NAVIGATE ESUS: Trial result shows that rivaroxaban does not prevent recurrent cryptogenic stroke more than aspirin

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Rivaroxaban has been found to be no better than aspirin in reducing the secondary occurrence of cryptogenic stroke and leads to a higher rate of bleeding. The results were presented at the European Stroke Organisation Conference (ESOC; 16–18 May 2018, Gothenburg, Sweden) and simultaneously published in the New England Journal of Medicine.

The trial, called Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS) (NAVIGATE ESUS), was stopped prematurely at the end of last year after the second interim analysis concluded that “in the absence of offsetting benefit, and with little chance of showing benefit if the study was completed, there is a clear risk of excess bleeding.”

While the increased rate of bleeding was anticipated when the study was designed it was expected that a substantially larger absolute reduction in stroke to offset the bleeding but the study showed that there was no reduction in stroke to offset the expected increase in major bleeding.

Robert Hart (McMaster University, Hamilton, Canada), co-principal investigator said of the results: “We were expecting and planning on a 25% reduction with rivaroxaban and were very disappointed and surprised at the outcome.”

NAVIGATE ESUS was a large, international, double-blinded, phase III randomised controlled trial looking at the prevention of stroke in patients with a specific type of stroke called embolic strokes, with an unknown source. The study enrolled 7,213 patients at 459 sites in 31 countries from 2014 to 2017. The hypothesis was that for secondary prevention, anticoagulants may be more efficacious than antiplatelets for most embolic sources.

About 20% of ischaemic strokes meet the criteria for ESUS, of uncertain cause but likely due to a clot that forms in the heart, leg veins or other vessels that then moves to the brain.

Hart said, “A group got together in 2012 and looked at the large fraction of ischaemic strokes that were cryptogenic and came up with the hypothesis that, with the new oral anticoagulants that are safer than warfarin perhaps, the new oral anticoagulants would be superior to aspirin, which is the standard, traditional secondary treatment.”

The trial compared a 15mg daily dose of rivaroxaban plus placebo with a daily dose of 100mg of aspirin plus placebo in patients who qualified under the ESUS definition who were at least 49 years old at the time of initial stroke.

Primary safety outcome was major haemorrhage as defined by the International Society on Thrombosis and Haemostasis (ISTH).

Primary outcome was recurrent stroke and systemic emboli and occurred in 5.1% of the rivaroxaban group compared to 4.6% aspirin (p=0.52). What was most noticeable within the primary outcomes was the significantly increased rate of haemorrhagic stroke in the rivaroxaban group compared to the aspirin group. The rate of haemorrhagic stroke was around 4 times as high (0.4% vs.0.1% [p=0.01])

The results of the study showed no reduction in recurrent stroke by rivaroxaban 15 mg daily vs. aspirin 100 mg/day, and major bleeding was increased. The study was stopped early with only 74% of planned primary events, but with adequate power to exclude >13% stroke reduction by rivaroxaban and there was a high rate of recurrent stroke (~5%/year) with either treatment.

Commenting on the results Hart said, “Both groups have a high rate of recurrent stroke, confirming the need for a better treatment option (even for aspirin) for these patients.”

As to why the study  did not succeed in showing that rivaroxaban was superior he said, “This will be something the investigators need to look at in the sub analyses. It is possible that our criteria for embolic stroke were not accurate in determining strokes that occurred from clots that formed in one place and migrate. In my view it’s likely that the serval different sources of emboli respond differently to the anticlotting drugs.”

As a result of these findings Hart is recommending that rivaroxaban is not used to treat ESUS and that ongoing randomised trials will clarify if the high stroke recurrence rates in ESUS patients can be reduced by alternative anticoagulants.

NAVIGATE ESUS was sponsored by Bayer AG and Janssen LLC.

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