GOTHENBURG, Sweden — In an "unfortunately negative trial," the factor Xa inhibitor rivaroxaban was not superior to aspirin in preventing recurrent stroke after a first embolic stroke of undetermined source (ESUS) but was associated with a significant increase in bleeding events, researchers report.
"Unfortunately and surprisingly to us, the trial was negative," co-principal study investigator Robert Hart, MD, said during a press briefing here at the 4th European Stroke Organisation Conference (ESOC).
Hart and colleagues randomly assigned 3609 people with cryptogenic stroke to 15 mg daily rivaroxaban (Xarelto, Bayer AG) and another 3604 to 100 mg daily aspirin. They found no significant difference between groups in the number of recurrent strokes and systemic emboli, the primary outcome of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial.
There were 172 such events in the rivaroxaban group vs 160 in the aspirin cohort at a median 11 months of follow-up, a difference that did not reach statistical significance. About 20% of ischemic strokes meet criteria for ESUS.
"We were expecting a 25% reduction by rivaroxaban and were very disappointed — and a bit surprised — that the two thrombotic medications were equal," said Hart, professor of neurology in the Department of Medicine at McMaster University and a senior scientist at the Population Health Research Institute in Hamilton, Ontario, Canada.
Both treatment groups had high rates of recurrent strokes, he noted. "This is a useful observation. It confirms we need something better than aspirin," Hart said.
Rate of major bleeding was the primary safety outcome. Hart reported a nearly threefold increase in major bleeding (hazard ratio [HR], 2.7) associated with use of rivaroxaban compared with aspirin. The difference was statistically significant (P < .001).
An independent monitoring committee stopped the trial in October 2017 based on the lack of benefit for stroke prevention and the safety findings.
Results of the international, double-blind, phase 3 randomized NAVIGATE-ESUS trial were simultaneously published online May 16 in The New England Journal of Medicine.
"Why did the study not succeed? That is something our investigators will have to discuss and sort out," Hart said. "It's possible our criteria for embolic stroke was not accurate for detecting emboli that occur in one place and migrate through the circulation."
Another possibility is that the different emboli included the study — cardioembolic, arteriogenic, and paradoxical — do not respond the same to factor Xa inhibition, he added.
"We hoped for a home run" based on previous studies in which Hart and colleagues showed a positive outcome associated with rivaroxaban and similar agents in patients with atrial fibrillation (Can J Cardiol. 2013;7 Suppl:S71-78; Nat Rev Nephrol. 2012;8:569-578).
The current study included 7213 people age 50 years and older who experienced a recent ischemic stroke presumed to be from cerebral embolism, but without arterial stenosis, lacune, or an identified cardioembolic source, from 459 sites in 31 countries from 2014 to 2017. Approximately 60% were men; the mean age was 67 years. National Institutes of Health Stroke Scale score at randomization was 1.0 in both groups.
The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis, and the primary safety outcome was the rate of major bleeding.
Recurrent stroke or systemic embolism occurred in 172 patients treated with rivaroxaban (annualized rate, 5.1%) vs 160 in the aspirin group (annualized rate, 4.8%) for an HR of 1.07 (95% confidence interval [CI], 0.87 - 1.33; P = .52).
Recurrent ischemic stroke was seen in 158 patients receiving rivaroxaban (annualized rate, 4.7%) and 156 receiving aspirin (annualized rate, 4.7%).
Major bleeding was significantly higher with rivaroxaban, occurring in 62 of those patients (annualized rate, 1.8%) and 23 in the aspirin group (annualized rate, 0.7%) (HR, 2.72; 95% CI, 1.68 - 4.39; P < .001).
Life-threatening or fatal bleeding, symptomatic intracranial hemorrhage (ICH), and clinically relevant nonmajor bleeding were also all significantly higher with rivaroxaban treatment.
Table. NAVIGATE-ESUS: Bleeding Endpoints
| Endpoint | Hazard Ratio (95% CI) | P Value |
|---|---|---|
| Major bleeding | 2.72 (1.68 - 4.39) | <.001 |
| Life-threatening or fatal bleeding | 2.34 (1.28 - 4.29) | .004 |
| Symptomatic ICH | 4.02 (1.51 - 10.70) | .003 |
| Clinically relevant nonmajor bleeding | 1.51 (1.13 - 2.00) | .004 |
A prespecified subanalysis of patients younger than 60 years showed they fared no better with rivaroxaban, Hall said. "In fact, the trend favors aspirin."
Two other ongoing trials are seeking to determine whether alternative anticoagulants can reduce the high stroke recurrence rates in patients with ESUS.
"It's a disappointing result. It's a flatline in terms of benefit and there is a risk there," Kennedy Lees, MD, professor of cerebrovascular disease at the University of Glasgow, United Kingdom, told Medscape Medical News when asked to comment on the study. "Dr Hart said this is a true negative [result], and I think he's right, and it showed there was potential harm there."
This does not necessarily mean that all factor Xa agents should never be used in this patient population, he added. More information is forthcoming from a similarly sized study of dabigatran for secondary stroke prevention that has not been halted, added Lees.
Bayer AG and Janssen sponsored the study. Hart disclosed that he receives research support, honoraria, and stipends from Bayer AG. Lees had no relevant disclosure related to rivaroxaban.
4th European Stroke Organisation Conference (ESOC) 2018. Presented May 16, 2018.
N Engl J Med. Published online May 16, 2018. Abstract
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Cite this: Rivaroxaban Not Superior to Aspirin for Recurrent Stroke After ESUS - Medscape - May 16, 2018.
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