant trial that evaluated apixaban (Eliquis, Bristol-Myers Squibb), to better understand of the use of thromboprophylaxis.
“There's a longstanding need for the oncology and hematology communities to address this issue holistically and understand the true burden blood clots and related conditions and hospitalizations have on [patients with] cancer,” Lyman said in the press release. “The results of these important trials will be intensely studied by the guideline panels to assess whether changes in current guideline recommendations are warranted.”
The AVERT and CASSINI trials collectively show a significant benefit of direct oral anticoagulants for the prevention of VTE with a low incidence of major bleeding, Giancarlo Agnelli, MD, professor of internal medicine at University of Perugia, Italy, and director of the department of internal and cardiovascular medicine and stroke unit at the University Hospital in Perugia, wrote in an accompanying editorial.
“The findings related to bleeding are quite reassuring, given the increase in bleeding observed with apixaban and rivaroxaban in studies on the prophylaxis of [VTE] involving medical patients without cancer,” Agnelli wrote.
However, looking at the trials combined, there was not a significant difference in mortality between direct oral anticoagulants and placebo.
“Will these trials change clinical practice?” Agnelli wrote. “Although the evidence provided by the two trials is quite compelling, some clinicians could still be reluctant to change their practice. Indeed, some of the most common cancers, such as colorectal, breast and prostate cancers, were underrepresented in the two trials.” – by John DeRosier
Disclosures: This study was funded by Janssen. Lyman reports no compensation for serving as co-chair of the Steering Committee of the CASSINI study or chair of the Data Safety Monitoring Committee of the AVERT study and has no personal financial disclosures related to the subject of this study. Lyman reports that his spouse received consultant fees from Janssen during the conduct of this study and from Bayer and Pfizer outside the submitted work. Please see the study for all other authors’ relevant financial disclosures. Agnelli reports personal fees from Pfizer.