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Patients with embolic stroke of undetermined source (ESUS) who are found to have signs of left ventricular dysfunction may benefit from anticoagulation to prevent a further stroke, a new exploratory analysis of the NAVIGATE ESUS trial suggests.

The NAVIGATE ESUS trial with rivaroxaban and another similar trial with dabigatran (RE-SPECT ESUS) both showed that anticoagulation was no better than aspirin at reducing the risk of recurrent stroke and systemic embolism among patients with ESUS.

But the new exploratory analysis of the NAVIGATE-ESUS shows that in the subgroup of patients with left ventricular dysfunction, defined as evidence of impaired left ventricular contractility and/or regional wall motion abnormalities, there was a substantial reduction in the primary endpoint of recurrent stroke or systemic embolism with rivaroxaban versus aspirin.

These latest results were published online in JAMA Neurology on October 25.

“We found a 64% reduction in stroke risk with rivaroxaban versus aspirin in this group. That is a huge effect,” lead author, Alexander E. Merkler, MD, Weill Cornell Medicine, New York City, amoxicillin 625 side effects told theheart.org | Medscape Cardiology.

“We thought it was likely that these patients may benefit from anticoagulation as previous studies have shown that patients with left ventricular dysfunction are at a higher risk of stroke. This makes sense as the poor contractility of the heart leads to blood pooling and clots forming,” Merkler explained.

“We have potentially identified left ventricular dysfunction as being a novel risk factor for stroke that is not currently taken into account,” he said.

But Merkler said it is too early for any firm recommendations on treatment based on this paper because it was an exploratory analysis. “We need a dedicated randomized trial to specifically look at this question. We are hoping to do such a trial, and are applying for funding for this now,” he added.

In the meantime, “My advice at present for clinicians based on this study would be to make sure that patients with embolic stroke of undetermined source are evaluated for left ventricular dysfunction as this may have been the cause of the stroke,” he said. “And patients should be referred to the cardio team to make sure any left ventricular dysfunction is optimally treated.”

High-Risk Cardioembolic Source

In the paper, the authors note that certain forms of left ventricular dysfunction, such as recent acute myocardial infarction or severe left ventricular systolic dysfunction, are already considered to be high-risk cardioembolic sources of stroke that respond to anticoagulation.

But other more common forms of left ventricular dysfunction — including impaired left ventricular contractility or regional wall motion abnormalities — are not currently considered high-risk sources of embolism, although they appear to be associated with thrombus formation and recurrent stroke. Patients with stroke who have these abnormalities are not routinely prescribed anticoagulation.

For the current report, Merkler and colleagues analyzed the NAVIGATE ESUS data to see if anticoagulation would be superior to antiplatelet therapy in reducing the risk of cardiac embolism and subsequent stroke in patients with ESUS and evidence of left ventricular dysfunction.

In the NAVIGATE ESUS trial, 7213 patients with recent embolic stroke of undetermined source were randomized to either rivaroxaban 15 mg or aspirin 100 mg once daily for the prevention of recurrent stroke.

The vast majority of patients (98.5%) included in the study had a documented assessment of left ventricular function at study entry and were included in the present analysis.

Global left ventricular contractility was graded as normal, mildly impaired, moderate to severely impaired, or uncertain. If the global assessment of contractility was marked as uncertain or not reported, a left ventricular ejection fraction less than 40% was used to define global moderate to severely impaired left ventricular contractility.

In this analysis, participants were considered to have left ventricular dysfunction if they had moderate to severely impaired global left ventricular contractility and/or a regional wall motion abnormality.

These markers of left ventricular dysfunction were selected because they had been previously found to be associated with thrombus formation and stroke, the authors explain.

Among the 7107 participants, 502 (7%) had left ventricular dysfunction by this definition. Of these, 81% had normal to mildly impaired left ventricular contractility with a regional wall motion abnormality, while 19% had moderate to severely impaired left ventricular contractility with or without a regional wall motion abnormality.

Over a median follow-up of 10.4 months, the primary outcome of recurrent stroke or systemic embolism occurred at a rate of 4.9% per year in the total population in this analysis.

For the 502 participants with left ventricular dysfunction, annualized rates of the primary outcome were 2.4% per year in those assigned to rivaroxaban vs 6.5% in those assigned to aspirin.

In contrast, among the 6605 participants without left ventricular dysfunction, annualized primary event rates were similar between those assigned to rivaroxaban (5.3% per year) vs aspirin (4.5% per year).

This observed heterogeneity of treatment effect was statistically significant (P = .03 for interaction).

Participants with left ventricular dysfunction randomly assigned to rivaroxaban vs aspirin had a significantly lower risk of the primary outcome (HR, 0.36; 95% CI, 0.14 – 0.93), whereas those without left ventricular dysfunction had similar risk (HR, 1.16; 95% CI, 0.93 – 1.46).

Similar results were seen for the secondary outcome, the composite of recurrent stroke, systemic embolism, myocardial infarction, or death from cardiovascular causes.

For the 502 participants with left ventricular dysfunction, rates of secondary outcome were 4.9% per year in those assigned to rivaroxaban vs 9.5% per year in those assigned to aspirin.

In contrast, among the 6605 participants without left ventricular dysfunction, annualized secondary event rates were similar between those assigned to rivaroxaban (6.2%) vs aspirin (5.4%).

Participants with left ventricular dysfunction assigned to rivaroxaban had a lower risk of experiencing the secondary outcome compared with those assigned to aspirin (HR, 0.51; 95% CI, 0.3 – 1.0) whereas there was no significant difference by assigned treatment among those without left ventricular dysfunction (HR, 1.1; 95% CI, 0.9 – 1.4).

The authors note that a previously published subgroup analysis of NAVIGATE ESUS reported that rivaroxaban was not superior to aspirin in participants with any type of left ventricular disease. But they point out that in that analysis, left ventricular disease was liberally defined to include diastolic dysfunction and left ventricular hypertrophy, neither of which has been found to be associated with cardiac embolism.

They conclude that: “In this analysis, we tested the hypothesis that specific forms of left ventricular dysfunction previously found to be associated with left ventricular thrombus formation and stroke would respond to anticoagulation. In this context, our results provide novel data suggesting that ESUS patients with evidence of impaired left ventricular contractility and/or regional wall motion abnormalities may benefit from anticoagulation.”

Merkler reported grants from the American Heart Association during the conduct of the study and has served as an expert witness regarding neurological disorders outside the submitted work.

JAMA Neurol. Published online October 25, 2021. Abstract

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