Today, I review, link to, and excerpt from 2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Stroke. 2024 Dec;55(12):e344-e424. doi: 10.1161/STR.0000000000000475. Epub 2024 Oct 21.
All that follows is from the above resource.
Abstract
Aim: The “2024 Guideline for the Primary Prevention of Stroke” replaces the 2014 “Guidelines for the Primary Prevention of Stroke.” This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke.
Methods: A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed.
Structure: Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association’s Life’s Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.
Keywords: AHA Scientific Statements; guideline; hemorrhagic stroke; ischemic stroke; stroke.
Top 10 Take-Home Messages
1. From birth to old age, every person should have access to and regular visits with a primary care health professional to identify and achieve opportunities to promote brain health.2. Screening for and addressing adverse social determinants of health are important in the approach to prevention of incident stroke. This updated guideline includes an orientation to social determinants of health, acknowledging its impact on access to care and treatment of stroke risk factors. Therefore, screening for social determinants of health is recommended in care settings where at-risk stroke patients may be evaluated, with the acknowledgment that evidence-based interventions to address adverse social determinants of health are evolving.3. The Mediterranean diet is a dietary pattern that has been shown to reduce the risk of stroke, especially when supplemented with nuts and olive oil. However, low-fat diets have had little impact on reducing the risk. This guideline recommends that adults with no prior cardiovascular disease and those with high or intermediate risk adhere to the Mediterranean diet.4. Physical activity is essential for cardiovascular health and stroke risk reduction. This guideline includes a summary of high-quality data showing that prolonged sedentary behavior during waking hours is associated with an increased risk of stroke. Therefore, we provide a new recommendation for screening for sedentary behavior and counseling patients to avoid being sedentary, as well as a call for new studies of interventions to disrupt sedentary behavior. This is in addition to the recommendation to engage in regular moderate to vigorous physical activity.5. Glucagon-like protein-1 receptor agonists have been shown to be effective not only for improving management of type 2 diabetes but also for weight loss and lowering the risk of cardiovascular disease and stroke. On the basis of these robust data, we provide a new recommendation for the use of these drugs in patients with diabetes and high cardiovascular risk or established cardiovascular disease.6. Blood pressure management is critical for stroke prevention. Randomized controlled trials have demonstrated that treatment with 1 antihypertensive medication is effective for reaching the blood pressure goal in only ≈30% of participants and that the majority of participants achieved the goal with 2 or 3 medications. Therefore, ≥2 antihypertensive medications are recommended for primary stroke prevention in most patients who require pharmacological treatment of hypertension.7. Antiplatelet therapy is recommended for patients with antiphospholipid syndrome or systemic lupus erythematosus without a history of stroke or unprovoked venous thromboembolism to prevent stroke. Patients with antiphospholipid syndrome who have had a prior unprovoked venous thrombosis likely benefit from vitamin K antagonist therapy (target international normalized ratio, 2–3) over direct oral anticoagulants.8. Prevention of pregnancy-related stroke can be achieved primarily through management of hypertension. Treatment of verified systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg during pregnancy and within 6 weeks postpartum is recommended to reduce the risk of fatal maternal intracerebral hemorrhage. In addition, adverse pregnancy outcomes are common and are associated with chronic hypertension and an elevated stroke risk later in life. Therefore, screening for these pregnancy outcomes is recommended to evaluate for and manage vascular risk factors, and a screening tool is included to assist with screening in clinical practice.9. Endometriosis, premature ovarian failure (before 40 years of age), and early-onset menopause (before 45 years of age) are all associated with an increased risk for stroke. Therefore, screening for all 3 of these conditions is a reasonable step in the evaluation and management of vascular risk factors in these individuals to reduce stroke risk.10. Understanding transgender health is essential to truly inclusive clinical practice. Transgender women taking estrogens for gender affirmation have been identified as having an increased risk of stroke. Therefore, evaluation and modification of risk factors could be beneficial for stroke risk reduction in this population.
1.4. Scope of the Guideline
This 2024 guideline parallels the 2014 AHA/ASA “Guidelines for the Primary Prevention of Stroke”13 in addressing both ischemic and hemorrhagic strokes.
The aim of the present guideline is to provide clinicians with evidence-based recommendations for prevention of the first stroke.Many guidelines have been publish Many guidelines have been published in the past several years that are focused specifically on the management of common stroke risk factors. Therefore, this guideline will not cover the following topics:• AF (covered in the 2019 American College of
Cardiology [ACC]/AHA AF focused update)14;
• Congenital heart disease (covered in the 2018
ACC/AHA guideline)15;
• Valvular heart disease (covered in the 2020 ACC/
AHA guideline)16;
• Prevention of stroke in the setting of acute coronary
syndromes (covered in the 2014 ACC/AHA guideline
for non–ST-segment–elevation myocardial infarction
[MI], and the 2017 ACC/AHA clinical performance
measures for ST-segment–elevation MI and non–STsegment–elevation MI)17,18;
• Subarachnoid hemorrhage (covered in the 2023
AHA/ASA guideline)19;
• Pediatric stroke, except as it pertains to sickle cell disease (SCD)20;• Secondary prevention of stroke (covered in the 2021
AHA/ASA guideline)21;
• Cerebral venous thrombosis (covered in the 2024
AHA scientific statement)22,23; and
• Pathways for the implementation and dissemination
of guideline recommendations in clinical practice.
This guideline is organized into topics that are inclusive of primary prevention of stroke across the life span
of adults. When the topics overlap with the 2014 guideline, studies and clinical trials published since 2014 have been summarized to underpin the current recommendations. There are 6 clinical sections:1. Patient assessment;2. Life’s Essential 81;
3. Atherosclerotic and nonatherosclerotic risk factors
(eg, migraine);
4. Special populations, including trans health (a first
for stroke primary prevention), SCD (the exception for including the pediatric population), genetic
stroke syndromes, coagulation and inflammatory
disorders, substance use, and sex-specific risk
factors (pregnancy and pregnancy complications,
endometriosis, hormonal contraception, menopause, and exogenous testosterone use);
5. Heart disease, specifically atrial cardiopathy and
left ventricular dysfunction; and
6. Antiplatelet use for primary prevention.
1.6. Abbreviations
2. GENERAL CONCEPTS2.1. Evaluation of Evidence for Primary Stroke
PreventionEligible studies included the following broadly defined
populations:• The general population of adults without established CVD;
• A population of adults with CVD but without a history of stroke or transient ischemic attack (TIA);
and
• A population of adults with CVD, including stroke
or TIA.3. PATIENT ASSESSMENT
Synopsis
Prevention of stroke in office-based care begins by
meeting with patients to identify behaviors and conditions that place them at risk. Prevention should begin
early in life because unidentified and unmanaged risk
causes damage to arteries, the brain, and the heart
years before disease is manifest. The most common
treatable behaviors and conditions that increase risk
are the AHA’s Life’s Essential 8,1 but others include AF
and substance use disorders.66 Talking with patients
will identify modifiable behaviors (eg, cigarette smoking, physical inactivity, sleep problems, and poorquality diet) and social, environmental, or economic factors that contribute to risk or affect remediation (Table 4).
Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report From the American Heart Association and American College of Cardiology [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. J Am Coll Cardiol. 2019 Jun 25;73(24):3153-3167. doi: 10.1016/j.jacc.2018.11.005. Epub 2018 Nov 10.
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Physical findings that should prompt offers of treatment include high weight and high BP. Findings on testing include dyslipidemia and hyperglycemia. Estimation of 10-year risk for atherosclerotic CVD, as described in a special report by the ACC/AHA,73* can inform shared decision-making. Screening and risk remediation are usually achieved in the context
of regular primary care. For women, their obstetriciangynecologist may be this source of primary care;
obstetrical complications (ie, preeclampsia) are associated with pregnancy-related stroke and risk for hypertension later in life.
*CAC Score Improves Coronary and CV Risk Assessment Above Statin Indication by ESC and AHA/ACC Primary Prevention Guidelines [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. JACC Cardiovasc Imaging. 2017 Feb;10(2):143-153. doi: 10.1016/j.jcmg.2016.03.022. Epub 2016 Sep 21.
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4. MANAGEMENT OF HEALTH BEHAVIORS
AND HEALTH FACTORS FOR PRIMARY
PREVENTION OF STROKE: LIFE’S ESSENTIAL 8Section 4 focuses on the components of cardiovascular health, or Life’s Essential 8 (Figure 3). This tool
includes a foundation of primordial and primary lifestyle,
health factors, and health behaviors with a wealth of
epidemiological data and clinical trials to support their
association with not only stroke and CVD but also cardiovascular health. In addition, this tool includes health
and well-being factors important for maintaining or
improving cardiovascular health. Important contextual
factors include psychological well-being and SDOH.
The 8 components include healthy diet, physical activity, healthy weight, healthy sleep, avoidance of tobacco products, and healthy levels of blood lipids, blood glucose, and BP.1
4.1. Diet Quality
Synopsis
Diet ranges from individual nutrients to broader dietary
patterns, which contribute to broader human health. In
the 2014 AHA/ASA guideline for the primary prevention
of stroke,13 there were few randomized trials examining
the effect of dietary interventions on the risk of stroke.
Subsequently, multiple randomized controlled trials
(RCTs) have been published investigating whether specific dietary interventions reduce the risk of CVD events,
including stroke. Here, we focus only on individual RCTs
and systematic reviews and meta-analyses of RCTs that
included stroke as an end point. Mediterranean diet and
sodium substitution with potassium were beneficial for
stroke reduction. Some benefits were seen with folic
acid and B-complex vitamins. No evidence of a benefit
was observed when the following supplements were
added to a diet: long-chain fatty acids, vitamin C, vitamin E, selenium, antioxidants, calcium without vitamin
D, calcium with vitamin D, and multivitamins. Limitations
included lack of stratified analyses by primary and secondary CVD prevention groups. Furthermore, most of the
trials were not powered for examining differences in incident stroke. We also examined the RCT evidence on the
following: reducing fat intake and supplementing with
vitamin B6, B-carotene, or vitamin B3 (niacin). Because
of specific limitations of these trials (Table 5), specific
recommendations were not included. Last, although the
DASH (Dietary Approaches to Stop Hypertension) diet
has been shown to lower BP,102 we found no RCTs that
examined the effect of the DASH diet on stroke. Therefore, no specific recommendations were included.
4.2. Physical Activity
Synopsis
Observational research demonstrates an association between more physical activity and lower risk
for coronary artery disease, stroke, and all-cause
mortality.114,116–127 The association is curvilinear, and benefits become apparent even with low durations of nonoccupational physical activity.109,120,122,128,129 As an example,
a recent meta-analysis of nonoccupational physical activity revealed that the benefit of physical activity in terms
of total CVD incidence, including stroke, improved more
as activity durations rose from 1 to 150 min/wk than for
increments above that109 (although benefits did continue
to improve with higher doses of activity). These data
support the idea that any physical activity is better than
none.128 The mechanism for the benefit of aerobic (and
isometric physical activity) on risk for ASCVD includes
improvements in BP, lipids, inflammatory markers, insulin
resistance, endothelial function, and weight.108,109,130–133
Because physical activity is associated with reduced risk
for stroke, coronary artery disease, diabetes, and other
conditions, the US Department of Health and Human
Services (2018) and other organizations recommend
that adults achieve at least 150 minutes of moderateintensity physical activity (eg, brisk walking), at least 75
minutes of vigorous-intensity activity (eg, running or jogging), or an equivalent combination.134,135 Although these
targets are widely accepted, newer data as discussed
previously suggest that even light physical activity can
be of benefit to those who may be unable or reluctant
to participate in moderate to vigorous physical activity.
Although achieving targets for physical activity, avoidance of excessive sedentary behavior may further reduce
risk for vascular disease, obesity, hypertension, and diabetes.104,115,136–138 Not surprisingly, the AHA includes
physical activity in Life’s Essential 8.1 Health care professionals can help their patients reach targets for physical
activity by screening and classifying their activity levels
and counseling those in need to help them reach their
targets.4.3. Weight and Obesity
Synopsis
The public health importance of obesity is undeniable,
and the prevalence has increased from 30.5% in 1999 to
2000 to >42% of the US population in 2017 to 2018.168
It is estimated that by 2030, almost 1 in 2 adults (48.9%)
in the United States will have obesity. Obesity, as defined
by body mass index (BMI), may be overestimated or
underestimated by this measure because it fails to distinguish the contribution of fat mass from fat-free mass
(ie, muscle mass) to overall weight. Other measures of
abdominal obesity (Table 6) also predict cardiovascular
risk, including stroke, independently of BMI.160,161 The
AHA therefore recommends annual measurement of
waist circumference (WC) in addition to BMI, especially in
non-White race and ethnicities, to improve cardiovascular
risk assessment.173
Consequences of obesity (eg, hypertension, inflammation, dyslipidemia, hyperglycemia) mediate most of the association between obesity and CVD and stroke.174–177 Intensive lifestyle interventions (Look AHEAD trial [Action for Health in Diabetes] for patients with diabetes) produced modest weight loss and reduced WC compared with controls, but the effect was not sustained, and there was no benefit in CVD prevention.178
However, recent meta-analyses provide strong evidence
that pharmacological treatments for diabetes that lower
both blood glucose and weight (ie, glucagon-like peptide receptor agonists) and bariatric surgery procedures in individuals with class II or III obesity, with and without diabetes, are associated with a reduced risk of cardiovascular events, including stroke, in selected patients.167,179,1804.4. Sleep
Synopsis
More than 30% of middle-aged men and 15% of middleaged women in North America have OSA.195 The prevalence of OSA has increased substantially as a result of the obesity epidemic.195 Recurrent episodes of obstruction of the upper airway during sleep, resulting in paused (apnea) or shallow (hypopnea) breathing, characterize OSA.196 Health care professionals diagnose OSA using the apnea-hypopnea index, which measures the number of obstructive respiratory events (apneas, hypopneas, or respiratory effort-related arousals) per hour of sleep.197 An apnea-hypopnea index of ≥5 events
per hour diagnoses OSA, and an increasing apnea-hypopnea index indicates higher OSA severity.197 An apnea-hypopnea index of 15 events per hour of sleep defines moderate to severe OSA.197 OSA is an independent risk factor for stroke.198,199 OSA also increases stroke risk through its indirect effects
on hypertension.200 CPAP effectively reduces daytime sleepiness and improves the quality of life of people with moderate to severe OSA.201 CPAP also reduces BP levels over the short term.201 CPAP is more effective than mandibular advancement devices in reducing apnea and hypopnea and improving sleep efficiency and oxygen levels in people with moderateto-severe apnea.201 Direct evidence of the effect of
CPAP on stroke risk reduction is lacking.4.5. Blood Sugar
Synopsis
More than 37 million people of all ages have diabetes (11.3% of the US population), of whom 8.5 million people (23%) are undiagnosed.216 Diabetes accounts for >95% of diabetes cases. Another 96 million adults ≥18 years of age have prediabetes (38% of the adult US population).216 Although diabetes usually develops in adults ≥45 years of age, diabetes increasingly
occurs in younger adults (18–44 years of age) as a result of the obesity epidemic.217,218 Health care professionals diagnose diabetes using hemoglobin A1c level, fasting plasma glucose level, an oral glucose tolerance test (Table 7), or a random blood glucose of ≥200 mg/dL with symptoms,204 with hemoglobin A1c preferred.
Diabetes, prediabetes, and type 1 diabetes are independent risk factors for stroke.219,220 In adults with diabetes, higher cumulative hyperglycemia levels are associated with higher stroke risk, with a 12% higher stroke risk per 1% hemoglobin A1c increase.220 Lifestyle interventions (most involving >360 minutes of contact) for people with obesity or overweight with
prediabetes are associated with lower diabetes incidence.203 For example, participants in the Diabetes Prevention Program were asked to participate in 16 sessions during the first 24 weeks (the “core curriculum”) in which they were trained in behavior modification, flexible approaches to improve diet and exercise,
and emphasis on self-esteem, empowerment, and social support. Good evidence shows that metformin is associated with a lower diabetes incidence.203 Thiazolidinediones and α-glucosidase also reduce diabetes risk but are less well tolerated.203 Direct evidence of the effect of these interventions and diabetes prevention on stroke risk reduction is lacking.4.6. Blood Pressure
Synopsis
Cohort and electronic records linkage studies document a strong, continuous, and progressive association between BP, especially SBP, and risk of ischemic
and hemorrhagic stroke.238,239 At any level of BP, CVD risk can vary >30-fold.240 BP-related absolute risk is usually higher at older age when high BP is often accompanied by other CVD risk factors, whereas the RR is usually higher in younger adults who often present with high BP as an isolated risk factor.238 In addition to stroke, high BP is associated with other CVD
complications, kidney disease, cognitive impairment, and dementia.241 Hypertension is customarily designated as the level of usual BP, accurately measured, at which antihypertensive medications are recommended in addition to BP-lowering lifestyle change interventions; it is therefore useful for treatment decisions. The ACC/AHA BP guideline defines stage 1 hypertension as an SBP of 130 to 139 mm Hg or DBP of 80 to 89 mm Hg and stage 2 hypertension as an SBP ≥140
mm Hg or DBP ≥90 mm Hg.68 In addition, hypertension is diagnosed when use of antihypertensive medication is reported. Approximately 46% of US adults have hypertension.684.7. Lipids
Synopsis
The relationship between cholesterol and lipid subclasses
and risk for first stroke is complex, partly because stroke
can occur through several mechanisms in addition to atherosclerosis. There are no primary prevention lipid management treatment trials with stroke as the primary end
point, although stroke is a secondary end point or part
of a composite primary end point for several studies (eg,
ASCOT LLA [Anglo-Scandinavian Cardiovascular Outcomes Trial–Lipid Lowering Arm],247 HOPE-3 [Heart Outcomes Prevention Evaluation–3]248). Nonetheless, these
studies were neither designed nor powered to detect an
independent effect on stroke reduction. Although lipid
management strategies to prevent a first stroke need to
be considered in the context of lowering the risk of other
forms of atherosclerotic vascular disease, meta-analyses
are consistent with a reduction in the risk of a first stroke
with lipid-lowering therapies in populations at risk.249
Comprehensive, US evidence-based recommendations
guiding the approach to lipid management for the prevention of atherosclerotic vascular disease, incorporating
stroke, have been published74,75,249 and supplemented by
an expert consensus document.251 Recommendations
related to lipid management from the 2019 ACC/AHA
guideline on the primary prevention of CVD249 are also
applicable to prevention of a first stroke and are supported by multiple meta-analyses.243,244,252,253 Within the context of general atherosclerotic vascular disease risk reduction,249 the present recommendations are focused on stroke prevention. Lifestyle and other interventions that may also affect lipids are reviewed elsewhere in this guideline. There has also been concern about low levels of LDL-C lead to an increased risk of hemorrhagic stroke. However, recent clinical trials and a meta-analysis provide no evidence that statins increase the risk of hemorrhagic stroke in a primary prevention population.244
4.8. Tobacco Use
Synopsis
Tobacco use is a major modifiable risk factor for stroke
worldwide. The prevalence of current smoking varies across the globe, with some regions facing current smoking rates as high as 50%.292 In the United States, the rate of cigarette smoking has declined to an all-time low of 11.5%, but smoking rates exceed 20% in parts of the Southeast, including many states in the Stroke Belt, where stroke mortality is highest.293 The use of
other forms of tobacco and related products such as ecigarettes is increasingly common as well.294 Tobacco use is responsible for 18% of stroke deaths and disability worldwide according to estimates from the Global Burden of Disease collaborators.295 A large body of epidemiological data demonstrate a robust association of cigarette smoking and environmental smoke exposure with stroke risk, with emerging data revealing similar risks for other tobacco and related products.254,255,257–263,265–267,269,279 Most smokers are interested in smoking cessation, and ≈50% of smokers in the United States report having tried to quit in the past year.296 However, ≈40% of smokers report not having received counseling to quit smoking,
and medications to assist with smoking cessation are underused.296 Therefore, these primary stroke prevention
recommendations center around screening for, treating
of, and preventing the use of and exposure to tobacco and related products, apart from policy-level interventions, for which there is also ample evidence297–3035. ATHEROSCLEROTIC AND
NONATHEROSCLEROTIC RISK FACTORS5.1. Asymptomatic Carotid Artery Stenosis
Synopsis
Atherosclerotic extracranial carotid artery stenosis and its
association with increased risk of stroke have been extensively described. With limited large-scale data on asymptomatic vertebral artery stenosis and stroke prevention,
we cannot develop comprehensive, evidence-based recommendations; hence, our focus is on the management
of ACS. Numerous large clinical trials have supported
that carotid revascularization in appropriately selected
patients with asymptomatic carotid stenosis results in
an RR reduction of stroke compared with medical management. However, contemporary medical management
has improved, and subsequent trials have tried to answer
whether optimal medical management and surgical treatment for asymptomatic atherosclerotic artery stenosis
may be equivalent.309,312–314 The quest to determine the
best way to reduce the risk of stroke in asymptomatic
patients has sparked much debate; however, we continue
to have the same pressing question: Is carotid revascularization as effective as contemporary medical management in reducing the risk of stroke in patients with ACS? Prior guidelines have addressed this controversial topic, encountering similar findings.321 There is an ongoing need to improve the selection of asymptomatic patients who would benefit from carotid artery revascularization withthe advent of contemporary medical treatment. CREST 2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) is underway and will, we hope, provide clarity on some of these questions. Our recommendations reflect the latest evidence-based knowledge to guide management strategies for patients
with ACS and mitigating the risk of stroke.5.2. Asymptomatic Cerebral SVD [Cerebral Small Vessel Disease], Including Silent Cerebral Infarcts
Synopsis
CSVD [Cerebral Small Vessel Disease] is one of the most frequently encountered conditions in neurology. CSVD is defined radiographically by the presence of white matter hyperintensities, recent small subcortical infarct, lacune of presumed vascular origin, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy.348,349 There are multiple CSVD subtypes, including the most common form related to arteriosclerosis or hypertensive arteriopathy.350,351 Other forms of CSVD include cerebral amyloid angiopathy, genetic syndromes such as cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL), and immune-mediated and infection-mediated subtypes.350,351 CSVD may remain asymptomatic for many years before clinical manifestations of ischemic and hemorrhagic stroke, cognitive impairment, gait impairment, or psychiatric disturbances become apparent.340,341,350,352,353 MRI studies obtained for other clinical indications may incidentally reveal radiographic findings of CSVD. Clinicians may therefore be faced with decisions about how to manage these patients in the absence of apparent CSVD clinical manifestations. In this section, we examine literature and trials that address the primary prevention of stroke in individuals with asymptomatic CSVD, including SCI [Silent Cerebral Infarct/Infarction]. More than 90% of silent infarcts are subcortical; therefore, these recommendations do not apply to individuals with silent cortical infarcts that are less likely to be related to CSVD. We focus on the most common subtype of CSVD; recommendations for other specific CSVD subtypes are covered elsewhere in the guideline.5.3. Migraine
Synopsis
Migraine is a recurrent headache disorder characterized
by moderate to severe headache lasting hours to days,
with typical associated features such as unilaterality,
aggravation with activity, photophobia, phonophobia, and
nausea.373 Migraine affects 14.4% of individuals and is a
leading cause of disability worldwide.374,375 Migraine disproportionately affects women 15 to 49 years pf age with
a prevalence between 20% and 30%.374 An association
between migraine, particularly migraine with aura, and
stroke risk has consistently been identified in observational studies.362–365 This association is stronger for ischemic stroke than for hemorrhagic stroke362 and is more
evident in young women.365 Vascular risk factors are common in patients with migraine and contribute to excess
stroke risk.366,368,369 The mechanistic links between
migraine and stroke are not well understood. Migraine
can directly cause stroke in rare instances (migrainous
infarction)376 and is associated with a higher prevalence
of white matter hyperintensities and cerebellar infarct-like
lesions,376 especially in the posterior circulation.377 Use of
combined hormonal contraception in those with migraine
with aura is associated with increased risk for ischemic
stroke.370 Migraine with aura is associated with patent
foramen ovale (PFO),378 but a benefit of PFO closure for
primary stroke prevention in patients with migraine has not
been demonstrated despite the association between PFO
and risk of both migraine and stroke. There is a dearth of
high-quality evidence to guide stroke prevention in patients
with migraine, and many areas of uncertainty remain.3796. SPECIFIC POPULATIONS
6.1. Sickle Cell Disease
31
Synopsis
SCD, estimated to occur in 1 in 365 African American
individuals,391 is caused by an abnormal hemoglobin
β-chain occurring through autosomal-recessive genetic
transmission. SCD includes all patients who have 1
copy of the sickle β-globin allele, along with a second
altered β-globin allele. The second β-globin allele may also carry the sickle mutation (Hb SS), a β-thalassemia
mutation (resulting in sickle beta0-thalassemia), or the
hemoglobin C mutation (resulting in Hb SC disease),
among others. Clinically, SCD causes chronic anemia or
acute vaso-occlusive crises, most commonly manifesting
as painful episodes. Complications include acute chest
syndrome, pulmonary hypertension, bacterial infections,
and organ infarctions, especially stroke. In addition, SCD
may be complicated by the development of moyamoya
syndrome, an intracranial angiopathy defined by stenoocclusion of terminal portion of internal carotid artery and
development of collateral vessels. Other SCD effects
include cognitive deficits related to SCI and otherwise
asymptomatic white matter hyperintensities.392,393 An
estimated 11% of patients with homozygous SCD have
an overt stroke by 20 years of age,394 and many more
have SCIs,391 demonstrated only with brain MRI. TCD
ultrasound identifies those at high risk of stroke, allowing
evidence-based decisions about optimal primary stroke
prevention.381,382 It is not clear whether the high velocities
in and of themselves increase stroke risk or if they are a
noncausative marker of high stroke risk; nonetheless, the
association is well established.
6.2. Genetic Stroke Syndromes
Synopsis
The role of genetics in stroke pathogenesis is increasingly
recognized. Monogenetic conditions are the most well understood. These include Fabry disease, CADASIL, HHT,
and type IV collagen (COL4A1/2) mutations, among others
(Table 10).
Although each individual genetic condition is rare, stroke risk in some can be modified with prophylactic therapy, and a diagnosis can aid in prognostic discussions, limit unnecessary testing, and facilitate natural history studies. Several factors, including rarity of each individual disorder, make high-quality studies of stroke prevention in these disorders challenging. Because genetic conditions typically affect multiple organs and systems, many of the high-quality randomized controlled studies report composite outcomes, limiting data on stroke-specific outcomes. In addition, variable expression inherent in many of these genetic disorders makes uniform recommendations for
stroke prevention challenging.6.3. Coagulation and Inflammatory Disorders
6.3.1. Inflammation in Atherosclerosis
Synopsis
Autoimmune conditions and inflammatory conditions,
cancers, and infections are established contributors to primary stroke risk. These conditions are thought to predispose to stroke through various interrelated mechanisms,
including hypercoagulability, accelerated atherosclerosis,
abnormal vasoreactivity, endothelial dysfunction, and
activation of intravascular leukocytes, among others.
Some conditions, including psoriasis, rheumatoid arthritis, lupus erythematosus, HIV/AIDS, and others, are atherosclerotic CVD risk enhancers (Table 8) and should
be considered in the determination of optimal lipid management; however, disease-specific treatments to lower
stroke risk are not established. In terms of cancer risk,
heterogeneity between cancer types and stroke mechanisms has led to limited data on risk stratification and
optimal preventive therapies.
6.3.2. Autoimmune Conditions
Synopsis
Autoimmune conditions cause inflammation, which contributes to vascular injury and hypercoagulability, which
increase the risk of stroke. Among these conditions,
acquired and hereditary hypercoagulable states (ie,
thrombophilias) are probably the most common and well
understood. Of these conditions, the presence of aPLs [antiphospholipid antibody (aPL)] is most convincingly associated with arterial thrombosis. APS (Anti-Phospholipid Syndrome) is defined as an autoimmune condition characterized by the presence of venous or arterial thrombosis or pregnancy-related complications in patients with aPLs.471APS can occur as a primary disease process or secondary to primarily autoimmune conditions (SLE, rheumatoid arthritis, Sjögren disease, or systemic sclerosis). APS is characterized by the persistent (repeat testing 12 weeks apart) presence of specific aPLs plus evidence of clinical criteria such as vascular thrombosis or pregnancy morbidity.471 Measurement of aPL titers (anticardiolipin antibodies or anti–β2-glycoprotein 1 antibodies and lupus anticoagulant) is used to define high-risk and low-risk aPL profiles.472Table 11. Definitions of Medium to High aPL Titers and of
High-Risk and Low-Risk aPL Profiles
“Antiphospholipid Syndrome and Stroke” from the European Stroke Organization. 2024.
6.3.3. Malignancy
Synopsis
Ischemic stroke risk begins to increase in the early stages
of some cancers.475,476,477 Heterogeneity between cancer
types and stroke mechanisms has led to limited data on
risk stratification and optimal preventive therapies. Cancerrelated stroke is now considered an embolic stroke of
unknown source subgroup, accounting for 5% to 10% of
these strokes.478,479 Pathological mechanisms for cancerrelated stroke include hypercoagulability, direct invasion
or compression of blood vessels, radiation arteriopathies,
nonbacterial thrombotic endocarditis, and secondary
effects of chemotherapy (eg, cardiac toxicity), among others.480 Arterial embolism in patients with cancer may be
related to VTE in the setting of a PFO, which is present
in ≈25% of the general population.481 Although hypercoagulability is common in patients with cancer, the benefit of antiplatelet or anticoagulant use, as well as in which situation, remains uncertain. Some evidence indicates that
aspirin may help lower the risk of developing some cancers
(eg, colorectal),482 but aspirin use for primary prevention of
cancer-related stroke is not well established.483,484 Although
low-molecular-weight-heparin agents are commonly used
empirically, their benefit is unclear,484 particularly in patients
with cancer with uncertain risk of hemorrhage.4856.3.4. Infection
Synopsis
Acute and chronic infections, including infections
requiring hospitalization, have been associated with an
increased risk of stroke. The mechanism underlying this
transient interval after infection during which patients
are predisposed to stroke may include inflammation,
thrombophilia, or other mechanisms.491–493 Bacteremia
is strongly associated with inflammation and thrombosis. Studies have reported a relative increased stroke
risk associated with sepsis492,494,495; however, the absolute stroke risk remains low (≈0.5% within a year). Most
infections in these studies were either respiratory or
urinary. The exact organisms were not typically known. Influenza is a prevalent viral illness, but specific diagnoses of influenza are not usually available. In a casecrossover study using California data,496 the odds of
ischemic stroke within 15 days after an influenza-like
illness were increased (OR, 2.88 [95% CI, 1.86–4.47]).
The risk decreased over time and was no longer significant after 60 days. During the COVID-19 pandemic
of 2019 to 2023, researchers observed a high risk of
stroke among infected patients. Stroke subtypes varied, including large-vessel occlusion and small-vessel,
cardioembolic, and cerebral venous thrombosis and
hemorrhages, suggesting that the mechanism may not
be specific to the viral syndrome but rather the result
of thrombophilia, endothelial dysfunction, thrombotic
microangiopathy, and nonspecific effects of inflammation.497–500 As an example of stroke risk related to
chronic infection, observational studies have found that
poor periodontal health and periodontitis are strongly
associated with an increased stroke risk.501–5056.4. Substance Use and Substance Disorders
Synopsis
No data directly support interventions that address the
use of recreational substances/prescribed medications in harmful ways (misuse) or substance use disorders (addictions) for primary stroke prevention. In the United States, 23.3% of adults >18 years of age engage in binge drinking, and 6.4% engage in heavy drinking.532 Alcohol has a dose-dependent relationship with stroke,506–510 conferring a 5.8% population attributable risk.10,518,533 US prevalence of recreational drug
use is reported as 21.4% in those ≥12 years of age.532 Cannabis use (including synthetic analogs) is rising, reflected in the AHA scientific statement “Medical Marijuana, Recreational Cannabis and Cardiovascular Health,”534 which demonstrates a dose-dependent relationship with stroke.511,535 Observational data identify that amphetamine, methamphetamine, opioid, khat, and cocaine use increases the odds of stroke515,516,518,536–539
and that temporal substance use is common in younger stroke presentations.513,514,540 Proposed mechanisms include hemodynamic alterations, platelet activation, electrophysiological effects, vasculopathy, and cardioembolism.534,541–543 In addition to addressing risk at an individual level, effective primary prevention requires
population-level approaches, targeting first the largest
proportion at risk (ie, those misusing substances).534 For
example, policy interventions (eg, taxation and alcohol outlet regulation) are cost-effective and reduce excessive alcohol consumption.544–5466.5. Sex- and Gender-Specific Factors
6.5.1. Pregnancy
6.5.1.1. Prevention of Pregnancy-Associated Stroke
Synopsis
Pregnant and postpartum individuals have approximately
triple the risk of stroke compared with young adults
of a similar age.567,568 Although pregnancy-associated
maternal stroke is rare, occurring in ≈30 per 100000
deliveries,567 stroke constitutes a leading cause of maternal morbidity and mortality,569–572 and significant racial
disparities are consistently observed.573 Mechanisms
of pregnancy-associated stroke are diverse,571,574–580
and the sequelae can be catastrophic (Figure 4).
Most pregnancy-related strokes occur postpartum, with the
highest-risk time point being the early postpartum period
(within the first 2 weeks of delivery).577,581–585
Patients with HDP (Table 12) represent a particularly high-risk
group for maternal stroke,574,583,587 and ICH is a leading
cause of death in these individuals.551,553–555 Additional
risk factors for maternal stroke include older age,588
migraine,574,589–591 assisted reproductive technology,592
obesity,590 heart disease,583,593 infections,594–596 and
SLE.567,597,598 There are no randomized trials on optimal
primary stroke prevention strategies in pregnancy and
postpartum; however, evidence supports BP control as
critical for the prevention of maternal morbidity, including fatal and nonfatal stroke.551–557,559–565 In patients with
unruptured brain arteriovenous malformations, optimal
management before and during pregnancy remains
unclear, but no evidence supports routine cesarean delivery for these individuals or for those with other unruptured intracranial vascular lesions.601–6086.5.1.2. Pregnancy and Long-Term Stroke Risk
Synopsis
The long-term effects of pregnancy on the maternal
brain remain an understudied area. However, mounting
data support that those who experience APOs, including HDP,609 recurrent pregnancy loss,614 gestational
diabetes,615 preterm birth,616,617 small-for-gestationalage infant,618 placental abruption,619 or stillbirth,614 have
increased risk and earlier onset of cerebrovascular disease (Table 13).610,613,633
The incidence of APOs in the United States is rapidly increasing,620,634 and major racial disparities persist.581 No RCTs have evaluated specific interventions after APOs to reduce the risk of future stroke, although small trials have investigated the impact of postpregnancy interventions to mitigate stroke risk factors.611,612,635,636 We recommend that clinicians screen parous adults for a history of APOs and discuss the
increased risk of stroke with these patients, who are often
unaware of their risk (Figure 5).637 These discussions may
also help patients make informed decisions about future
pregnancies. Particular attention to the identification of
modifiable vascular risk factors is advised for patients
with a history of APOs. Even young adults with a history of APOs, especially HDP, have an increased risk of
developing chronic hypertension as soon as 2 years after
the index pregnancy.638 Early diagnosis and treatment of
chronic hypertension in these individuals may reduce the
risk of cerebrovascular disease in midlife and beyond.
6.5.2. Endometriosis
Synopsis
Emerging evidence supports endometriosis as a femalespecific risk factor for stroke. Endometriosis, defined by
the occurrence of endometrial tissue outside the uterus,
is a chronic gynecological condition that is associated
with chronic inflammation, immune activation, and hormonal disruption. Diagnosis is usually made during the
reproductive years, with a diagnosed prevalence of ≈1
in 10, but the true prevalence of endometriosis is uncertain because definitive diagnosis requires laparoscopy.654
Endometriosis has been associated with cardiovascular
risk factors, including increased risk of hypertension655
and hypercholesterolemia.655 In recent years, evidence
has shown an increased risk of CVD649,650,652 and coronary heart disease.656 Among those with endometriosis, studies have shown a consistently increased risk of stroke.649–653 To evaluate stroke risk, performing a gynecological and reproductive history, including assessment of endometriosis, is likely to be beneficial. Young individuals with endometriosis are a subgroup who might benefit from enhanced attention to cardiovascular risk assessment and prevention strategies; however, definitive studies are lacking.6.5.3. Hormonal Contraception
Synopsis
According to the US Department of Health and Human
Services, in 2017 to 2019, ≈65% of women in the United States who were 15 to 49 years of age were using contraception.671 Common forms include oral contraceptive
pills (14%) and long-acting reversible hormonal contraceptives such as intrauterine device and implantation (10.4%).671 Oral contraceptive pill use is highest in young women, those 15 to 29 years of age, whereas overall contraception use is lower in this age group (age 15–19 years rate, 38.7%; and age 20–29 years rate, 60.9%). Contraceptive choices and preferences have
broadened over the past 15 years to include transdermal contraception, newer intrauterine devices, differing dosages of estrogen-containing pills, and different types of progestin; thus, the risk of stroke with these different choices needs to be evaluated. Recent registry data report a lower rate of stroke in women using combined hormonal contraception (8.8 versus 21.4 events per 100000 person-years).660,672 The overall rate of stroke in women using hormonal contraception is lower than the rate of stroke in women from pregnancy (30 in 100000
pregnancies).673 Data on the relationship between hormonal contraception and risk of incident stroke are from observational case-control cohorts and meta-analysis of this data. The amount of control of other risk factors varies widely between these studies.Recommendation-Specific Supporting Text
1. Research has identified a direct, linear relationship between a higher dose of estrogen in CHC
and an increased risk of stroke. Conversely, lower
estrogen content is associated with reduced
risk.658,659,661,662,665,670 Women who used a CHC
with <50 μg estrogen have a lower risk of stroke
compared with women who use preparations with
a higher estrogen content (RR, 2.08 [95% CI,
1.55–2.8] versus RR, 4.53 [95% CI, 2.17–9.5];
P=0.01).668 More recently, 1 group performed
a meta-analysis using 6 cohorts and 12 casecontrol studies to evaluate stroke risk associated
with every 10 μg estrogen use (OR, 1.19 [95% CI,
1.16–1.23]). These risks were consistent for both
ischemic stroke (OR, 1.24 [95% CI, 1.17–1.22])
and hemorrhagic stroke (OR, 1.10 [95% CI, 1.04–
1.16]).659 Duration of use increases stroke risk
after 1 year658 for every 5 years of use.
2. Contraceptive choice is affected by many medical and personal factors for the patient. Shared
decision-making is recommended to weigh the
benefits and risks of these choices. For example,
the absolute stroke risk when evaluating the 6-
fold increase stroke risk associated with migraine
with aura using CHC is different for a person 18
years of age than for a person 45 years of age
(20.4 versus 386.4 events per 100 000 personyears).370,672 Consideration of the risk of stroke
from contraceptive choice should also be balanced by consideration of the effectiveness of each contraception option (Table 14) and the stroke risk associated with pregnancy.
Similar risk factors increasing the risk of stroke from CHC
(ie, hypertension, smoking, migraine with aura) also increase the stroke risk from pregnancy. A thoughtful discussion of absolute risk between the health care professional and patient can improve patient-centered care, patient engagement, and stroke reduction.3. CHC can synergistically increase existing stroke
risk factors. Lidegaard et al672 demonstrated
an exponential stroke risk increase with age using CHC, growing from 3.4 to 64.4 events per 100 000 person-years for individuals 15 to 49 years of age. Further studies have confirmed an increased risk related to CHC use with increased age, especially when 35 years of age is used as a cutoff.660,665,670 CHC synergistically increases the risk of hypertension up to 4-fold, smoking up to 3-fold,670 and migraine with aura up to 6-fold.370 Higher estrogen doses significantly increased the risk of stroke in those who
smoke.668 Progestin-only contraception in all routes is not associated with an overall increased stroke risk.663,664,666,667,669 However, progestin only contraception use in the setting of hypertension can increase stroke risk.669 The RATIO study (Risk of Arterial Thrombosis in Relation to Oral Contraceptives) demonstrated a higher risk
of stroke in women with cardiovascular risk factors than women without in combinations containing 30 g of estrogen plus second or third generation progestins.670 However, the different generations of progestin stroke risk did not differ
in women without stroke risk factors.672Knowledge Gaps and Future Research
The average age of stroke incidence continues to decrease with increased prevalence of common stroke risk factors.
• There is a lack of new cohort data to reflect the
changes rates of stroke with CHC in our current
population.
• There are gaps in direct comparison of stroke risks
related to CHC versus pregnancy6.5.4. Menopause
Synopsis
Menopause is the loss of ovarian follicular activity and
subsequent decline in estrogen production. Onset occurs between 45 and 56 years of age in 90% of women (mean, 51.4 years of age).684 Premature menopause (onset before 40 years of age) and early menopause (before 45 years of age) can be due to primary ovarian insufficiency, surgical oophorectomy, or
medication-induced menopause.684 Surgical menopause is the result of bilateral oophorectomy performed before natural menopause. Reproductive life span, defined as the time between the onset of menarche and the age at menopause, if <30 years,
has been identified as a potential risk factor for stroke.674,685 More than 50% of women experience frequent vasomotor symptoms during the menopausal period.684 Severe and frequent symptoms are associated with an increased risk of CVD.684 Women with more severe vasomotor symptoms tend to be older, heavier, or Black/African American and tend to have lower socioeconomic status and a higher-risk CVD profile.686 Whether vasomotor symptoms are independently associated with the risk of stroke is uncertain.679,686–689 Estrogen-based therapies are the most effective treatments for moderate to severe vasomotor symptoms. However, HT, particularly oral HT, has been associated with risk of CVD in multiple RCTs and meta-analyses.658,680–683 Thus, risk factor assessment and evaluation of the individual benefits and risks of HT must be carefully considered (Figure 6). It is also
important to note that topical estrogen treatments are not associated with stroke risk.691fig52 (fig6) when server ready
Recommendation-Specific Supporting Text
1. Approximately 5% of women experience a natural
menopause before 45 years of age, and many others have bilateral oophorectomy before 45 years of age. The preponderance of data support that early menopause (before 45 years of age) is a risk factor for stroke specifically. Multiple prospective studies have consistently shown an increased risk of
stroke among those with premature or early menopause,674,675,677 with other analyses showing similar
trends.685,692 In a meta-analysis of individual data
from 15 prospective studies, those with menopause
before 40 years of age had a 32% increased risk of
stroke (95% CI, 1.43–2.07) and those with menopause between 40 and 44 years of age had an HR of 1.09 (95% CI, 1.18–1.43).676 Findings for stroke
mortality have been less consistent.692,693 The type
of menopause, natural or surgical, does not appear
to modify the association with stroke.
2. During the decline of estradiol levels in the
menopausal transition, LDL levels generally rise
and high-density lipoprotein levels decline.694 In
many women, menopause contributes to a rise
in BP, warranting monitoring during the menopausal transition.695 Premature menopause and early menopause have been associated with a substantially increased risk of stroke and advance the time of onset of changes in lipids
and BP.674,675,677,679 Data are lacking on whether
hormone replacement therapy, at least until the
average age of menopause, might modify this risk.
The ACC/AHA 2018 guideline on cholesterol management included premature menopause as a risk-enhancing factor to be considered in cholesterol management decisions.75 Primary prevention of CVD and screening for and managing risk factors are warranted for those with a history of premature and early menopause.
3. The excess risk of stroke with the use of estrogen containing HT is well established, but the majority
of the RCT data come from the Women’s Health
Initiative, in which the mean age was 67 years. The
USPSTF in 2022 estimated that use of estrogen only formulations results in 79 (95% CI, 15–159)
more strokes per 10000 women treated, and
estrogen/progestin formulation results in 52 (95%
CI, 12–104) more strokes per 10000 women
treated.696 A synthesis of systematic reviews of 17
RCTs reported a cumulative RR of 1.17 (95% CI,
1.05–1.29) and an RR of 1.35 (95% CI, 1.08–1.69)
for nonfatal stroke with HT use.680 Another metaanalysis showed a 32% risk during HT (HR, 1.32
[95% CI, 1.12–1.56]) but among those with past use
(HR, 1.00 [95% CI, 0.85–1.28]).682 Observational data from the UK Biobank showed a small but significant increase in the risk of ischemic stroke with HT and a 33% increased risk of subarachnoid hemorrhage (HR, 1.33 [95% CI, 0.14–1.71]).658 According to the Menopause Society, settings where estrogen based HT may be most appropriate include the use of the lowest effective dose of estrogen in women <60 years of age with low cardiovascular, thromboembolic, and breast cancer risk profiles who do not have unexplained vaginal bleeding or liver disease697 (Figure 6). Transdermal formulations of estrogen
(especially low dose) were not associated with a clear risk of stroke.691,698,6996.5.5. Transgender Health
Synopsis
Transgender and gender-diverse people experience
disparate access to and outcomes within health care,
including stroke.37 Studies suggest that transfeminine
people using gender-affirming HT may have a higher
incidence700,701 and prevalence702,703 of stroke. Similar
outcomes have not been described in transmasculine
people using gender-affirming HT, but this population
tends to be much younger.700–703 There are limitations
in available data that inhibit the ability to define more
precisely the potential risk, to identify the mechanisms
driving this effect, and to assess interventions. The lack
of standardized and inclusive gender identity collection
in population health studies, stroke cohort studies, and
electronic health records obscures health data in these
populations. Research has exclusively included transgender and gender-diverse people using gender-affirming HT, leading to a gap in knowledge of the cerebrovascular health of those who do not use gender-affirming HT and a potential bias in the interpretation of the role of gender-affirming HT in stroke risk. In addition, the research populations have included few individuals >50 years of age, the age at which strokes are more likely to occur. Current data lack detailed sociocultural information and measures of minority stress that may be important mechanisms for stroke disparities in transgender
and gender-diverse people. Despite these limitations, it
is reasonable to evaluate and address risk factors in
transfeminine people using gender-affirming HT given
the current research findings.6.5.6. Testosterone Use
Synopsis
The potential increased risk of stroke in men with confirmed hypogonadism using exogenous testosterone has been debated for several years. Observational studies and small randomized clinical trials showed conflicting results, leading the US Food and Drug Administration to issue a warning about the potential for increased risk of stroke and heart attacks in 2015.707 Recent data suggest that initiation or continuation of transdermal testosterone therapy in individuals with appropriate indications is reasonable and does not increase the risk of stroke.
7. HEART DISEASE
7.1. Cardiomyopathy
Synopsis
Cardiomyopathies, including diseases of the atria and
ventricles, can increase risk of stroke, even in the absence
of AF. In atrial cardiopathy, structural, electrophysiological, imaging, and serum biomarker abnormalities can predate
AF and lead to thrombus formation and embolization.712,713
An abnormally increased P-wave terminal force in lead
V1 on electrocardiography714–716 and echocardiographic
abnormalities of the left atrium717,718 have consistently
been associated with incident stroke. A shortcoming of
these studies is the variable intensity in identifying prior or
incident AF, which may be present with increased surveillance. Nonetheless, measures of atrial cardiopathy may
have utility for stroke risk stratification. Cardiomyopathy
with reduced left ventricular ejection fraction is also a risk
factor for stroke. Thrombin-related pathways may induce
inflammation, endothelial dysfunction, and arterial and
venous thrombosis,708,719 and there is interest in antiplatelet and anticoagulation medications to reduce thromboembolic events.708–710,720–724 Two RCTs—one of warfarin
versus aspirin in patients with cardiomyopathy and no
evidence of AF711 and one of rivaroxaban versus placebo
in patients with worsening heart failure, coronary artery
disease, and no evidence of AF725—showed no difference
in the primary composite outcome of major adverse cardiovascular events, a modest reduction in the secondary
outcome of stroke, and increased risk of bleeding.Recommendation-Specific Supporting Text
1. Based on the WARCEF trial (Warfarin Versus
Aspirin in Reduced Cardiac Ejection Fraction)711 in which there was no difference in the primary composite outcome of ischemic stroke, ICH, or death but a significant reduction in ischemic stroke, the 2014 guideline on primary stroke prevention13 recommended anticoagulant or antiplatelet agents as reasonable for patients with heart failure and no AF. Since publication, 2 subanalyses
from WARCEF708,711 and an RCT of rivaroxaban
versus placebo725 also have demonstrated no difference in the primary composite outcome, modestly reduced stroke events, and increased risk of bleeding. In COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure),725 compared with placebo, there was no difference in major cardiovascular events (25.0% versus 26.2; HR, 0.94
[95% CI, 0.84–1.05]; P=0.27), rates of stroke were
2.0% versus 3.0% (HR, 0.66 [95% CI, 0.47–0.95]),
and major bleeding occurred in 3.3% versus 2.0%
(HR, 1.68 [95% CI,1.18–2.39]), respectively. Taken
together, there is no clear net benefit and possible
harm in prescribing anticoagulation for patients
with cardiomyopathy and reduced left ventricular
ejection fraction who have no other indication for
anticoagulation.710,726Knowledge Gaps and Future Research
• Atrial cardiopathy without clinical AF is a risk factor for stroke, yet gaps remain in how to reduce
this risk. Studies of anticoagulation in patients with
atrial high-rate events, a precursor to stroke, and
in patients with cryptogenic stroke, which may be
secondary to subclinical AF, have not been effective
in preventing stroke. Although these studies did not
enroll patients on the basis of echocardiographic or
echocardiographic criteria of atrial cardiopathy, they
suggest that subclinical AF and other tachyarrhythmias with subsequent thromboembolism may not
be the only mechanism responsible for increased
stroke risk. More studies are needed to understand
the cause and management of stroke risk in patients
with atrial cardiopathy without AF.
• Among patients with cardiomyopathy and reduced
left ventricular ejection fraction, the 2 major clinical
trials show a signal for reduced ischemic strokes
with anticoagulation; however, the primary outcomes of these studies are negative, stroke events
are low, and there is a significantly higher bleeding
risk. Therefore, the net benefit for any one patient
remains unknown. Future trials of anticoagulation
in patients with cardiomyopathy and reduced left
ventricular systolic function should select people at
highest risk for stroke and consider more individualized estimation of risk/benefit thresholds.
• There are no data assessing the use of antiplatelet
therapy (versus placebo) for primary stroke prevention in patients with cardiomyopathy, which may be
an area for future research.8. ANTIPLATELET USE FOR PRIMARY
PREVENTION
Synopsis
Several medical conditions predispose to vascular disease progression over a period of years. These risk factors can contribute to large-vessel atherosclerosis, SVD [small vessel disease], or both. It is common for vascular disease to evolve from nonstenotic plaques to areas of stenosis or occlusion. Before producing overt symptoms, prophylactic use of aspirin could be useful for preventing MI or ischemic stroke. However, the use of aspirin can also increase the tendency for major or minor bleeding events. Therefore, research has focused on the identification of patients at increased risk for thrombotic events and acceptably low bleeding risk, for whom the balance could favor use of aspirin. Several recent trials in important patient groups (elderly, people with diabetes) have not shown benefit for stroke prevention with aspirin use.
Recommendation-Specific Supporting Text
1. In patients with a single risk factor or multiple risk
factors, the use of aspirin to prevent major vascular events, including stroke, has been tested. In the ARRIVE trial (Use of Aspirin to Reduce Risk of Initial Vascular Events in Patients at Moderate Risk of Cardiovascular Disease), 12546 patients judged to be at moderate risk for vascular events were randomized to aspirin 100 mg/d versus placebo.727 The
primary composite end point did not differ between the 2 groups, and there was no difference in the rate of fatal or nonfatal stroke (aspirin, 1.20%; placebo, 1.07%). In addition, this trial included an intermediate-risk sample with risk factors treated more proportionately than in prior aspirin trials (75%
on antihypertensive medications and 43% on statins). The JPPP trial (Japanese Primary Prevention Project) enrolled participants between 60 and 85 years of age with a history of hypertension, diabetes, or hyperlipidemia.728 The primary end point was stroke, MI, and vascular death. The study was stopped for futility after 60 months of follow-up. The primary end point was 2.77% with aspirin and 2.96% with placebo. prevention trials. The rates of major bleeding were also higher in the 90-mg and 60-mg ticagrelor groups (2.3% and 2.6%, respectively) compared with placebo (1.06%). 3. Advanced age is a vascular risk factor. The ASPREE
trial (Aspirin in Reducing Events in the Elderly)
enrolled patients ≥70 years of age to compare aspirin 100 mg/day with placebo.360 The primary end
point was fatal coronary heart disease, nonfatal MI,
fatal or nonfatal stroke, or hospitalization for heart
failure. With a median age of 74 years and a median
of 4.7 years of follow-up, there was no reduction in
the primary end point or stroke with aspirin therapy. A
prespecified secondary analysis of ASPREE found
a small increase in intracranial bleeding with aspirin
use (0.7% absolute increase).735 In a subanalysis of
JPPP focused on stroke, there was no reduction in
stroke associated with aspirin use among Japanese
patients with a mean age of 71 years.733 4. For patients with chronic kidney disease, a metaanalysis compared major vascular event outcomes
with aspirin or placebo.734 Among 4468 study participants, no clear benefit was seen with aspirin for
major vascular events (HR, 0.92 [95% CI, 0.49–
1.73]) or stroke (HR, 0.86 [95% CI, 0.48–1.56]).Knowledge Gaps and Future Research
• With several large clinical trials demonstrating lack
of benefit for aspirin in the primary prevention setting, the question arises whether a patient profile
exists that could benefit from aspirin use. Additional
studies could be focused on patient groups with a
potentially favorable risk/benefit equation such as
the following:
– Patients with asymptomatic but demonstrable
vascular disease such as asymptomatic carotid
stenosis,
– Patients with elevated coronary calcium scores,
– Patients with abnormal ankle-brachial index ratios,
– Subjects with familial hypercholesterolemia,
– Patients with elevated lipoprotein(a) levels, and
– Patients with asymptomatic intracranial stenosis.
• Further information is also needed on prophylactic use of aspirin in higher-risk communities such
as individuals who are Black, Hispanic, Native
American, or Asian.
