American Heart Association

prevention

The Effects of Age on Traditional Risk Factors for Stroke

Wern Yew Ding, MBChB

Ahmed A, Pinto Pereira SM, Lennon L, Papacosta O, Whincup P, Wannamethee G. Cardiovascular Health and Stroke in Older British Men: Prospective Findings From the British Regional Heart Study. Stroke. 2020.

I read with interest the cohort study by Ahmed and colleagues, which sought to evaluate the influence of cardiovascular health on stroke risk. The authors used data from the British Regional Heart Study to identify men with no prior history of cardiovascular disease at baseline who were then re-examined 20 years later. Cardiovascular health was assessed using 7 traditional health metrics, including smoking status, body mass index, level of physical activity, dietary patterns, total cholesterol, blood pressure, and fasting glucose. Outcome data comprised of fatal and non-fatal stroke.

At baseline, there was a total of 7274 men with a mean age of 50 years. As highlighted by the authors, blood pressure was the only parameter at both baseline and 20-year follow-up that was consistently associated with stroke risk in this population. Better levels of physical activity and smoking status at baseline were related to reduced stroke risk, but similar results were not observed using data from 20-year follow-up when the mean age was 69 years. Overall, the authors concluded that stroke prevention strategies should prioritize blood pressure control and other risk factors.

Fire and Forget, or Treat to Target?

Vera Sharashidze, MD
@SharashidzeVera

Endres M, Kernan WN. LDL (Low-Density Lipoprotein) Cholesterol Below 70: Good to Go! Stroke. 2020;51:2276–2278.

The current guidelines of the American Heart Association/American Stroke Association (AHA/ASA) recommend high-intensity statin therapy initiation or continuation with the aim of achieving a 50% or greater reduction in low-density lipoprotein cholesterol (LDL-C) levels in patients with stroke who are 75 years of age or younger. In patients who are unable to tolerate high-intensity therapy, moderate intensity statins should be started with the goal of achieving a 30% to 49% reduction in LDL-C levels.

The first evidence that stroke patients could benefit from statins came out from the Heart Protection Study that was a double-blind, randomized, placebo-controlled study in which patients received either placebo or simvastatin 40 mg daily. This study showed that in patients with high risk for cardiovascular disease, cholesterol lowering with simvastatin was associated with reduction in all-cause mortality and major vascular event risk.

Article Commentary: “Impact of Multiple Social Determinants of Health on Incident Stroke”

Jennifer Harris, MD
@JenHarrisMD

Reshetnyak E, Ntamatungiro M, Pinheiro LC, Howard VJ, Carson AP, Martin KD, Safford MM. Impact of Multiple Social Determinants of Health on Incident Stroke. Stroke. 2020.

Health disparities have emerged as one of the great challenges to our health care system and a critical concern for the health of our U.S. population. Among the most dramatic disparities are seen in cardiovascular disease (CVD). Disparities in stroke outcomes are also widely reported in the literature. Whereas stroke rates in the U.S. have declined over the last decades, stroke mortality rates in nonwhites (predominantly Non-Hispanic (NH) Blacks) have remained substantially higher than in NH Whites [1]. This disparity may be due to differences in stroke incidence, with relative risk=2.77 (95%CI 1.37-5.62) between NH blacks and NH whites among those <55 years of age and 2.23 (95%CI 1.66-3.00) in those >55 years of age [2]. Data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study suggest that the prevalence of stroke risk factors, particularly hypertension and diabetes, while clearly higher among NH Blacks, account for only 40% of the Black-White disparities in stroke incidence. The reasons for the remaining 60% are elusive [3].

Various socioeconomic determinants of health have been shown to predispose patients to developing CVD and stroke. According to national health disparities data for cardiovascular disease outcomes, there are several social determinants of health (SDOH) that may help explain stroke disparities. SDOH are defined as economic and social conditions that influence individual and group differences in health status. SDOH include low education, low income, living in an impoverished area, social isolation, and lacking health insurance, among others. To further investigate the association between incident stroke and SDOH, Reshetnyak et al. analyzed data from the REGARDS study to determine the individual and cumulative effect of SDOH on incident stroke.

PICASSO Trial: The Shades of Anti-Platelets

Rachel Forman, MD

Kim BJ, Kwon SU, Park J-H, Kim Y-J, Hong K-S, Wong LKS, et al. Cilostazol Versus Aspirin in Ischemic Stroke Patients With High-Risk Cerebral Hemorrhage: Subgroup Analysis of the PICASSO Trial. Stroke. 2019.

One of the most common discussions on any given stroke service involves the balance of preventing ischemic strokes (IS) and preventing intracranial hemorrhage (ICH). Whether it is about resuming anticoagulation in a hemorrhage patient or resuming aspirin in a patient with cerebral amyloid angiopathy there is always much debate on timing and decisions.  The decision to resume aspirin in a patient with an MRI full of cerebral microbleeds (CMBs) is often difficult. This paper looks into an alternative agent, cilostazol, for reducing hemorrhage risk in patients who warrant anti-platelet therapy. The background of the study is that cilostazol has shown to have less hemorrhagic events than aspirin among patients with ischemic stroke. 

The PICASSO trial (Prevention of Cardiovascular Events in Asian Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage) was an Asian trial that aimed to determine which antiplatelet agent is more effective and safe in patients with prior hemorrhagic stroke or multiple CMBs. Cilostazol is an antiplatelet agent with additional vasodilatory effects. The trial, published in 2018, showed that cilostazol was noninferior to aspirin in preventing a composite of major vascular events; however, it failed to reduce ICH. This paper reviews the subgroup analysis to identify patients who would show greater benefit with cilostazol. 

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.