Predictors of Recurrent Ischemic Stroke in Patients with Embolic Strokes of Undetermined Source and Effects of Rivaroxaban Versus Aspirin According to Risk Status: The NAVIGATE ESUS Trial
Introduction
Ischemic strokes of uncertain cause (ie, cryptogenic strokes) remain frequent despite diagnostic advances aimed at determining stroke etiology.1, 2 Most nonlacunar cryptogenic ischemic strokes are likely due to emboli originating from one of several potential cardiac and arterial sources and occasionally from venous thromboembolism (ie, via paradoxical embolism),3 and the construct of embolic strokes of undetermined source (ESUS) has been proposed.1 ESUS criteria identify patients with a rate of recurrent ischemic stroke that averages about 5% per year.4, 5, 6
In 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) randomized trial, we compared rivaroxaban (an anticoagulant), a selective direct factor Xa inhibitor, with aspirin (an antiplatelet drug) for prevention of recurrent stroke in ESUS patients.7 Rates of recurrent ischemic stroke were similar in both treatment arms.5 Here, we analyze independent predictors of recurrent ischemic stroke and the relative effects of rivaroxaban versus aspirin among high-risk ESUS patients.8 Because the presumed underlying potential embolic sources were heterogeneous, treatment interactions with individual risk factors for recurrent stroke were explored in order to potentially shed light on the overall neutral trial results. Seeking pathomechanistic insights, we additionally assessed differences in independent predictors between antithrombotic treatment arms and on recurrent strokes classified as recurrent ESUS.
Section snippets
Methods
NAVIGATE ESUS (ClinicalTrials.gov number NCT02313909) was an international, double-blinded, randomized phase III trial conducted at 459 centers in 31 countries and involved 7213 participants. The study rationale, design, participant features, and main results have been previously published.1, 5, 7, 9 Patients with recent (7 days to 6 months) ischemic stroke visualized by neuroimaging were eligible if they met criteria for ESUS as proposed by the Cryptogenic Stroke/ESUS International Working
Results
The 7213 participants were recruited from Europe (59%), East Asia (19%), North America (13%), and Latin America (10%). The mean participant age was 67 years, 62% were men, and history of hypertension, diabetes, and prior stroke or TIA was present in 77%, 25%, and 17%, respectively. Participants were randomized, on average, 37 days after the qualifying ESUS. During a median follow-up of 11 months, first recurrent ischemic strokes occurred in 309 participants (annualized rate 4.6% per year), with
Discussion
In undertaking these exploratory analyses, we sought to identify a distinctive pattern of recurrent stroke predictors that would be relatively specific to ESUS patients and that would offer pathomechanistic insights into the heterogeneous underlying embolic sources and to their responses to antiplatelet versus anticoagulant therapy. Prior stroke or TIA was the strongest and most consistent predictor of recurrent ischemic stroke (and also of recurrent ESUS), but this feature does not offer clues
Conflict of Interest
All authors received payments for participating in the NAVIGATE ESUS randomized trial except for HM, SDB and GP who were employed by the trial sponsors (Bayer AG, Janssen Research and Development LLC).
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Cited by (28)
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2024, American Journal of CardiologyCardiovascular outcomes and mortality after incident ischaemic stroke in patients with a recent cancer history
2023, European Journal of Internal MedicineCitation Excerpt :There are conflicting reports from previous studies assessing the risk of recurrent stroke in patients with acute ischaemic stroke and a history of cancer. While studies of patients in hospital or emergency department settings demonstrate a high risk of recurrent stroke in the short-term post-stroke period in those with active cancer [11,21,22], an exploratory study of participants with ischaemic stroke in the NAVIGATE ESUS randomised trial found that history of cancer was not independently associated with risk of recurrent ischaemic stroke [23]. Using Cox proportional hazard regression models, our study found no significant difference in the long-term and short-term risk of recurrent stroke and other cardiovascular outcomes in patients with recent cancer history compared with those with no history of cancer and supports the findings from the NAVIGATE ESUS trial.
Embolic Stroke of Undetermined Source: Current Perspectives on Diagnosis, Investigations, and Management
2023, Canadian Journal of CardiologyCitation Excerpt :A history of stroke/transient ischemic attack (TIA) was the strongest independent risk factor for recurrence across the NAVIGATE ESUS and RE-SPECT ESUS trials and the YOUNG ESUS registry. Other independent risk factors for recurrence in NAVIGATE ESUS included current tobacco use, older age, diabetes, multiple acute infarcts on imaging, aspirin use before stroke, and shorter time from qualifying stroke to randomization.20 A substudy of NAVIGATE ESUS showed no significantly increased risk of recurrence for any potential embolic source.18
A Systematic Review and Meta-Analysis of Carotid Artery Stenting for the Treatment of Cervical Carotid Artery Dissection
2022, European Journal of Vascular and Endovascular SurgeryCitation Excerpt :Additionally, the primary stenting subgroup performed worse regarding neurological outcomes (mRS 0 – 2 of 88.5% vs. 94.1%) and in stent thrombosis and occlusion rates (5.24% vs. 0%). The high number of patients presenting with stroke in the primary stenting subgroup (63% vs. 32.3%) might help the interpretation of these results since patients presenting with stroke are at an increased risk of recurrence.29,31 Even though the ischaemic stroke rate of primary stenting in this analysis appears comparable with the rates presented by CADISS and TREAT-CAD, almost 40% of the patients in the primary stenting subgroup presented with no symptoms, contrary to 100% for both these randomised controlled trials (RCTs).
The Utility of the Markers of Coagulation and Hemostatic Activation Profile in the Management of Embolic Strokes of Undetermined Source
2021, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :For a cryptogenic stroke to be classified as ESUS, it must be non-lacunar, have no atherosclerotic disease causing ≥ 50% ipsilateral stenosis, with no major underlying cardioembolic source, and no other obvious causes of stroke.5 Among these patients, the stroke recurrence rate is approximately 5% per year.6 Post-stroke evaluations can identify occult paroxysmal atrial fibrillation, atrial cardiopathy, aortic arch disease, occult malignancy, and hypercoagulable states as etiologies for embolic strokes in patients with ESUS which also can definitively alter patient management via medical and invasive interventions.
Diagnosis and Treatment for embolic stroke of undetermined source: Consensus statement from the Taiwan stroke society and Taiwan society of cardiology
2021, Journal of the Formosan Medical AssociationCitation Excerpt :Notably, the long-term mortality risk for ESUS patients is lower than that for cardioembolic stroke, despite similar composite cardiovascular endpoints and recurrence rates. Some clinical characteristics are independent determinants for recurrent ischemic stroke in ESUS patients, including prior stroke or transient ischemic attack (TIA) before ESUS, advanced age, current tobacco use, multiple acute infarcts on neuroimaging, and diabetes.12 Compared with the low-risk CHA2DS2-VASc group (men, score 0; women, 1), patients in the high-risk group (men, score ≥ 2; women, ≥ 3) have higher risks of recurrent ischemic stroke or TIA (∼3-fold) and death (∼13-fold).13