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Rivaroxaban effective as thromboprophylaxis during anticancer treatment
SAN DIEGO — Rivaroxaban prophylaxis significantly reduced thromboembolic events among patients receiving systemic cancer therapy, according to findings of a double-blind, randomized, placebo-controlled study presented at the late-breaking abstract session of ASH Annual Meeting and Exposition.
“It has been known for 100 years, if not longer, that patients with cancer often suffer from blood clots, typically venous clots,” Alok A. Khorana, MD, Sondra and Stephen Hardis chair in oncology research and vice chair for clinical services of Taussig Cancer Institute and director of the gastrointestinal malignancies program at Cleveland Clinic, told HemOnc Today. “Most clots occur in the outpatient setting. From a public health perspective, that’s really important, because almost all of our efforts at preventing blood clots have taken place in an inpatient setting.”
Khorana suggested that a risk-adapted approach using the Khorana scoring system, along with 10 mg rivaroxaban (Xarelto, Janssen) once daily, may improve on previous attempts at thromboprophylaxis in populations of patients with cancer.
A way of measuring efficacy of thromboprophylaxis is to determine the number of patients needed to treat in order to prevent one event, he added.
“Around 50 patients would need to take an injection every day for one of them not to get a blood clot,” he said, noting that these findings were reported in previous studies.
In the parallel-group, multicenter study, Khorana and colleagues evaluated the safety and efficacy of rivaroxaban compared with placebo among 841 ambulatory patients with cancer who were initiating new systemic cancer therapy and were deemed high risk for venous thromboembolism, defined as a Khorana score of 2 or greater.
In total, 274 (32.6%) had pancreatic cancer, 698 (83%) were white and 428 (50.9%) were men.
Researchers randomly assigned patients 1:1 to 10 mg once daily rivaroxaban or placebo up to day 180.
A composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal deep vein thrombosis, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism, and VTE-related death served as the primary efficacy endpoint.
The primary efficacy endpoint occurred in 5.95% of patients on active treatment and 8.79% of those in the placebo group (HR = 0.66; 95% CI, 0.4-1.09).
However, Khorana noted that 37.8% of those events occurred in patients who had discontinued the drug.
“It was a challenge to keep patients on the study for 6 months,” Khorana told HemOnc Today. “Many of them went off the study at a certain time point. On average, patients stayed on the study drug for 4.5 months, but we still kept them in the active therapy group. We used a very conservative methodology so our data would be robust.”
Thus, when the group looked at events for patients while on treatment, the thromboembolic event rates were 2.62% for rivaroxaban and 6.41% for placebo (HR = 0.4; 95% CI, 0.2-0.8).
Rates of the secondary endpoint — which was a composite of the primary endpoint and all-cause mortality through 180 days — were 23.1% in the active therapy group and 29.5% for placebo (HR = 0.75; 95% CI, 0.57-0.97).
Results of an analysis of the number of patients needed to treat to prevent an event showed that, using the primary endpoint, it would require treating 26 patients to prevent one event. When the primary efficacy endpoint plus arterial and visceral VTE were included while on treatment, that number dropped to 20 patients.
Moreover, the number of patients who would undergo treatment before experiencing an event was 101 for major bleeding and 135 for nonmajor bleeding.
“This number needed to treat is a model we use for public health issues in a large population of patients,” Khorana said. “If you’re in the 20 to 30 range, you’re doing well; this has good public health significance. In our study, if you count all events, that number is 17.”
Safety outcomes showed that major bleeding occurred in 1.98% of patients in the rivaroxaban group and 0.99% of those in the placebo group (HR = 1.96; 95% CI, 0.59-6.49). Clinically nonrelevant major bleeding rates also were slightly higher in the rivaroxaban group, at 2.72% vs. 1.98% (HR = 1.34; 95% CI, 0.54-3.32).
“There were no abnormal safety signals,” Khorana said. “Major bleeding rates were quite low.
“These findings should inform future recommendations regarding thromboprophylaxis
for higher-risk ambulatory cancer patients,” he added. – by Rob Volansky
Reference:
Khorana A, et al. Abstract LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Khorana reports relationships with AngioDynamics, Bayer, Halozyme, Janssen, LeoPharma, Medscape/WebMD, Parexel, Pfizer, Pharmacyclics, PharmaCyte, Sanofi, Seattle Genetics and TriSalus. Please see the abstract for all other authors’ relevant financial disclosures.
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Cancer notably elevates risk for VTE. With 20% of VTEs occurring among patients with cancer, preventive measures are routinely administered during hospitalization for surgery or medical treatment. However, most VTE episodes occur among ambulatory patients. In fact, the condition is the second leading cause of death among patients with ambulatory cancer.
Under current guidelines, ambulatory patients with cancer generally receive treatment with anticoagulant drugs only if they have experienced a DVT or PE, as it has been difficult to determine if there is any benefit of thromboprophylaxis. With the results of the CASSINI study, however, that situation may be changing.
There are multiple reasons patients with cancer might be more likely than the general population to experience thrombosis. These extend to all three corners of Virchow’s triad, the broad categories of factors thought to contribute to thrombosis: hypercoagulability, venous stasis and endothelial disruption. Endothelial disruption primarily stems from treatments such as radiotherapy, some forms of chemotherapy and the venous catheters used to infuse chemotherapeutic agents, as well as cancer surgery. Patient-related factors — such as immobility, advanced age and the presence of cardiovascular risk factors — contribute to venous stasis. And hypercoagulability is a product of cancer itself, as malignant cells alter the tumor microenvironment to gain protection from immune infiltration and other influences.
This pathophysiological connection between cancer and thrombosis is of interest because it suggests a role for thrombosis in the progression of disease. Recent research suggests that VTEs, and other effects of thrombosis, may have a substantial impact on the fate of a patient with cancer. A 2016 study of 4,450 individuals with cancer showed that those at the highest risk for VTE had a nearly 10-fold chance of dying within 120 days compared with those at lowest risk, whether or not they actually experienced a clot.
Further, people who experienced an unprovoked VTE are at elevated risk for being diagnosed with cancer in the year after the incident, and studies have showed that patients with cancer on long-term anticoagulant therapy have longer PFS. Such studies, though preliminary, suggest that thrombosis is not just a result of cancer, but a clinically relevant aspect of malignancy.
In general, however, oncologists have not treated thrombosis as an integral part of the disease process beyond cancer types such as multiple myeloma, where thrombosis presents a clear and present danger. This is understandable considering the treatments that have been available. Low-molecular-weight heparins require regular subcutaneous injection, which may be onerous for patients. Warfarin requires regular monitoring and increases the risk for bleeding. But if studies like CASSINI continue to provide evidence for the benefits of thromboprophylaxis, newer nonmonitored oral anticoagulants may play a more prominent role in the oncologist’s toolbox.
Looking even farther into the future, we may begin to understand in detail how cancer cells benefit from encouraging coagulation. Just as we have begun to use our knowledge of immune system checkpoints and other mechanisms in cancer treatment, we might someday develop drugs to take advantage of the relationship between cancer and coagulation, turning a relationship that was once underappreciated into a new therapeutic opportunity.
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Dr. Khorana’s study is very important because, as he articulated during his presentation, VTE — either DVT or PE — is a very common in patients undergoing treatment for cancer. In an ideal world, they would be completely or largely preventable.
We’ve never before had good-quality evidence that an intervention that is easy to use, relatively inexpensive compared with the cost of cancer therapy, and very tolerable could actually reduce the risk for VTE.
It’s not just preventing death from VTE. If you’re undergoing treatment for breast cancer or colon cancer, the last thing you want is for an additional complication to develop. DVT may require hospitalization. In our current treatment algorithms, many of those patients would receive treatment with a low-molecular-weight heparin, which is an injection. So, we’re really avoiding not just complexity, but an event that is unpalatable to a patient.
This represents a major advance, particularly because there is a confirmatory study coming along very closely afterward that will support the hypothesis that selected high-risk patients will benefit from prophylaxis.
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