CORRECTED December 5, 2018 // A new study that explored the use of the oral agent rivaroxaban (Xarelto, Janssen) as prophylaxis against venous thromboembolism (VTE) in ambulatory cancer patients who were being treated in the outpatient setting failed to meet its primary endpoint.
At 180 days, the rate of thrombotic events was not statistically significantly different between the patients who received rivaroxaban (5.95%) and those who received placebo (~8.79%).
However, this was primarily because a large proportion of patients stopped taking the medication before the end of the study period, explained lead study author Alok A. Khorana, MD, of Cleveland Clinic Lerner College of Medicine and Case Western Reserve University, Ohio.
More than half of patients who were randomly assigned to receive placebo and almost 44% of those taking rivaroxaban stopped the regimen before 180 days, and more than one third of clotting events occurred after participants had discontinued their assigned regimen, he noted.
In a prespecified analysis that only evaluated the on-treatment period, the difference between the two groups was greater and was statistically significant. In the rivaroxaban group, 2.6% of patients experienced an event, as compared to 6.4% of patients who received placebo (P = .007).
Khorana presented the study (abstract LBA-1) here at the American Society of Hematology (ASH) 2018, and it was highlighted at an ASH press briefing.
Something Better Needed
Commenting on the study, Christopher Walsh, MD, PhD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, New York City, noted that the risk for blood clots in cancer patients is high and that the standard of care is the use of subcutaneous low-molecular-weight heparin (LMWH).
"The abstract presents evidence that the oral drug rivaroxaban can decrease the number of blood clots in cancer patients who are being treated and not in the hospital," he told Medscape Medical News. "However, the study design compared rivaroxaban to placebo and not to LMWH. Obviously, something taken orally is easier to use, but its efficacy against current standard wasn't performed."
Another expert noted that aside from not reaching the primary endpoint, the number of patients who achieved a benefit was very small.
"The experimental arm had less thrombosis, but it's not conclusive," said Henry Fung, MD, vice chair, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. "It's a trend, and the trend is towards improvement, but it is not clinically significant because of the small numbers and the small number of events. This is a borderline benefit.
Overall, this study showed that rivaroxaban yielded marginal benefits, "but the bottom line is that we need something better," Hung concluded.
"We also need a cost analysis to gauge the financial toxicity. The drug is very expensive," he added.
Ambulatory Cancer Patient Population
Cancer patients are at an increased risk for VTE. For such patients who are hospitalized, thromboprophylaxis is recommended. "Almost all of our efforts at preventing blood clots have been focused on the inpatient setting," commented Khorana. However, most chemotherapy is given in the outpatient setting.
Two previous large, randomized controlled trials that were conducted in a population of cancer outpatients showed a reduction in the rate of VTE with prophylaxis, but the rate of events was low. This led to efforts to identify those patients who are at greatest risk, in order to target prophylaxis for greater clinical benefit, he pointed out.
About 10 years ago, Khorana and colleagues developed a risk score that could help predict which patients were at risk of developing a clot. "This is important, because if you target your approach to primary prevention to high-risk patients, the clinical benefit to patients is greater," he said.
Injectable LMWH is the standard of care for treating and preventing recurrence of acute VTE in cancer patients. The newer direct-acting oral anticoagulants (DOACs) such as rivaroxaban are similar in efficacy, and they have been associated with less frequent and less severe bleeding. They are widely used to treat VTEs in individuals without cancer. But whether they could be a viable alternative for cancer-associated VTE has been unclear.
Two recent studies showed that oral agents may an alternative to LMWH for cancer-associated VTE and in fact could replace them for most patients.
However, the benefit of extended outpatient thromboprophylaxis with heparins is uncertain, and DOACs have not been evaluated in this setting. The new study set out to examine this question.
Adherence Makes a Difference
The study was conducted in 841 cancer patients who were free of deep-vein thrombosis (DVT) at baseline. The patients were randomly assigned in a 1:1 ratio to receive either rivaroxaban 10 mg once daily or placebo up to day 180. The patients had various solid tumors/lymphomas. All were starting on systemic chemotherapy regimens and were at high risk for VTE (Khorana score ≥2).
The primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism, and VTE-related death.
Of this population, this primary efficacy endpoint was met by 25 of 420 patients (5.95%) who received rivaroxaban and by 37 of 421 patients (8.79%) who received placebo (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.40 - 1.09; P = .101).
Among patients with VTE, 38.7% experienced events after they had stopped using rivaroxaban.
"On average, patients took the drug for about 4.5 months," said Khorana. "Even if they stopped at month 4, we still evaluated them at month 6 to see if there were any events. So if we just looked up until month 4, there is a much larger suppression of events.
"But when the drug is stopped, the risk goes back up again," he continued. "We did identify a high-risk population and found that you need to be adherent to the drug to get a benefit."
In a prespecified analysis of all patients during the on-treatment period, the primary endpoint was met in 11 patients who received rivaroxaban (2.62%) and in 27 patients who received placebo (6.41%) (HR, 0.40; 95% CI, 0.20 - 0.80; P = .007; number needed to treat, 26).
Major bleeding occurred in 8 of 405 patients (1.98%) in the rivaroxaban group and in 4 of 404 patients (0.99%) in the placebo group (HR, 1.96; 95% CI, 0.59 - 6.49; P = .265; number needed to harm [NNH], 101).
In addition, clinically relevant nonmajor bleeding occurred in 2.72% of the patients taking rivaroxaban and in 1.98% of the patients taking placebo (HR, 1.34; 95% CI, 0.54 - 3.32; P = .53; NNH, 135).
For secondary endpoints, the rate of all-cause mortality was 20.0% of patients in the rivaroxaban group and 23.8% in the placebo group (HR, 0.83; P = .213). A prespecified composite of the primary endpoint with all-cause mortality occurred in 23.1% of patients in the rivaroxaban group and in 29.5% of patients in the placebo group (HR, 0.75; P = .03).
"We wonder if there should be screening for patients beginning therapy," said Khorana. "But regardless of that issue, given our findings, we believe that future recommendations regarding primary prevention of thrombotic events should be informed by the findings of this study."
Heparin is usually used, but it is delivered by injection and can be inconvenient to use. "Injectable drugs can be a problem for reimbursement, especially for Medicare," he said. "There are also quality-of-life issues."
The study was funded by Janssen. Dr Khorana has relationships with Parexel, Sanofi, Pfizer, Janssen, TriSalus, Halozyme, Seattle Genetics, AngioDynamics, LEO Pharma, Medscape/WebMD, Pharmacyclics, and Bayer.
American Society of Hematology (ASH) 2018. Abstract LBA-1, presented December 4, 2018
Correction: An earlier version of this story erroneously attributed the "marginal benefit" comment to Dr Khorana, whereas the comment was made by Dr Hung.
Medscape Medical News © 2018
Cite this: 'Marginal Benefit' With Rivaroxaban in Cancer Patients - Medscape - Dec 04, 2018.