Lack of superiority of rivaroxaban for secondary prevention of embolic stroke of undetermined source

1. At a median follow-up of eleven months, rivaroxaban was not superior to aspirin for prevention of secondary stroke after an initial primary embolic stroke of undetermined source.

2. Use of rivaroxaban was associated with a higher rate of major bleeding relative to aspirin.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Improvements in medical diagnostics have led to the identification of the likely etiology of stroke in most cases. The twenty percent of strokes for which a source cannot be identified are termed cryptogenic. It has been hypothesized that some of these strokes could be embolic in origin, therefore treatment with an anticoagulant might reduce risk of recurrent stroke. The investigators of this study tested this hypothesis by randomizing participants with considered to have an initial embolic stroke of undetermined source to either aspirin 100mg or rivaroxaban 15mg daily and followed them for a median of eleven months to determine efficacy of all-cause stroke risk reduction. They found no evidence of a difference between the two drugs regarding secondary stroke prevention. Rivaroxaban was associated with a significantly higher risk of major bleeding. These data do not support the use of rivaroxaban over aspirin in patients with embolic strokes of undetermined source.

A major strength of this study is the randomized controlled design and determination of adherence via interviews and pill counts. One weakness is that intracranial imaging was optional, therefore the trial might have included patients with stenosis of intracranial vessels as the etiology of their stroke who would theoretically not benefit from anticoagulation.

Click to read the study in NEJM

Relevant Reading: Embolic strokes of undetermined source: the case for a new clinical construct

In-Depth [randomized controlled trial]: This was an international, multicenter, randomized controlled trial that randomized 7213 participants to either aspirin 100mg (n = 3604) or rivaroxaban 15mg (n = 3609) daily. Inclusion criteria included age greater than 49 and the occurrence of ischemic stroke identified by imaging seven days to six months before screening. Strokes that were lacunar, associated with extracranial vessel atherosclerosis >50%, or with a known risk factor for cardiac embolism were excluded (with at least 20 hours of cardiac rhythm monitoring). Imaging of intracranial vessels was not required, but if >50% stenosis was identified those strokes were excluded. Initial strokes resulting in severe disablement were excluded. The primary outcome was first recurrent ischemic or hemorrhagic stroke or systemic embolism of any etiology and was evaluated in a time-to-event manner. A primary safety outcome was occurrence of major bleeding.

At a median of eleven months follow-up the investigators found no evidence of difference in rates of secondary stroke between rivaroxaban or aspirin treated patients (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.87 to 1.33, p = 0.52). Rates of major bleeding were higher in the rivaroxaban (annualized rate, 1.8%) compared to aspirin group (annualized rate, 0.7%; HR, 2.72; 95% CI, 1.68 to 4.39; p < 0.001). A secondary outcome of death from any cause showed no significant difference between the two groups.

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