American Heart Association

prevention

Stroke Secondary to Atherosclerotic Aortic Arch Plaques: A Reminder

Victor J. Del Brutto, MD

Ntaios G, Pearce LA, Meseguer E, Endres M, Amarenco P, Ozturk S, et al. Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial. Stroke. 2019

When it comes to establishing the mechanism of injury in a stroke victim, the label “unknown/undetermined” deprives the patient of receiving the appropriate prognosis and strategy for secondary prevention. One-fourth of ischemic strokes are identified as cryptogenic without a definite understanding of the cause, and a sizable proportion of them will fit into the concept of embolic stroke of undetermined source (ESUS). The cause of ESUS could be an under-recognized cardiac source or a non-stenosing arterial lesion. Despite seminal studies in the 1990s that have identified a causal association between protruding plaques in the aortic arch and ischemic stroke, aortic arch atherosclerosis (AAA) is often overlooked during routine stroke work-up, thus falling into the category of stroke of undetermined etiology.

The current manuscript published by Ntaios and colleagues reports the exploratory analysis of the subgroup of individuals who participated 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) trial and underwent transesophageal echocardiogram (TEE) for evaluation of AAA. The authors found a prevalence of 19% of AAA among patients with ESUS, from which one-third (8% of the total cohort) were considered to have high-risk complex plaques as defined by the presence of ulceration, thickness greater than 4 mm, or presence of a mobile thrombus. As noticed by the authors, the prevalence of AAA might be underestimated due to lower atherosclerotic risk factors in those who underwent TEE. Increasing age, diabetes mellitus and aortic valve disease, as well as geographic region (east Asia and eastern Europe), were significant determinants of AAA in the multivariable analysis. In addition, chronic infarcts and multi-territorial infarcts were associated with AAA, arguing against the common belief that multifocal strokes are exclusively cardioembolic. There was a non-significant trend for higher rate of stroke recurrence in patients with complex AAA (7.2% annualized rate) when compared to those without AAA (5.6% annualized rate). Data from this analysis was merged with two other randomized controlled trials to construct a meta-analysis of anticoagulation versus antiplatelet therapy in patients with cryptogenic stroke and AAA. The meta-analysis found no significant difference in the rate of stroke recurrence between the two antithrombotic approaches.

ESUS Subpopulation with Carotid Atherosclerosis: Do the Overall Results Differ?

Piyush Ojha, MBBS, MD, DM

Ntaios G, Swaminathan B, Berkowitz SD, Gagliardi RJ, Lang W, Siegler JE, et al. Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis. Stroke. 2019;50:2477–2485.

Embolic stroke of undetermined source (ESUS), accounting for approximately 20% of all ischemic strokes, has been a hotly debated topic in the stroke community. The term encompasses cryptogenic strokes believed to be embolic in origin, which are not lacunar and without a cardiac or proximal large artery source. Patients qualifying as ESUS show a lot of pathophysiological heterogeneity, reflecting in the lack of sufficient evidence of trend towards a particular class of drugs and hence difficult to formulate a pharmacological plan. Multiple possible sources of emboli in these patients may explain the non-uniform response to anticoagulation over antiplatelets.

Several studies (including two major trials, NAVIGATE ESUS and RE-SPECT ESUS) have compared direct oral anticoagulants and aspirin in patients with recent ESUS for secondary stroke prevention, and failed to show any benefit of anticoagulation over antiplatelets, with associated higher risk of bleeding.

Article Commentary: “Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non–Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention”

Yan Hou, MD, PhD

Paciaroni M, Agnelli G, Caso V, Silvestrelli G, Seiffge DJ, Engelter S, et al. Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non–Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention: The RENo Study. Stroke. 2019;50:2168–2174

Non–vitamin K antagonist oral anticoagulants (NOACs) are currently recommended as the stroke prevention for patients with nonvalvular atrial fibrillation (AF). Despite compliance with NOAC, patients with nonvalvular AF may still experience ischemic cerebrovascular events. The RENO study is a multicenter case-control study to identify the etiology and risk factors for ischemic events occurring during NOACs (dabigatran, apixaban, rivaroxaban, or edoxaban) therapy in patients with nonvalvular AF.

The study included 713 cases (641 ischemic strokes and 72 TIA) and 700 controls (patients did not experience cerebrovascular events). Cases who did not guarantee compliance or who had suspended NOAC at least 24 hours before the cerebrovascular event were excluded. Most strokes (64%) occurring during NOACs therapy were caused by cardioembolism, but about 30% of strokes were found due to non-cardioembolic etiology. Among the risk factors (age, sex, hypertension, diabetes mellitus, current cigarette smoking, hyperlipidemia, ischemic heart disease, peripheral artery disease, alcohol abuse, obesity, previous stroke/transient ischemic attack, creatinine clearance, duration of NOAC treatment, doses of NOACs, AF classification, CHA2DS2-VASc score, left atrial enlargement on echo), off-label low doses of NOACs (OR, 3.18), atrial enlargement (OR, 6.64), hyperlipidemia (OR, 2.40), and high CHA2DS2-VASc score (OR, 1.72 for each point increase) were associated with ischemic events. The reasons for prescribing low doses of NOAC included fear of bleeding, history of bleeding, concomitant antiplatelet therapy, recurrent falls, amyloid angiopathy, anemia, history of cancer, age, gastrointestinal discomfort, and hypertension or other causes. Low clearance of creatinine (OR, 0.98 for 1 mL/min increase) and high CHA2DS2-VASc score (OR, 1.35 for each point increase) were also found associated with prescription of low-dose NOACs.   

Interview: Professor Dr. Hans-Christoph Diener on “Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source”

Professor Dr. Hans-Christoph Diener

Professor Dr. Hans-Christoph Diener

A conversation with Professor Dr. Hans-Christoph Diener, Faculty of Medicine at the University of Duisburg-Essen, on the recently published randomized clinical trials assessing the safety and efficacy of non-vitamin K oral anticoagulants (NOACs) in patients with embolic strokes of undetermined source (ESUS), and on the future of anticoagulation in the secondary prevention of cryptogenic cerebral ischemia.

Interviewed by Aristeidis H. Katsanos, Research Fellow at the Department of Neurology, Ruhr University of Bochum.

They will be discussing the paper “Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source,” published in the May 16, 2019 issue of the New England Journal of Medicine.

Dr. Katsanos: Can you please summarize for the readers of the blog the main hypothesis and findings of the RE-SPECT ESUS trial?

Prof. Diener: Patients with ESUS (embolic stroke of undetermined source) have high risk of recurrent stroke, and the risk of recurrent stroke per year is about 5%. We assume that the majority of these recurrent strokes have an embolic source. Therefore, oral anticoagulation should be superior to antiplatelet therapy in patients with ESUS.

Defining the Optimal Duration of Dual Antiplatelet Therapy after Ischaemic Stroke or Transient Ischaemic Attack

Alan C. Cameron, MB ChB, BSc (Hons), MRCP

Rahman H, Khan SU, Nasir F, Hammad T, Meyer MA, Kaluski E. Optimal Duration of Aspirin Plus Clopidogrel After Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis. Stroke. 2019;50:947–953.

Through a systemic review and meta-analysis of 10 randomised trials comparing dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel versus aspirin alone in over 15,000 patients with ischaemic stroke (IS) or transient ischaemic attack (TIA), Rahman and colleagues demonstrate that £1 month of DAPT reduces the relative risk of recurrent IS by almost 50% with no increase in major bleeding. In contrast, £3 months of DAPT reduces IS by 28% but increases major bleeding, whilst >3 months of DAPT does not reduce recurrent IS and increases major bleeding. The reduction in risk of recurrent IS with £3 months of DAPT may be due to substantial early benefit within the first few days or weeks. The POINT and CHANCE trials suggest maximum benefit is achieved when DAPT is initiated within the first 24 hours after minor IS or high-risk TIA, which highlights a need for services that allow patients to be reviewed within this timeframe.

The risk of bleeding was greater in aspirin naïve patients in analysis of the EXPRESS and FASTER studies, highlighting a need to screen carefully for bleeding risk factors in this group of patients. Better blood pressure control combined with screening and management of bleeding risk factors is essential to ensure benefits from antiplatelet therapy are not offset by increased bleeding. Overall, we can be confident that DAPT is most effective and safe in the early weeks after minor IS or high-risk TIA to reduce the risk of recurrence.

A New Look at ICAS from the SAMMPRIS Data

Richard Jackson, MD

Wabnitz AM, Derdeyn CP, Fiorella DJ, Lynn MJ, Cotsonis GA, Liebeskind DS, et al. Hemodynamic Markers in the Anterior Circulation as Predictors of Recurrent Stroke in Patients With Intracranial Stenosis. Stroke. 2018;50:143–147.

Ashley M. Wabnitz MD et al. introduced the finding that despite the superiority of aggressive medical management (AMM) in intracranial atherosclerotic arterial stenosis (ICAS), 15% of patients still had primary end point of stroke during a median follow up of 32.4 years.

The study was a post-hoc analysis of 154 patients of the total 227 patients with intracranial stenosis randomized to AMM, 49 ICA and 105 MCA. Non-MCA territory infracts and stenosis were excluded, as well as 53 patients for baseline imaging not corresponding to the qualifying event. All patients included in SAMMPRIS had angiographically verified 70-99% stenosis of ICA, MCA, vertebral or basilar arteries. Infarct patterns were classified into core, perforator, internal borderzone, or cortical borderzone based on published templates from a retrospective analysis of WASID lesions. Interobserve agreement for infarct patterns was k=0.8. Evaluation of collaterals was assessed by a validated scale by the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology; however, collaterals were assessed as impaired versus not impaired despite the validated scale having 4 grades.

Carotid Endarterectomy is Safe After Intravenous Thrombolysis

Mohammad Anadani, MD

Ijäs P, Aro E, Eriksson H, Vikatmaa P, Soinne L, Venermo M. Prior Intravenous Stroke Thrombolysis Does Not Increase Complications of Carotid Endarterectomy. Stroke. 2018

The benefit of carotid endarterectomy (CEA) for symptomatic carotid stenosis is well established; however, the optimal timing of procedure after stroke is still a matter of debate. Although few studies showed an increased risk of periprocedural stroke and death with early CEA (within 48 hours), others did not. In patients who receive intravenous thrombolysis (IVT), CEA is often delayed due to a concern of increased risk of intracerebral hemorrhage (ICH). However, this delay may result in a theoretical increase in risk of recurrent stroke while waiting for CEA.

In this study, Ijäs and colleagues underwent a retrospective registry study to investigate the safety and optimal timing of CEA after IV thrombolysis (IVT).

Omega-3 Fatty Acid Biomarkers: A Potential Marker of Incident Ischemic Stroke Risk?

Mark R. Etherton, MD, PhD

Saber H, Yakoob MY, Shi P, Longstreth Jr. WT, Lemaitre RN, Siscovick D, et al. Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts. Stroke. 2017

In this entry, I discuss a recent publication by Hamidreza Saber and colleagues regarding the relationship of circulating omega-3 fatty acids levels and incident ischemic stroke.

The authors set out to clarify the impact of omega-3 fatty acids on ischemic stroke incidence. Observational studies of self-reported omega-3 fatty acid consumption and omega-3 fatty acid supplementation trials have previously produced disparate results. As such, the authors quantified circulating omega-3 fatty acid levels in association with ischemic stroke incidence from 3 separate prospective cohort studies.

The authors used data from the Cardiovascular Health Study (CHS), Nurses’ Health Study (NHS), and Health Professionals Follow-Up Study (HPFS). Each of these three cohort studies represent distinct patient populations, which does influence the overall generalizability of these results. CHS is a prospective cohort study of adults aged 65 years and older. The NHS is a prospective cohort study of female registered nurses 30 to 55 years of age. Lastly, HPFS is a cohort study of U.S. male health professionals 40 to 75 years of age. Most participants in each study were white (88% in CHS, for example). The analysis of NHS and HPFS was based on a nested case-control study of age and vascular-risk factor matched controls. Ischemic stroke was subdivided into atherothrombotic, cardioembolic, or other. At the time of enrollment in the studies, blood samples were collected and stored for later analysis of omega-3 fatty acid levels. Of note, there were some differences in collection and storage of blood samples for fatty acid analysis between the three studies.

Author Interview: George Ntaios, MD

George Ntaios

George Ntaios

A conversation with George Ntaios, MD, MSc (ESO Stroke Medicine), PhD, Assistant Professor of Internal Medicine, Department of Medicine, University of Thessaly

Interviewed by Stephen Makin, PhD, Clinical Lecturer at Glasgow University

They will be discussing the paper, “Real-World Setting Comparison of Nonvitamin-K Antagonist Oral Anticoagulants Versus Vitamin-K Antagonists for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis,” being published in the September 2017 issue of Stroke.

Dr. Makin: Thank you for taking the time to talk to us.

Prof. Ntaios: Thank you for the invitation to discuss our study.

Dr. Makin: Could I begin by asking you to summarize your study and its findings?

Prof. Ntaios: We aimed to summarize all available evidence from high-quality real-world observational studies about the efficacy and safety of non-vitamin-K-oral-anticoagulants (NOACs) compared to vitamin-K-antagonists (VKAs) in patients with atrial fibrillation (AF). Based on 28 identified studies, we found that dabigatran, rivaroxaban and apixaban, as compared to VKAs, are associated with lower risk of intracranial haemorrhage and similar risk of ischemic stroke and ischemic stroke or systemic embolism; apixaban and dabigatran with lower risk of mortality; apixaban with fewer gastrointestinal and major haemorrhages; dabigatran and rivaroxaban with higher risk of gastrointestinal haemorrhage; and dabigatran and rivaroxaban with a similar rate of myocardial infarction.

Elevated Blood Pressure Significantly Associated with Risk of Vascular Dementia

Danny R. Rose, Jr., MD


Vascular dementia is the second most common cause of dementia, but many aspects of the disease are poorly understood. In particular, there is conflicting evidence regarding the relationship between blood pressure and vascular dementia. Elevated blood pressure in midlife has been found to have a positive association with future development of dementia, but several other studies have found low blood pressure in old age to be associated with an increased risk of dementia. One possible explanation of these findings is that it represents “reverse causality,” meaning vascular dementia is responsible for low blood pressure by decreasing sympathetic drive. Blood pressure medication may also play a confounding role in this association. Emdin et al. sought to further clarify this association by conducting an analysis of 4.28 million individuals without vascular disease or dementia, supplemented with an analysis of a prospective population-based cohort of patients with TIA and stroke.

The study included patients from age 30 to 90 and excluded patients with pre-existing cardiovascular disease to minimize the potential of reverse causality related to advanced age and cardiovascular disease causing reduced blood pressure, respectively. The endpoint of the primary analysis was an inclusive definition of vascular dementia based on ICD 10 coding and was inclusive of patients with co-existing Alzheimer’s disease. Secondary analysis excluded these patients and excluded patients treated with medications commonly used to treat AD. The first four years of follow-up were excluded in the primary analysis to mitigate the effect of patients with undiagnosed dementia. Cox models, stratified by practice, were used to determine hazard ratios for the association for clustering of patients by practice. The primary analysis was adjusted for age, sex, body mass index and smoking status. The Oxford Vascular Study cohort was used to confirm findings independently.

Out of a cohort of 4.28 million individuals free of vascular disease and dementia, 14,934 cases were reported to have vascular dementia. After excluding for presentations during the first four years of follow-up, 11,114 cases were included. The association between usual SBP and risk of vascular dementia followed a linear progression within the age groups of 30-50 and 51-70. The age group of 71-90 did not show a significant association. The strength of association decreased with increasing age category. Overall for individuals aged 70 years or less at baseline, 20 mm Hg higher usual SBP was associated with a 26% higher risk of vascular dementia (HR 1.26 CI 1.17, 1.34). Significant negative associations with systolic and diastolic blood pressures were observed for the age group 71-90, but after excluding for the first eight years of follow-up, no significant association was observed. Adjusting for patients in the primary care cohort that had TIA and stroke events reduced the HR to 1.18, indicating that 30% of the excess risk of vascular dementia per 20mm Hg higher SBP is mediated through risk of future stroke and TIA. The OXVASC cohort did not show a relationship between the most recent SBP or DBP in patients relative to their diagnosis of new dementia, but did show significant positive associations with DBP and SBP in 5-9 years prior to the TIA/stroke and particularly 10-20 years prior.

This study supports prior positive associations between blood pressure in mid-life and vascular dementia and also suggests that elevated blood pressure attributes a significant risk for the development of vascular dementia at least until the age of 70. The authors’ rationale for excluding confounders in the cohort appears to be sound and had the intended effect of strengthening the associations studied. The study refutes previous reports of a negative association with blood pressure and vascular dementia in the elderly, likely in part due to the aforementioned adjustments, strengthening the authors’ hypothesis of reverse causality. This study represents by far the largest analysis of the association between blood pressure and risk of vascular dementia and although it is susceptible to limitations related to the diagnosis of dementia in a primary care setting, it represents a significant advancement in our understanding of the complex pathophysiology of vascular dementia.