Kanjana S. Perera

Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update

Background and Purpose— Embolic stroke of undetermined source (ESUS) designates patients with nonlacunar cryptogenic ischemic strokes in whom embolism is the likely stroke mechanism. It has been hypothesized that anticoagulation is more efficacious than antiplatelet therapy for secondary stroke prevention in ESUS patients. We review available information about ESUS. Methods— Systematic literature review to assess the frequency of ESUS, patient features, and prognosis using PubMed from 2014 to present, unrestricted by language. Results— On the basis of 9 studies, the reported frequency of ESUS ranged from 9% to 25% of ischemic strokes, averaging 17%. From 8 studies involving 2045 ESUS patients, the mean age was 65 years and 42% were women; the mean NIH stroke score was 5 at stroke onset (4 studies, 1772 ESUS patients). Most (86%) ESUS patients were treated with antiplatelet therapy during follow-up, with the annualized recurrent stroke rate averaging 4.5% per year during a mean follow-up of 2.7 years (5 studies, 1605 ESUS patients). Conclusions— ESUS comprises about 1 ischemic stroke in 6. Patients with ischemic stroke meeting criteria for ESUS were relatively young compared with other ischemic stroke subtypes and had, on average, minor strokes, consistent with small emboli. Retrospective methods of available studies limit confidence in stroke recurrence rates but support a substantial (>4% per year) rate of stroke recurrence during (mostly) antiplatelet therapy. There is an important need to define better antithrombotic prophylaxis for this frequently occurring subtype of ischemic stroke.

Embolic strokes of undetermined source: Prevalence and patient features in the ESUS Global Registry:

Background Recent evidence supports that most non-lacunar cryptogenic strokes are embolic. Accordingly, these strokes have been designated as embolic strokes of undetermined source (ESUS). Aims We undertook an international survey to characterize the frequency and clinical features of ESUS patients across global regions. Methods Consecutive patients hospitalized for ischemic stroke were retrospectively surveyed from 19 stroke research centers in 19 different countries to collect patients meeting criteria for ESUS. Results Of 2144 patients with recent ischemic stroke, 351 (16%, 95% CI 15% to 18%) met ESUS criteria, similar across global regions (range 16% to 21%), and an additional 308 (14%) patients had incomplete evaluation required for ESUS diagnosis. The mean age of ESUS patients (62 years; SD = 15) was significantly lower than the 1793 non-ESUS ischemic stroke patients (68 years, p ≤ 0.001). Excluding patients with atrial fibrillation (n = 590, mean age = 75 years), the mean age of the remaining 1203 non-ESUS ischemic stroke patients was 64 years (p = 0.02 vs. ESUS patients). Among ESUS patients, hypertension, diabetes, and prior stroke were present in 64%, 25%, and 17%, respectively. Median NIHSS score was 4 (interquartile range 2–8). At discharge, 90% of ESUS patients received antiplatelet therapy and 7% received anticoagulation. Conclusions This cross-sectional global sample of patients with recent ischemic stroke shows that one-sixth met criteria for ESUS, with additional ESUS patients likely among those with incomplete diagnostic investigation. ESUS patients were relatively young with mild strokes. Antiplatelet therapy was the standard antithrombotic therapy for secondary stroke prevention in all global regions.

Global Survey of the Frequency of Atrial Fibrillation-Associated Stroke: Embolic Stroke of Undetermined Source Global Registry.

Background and Purpose— Atrial fibrillation (AF) is increasingly recognized as the single most important cause of disabling ischemic stroke in the elderly. We undertook an international survey to characterize the frequency of AF-associated stroke, methods of AF detection, and patient features. Methods— Consecutive patients hospitalized for ischemic stroke in 2013 to 2014 were surveyed from 19 stroke research centers in 19 different countries. Data were analyzed by global regions and World Bank income levels. Results— Of 2144 patients with ischemic stroke, 590 (28%; 95% confidence interval, 25.6–29.5) had AF-associated stroke, with highest frequencies in North America (35%) and Europe (33%) and lowest in Latin America (17%). Most had a history of AF before stroke (15%) or newly detected AF on electrocardiography (10%); only 2% of patients with ischemic stroke had unsuspected AF detected by poststroke cardiac rhythm monitoring. The mean age and 30-day mortality rate of patients with AF-associated stroke (75 years; SD, 11.5 years; 10%; 95% confidence interval, 7.6–12.6, respectively) were substantially higher than those of patients without AF (64 years; SD, 15.58 years; 4%; 95% confidence interval, 3.3–5.4; P<0.001 for both comparisons). There was a strong positive correlation between the mean age and the frequency of AF (r=0.76; P=0.0002). Conclusions— This cross-sectional global sample of patients with recent ischemic stroke shows a substantial frequency of AF-associated stroke throughout the world in proportion to the mean age of the stroke population. Most AF is identified by history or electrocardiography; the yield of conventional short-duration cardiac rhythm monitoring is relatively low. Patients with AF-associated stroke were typically elderly (>75 years old) and more often women.

Frequency and features of embolic stroke of undetermined source in young adults

Introduction The sources of emboli in those with embolic stroke of undetermined source may differ in old and young. We assessed the frequency, features and potential embolic sources of younger vs. older embolic stroke of undetermined source patients in the embolic stroke of undetermined source Global Registry. Patients and methods Cross-sectional study of consecutive patients over age 18 years, with recent ischaemic strokes at 19 centres conducted in 2013–2014. Characteristics of embolic stroke of undetermined source patients who aged ≤50 years were analysed and compared with embolic stroke of undetermined source patients who aged >50 years. Results Among 2144 patients with ischaemic stroke, 323 (15.1%, 95% confidence interval: 13.6–16.7%) were ≤50 years old and, 1821 >50 years. 24% (n = 78) of young vs. 15% (n = 273) of older patients met embolic stroke of undetermined source criteria. The mean age of young embolic stroke of undetermined source patients was 40 years (standard deviation +/−9), 33% were women and the most prevalent vascular risk factor was hypertension (38%). Conventional vascular risk factors were less frequent in younger embolic stroke of undetermined source patients. Fewer young embolic stroke of undetermined source patients (63%) had potential minor risk embolic sources identified vs. older embolic stroke of undetermined source patients (77%) (p = 0.02). Stroke severity on admission was similar in younger vs. older patients (National Institute of Health Stroke Scale (NIHSS) 3 vs. 4, p = 0.06). Discussion Young embolic stroke of undetermined source patients comprise an important subset of ischaemic stroke patients around the world. Severity of stroke on admission and 30-day mortality rates are similar among young and older patients. However, there are important differences between younger vs. older embolic stroke of undetermined source patients with respect to risk factors, and potential embolic sources that could affect response to anticoagulants vs. antiplatelet therapies. Conclusion This study provides a benchmark for the global frequency and characteristics of young embolic stroke of undetermined source patients and shows consistent high frequency of embolic stroke of undetermined source in young adults.

Predictors of Mortality in Patients With Atrial Fibrillation (from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ACTIVE A])

The mortality rate of most patients with atrial fibrillation (AF) exceeds the stroke rate, but predictors of mortality have not been well defined. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A) recruited patients with AF who were unsuitable to receive vitamin K-antagonists and were randomized to aspirin alone versus aspirin plus clopidogrel. We investigated independent predictors of all-cause mortality by multivariable Cox regression analysis and explored interactions with assigned antiplatelet therapy. Of the 7,554 patients enrolled with a mean age of 71 years, 1,687 (22%) patients died during the median follow-up of 3.7 years (annualized mortality rate 6.4%/year). Assignment to dual antiplatelet therapy had no effect on mortality (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90 to 1.1) or on vascular and nonvascular death. Independent predictors of all-cause mortality were advancing age, lower body mass index (HR 1.4 < 25 kg/m2, 95% CI 1.3 to 1.6), diabetes mellitus, Latin American ethnicity (HR 1.4, 95% CI 1.1 to 1.6), previous stroke or transient ischemic attack, peripheral artery disease, increased resting heart rate (HR 1.3, 95% CI 1.1 to 1.4 per 30 bpm), lower diastolic blood pressure, coronary artery disease, heart failure, left ventricular systolic dysfunction, hemoglobin level of <13 mg/dl, and reduced estimated glomerular filtration rate. In conclusion, in this large clinical trial cohort of patients with AF, treatment with clopidogrel plus aspirin versus aspirin monotherapy did not affect all-cause mortality, vascular death, or nonvascular death. Novel independent predictors of increased mortality included lower diastolic blood pressure and Latin American ethnicity.

Stroke type and severity in patients with subclinical atrial fibrillation: An analysis from the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT)

Background: The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) demonstrated that subclinical atrial fibrillation (SCAF) was associated with a 2.5‐fold increased risk of stroke. However, the absolute stroke rate was only 1.7% per year and fewer than 20% patients with stroke had SCAF in the preceding 30 days. This raises the possibility that SCAF is merely a risk marker for stroke rather than the cause. Systematic characterization of stroke subtypes among patients with SCAF would help clarify this issue. Methods: All ischemic strokes that occurred in the ASSERT trial were blindly adjudicated by stroke neurologists, classified as cortical versus subcortical, and subtyped using modified TOAST criteria. Stroke severity was measured using the modified Rankin Score. Results: Of the 44 participants who had an ischemic stroke, 14 had SCAF before stroke. Among patients with SCAF who had stroke, 57% of strokes (n = 8) were judged to be cardioembolic, 36% to be lacunar (n = 5), and 7% (n = 1) to be large artery disease. However, of 5 patients who had SCAF detected within 30 days before their index stroke, 4 patients had a cardioembolic stroke. The average duration of SCAF in these 4 patients was 6.0 ± 6.1 h/d. The modified Rankin score at 30 days was similar between patients with (2.7 ± 2.3) and without SCAF (2.3 ± 2.0; P = .68). Conclusions: In patients with SCAF and stroke, SCAF seems probably causal in many cases; however, in more than 40%, it seems to be acting only as a risk marker.

Age disparity in diagnostic evaluation of stroke patients: Embolic Stroke of Undetermined Source Global Registry Project

Introduction: Incomplete evaluation of stroke patients may result in an unclear diagnosis. Our objective was to determine if older stroke patients more often undergo incomplete diagnostic evaluations versus younger patients in an international cohort. Patients and methods: The Embolic Stroke of Undetermined Source Global Registry was a retrospective cohort of consecutive stroke patients evaluated at 19 stroke centers in 19 countries. Diagnostic evaluation was considered as complete if the patient had, at a minimum, brain computed tomography or magnetic resonance imaging with evidence of infarction, extracranial and intracranial vascular imaging, electrocardiography, ≥24 h of cardiac rhythm monitoring, and echocardiography. Patients were diagnosed with Embolic Stroke of Undetermined Source if brain imaging confirmed a nonlacunar infarction and no stroke etiology was determined after complete evaluation. Completeness of evaluation was compared between patients ≥75 versus <75 years old. Results: The registry included 2132 patients with recent ischemic stroke during 2013–2014, of which 349 were diagnosed with Embolic Stroke of Undetermined Source. Embolic Stroke of Undetermined Source patients ≥75 years were less likely to undergo brain magnetic resonance imaging (74% versus 89%, p = 0.001), transesophageal echocardiography (22% versus 39%, p = 0.005), and combination transthoracic and transesophageal echocardiography (16% versus 32%, p = 0.005) compared with Embolic Stroke of Undetermined Source patients <75 years. Discussion: Our study has identified an international age disparity in fundamental diagnostic testing for older patients with stroke of unknown etiology. Some testing biases were affected by geographic location (e.g., brain MRI was less frequently used in European ESUS patients), whereas other testing was implemented less frequently in the elderly regardless of location (e.g., transesophageal echocardiogram). Conclusion: Older patients in this international cohort had less sophisticated diagnostic testing for stroke, despite advanced age being well established as an independent risk factor for recurrent stroke. This was a global problem and further investigations are warranted to explore the cause.

What's new in stroke? Phase III randomized clinical trials of 2012-2014

Background Randomized clinical trials provide the most reliable evidence to guide the management of stroke and threatened stroke and reflect the interests of the stroke research community. The spectrum of phase III randomized clinical trials in stroke has not been previously characterized. Methods Phase III stroke randomized clinical trials published between 2012 and 2014 were identified by search of the Cochrane Central Register of Controlled Trials supplemented by recent publications known to the co-authors. Results Thirty-four randomized clinical trials were included involving 85 770 participants: 20 acute stroke randomized clinical trials (32 590 patients), 11 stroke prevention randomized clinical trials (28 964 patients), and three randomized clinical trials in which stroke was a major component of a composite primary outcome involving nonstroke patients (24 216 patients). Twenty-two (65%) trials were international, and eight (24%) were industry sponsored. Drugs were tested in 21 (62%) randomized clinical trials, with devices (n = 9), surgery (n = 3), and diet (n = 1) in the remainder. Thirteen (38%) randomized clinical trials were stopped early: seven for futility, three for efficacy, two for harm, and one for budget/administrative reasons. Overall, the results of seven (21%) randomized clinical trials were positive, five (15%) equivocal, 18 (53%) negative, and four (12%) inconclusive. Considering positive and definitively negative randomized clinical trials testing currently used interventions, 11 (32%) randomized clinical trials have direct implications for clinical management. Conclusions The diversity of interventions, high-quality, and worldwide origins of recently published phase III randomized clinical trials reflects a vibrant international stroke research community. The current generation of stroke randomized clinical trials provides important guidance for stroke prevention and acute stroke care.