Embolic Strokes of Undetermined Source in the Athens Stroke Registry
An Outcome Analysis
Background and Purpose—Information about outcomes in Embolic Stroke of Undetermined Source (ESUS) patients is unavailable. This study provides a detailed analysis of outcomes of a large ESUS population.
Methods—Data set was derived from the Athens Stroke Registry. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group criteria. End points were mortality, stroke recurrence, functional outcome, and a composite cardiovascular end point comprising recurrent stroke, myocardial infarction, aortic aneurysm rupture, systemic embolism, or sudden cardiac death. We performed Kaplan–Meier analyses to estimate cumulative probabilities of outcomes by stroke type and Cox-regression to investigate whether stroke type was outcome predictor.
Results—2731 patients were followed-up for a mean of 30.5±24.1months. There were 73 (26.5%) deaths, 60 (21.8%) recurrences, and 78 (28.4%) composite cardiovascular end points in the 275 ESUS patients. The cumulative probability of survival in ESUS was 65.6% (95% confidence intervals [CI], 58.9%–72.2%), significantly higher compared with cardioembolic stroke (38.8%, 95% CI, 34.9%–42.7%). The cumulative probability of stroke recurrence in ESUS was 29.0% (95% CI, 22.3%–35.7%), similar to cardioembolic strokes (26.8%, 95% CI, 22.1%–31.5%), but significantly higher compared with all types of noncardioembolic stroke. One hundred seventy-two (62.5%) ESUS patients had favorable functional outcome compared with 280 (32.2%) in cardioembolic and 303 (60.9%) in large-artery atherosclerotic. ESUS patients had similar risk of composite cardiovascular end point as all other stroke types, with the exception of lacunar strokes, which had significantly lower risk (adjusted hazard ratio, 0.70 [95% CI, 0.52–0.94]).
Conclusions—Long-term mortality risk in ESUS is lower compared with cardioembolic strokes, despite similar rates of recurrence and composite cardiovascular end point. Recurrent stroke risk is higher in ESUS than in noncardioembolic strokes.
A new clinical entity termed Embolic Stroke of Undetermined Source (ESUS) was recently introduced by the Cryptogenic Stroke/ESUS International Working Group, which describes stroke patients for whom the source of embolism remains undetected despite recommended investigation; potential embolic sources include the mitral and aortic valves, the left cardiac chambers, the proximal cerebral arteries of the aortic arch, and the venous system via paradoxical embolism.1 ESUS has been proposed as a potential therapeutic entity with an indication for anticoagulation, a hypothesis which is currently tested in randomized controlled trials.2,3
Recently, we presented a descriptive analysis of an ESUS population originating from the Athens Stroke Registry.4 Among the overall stroke population, 10% of patients were classified as ESUS.4 These strokes were of mild–moderate severity, and covert atrial fibrillation (AF) was identified as the underlying etiopathogenetic mechanism in ≈40% of ESUS patients.4
In routine clinical practice, and based on randomized studies,5,6 the vast majority of ESUS patients are treated with antiplatelets for secondary stroke prevention. However, given that covert AF is the underlying pathogenesis in ≈40% of ESUS patients, this antithrombotic strategy might be suboptimal, which in turn could have important consequences on their outcome. Therefore, information about outcomes in this patient group would be valuable; unfortunately, no such data are currently available for patients with ESUS because this is defined by the Cryptogenic Stroke/ESUS International Working Group.1
The aim of the present study is to provide a detailed analysis of outcomes of a large ESUS population derived from a large prospective stroke registry during a long follow-up period.
Study Population and Definitions
The study population was derived from the Athens Stroke Registry, which includes all consecutive patients with an acute first-ever ischemic stroke admitted in Alexandra University Hospital, Athens, Greece, between June 1992 and December 2011.7 Patients with recurrent stroke have not been included in the registry. The scientific use of the data collected in the Athens Stroke Registry was approved by the local Ethics Committee.
The methodology followed to register data in the Athens Stroke Registry was described elsewhere.4 With regard to AF detection, all patients had a 12-lead ECG at admission. In patients on sinus rhythm, AF paroxysms were sought by (1) repeated ECGs during hospital stay, (2) continuous ECG monitoring for 1 week or until discharge for patients treated in the acute stroke unit; ECG was observed by trained nurse personnel and intermittently analyzed by the treating physician, and (3) 24-hour Holter ambulatory ECG monitoring in cases that AF was strongly suspected from the clinical presentation and brain imaging findings (eg, multiterritorial infarcts, strokes presenting with maximum severity at onset, largely dilated left atrium), and a and b were negative.
ESUS was defined according to the criteria proposed by the Cryptogenic Stroke/ESUS International Working Group as a visualized nonlacunar brain infarct in the absence of (1) extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischemia, (2) major-risk cardioembolic source, and (3) any other specific cause of stroke (eg, arteritis, dissection, migraine/vasospasm, drug misuse).1 ESUS patients were classified without knowledge of follow-up outcomes. Large-artery atherosclerotic stroke was defined as a stroke with clinical and brain imaging findings of either significant (>50%) stenosis or occlusion of a major brain artery or branch cortical artery, presumably because of atherosclerosis.8 Cardioembolic stroke was defined as a stroke as a result of embolus arising in the heart.8 Lacunar stroke was defined as a subcortical brain infarct ≤1.5 cm in largest dimension in the distribution of the small, penetrating cerebral arteries.1 A stroke was characterized as miscellaneous when a specific cause other than large-artery atherosclerotic, cardioembolic, or lacunar stroke was identified. Patients without identification of the underlying etiopathogenic mechanism because of incomplete evaluation were classified as undetermined other than ESUS. According to the imaging protocol, patients had a computed tomography (CT) during admission and a second CT or magnetic resonance imaging (MRI) at 7 to 10 days. The choice of CT or MRI for the 7 to 10 days imaging depended on available resources and clinical presentation (eg, in patients with symptoms suggestive of posterior circulation infarct, MRI was preferred). Patients who had an early recurrent strokes in hospital before the investigations were finished and were included in the ESUS group if the pathogenesis of stroke was not identified after the completion of all necessary investigations.
Outcomes and Follow-Up
The primary end-point of the study was mortality. The secondary outcomes were stroke recurrence, functional outcome (favorable functional outcome was defined as modified Rankin Scale Score ≤2), and a composite cardiovascular end point comprising of recurrent stroke, myocardial infarction, aortic aneurysm rupture, systemic embolism, or sudden cardiac death. Death was assessed from death certificates, patients’ hospital records, and information from general practitioners or family physicians.
Recurrent stroke was defined as a cerebrovascular event of sudden onset, lasting >24 hours, subsequent to the initial stroke, which clearly resulted in a new neurological deficit or an increase in an existing deficit.9 Visualization of a new lesion on brain imaging, involving an anatomic site or vascular territory different from that of the index event, was mandatory to support the diagnosis of recurrent stroke during the first 3 weeks after stroke onset to ensure that systemic causes of clinical deterioration after an initial stroke (eg, hypoxia, hypotension, hyperglycemia, infection) and worsening of symptoms because of progression of the initial stroke were not misclassified as a recurrent cerebrovascular event. To determine the occurrence of recurrent ischemic stroke or intracerebral hemorrhage, we evaluated all the available information obtained from death certificates, hospital records, physicians’ notes in private practice, necropsy findings, and the patients’ clinical presentation at the regular follow-up assessments.
The time of initial stroke was the inception of follow-up. Patients were prospectively followed-up at 1, 3, and 6 months after discharge and yearly thereafter. Follow-up was routinely performed in the outpatient clinic. In case of patients with severe handicap, clinical follow-up was assessed at patient’s residence or by telephone interview. Lost-to-follow-up was defined as inability to reach the patient or the patient’s proxies at a scheduled time point.
Continuous data are summarized as mean value and standard deviation and categorical data as absolute numbers and proportion. For patients lost during follow-up, survival data were censored at the last time known to be alive. Patients who experienced >1 composite vascular event during the follow-up period were censored at the time of the first event.
The Kaplan–Meier product limit method was used to estimate the cumulative probability of each outcome by stroke type (ie, ESUS, cardioembolic, large-artery atherosclerotic, lacunar, undetermined other than ESUS, and miscellaneous). Differences in Kaplan–Meier curves were evaluated with the log-rank test.
Univariate and multivariate Cox-regression analyses were performed to investigate whether stroke type was a predictor of outcomes. The covariates entered in the analyses included age, sex, stroke severity (evaluated by the national Institute of Health Stroke Scale [NIHSS] score), stroke type (as described earlier), cardiovascular risk factors and comorbidities (history of hypertension, diabetes mellitus, smoking, dyslipidemia, heart failure, coronary artery disease, atrial fibrillation, admission blood pressure, and glucose), and in-hospital treatment (thrombolysis, antithrombotics). Factors that were significant in the univariate analyses were included in the multivariate Cox model. For the univariate analysis, the level of significance was set at 10% to reduce the risk of a type II error. In the final multivariate analyses, the level of significance was set at 5%. Associations are presented as hazard ratios with their corresponding 95% confidence intervals (95% CI) using the ESUS type as the comparator. Statistical analyses were performed with the Statistical Package for Social Science (SPSS Inc, version 17.0 for Windows; Chicago, IL).
Among 2731 patients admitted between June 1992 and December 2011 and included in this analysis, 275 patients (10.0%) were classified as ESUS. The baseline characteristics of these patients, as well as their diagnostic investigation, pattern of symptomatology, arterial territory of the ischemic lesion, and the potential underlying causes have been described in detail elsewhere4 and are provided as supplemental files (Table I and Figure I in the online-only Data Supplement). All patients had a CT at admission; 1401 (51.3%) patients had a second CT at 7 to 10 days, 729 (26.7%) had an MRI, and 208 (7.6%) had both a second CT and an MRI. From the 264 ESUS patients alive at discharge, the majority (n=194, 73.5%) were treated with an antiplatelet, 44 (16.7%) were treated with anticoagulant, 14 (5.3%) were treated with a combination of antiplatelet and anticoagulant, and 12 (4.5%) were not treated with an antithrombotic.
Fifty-nine (2.16%) patients were lost-to-follow-up immediately after hospital discharge. 248 (9.1%) were lost-to-follow-up at some point during their follow-up (ie, between 3 and 57 months). The mean follow-up of the overall and the ESUS populations were 30.5±24.1 and 38.7±22.1 months corresponding to 83 295 and 10 642 patient-years, respectively.
There were 890 (32.6%) deaths in the overall population during the follow-up corresponding to 12.8 deaths per 100 patient-years. In particular, there were 73 (26.5%) deaths in the ESUS group (8.2 deaths per 100 patient-years), 449 (51.6%) in cardioembolic (27 deaths per 100 patient-years), 106 (21.3%) in large-artery atherosclerotic (7.0 deaths per 100 patient-years), 78 (12.5%) in lacunar (4.1 deaths per 100 patient-years), 159 (43.4%) in undetermined stroke other than ESUS (22.0 deaths per 100 patient-years), and 25 (25%) in patients with miscellaneous causes of stroke (8.7 deaths per 100 patient-years). The cumulative probability of survival in the ESUS group was 65.6% (95% CI, 58.9%–72.2%) which was significantly higher compared with the cumulative probability in patients with cardioembolic stroke (38.8%, 95% CI, 34.9%–42.7%) and undetermined stroke other than ESUS (46.4%, 95% CI, 40.1%–52.7%), similar to the large-artery atherosclerotic group (72.8%, 95% CI, 68.3%–77.3%) and significantly lower compared with the lacunar group (81.0%, 95% CI, 77.1%–84.9%; Table, Figure 1A). In the Cox-regression analysis, there was significantly higher mortality risk in patients with cardioembolic stroke (adjusted hazard ratios, 1.67 [95% CI, 1.29–2.15], P<0.01) and in patients with undetermined stroke other than ESUS (adjusted hazard ratios, 1.87 [95% CI, 1.41–2.48], P<0.01) compared with ESUS (Figure 2).
There were 364 (13.3%) stroke recurrences in the overall population during the follow-up corresponding to 5.2 per 100 patient-years, of which there were 164 (45%) confirmed ischemic strokes and 9 (2.5%) confirmed hemorrhagic strokes, whereas for the rest 191 (52.5%), the stroke type was unknown. In particular, there were 60 (21.8%) recurrences in the ESUS group (6.8 per 100 patient-years), 117 (13.5%) in cardioembolic (7.0 per 100 patient-years), 83 (13.3%) in lacunar (4.4 per 100 patient-years), 65 (13.1%) in large-artery atherosclerotic (4.3 per 100 patient-years), 38 (10.4%) in undetermined stroke other than ESUS (5.3 per 100 patient-years), and 1 (1.0%) in patients with miscellaneous causes of stroke (0.3 per 100 patient-years). The cumulative probability of stroke recurrence in ESUS patients was 29.0% (95% CI, 22.3%–35.7%), which was similar to patients with cardioembolic stroke (26.8%, 95% CI, 22.1%–31.5%; Table, Figure 1B). In the Cox-regression analysis, ESUS patients had significantly higher risk of recurrence compared with all other stroke types, with the exception of cardioembolic strokes where a strong but statistically not significant trend was identified (Figure 2).
At the end of follow-up, 172 (62.5%) ESUS patients had favorable functional outcome compared with 280 (32.2%) in cardioembolic, 303 (60.9%) in large-artery atherosclerotic, 516 (82.2%) in lacunar, 151 (41.2%) in undetermined other than ESUS, and 71 (69.6%) in miscellaneous strokes. The distribution of functional outcome across the modified Rankin Scale in the different stroke types is presented in Figure 3.
There were 597 (21.9%) composite cardiovascular events in the overall population during the follow-up corresponding to 8.6 events per 100 patient-years. In particular, there were 80 (29.1%) events in the ESUS group (9.0 per 100 patient-years), 192 (22.1%) in cardioembolic (11.6 per 100 patient-years), 123 (19.8%) in lacunar (6.5 per 100 patient-years), 111 (22.3%) in atherosclerotic (7.3 per 100 patient-years), 73 (19.9%) in undetermined other than ESUS (10.1 per 100 patient-years), and 18 (17.6%) in patients with miscellaneous causes of stroke (6.3 per 100 patient-years). The cumulative probability of the composite cardiovascular event was similar across different stroke types (Table, Figure 1C). In the Cox-regression analysis, ESUS patients had similar risk of the composite cardiovascular event with all other stroke types, with the exception of patients with lacunar strokes who had significantly lower risk (adjusted hazard ratios 0.70 [95% CI, 0.52–0.94], P<0.05; Figure 2).
This is the first description of long-term outcomes of a large ESUS population defined according to the criteria proposed recently by the Cryptogenic Stroke/ESUS International Working Group.1 Mortality in ESUS patients was lower compared with patients with cardioembolic stroke and patients with undetermined stroke other than ESUS, but similar to patients with lacunar or large-artery atherosclerotic stroke. Functional outcome in ESUS patients was similar to large-artery atherosclerotic and better than in patients with cardioembolic. Stroke recurrence in ESUS was higher compared with all other stroke types, with the exception of cardioembolic strokes where a strong but statistically not significant trend was identified. The risk of composite cardiovascular event was similar to all other stroke types, with the exception of patients with lacunar strokes who had significantly lower risk.
Mortality was significantly higher in patients with cardioembolic stroke compared with ESUS patients. The fact that the risks of stroke recurrence and composite cardiovascular event were similar in these 2 groups shows that the difference in mortality was not driven by the rate of vascular events which occurred during follow-up. A more plausible explanation is that the difference in mortality was the result of different characteristics of the recurrent strokes between the 2 groups, that is, recurrent strokes may have been more severe or may have occurred in older age in patients with cardioembolic index stroke compared with patients with ESUS index stroke. This may be hypothesized based on the similar finding when comparing the severity of the index strokes: as we showed previously, the index stroke in patients with cardioembolic stroke was of higher severity (NIHSS, 13 versus 5) and occurred in older patients (76 versus 68 years) compared with ESUS.4 NIHSS and age are 2 important predictors of functional outcome10,11 and mortality,12 and if our hypothesis is correct, they could possibly explain the difference in mortality and functional outcome between ESUS and cardioembolic strokes. A similar explanation could perhaps explain also the difference in functional outcome between ESUS and cardioembolic strokes. Unfortunately, we do not have data about the severity of the recurrent strokes to confirm this hypothesis.
Covert AF was the potential etiopathogenetic mechanism in ≈44% of our ESUS patients.4 The vast majority of these patients was treated with an antiplatelet rather than an anticoagulant for secondary stroke prevention, that is, was inadequately treated given that anticoagulants are more efficacious than antiplatelets in patients with AF-related stroke.13 This seems to be the most plausible explanation for the finding of the present study that the risk of stroke recurrence was higher in ESUS patients compared with noncardioembolic stroke types. In addition, these results emphasize further the need for prolonged monitoring of heart rhythm in patients with cryptogenic stroke (as shown recently in the 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation After a Cerebral Ischemic Event study [EMBRACE]14 and in the Study of Continuous Cardiac Monitoring to Assess Atrial Fibrillation After Cryptogenic Stroke [CRYSTAL-AF]15). Also, our results seem to provide further support to the rationale of the randomized controlled trials of anticoagulants in ESUS patients (like the recently announced Randomized Evaluation in Secondary Stroke Prevention Comparing the Thrombin Inhibitor Dabigatran Etexilate Versus Aspirin in Embolic Stroke of Undetermined Source [RE-SPECT ESUS]3 and Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source [NAVIGATE ESUS]2 trials).
The main strengths of this first description of vascular outcomes of an ESUS population are the large size of the study population involving consecutive patients, the long follow-up, the assessment of hard clinical end points, including mortality and stroke recurrence, and the definition of ESUS according to the criteria proposed by the Cryptogenic Stroke/ESUS International Working Group.1
Nonetheless, this study is characterized by the inherent limitations of any retrospective analysis of prospectively collected data, such as collection and registration bias. Also, it is a single-center study which may have introduced selection bias. In addition, other potential confounders were not systematically assessed, such as crossover treatment allocations, adherence to antithrombotic, antihypertensive, and lipid-lowering drugs, and efficiency of anticoagulation in patients treated with vitamin K antagonists. In addition, continuous ECG monitoring was not automated, and it is possible that some AFs may have been missed. Also, the proportion of ESUS might have been larger if further work-up were performed in patients with cryptogenic strokes because of incomplete investigations. Finally, in approximately half of stroke recurrences, we were not able to classify whether the event was ischemic or hemorrhagic.
ESUS is a recent clinical entity1 and further research is warranted to implement it in clinical practice; the RE-SPECT-ESUS3 and NAVIGATE ESUS2 trials aim to identify the optimal antithrombotic treatment in this population. Also, it would be clinically useful to identify the predictors of covert AF in the ESUS population because this would obviously influence the choice of antithrombotic treatment. In addition, the prognostic validity of stroke prognostication scores like the ASTRAL score,10 the CHADS2 score,16,17 and the CHA2DS2-VASc score18,19 needs to be confirmed in the ESUS population. Also, it would be interesting to see whether outcomes differ between AF-related and non–AF related ESUS patients.
In conclusion, the mortality risk in ESUS patients is lower compared with patients with cardioembolic stroke despite similar rates of stroke recurrence and composite cardiovascular events. Also, the risk of stroke recurrence is higher in ESUS patients than in patients with noncardioembolic strokes, which could be a sign that the current antithrombotic strategy of treating ESUS patients with antiplatelets is suboptimal. In any case, the current findings suggest that ESUS patients are heterogeneous, requiring ongoing monitoring for stroke causes, risk factors, and preventive strategies.
Dr Ntaios was responsible for study concept, statistical analysis and interpretation, preparation of article, and study supervision. Dr Papavasileiou was responsible for statistical analysis and interpretation and critical revision of the article. Dr Milionis was responsible for critical revision of the article. Dr Makaritsis was responsible for critical revision of the article. Dr Vemmou was responsible for acquisition of data and critical revision of the article. Dr Koroboki was responsible for acquisition of data and critical revision of the manuscript. Dr Manios was responsible for critical revision of the manuscript. Dr Spengos was responsible for critical revision of the manuscript. Dr Michel was responsible for critical revision of the manuscript. Dr Vemmos was responsible for acquisition of data, statistical analysis and interpretation, critical revision of manuscript, and study supervision.
Dr Ntaios discloses honoraria from Boehringer-Ingelheim and Bayer. Dr Spengos discloses honorarium from Boehringer-Ingelheim. Dr Michel discloses research grants from the Swiss National Science Foundation and the Swiss Heart Foundation; speakers’ bureau from Bayer, Boehringer-Ingelheim, Covidien, and St. Jude Medical; Consultant or advisory board from Boehringer-Ingelheim, Bayer, Pfizer, Amgen, and Pierre-Fabre. All this money is used for research and education. The other authors report no conflicts.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.009334/-/DC1.
- Received March 4, 2015.
- Revision received June 6, 2015.
- Accepted June 9, 2015.
- © 2015 American Heart Association, Inc.
- 2.↵NAVIGATE ESUS. https://clinicaltrials.gov/ct2/show/nct02313909. Accessed February 1, 2015.
- 3.↵RE-SPECT ESUS. https://clinicaltrials.gov/ct2/show/nct02239120. Accessed February 1, 2015.
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