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Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515).

SummaryBackground Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months.

IMPORTANCE The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF).OBJECTIVE To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. DESIGN, SETTING, AND PARTICIPANTS Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. INTERVENTION Rivaroxaban treatment vs aspirin. MAIN OUTCOMES AND MEASURES Risk of ischemic stroke.RESULTS Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02). CONCLUSIONS AND RELEVANCEThe HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.

Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. Main hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred.

Background and Purpose— Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods— The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results— Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P <0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P =0.002), and aortic valvulopathy (10 versus 20 versus 20; P <0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA ( P =0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53–2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions— Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.

Background and Purpose— The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods— Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%–49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results— Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39–1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86–1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63–8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73–1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99–1.54). Conclusions— In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.