Rivaroxaban May Reduce Stroke After ESUS With Large Left Atrium

Marlene Busko

October 30, 2018

MONTREAL — In the NAVIGATE ESUS trial, among patients with embolic stroke of undetermined source (ESUS) who also had an enlarged left atrium, the rate of recurrent stroke was lower for those who received rivaroxaban (Xarelto, Janssen) as opposed to aspirin, researchers report.

Positive results in this subgroup analysis contrast with negative findings in the overall trial, as reported earlier this year in the New England Journal of Medicine. In that trial, rivaroxaban was not superior to aspirin in preventing recurrent stroke after ESUS and was associated with a higher risk of bleeding.

"We're seeing an intriguing finding here," David J. Gladstone, MD, PhD, from the Department of Medicine, University of Toronto, and the Sunnybrook Research Institute, said of the subgroup result, which was presented at the 11th World Stroke Congress (WSC) 2018.

"But we urge caution, because this is an exploratory subgroup analysis from an overall negative trial," he stressed. "It needs to be replicated."

"About 1 in 10 patients with an embolic stroke of undetermined source in this trial had a left atrial diameter >4.6 cm," Gladstone pointed out to theheart.org | Medscape Cardiology. "If this result is confirmed in other trials, then left atrial enlargement might well become a future treatment target for anticoagulation in secondary stroke prevention."

The findings, he said, "support the atrial myopathy hypothesis that suggests that some embolic strokes of unknown cause may arise from atrial embolism from an enlarged or dysfunctional left atrium, in the absence of atrial fibrillation [AF]."

Invited to comment, Rolf Wachter, MD, from the University Hospital Leipzig, Germany, agreed that this small substudy is "very interesting, but also has to be seen with caution, because numbers were low.

"We need more data to confirm these findings," he told theheart.org | Medscape Cardiology. Moreover, he added, "I think we definitely need data from biomarkers," such as amino terminal pro–B-type natriuretic peptide, he added.

Data from subgroups in the WARSS trial, which was conducted 20 years ago and that compared warfarin with aspirin, showed that this peptide can identify patients who would benefit from anticoagulation. Now biomarker analysis from patients in newer trials of NOACs vs aspirin is needed.

"Great Need" to Improve Stroke Prevention in ESUS

"There continues to be a great need to improve stroke prevention for the roughly 20% of ischemic strokes that are classified as ESUS," said Gladsone. For such patients, the rate of stroke recurrence is around 5% per year, he said.

The NAVIGATE ESUS trial was stopped early when the rate of ischemic stroke was found to be identical for patients who received either rivaroxaban or aspirin (4.7% per year), but the rate of major hemorrhage was found to be higher in the rivaroxaban group (1.8% vs 0.7% per year; hazard ratio [HR] 2.7; 95% confidence interval [CI], 1.7 - 4.4; P < .001).

The current analysis aimed to assess the effect of rivaroxaban 15 mg daily vs aspirin 100 mg daily on the rate of recurrent ischemic stroke in the subset of ESUS patients who had risk factors for AF or an enlarged left atrium.

NAVIGATE ESUS included 7213 participants with ESUS in 31 countries. In this exploratory analysis, the researchers analyzed data from the 4022 participants with ESUS for whom measurements of left atrial diameter were available.

The investigators determined the frequency of Holter-detected premature atrial contractions (PACs) and assessed HAVOC scores.

In the EMBRACE trial, a high frequency of PACs "was the strongest predictor of AF," and that has been shown to be a predictor of ischemic stroke independently of AF, Gladstone explained.

The HAVOC score is based on age (≥75 years) and the presence of obesity, congestive heart failure, hypertension, coronary artery disease, peripheral vascular disease, and valve disease. Scores range from 0 (best) to 14 (worst). It is "a clinical scale that is predictive of AF in a cryptogenic stroke population," said Gladstone.

The researchers assessed two prespecified subgroups:

  • patients with moderate or severe left atrial enlargement, defined as left atrial diameter >4.6 cm, and

  • patients with PAC frequency >720/24 hr.

In this subanalysis, the mean age of the patients, as in the overall trial, was 67 years, and 62% were men. Most (77%) had a history of hypertension; their median CHADSVASC score was 4.

The patients' mean HAVOC score was 2.4, and 90% had a HAVOC score of 4 or less, placing them in the very low risk category.

For patients in different tertiles of HAVOC scores, there was no difference in risk for recurrent stroke if they had received rivaroxaban or aspirin.

The median PAC frequency was 48 PACs/24 hr (interquartile range, 13 to 22), which was also relatively low.

Among the 302 patients (13.3%) with PAC > 720/24 hr, there was no difference in risk for stroke if patients had received rivaroxaban or aspirin.

The mean left atrial diameter was 3.8 cm, which is in the normal range.

However, for the 361 patients (9.0%) with moderate or severe enlargement of the left atrium, there was a substantial reduction in recurrent stroke among those who received rivaroxaban (1.7% per year) vs aspirin (6.5% per year; HR, 0.26; 95% CI, 0.07 - 0.94; P = .02).

Only 6.4% of patients had been clinically diagnosed with AF. It is likely that the rate of AF was underestimated, because patients did not undergo prolonged, continuous heart monitoring.

The major bleeding rate was similar to that in the overall cohort.

Study limitations, Gladstone acknowledged, include the short follow-up (mean, 11 months) and possible error in measuring left atrium diameter. "Left atrial volume would have been better," he said.

Nevertheless, he said, the results have "definite biological plausibility" and now "must be independently validated in other trials.

"We hope that the RESPECT-ESUS investigators will look at this issue," he said. "We're very much looking forward to the forthcoming results of the ARCADIA trial, which is directly testing this hypothesis."

The trial was funded by Bayer AG and Janssen. Dr Gladstone receives research support from the Heart and Stroke Foundation of Canada, the Sunnybrook Health Sciences Center, and the Department of Medicine of the University of Toronto. He also serves as medical safety monitor of the ARCADIA trial.

11th World Stroke Congress (WSC) 2018. Presented October 18, 2018.

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