Professional Documents
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Stroke - Aha
Stroke - Aha
James F. Meschia, MD, FAHA, Chair; Cheryl Bushnell, MD, MHS, FAHA, Vice-Chair;
Bernadette Boden-Albala, MPH, DrPH; Lynne T. Braun, PhD, CNP, FAHA;
Dawn M. Bravata, MD; Seemant Chaturvedi, MD, FAHA; Mark A. Creager, MD, FAHA;
Robert H. Eckel, MD, FAHA; Mitchell S.V. Elkind, MD, MS, FAAN, FAHA;
Myriam Fornage, PhD, FAHA; Larry B. Goldstein, MD, FAHA;
Steven M. Greenberg, MD, PhD, FAHA; Susanna E. Horvath, MD; Costantino Iadecola, MD;
Edward C. Jauch, MD, MS, FAHA; Wesley S. Moore, MD, FAHA; John A. Wilson, MD;
on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke
Nursing, Council on Clinical Cardiology, Council on Functional Genomics and Translational Biology,
and Council on Hypertension
Abstract—The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the
prevention of stroke among individuals who have not previously experienced a stroke or transient ischemic attack. Evidence-
based recommendations are included for the control of risk factors, interventional approaches to atherosclerotic disease of
the cervicocephalic circulation, and antithrombotic treatments for preventing thrombotic and thromboembolic stroke. Further
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recommendations are provided for genetic and pharmacogenetic testing and for the prevention of stroke in a variety of other
specific circumstances, including sickle cell disease and patent foramen ovale. (Stroke. 2014;45:3754-3832.)
Key Words: AHA Scientific Statements ◼ atrial fibrillation ◼ diabetes mellitus ◼ hyperlipidemias ◼ hypertension
◼ intracranial aneurysm ◼ ischemia ◼ prevention and control ◼ smoking ◼ stroke
3754
Meschia et al Guidelines for the Primary Prevention of Stroke 3755
cognitive deficits.1 Stroke changes the lives not only of those review published in 2011 to October 2012. They also reviewed
who experience a stroke but also of their family and other care- contemporary published evidence-based guidelines, personal
givers. A major stroke is viewed by more than half of those at files, and published expert opinion to summarize existing evi-
risk as being worse than death.4 Despite the advent of reperfu- dence, to indicate gaps in current knowledge, and, when appro-
sion therapies for selected patients with acute ischemic stroke, priate, to formulate recommendations using standard AHA
effective prevention remains the best approach for reducing the criteria (Tables 1 and 2). All members of the Writing Group
burden of stroke.5–7 Primary prevention is particularly important had the opportunity to comment on the recommendations
because >76% of strokes are first events.1 Fortunately, there are and approved the final version of this document. The guide-
enormous opportunities for preventing stroke. An international line underwent extensive peer review, including review by the
case-control study of 6000 individuals found that 10 potentially Stroke Council Leadership and Scientific Statements Oversight
modifiable risk factors explained 90% of the risk of stroke.8 As Committees, before consideration and approval by the AHA
detailed in the sections that follow, stroke-prone individuals can Science Advisory and Coordinating Committee. Because of the
readily be identified and targeted for effective interventions. diverse nature of the topics covered, it was not possible to pro-
This guideline summarizes the evidence on established and vide a systematic, uniform summary of the magnitude of the
emerging stroke risk factors and represents an update of the last effect associated with each of the recommendations. As with
American Heart Association (AHA) statement on this topic, all therapeutic recommendations, patient preferences must be
published in 2011.9 Targets for stroke prevention have been considered. Risk factors, which directly increase disease prob-
reordered to align with the AHA’s public health campaign for ability and if absent or removed reduce disease probability,
ideal cardiovascular health known as Life’s Simple 7.10 As with or risk markers, which are attributes or exposures associated
the earlier document, the guideline addresses prevention of both with increased probability of disease but are not necessarily
hemorrhagic and ischemic stroke. The traditional definition of causal12 of a first stroke, were classified according to their
ischemic stroke as a clinical event is used in most instances out potential for modification.7 Although this distinction is some-
of necessity because of the design of most stroke prevention what subjective, risk factors considered both well documented
studies; however, where permitted by the evidence, the Writing and modifiable were those with clear, supportive epidemiolog-
Group has adopted the updated tissue-based definition of isch- ical evidence and evidence of risk reduction when modified
emic stroke as infarction of central nervous system tissue.11 in the context of randomized clinical trials. Less well-docu-
Differences in stroke risk among men and women are well mented or potentially modifiable risk factors were those either
recognized, and certain risk factors are specific to women’s with less clear epidemiological evidence or without evidence
health (eg, oral contraceptives [OCs] and hormone replace- from randomized clinical trials demonstrating a reduction of
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ment therapy). To increase awareness of these important stroke risk when modified.
issues and to provide sufficient coverage of the topic, the AHA
has issued a guideline on the prevention of stroke in women.11a Assessing the Risk of First Stroke
Key recommendations are summarized in the current docu- It may be helpful for healthcare providers and patients to be
ment but not reiterated in full. Readers are encouraged to able to estimate risk for a first stroke for an individual patient.
review the new guideline. Patients prefer being told their own individual risk through
The committee chair nominated Writing Group members the use of a global risk assessment tool, although it has only
on the basis of their previous work in relevant topic areas. a small effect on preferences for reducing risk and no effect
The AHA Stroke Council’s Scientific Statement Oversight on patient beliefs or behavior compared with standard risk
Committee and the AHA’s Manuscript Oversight Committee factor education.13 As detailed in other sections, numerous
approved all Writing Group members. In consultation with 2 individual factors can contribute to stroke risk. The levels
research librarians, we developed individual search strategies of evidence supporting a causal relationship among several
for each topic section and for each database to identify poten- of these factors and stroke vary, and specific or proven treat-
tially relevant studies from the PubMed, Ovid MEDLINE, Ovid ments for some may be lacking. Although most risk factors
Cochrane Database of Systematic Reviews, and Ovid Central have an independent effect, there may be important interac-
Register of Controlled Trials databases. The Internet Stroke tions between individual factors that need to be considered in
Center/Clinical Trials Registry (http://www.strokecenter.org/ predicting overall risk or choosing an appropriate risk modifi-
trials/) and National Guideline Clearinghouse (http://guideline. cation program. Risk assessment tools taking into account the
gov/) were also searched. Articles included were limited to those effect of multiple risk factors have been used in community
that were randomized, controlled trials; systematic reviews; stroke screening programs and in some guideline statements
meta-analyses; and in some cases, cohort studies. The database to select certain treatments for primary stroke prevention.14,15
searches were also limited to articles with English-language Some of the goals of such risk assessment tools are to identify
citations, with human subjects, and published between January people at elevated risk who might be unaware of their risk,
1, 2009, and varying end dates, (between October 2, 2012, and to assess risk in the presence of >1 condition, to measure an
December 6, 2012). Medical subject headings (MeSH) and key individual’s risk that can be tracked and lowered by appropri-
words, including stroke; ischemic attack, transient; cerebral ate modifications, to estimate risk for selecting treatments or
infarction; cerebral hemorrhage; ischemia; and cerebrovascular stratification in clinical trials, and to guide appropriate use of
disorders, in addition to select MeSH and key words on each further diagnostic testing.
topic, were used in the search strategy. The writers used sys- Although stroke risk assessment tools exist, the complexi-
tematic literature reviews covering the time period since the last ties of the interactions of risk factors and the effects of certain
3756 Stroke December 2014
A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not
lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.
*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior
myocardial infarction, history of heart failure, and prior aspirin use.
†For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve
direct comparisons of the treatments or strategies being evaluated.
risk factors stratified by age, sex, race/ethnicity, and geography atrial fibrillation (AF), and left ventricular hypertrophy on
are incompletely captured by available global risk assessment ECG. Additional refinements include a measure of carotid
tools. In addition, these tools tend to be focused and generally intima-media thickness (IMT); however, these refinements
do not include the full range of possible contributing factors. result in only a small improvement in 10-year risk predic-
Some risk assessment tools are sex specific and give 1-, 5-, or tion of first-time MI or stroke that is unlikely to be of clinical
10-year stroke risk estimates. The Framingham Stroke Profile importance.17 FSP scores can be calculated to estimate sex-spe-
(FSP) uses a Cox proportional hazards model with risk factors cific, 10-year cumulative stroke risk. The initial FSP has been
as covariates and points calculated according to the weight of updated to account for the use of antihypertensive therapy and
the model coefficients.16 Independent stroke predictors include the risk of stroke and stroke or death among individuals with
age, systolic blood pressure (SBP), hypertension, diabetes new-onset AF.18,19 Despite its widespread use, the validity of
mellitus, current smoking, established cardiovascular disease the FSP among individuals of different age ranges or belonging
(CVD; myocardial infarction [MI], angina or coronary insuffi- to different race/ethnic groups has been inadequately studied.
ciency, congestive heart failure, and intermittent claudication), The FSP has been applied to ethnic minorities in the United
Meschia et al Guidelines for the Primary Prevention of Stroke 3757
Table 2. Definition of Classes and Levels of Evidence Used in Recent guideline statements from the AHA/American
AHA/ASA Recommendations Stroke Association have emphasized the importance of includ-
Class I Conditions for which there is evidence ing both stroke and coronary heart disease events as outcomes
for and/or general agreement that in risk prediction instruments intended for primary preven-
the procedure or treatment is useful tion.24 The AHA/American College of Cardiology (ACC) CV
and effective. Risk Calculator is available online for use in estimating risk at
Class II Conditions for which there is conflicting http://my.americanheart.org/cvriskcalculator.
evidence and/or a divergence
of opinion about the usefulness/
Assessing the Risk of First Stroke: Summary
efficacy of a procedure or treatment.
and Gaps
Class IIa The weight of evidence or opinion is in
An ideal stroke risk assessment tool that is simple, is widely
favor of the procedure or treatment.
applicable and accepted, and takes into account the effects of
Class IIb Usefulness/efficacy is less well
multiple risk factors does not exist. Each available tool has limi-
established by evidence or opinion.
tations. Newer risk factors for stroke such as obstructive sleep
Class III Conditions for which there is evidence
apnea, not collected in older studies, need to be considered.25
and/or general agreement that the
procedure or treatment is not useful/
Risk assessment tools should be used with care because they
effective and in some cases may be do not include all the factors that contribute to disease risk.25
harmful. Some potential for harm exists from unnecessary application
Therapeutic recommendations of interventions that may result from inappropriate use of risk
Level of Evidence A Data derived from multiple randomized
assessment tools or from the use of poorly adjudicated tools. The
clinical trials or meta-analyses utility of the FSP or other stroke risk assessment scales as a way
Level of Evidence B Data derived from a single randomized
of improving the effectiveness of primary stroke prevention is
trial or nonrandomized studies not well studied. Research is needed to validate risk assessment
Level of Evidence C Consensus opinion of experts, case
tools across age, sex, and race/ethnic groups; to evaluate whether
studies, or standard of care any of the more recently identified risk factors add to the predic-
Diagnostic recommendations
tive accuracy of existing scales; and to determine whether the
use of these scales improves primary stroke prevention.
Level of Evidence A Data derived from multiple prospective
cohort studies using a reference
standard applied by a masked Assessing the Risk of First Stroke: Recommendations
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evaluator
1. The use of a risk assessment tool such as the AHA/
Level of Evidence B Data derived from a single grade A
study or one or more case-control ACC CV Risk Calculator (http://my.americanheart.
studies, or studies using a reference org/cvriskcalculator) is reasonable because these
standard applied by an unmasked tools can help identify individuals who could benefit
evaluator from therapeutic interventions and who may not be
Level of Evidence C Consensus opinion of experts treated on the basis of any single risk factor. These
calculators are useful to alert clinicians and patients
AHA/ASA indicates American Heart Association/American Stroke Association
of possible risk, but basing treatment decisions on
the results needs to be considered in the context of
Kingdom and found to vary across groups, but the suitability of the overall risk profile of the patient (Class IIa; Level
the scale to predict outcomes has not been fully established.20 of Evidence B).
Alternative prediction models have been developed using
other cohorts and different sets of stroke risk factors. Retaining
Generally Nonmodifiable Risk Factors
most of the Framingham covariates, one alternative stroke risk
scoring system omits cigarette smoking and antihypertensive
and Risk Assessment
medication and adds “time to walk 15 feet” and serum creati- Age
nine.21 Another score is derived from a mixed cohort of stroke The cumulative effects of aging on the cardiovascular sys-
and stroke-free patients and includes history of stroke, marital tem and the progressive nature of stroke risk factors over a
status, blood pressure (BP) as a categorical variable, high-den- prolonged period substantially increase the risk of ischemic
sity lipoprotein (HDL) cholesterol, impaired expiratory flow, stroke and intracerebral hemorrhage (ICH). An analysis of
physical disability, and a depression score.22 Several studies data from 8 European countries found that the combined risk
have generated risk assessment tools for use in patients with AF of fatal and nonfatal stroke increased by 9%/y in men and
(see Atrial Fibrillation). Risk models have also been developed 10%/y in women.26 The incidence of ICH increases with age
for other populations. For example, a stroke prediction model from <45 years to >85 years, and the incidence rates did not
derived for use in Chinese adults in Taiwan included age, sex, decrease between 1980 and 2006.27 Disturbing trends have
SBP, diastolic BP (DBP), family history of stroke, AF, and dia- been observed in the risk of stroke in younger individuals. In
betes mellitus and was found to have a discriminative capacity Greater Cincinnati/Northern Kentucky, the mean age of stroke
similar to or better than those of other available stroke models.23 decreased from 71.2 years in 1993 to 1994 to 69.2 years in
The model, however, has not been independently validated. 2005 because of an increase in the proportion of stroke in
3758 Stroke December 2014
individuals between 20 to 54 years of age.28 The Nationwide age was associated with a 3-fold increase in the risk of stroke in
Inpatient Sample showed that the rates of stroke hospitaliza- offspring.56 The odds of both monozygotic twins having strokes
tion increased for individuals between 25 and 34 years of is 1.65-fold higher than for dizygotic twins.55 Stroke heritabil-
age and between 35 and 44 years of age from 1998 to 2007.29 ity estimates vary with age, sex, and stroke subtype.57,58 Younger
Stroke occurring at younger ages has the potential to cause stroke patients are more likely to have a first-degree relative with
greater lifetime impairment and disability. The Framingham stroke.57 Women with stroke are more likely than men to have a
Heart Study estimated the lifetime risk of stroke to be 1 in 6 or parental history of stroke.58 Recent estimates of heritability using
more for middle-aged adults.30 genome-wide common variant single-nucleotide polymorphism
(SNP) data show similar heritability for cardioembolic (32.6%)
Low Birth Weight and large-vessel disease (40.3%) but lower heritability for small-
Low birth weight has been associated in several populations vessel disease (16.1%).59 These estimates, however, do not con-
with risk of stroke in later life. Stroke mortality rates among sider the potential contribution of rare variants.
adults in England and Wales are higher among people with Genetic influences on stroke risk can be considered on the
lower birth weights.31 The mothers of these low-birth-weight basis of their influence on individual risk factors, the genet-
babies were typically poor, were malnourished, had poor ics of common stroke types, and uncommon or rare familial
overall health, and were generally socially disadvantaged.31 A causes of stroke. Many of the established and emerging risk
similar study compared a group of South Carolina Medicaid factors that are described in the sections that follow such as
beneficiaries <50 years of age who had stroke with population arterial hypertension, diabetes mellitus, and hyperlipidemia
control subjects.32 The odds of stroke was more than double have both genetic and environmental or behavioral compo-
for those with birth weights <2500 g compared with those nents.60–62 Genome-wide association studies have identified
weighing 4000 g (with a significant linear trend for intermedi- common genetic variants for these risk factors. Studies that
ate birth weights). A US nationally representative longitudinal assess the effect of the cumulative burden of risk alleles of
study found an odds ratio (OR) of 2.16 (P<0.01) for low-birth- stroke risk factors, as measured by a so-called genetic risk
weight babies compared with normal-birth-weight babies for score, are beginning to emerge. For example, the burden of
the risk of stroke, MI, or heart disease by 50 years of age.33 risk alleles for elevated BP was associated with a modest but
Differences in birth weight may reflect differences in birth- significant increase in risk for ICH (OR, 1.11; 95% CI, 1.02–
place, and these geographic differences may relate to differ- 1.21; P=0.01) in 1025 cases and 1247 controls of European
ences in stroke mortality.34 Whether the association of birth ancestry.63 Whether a genetic risk score will provide clini-
weight with stroke risk is causal remains to be clarified. cally useful information beyond that afforded by clinical risk
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near the HDAC9 gene, encoding a protein involved in histone Enzyme replacement therapy appears to improve cerebral ves-
deacetylation.76,77 A variant in the PRKCH gene encoding a sel function. Two prospective, randomized studies using human
protein kinase has been associated with small-vessel stroke recombinant lysosomal α-galactosidase A found a reduction in
in Asians.78 The genetic variants described to date account for microvascular deposits and reduced plasma levels of globotri-
only a small proportion of stroke risk. Even combined, their aosylceramide.89–91 These studies had short follow-up periods,
predictive value is likely to be low. and no reduction in stroke incidence was found. Agalsidase-α
Personalizing medicine through genetic testing has the and agalsidase-β given at the same dose of 0.2 mg/kg have
potential to improve the safety of primary prevention pharma- similar short-term effects in reducing left ventricular mass.85,92
cotherapies. For example, genetic variability in cytochrome Many coagulopathies are inherited as autosomal-dominant
P450 2C9 (CYP2C9), vitamin K oxide reductase complex 1 traits.93 These disorders, including protein C and S deficien-
(VKORC1), and rare missense mutations in the factor IX pro- cies, the factor V Leiden mutation, and various other factor
peptide affect sensitivity of patients to vitamin K antagonists. deficiencies, can lead to an increased risk of cerebral venous
This has led to testing of various genotype-guided dosing thrombosis.94–97 As discussed below, there has not been a
protocols. A 12-week randomized trial of 455 patients treated strong association between several of these disorders and
with warfarin showed significantly more time in therapeutic arterial events such as MI and ischemic stroke.98,99 Some
range for the international normalized ratio (INR) for patients apparently acquired coagulopathies such as the presence of a
assigned to the genotype-guided dosing regimen versus stan- lupus anticoagulant or anticardiolipin antibody (aCL) can be
dard dosing (67.4% versus 60.3%; P<0.001).79 A 4-week ran- familial in ≈10% of cases.100,101 Inherited disorders of various
domized trial of 1015 patients treated with warfarin showed no clotting factors (ie, factors V, VII, X, XI, and XIII) are auto-
significant difference in the time in therapeutic range for the somal-recessive traits and can lead to cerebral hemorrhage
INR (45.2% versus 45.4%; P=0.91).80 A 12-week randomized in infancy and childhood.102 Arterial dissections, moyamoya
trial of 548 patients treated with acenocoumarol or phencou- syndrome, and fibromuscular dysplasia have a familial com-
mon showed no significant difference in the time in therapeu- ponent in 10% to 20% of cases.103,104
tic range for the INR (61.6% versus 60.2%; P=0.52).81 Intracranial aneurysms are a feature of certain mendelian
A genome-wide association study of individuals taking disorders, including autosomal-dominant polycystic kidney
80 mg simvastatin identified common variants on SLCO1B1 disease and Ehlers-Danlos type IV syndrome (so-called vas-
that are associated with myopathy.82 This may prove useful cular Ehlers-Danlos). Intracranial aneurysms occur in ≈8%
in screening for patients being considered for simvastatin of individuals with autosomal-dominant polycystic kidney
therapy, although randomized validation studies demonstrat- disease and 7% with cervical fibromuscular dysplasia.105,106
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ing the clinical and cost-effectiveness of its use are lacking. Ehlers-Danlos type IV is associated with dissection of verte-
Several monogenic disorders are associated with stroke. bral and carotid arteries, carotid-cavernous fistulas, and intra-
Although rare, their effect on the individual patient is substan- cranial aneurysms.107
tial because individuals carrying a mutation are likely to develop Loss-of-function mutations in KRIT1, malcavernin, and
stroke or other clinical characteristics of disease. Thus, iden- PDCD10 genes cause cerebral cavernous malformation syn-
tification of the underlying gene for these disorders is impor- dromes CCM1, CCM2, and CCM3, respectively.108 Mutations in
tant for diagnosis, counseling, and patient management. With the amyloid precursor protein gene, cystatin C, gelsolin, and BRI2
the exception of sickle cell disease (SCD; discussed below), can cause inherited cerebral amyloid angiopathy syndromes.109
no treatment based specifically on genetic factors has yet been
shown to reduce incident stroke. Cerebral autosomal-dominant Genetic Factors: Summary and Gaps
arteriopathy with subcortical infarcts and leukoencephalopa- The cause of ischemic stroke remains unclear in as many as
thy is characterized by subcortical infarcts, dementia, migraine 35% of patients. The use of DNA sequence information, in
headaches, and white matter changes that are readily apparent conjunction with other “omics” (eg, transcriptomics, epig-
on brain magnetic resonance imaging (MRI).83 Cerebral autoso- enomics) and clinical information to refine stroke origin,
mal-dominant arteriopathy with subcortical infarcts and leuko- although promising, has not yet proven useful for guiding
encephalopathy is caused by any one of a series of mutations in preventive therapy. Genetic factors could arguably be clas-
the NOTCH3 gene.83,84 Genetic testing for NOTCH3 mutations sified as potentially modifiable, but because specific gene
is available. Retinal vasculopathy with cerebral leukodystrophy therapy is not presently available for most conditions, genetic
is caused by mutation in the TREX1 gene, a DNA exonuclease factors have been classified as nonmodifiable. It should be
involved in the response to oxidative DNA damage.85 Mutations recognized that treatments are available for some, such as
in the COL4A1 gene can cause leukoaraiosis and microbleeds Fabry disease and SCD.
and can present with ischemic or hemorrhagic stroke or as the
hereditary angiopathy with nephropathy, aneurysm, and muscle
Genetic Factors: Recommendations
cramps syndrome.86,87
Fabry disease is a rare inherited disorder that can also lead 1. Obtaining a family history can be useful in identify-
to ischemic stroke. It is caused by lysosomal α-galactosidase A ing people who may have increased stroke risk (Class
deficiency, which causes a progressive accumulation of globo- IIa; Level of Evidence A).
triaosylceramide and related glycosphingolipids.88 Deposition 2. Referral for genetic counseling may be considered for
affects mostly small vessels in the brain and other organs, patients with rare genetic causes of stroke (Class IIb;
although involvement of the larger vessels has been reported. Level of Evidence C).
3760 Stroke December 2014
3. Treatment of Fabry disease with enzyme replacement or light activity; RR, 0.72 for high intensity versus no or light
therapy might be considered, but has not been shown activity).111 In contrast, the prospective Northern Manhattan
to reduce the risk of stroke, and its effectiveness is Study (NOMAS) suggested that moderate- to high-intensity
unknown (Class IIb; Level of Evidence C). physical activity was protective against risk of ischemic stroke
4. Noninvasive screening for unruptured intracranial in men (hazard ratio [HR], 0.37; 95% CI, 0.18–0.78) but not
aneurysms in patients with ≥2 first-degree relatives women (HR, 0.93; 95% CI, 0.57–1.50).117 Increased physical
with SAH or intracranial aneurysms might be rea- activity has also been associated with a lower prevalence of
sonable (Class IIb; Level of Evidence C).110
brain infarcts.118 Vigorous physical activity, regardless of sex,
5. Noninvasive screening may be considered for unrup-
was associated with a decreased incidence of stroke in the
tured intracranial aneurysms in patients with auto-
somal-dominant polycystic kidney disease and ≥1 National Runners’ Health Study.119
relatives with autosomal-dominant polycystic kidney The protective effect of physical activity may be partly
disease and SAH or ≥1 relatives with autosomal- mediated through its role in reducing BP120 and controlling
dominant polycystic kidney disease and intracranial other risk factors for CVD,121,122 including diabetes melli-
aneurysm (Class IIb; Level of Evidence C). tus120 and excess body weight. Physical activity also reduces
6. Noninvasive screening for unruptured intracranial plasma fibrinogen and platelet activity and elevates plasma
aneurysms in patients with cervical fibromuscu- tissue plasminogen activator activity and HDL cholesterol
lar dysplasia may be considered (Class IIb; Level of concentrations.123–125 Physical activity may also exert positive
Evidence C). health effects by increasing circulating anti-inflammatory
7. Pharmacogenetic dosing of vitamin K antagonists cytokines, including interleukin-1 receptor antagonist and
may be considered when therapy is initiated (Class interleukin-10, and modulating immune function in addi-
IIb; Level of Evidence C). tional ways.126
8. Noninvasive screening for unruptured intracranial A large and generally consistent body of evidence from
aneurysms in patients with no more than 1 relative
prospective, observational studies indicates that routine physi-
with SAH or intracranial aneurysms is not recom-
cal activity prevents stroke. The 2008 physical activity guide-
mended (Class III; Level of Evidence C).
9. Screening for intracranial aneurysms in every car- lines for Americans recommend that adults should engage
rier of autosomal-dominant polycystic kidney disease in ≥150 min/wk of moderate-intensity (eg, fast walking) or
or Ehlers-Danlos type IV mutations is not recom- 75 min/wk of vigorous-intensity aerobic physical activity
mended (Class III; Level of Evidence C). (eg, running) or an equivalent combination of moderate- and
10. Genetic screening of the general population for the vigorous-intensity aerobic activity. These guidelines also note
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prevention of a first stroke is not recommended (Class that some physical activity is better than none and that adults
III; Level of Evidence C). who participate in any amount of physical activity gain some
11. Genetic screening to determine risk for myopathy is health benefits.111 The 2013 AHA/ACC guideline on lifestyle
not recommended when initiation of statin therapy to reduce cardiovascular risk encourages moderate to vigorous
is being considered (Class III; Level of Evidence C). aerobic physical activity for at least 40 minutes at a time to be
done at least 3 to 4 d/wk for the purpose of reducing BP and
Well-Documented and Modifiable Risk Factors improving lipid profile.127
Physical Inactivity
Physical inactivity is associated with numerous adverse health Physical Inactivity: Summary and Gaps
effects, including an increased risk of total mortality, cardio- A sedentary lifestyle is associated with several adverse health
vascular morbidity and mortality, and stroke. The 2008 physi- effects, including an increased risk of stroke. Indeed, the
cal activity guidelines for Americans provide an extensive global vascular risk prediction scale including the addition of
review and conclude that physically active men and women physical activity, waist circumference, and alcohol consump-
generally have a 25% to 30% lower risk of stroke or mortality tion improved prediction of 10-year event rates in multiethnic
than the least active.111 Two meta-analyses of physical activ- communities compared with traditional Framingham vari-
ity reached the same conclusion.112,113 The benefits appear to ables.128 Clinical trials documenting a reduction in risk of a
occur from a variety of activities, including leisure-time phys- first or recurrent stroke with regular physical activity have not
ical activity, occupational activity, and walking. Overall, the been conducted. Evidence from observational studies is suf-
relationship between activity and stroke is not influenced by ficiently strong to make recommendations for routine physical
age or sex, but some data suggest linkages between these fac- activity to prevent stroke.127
tors and activity levels.114–116
The relationship between the amount or intensity of physi-
Physical Inactivity: Recommendations
cal activity and stroke risk remains unsettled and includes the
possibility of a sex interaction. One study suggested an increas- 1. Physical activity is recommended because it is associ-
ing benefit with greater intensity in women (median relative ated with a reduction in the risk of stroke (Class I;
risk [RR], 0.82 for all strokes for moderate-intensity versus Level of Evidence B).
no or light activity; RR, 0.72 for high-intensity versus no or 2. Healthy adults should perform at least moderate- to
light activity). In men, there was no apparent benefit of higher vigorous-intensity aerobic physical activity at least 40
intensity (median RR, 0.65 for moderate intensity versus no min/d 3 to 4 d/wk127 (Class I; Level of Evidence B).
Meschia et al Guidelines for the Primary Prevention of Stroke 3761
according to risk categories ranging from <5% to >30% 5-year Although the new guidelines shift focus away from specific
risk of a major cardiovascular event.158 The risk of major vas- lipid targets, values for total cholesterol and HDL are incor-
cular events was lowered by 21% (95% CI, 23–29) for each porated into the cardiovascular risk calculator, along with age,
39-mg/dL reduction in LDL cholesterol. For every 39-mg/dL sex, race, SBP, hypertension treatment, diabetes mellitus, and
reduction in LDL, there was a 24% (95% CI, 5–39) reduction cigarette smoking.
in the risk of stroke in participants with an estimated 5-year risk The benefits of lipid-modifying therapies other than statins
of major vascular events <10%, which was similar to the rela- on the risk of ischemic stroke are not established. A meta-
tionship seen in higher-risk categories. Similarly, another meta- analysis of 78 lipid-lowering trials involving 266 973 patients
analysis, which included 14 trials reporting stroke outcomes reported that statins decreased the risk of total stroke (OR,
in patients with an estimated 10-year risk of cardiovascular 0.85; 95% CI, 0.78–0.92), whereas the benefits of other lipid-
events of <20%, found that the RR of stroke was significantly lowering interventions were not significant, including diet
lower among statin recipients than among control subjects (RR, (OR, 0.92; 95% CI, 0.69–1.23), fibrates (OR, 0.98; 95% CI,
0.83; 95% CI, 0.74–0.94).159 In addition, in Justification for the 0.86–1.12), and other treatments (OR, 0.81; 95% CI, 0.61–
Use of statins in Prevention: An Intervention Trial Evaluating 1.08).170 Reduction in the risk of stroke is proportional to the
Rosuvastatin (JUPITER), statin treatment reduced the inci- reduction in total and LDL cholesterol; each 1% reduction in
dence of fatal and nonfatal stroke compared with placebo (HR, total cholesterol is associated with a 0.8% reduction in the risk
0.52; 95% CI, 0.34–0.79) in healthy men and women with LDL of stroke. Similarly, another meta-analysis of 64 randomized,
cholesterol levels <130 mg/dL and high-sensitivity C-reactive controlled trials reported that treatment-related decreases in
protein (hs-CRP) levels ≥2.0 mg/L.160 LDL cholesterol were associated with decreases in all strokes
Concerns about lowering of LDL cholesterol by statin (RR reduction, 4.5% per 10-mg/dL reduction; 95% CI, 1.7–
therapy increasing the risk of hemorrhagic stroke are not sup- 7.2); however, there was no relationship between triglycerides
ported. One meta-analysis of 31 trials comparing statin ther- and stroke.152
apy with a control reported that statin therapy decreased total Niacin increases HDL cholesterol and decreases plasma levels
stroke (OR, 0.84; 95% CI, 0.78–0.91) and found no difference of lipoprotein(a) [Lp(a)]. The Coronary Drug Project found that
in the incidence of ICH (OR, 1.08; 95% CI, 0.88–1.32).161 treatment with niacin reduced mortality in men with prior MI.171
These findings are consistent with another meta-analysis that In the Atherothrombosis Intervention in Metabolic Syndrome
included 23 randomized trials and found that statins were not with Low HDL/High Triglycerides: Impact on Global Health
associated with an increased risk of ICH (RR, 1.10; 95% CI, Outcomes (AIM-HIGH) study of patients with established CVD,
0.86–1.41).162 The intensity of cholesterol lowering did not the addition of extended-release niacin to intensive simvastatin
correlate with risk of ICH. therapy did not reduce the risk of a composite of cardiovascular
Meschia et al Guidelines for the Primary Prevention of Stroke 3763
events, which included ischemic stroke.172 In a meta-analysis of as recommended in the 2013 “ACC/AHA Guideline
11 studies comprising 9959 subjects, niacin use was associated on the Treatment of Blood Cholesterol to Reduce
with a significant reduction in cardiovascular events, including a Atherosclerotic Cardiovascular Risk in Adults”169
composite of cardiac death, nonfatal MI, hospitalization for acute (Class I; Level of Evidence A).
coronary syndrome, stroke, or revascularization procedure (OR, 2. Niacin may be considered for patients with low HDL
0.66; 95% CI, 0.49–0.89). There was an association between cholesterol or elevated Lp(a), but its efficacy in pre-
niacin therapy and coronary heart disease event (OR, 0.75; 95% venting ischemic stroke in patients with these con-
CI, 0.59–0.96) but not with the incidence of stroke (OR, 0.88; ditions is not established. Caution should be used
with niacin because it increases the risk of myopathy
95% CI, 0.5–1.54).173 However, there are serious safety concerns
(Class IIb; Level of Evidence B).
about niacin therapy. The Heart Protection Study 2—Treatment
3. Fibric acid derivatives may be considered for patients
of HDL to Reduce the Incidence of Vascular Events (HPS2-
with hypertriglyceridemia, but their efficacy in pre-
THRIVE) trial involving 25 693 patients at high risk for vascu- venting ischemic stroke is not established (Class IIb;
lar disease showed that extended-release niacin with laropiprant Level of Evidence C).
(a prostaglandin D2 signal blocker) caused a significant 4-fold 4. Treatment with nonstatin lipid-lowering therapies such
increase in the risk of myopathy in patients taking simvastatin.174 as fibric acid derivatives, bile acid sequestrants, niacin,
Fibric acid derivatives such as gemfibrozil, fenofibrate, and and ezetimibe may be considered in patients who cannot
bezafibrate lower triglyceride levels and increase HDL cho- tolerate statins, but their efficacy in preventing stroke is
lesterol. The Bezafibrate Infarction Prevention study, which not established (Class IIb; Level of Evidence C).
included patients with prior MI or stable angina and HDL cho-
lesterol ≤45 mg/dL, found that bezafibrate did not significantly
Diet and Nutrition
decrease either the risk of MI or sudden death (primary end point)
A large and diverse body of evidence has implicated several
or stroke (secondary end point).175 The Veterans Administration
aspects of diet in the pathogenesis of high BP, the major modifi-
HDL Intervention Trial of men with coronary artery disease and
able risk factor for ischemic stroke. A scientific statement from
low HDL cholesterol found that gemfibrozil reduced the risk
the AHA concluded that several aspects of diet lead to elevated
of all strokes, primarily ischemic strokes.176 In the Fenofibrate
BP.182 Specifically, dietary risk factors that are causally related to
Intervention and Event Lowering in Diabetes (FIELD) study,
elevated BP include excessive salt intake, low potassium intake,
fenofibrate neither decreased the composite primary end point
excessive weight, high alcohol consumption, and suboptimal
of coronary heart disease death or nonfatal MI nor decreased dietary pattern. Blacks are especially sensitive to the BP-raising
the risk of stroke. In the Action to Control Cardiovascular Risk
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obtain only 64% and 50% of the recommended daily con- with a lower risk of stroke. Additionally, a meta-analysis of
sumption of vegetables and fruits, respectively.188 prospective studies concluded that intake of fresh, processed,
A randomized, controlled trial of the Mediterranean diet and total red meat is associated with an increased risk of isch-
performed in 7447 individuals at high cardiovascular risk emic stroke.215 Potentially, the source of dietary protein may
showed that those on an energy-unrestricted Mediterranean affect stroke risk. In the absence of a clinical syndrome of a
diet supplemented by nuts (walnuts, hazelnuts, and almonds) specific vitamin or nutrient deficiency, there is no conclusive
had a lower risk of stroke than people on a control diet (3.1 evidence that vitamins or other supplements prevent incident
versus 5.9 strokes per 1000 person-years; P=0.003) and that stroke.
those on an energy-unrestricted Mediterranean diet supple-
mented by extra virgin olive oil had a lower risk of stroke Diet and Nutrition: Summary and Gaps
than people on a control diet (4.1 strokes per 1000 person- From epidemiological studies and randomized trials, it is
years; P=0.03).189 likely that diets low in sodium and rich in fruits and vegeta-
In ecological studies,190 prospective studies,191,192 and meta- bles, such as the Mediterranean and DASH-style diets, reduce
analyses,193,194 a higher level of sodium intake was associ- stroke risk. Few randomized trials with clinical outcomes have
ated with an increased risk of stroke. In prospective studies, been conducted. US Dietary Guidelines for Americans recom-
a higher level of potassium intake was also associated with mend a sodium intake of <2300 mg/d (100 mmol/d) for the
a reduced risk of stroke.195–198 It should be emphasized that general population. In blacks, individuals with hypertension,
a plethora of methodological limitations, particularly dif- those with diabetes mellitus, those with chronic kidney dis-
ficulties in estimating dietary electrolyte intake, hinder risk ease, and individuals ≥51 years of age, a sodium intake of
assessment and may lead to false-negative or even paradoxical <1500 mg is recommended.188 The AHA recommends <1500
results in observational studies. mg sodium per day.216 The ideal lower limit of dietary salt
One trial tested the effects of replacing regular salt (sodium intake remains ill defined and may depend on comorbidi-
chloride) with a potassium-enriched salt in elderly Taiwanese ties such as diabetes mellitus and heart failure managed with
men.199 In addition to increased overall survivorship and diuretic medications.217 US Dietary Guidelines for Americans
reduced costs, the potassium-enriched salt reduced the risk recommend that potassium intake be at least 4700 mg/d (120
of mortality from cerebrovascular disease (RR, 0.50). This mmol/d).188
trial did not present follow-up BP measurements; hence, it
is unclear whether BP reduction accounted for the beneficial Diet and Nutrition: Recommendations
effects of the intervention. In contrast, in the Women’s Health
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Initiative, a low-fat diet that emphasized consumption of 1. Reduced intake of sodium and increased intake of
whole grains, fruits, and vegetables did not reduce stroke inci- potassium as indicated in the US Dietary Guidelines
dence; however, the intervention did not achieve a substantial for Americans are recommended to lower BP (Class
increase in fruit and vegetable consumption (mean difference, I; Level of Evidence A).
only 1.1 servings per day) or decrease in BP (mean difference, 2. A DASH-style diet, which emphasizes fruits, vegeta-
<0.5 mm Hg for both SBP and DBP).200 bles, and low-fat dairy products and reduced satu-
The effects of sodium and potassium on stroke risk are rated fat, is recommended to lower BP127,218 (Class I;
likely mediated through direct effects on BP and effects inde- Level of Evidence A).
pendent of BP.201 In clinical trials, particularly dose-response 3. A diet that is rich in fruits and vegetables and thereby
studies, the relationship between sodium intake and BP is high in potassium is beneficial and may lower the risk
of stroke (Class I; Level of Evidence B).
direct and progressive, without an apparent threshold.202–204
4. A Mediterranean diet supplemented with nuts may
Blacks, hypertensives, and middle-aged and older adults are
be considered in lowering the risk of stroke (Class
especially sensitive to the BP-lowering effects of a reduced
IIa; Level of Evidence B).
sodium intake.205 In other trials, an increased intake of potas-
sium was shown to lower BP206 and to blunt the pressor effects
of sodium.207 Diets rich in fruits and vegetables, including Hypertension
those based on the Dietary Approaches to Stop Hypertension The Seventh Joint National Committee defined hypertension
(DASH) diet (rich in fruits, vegetables, and low-fat dairy as SBP >140 mm Hg and DBP >90 mm Hg.219 The most recent
products and reduced in saturated and total fat), lower BP.208– panel appointed by the National Heart, Lung, and Blood
210
As documented in a study by the Institute of Medicine,211 Institute to review hypertension management guidelines was
sodium intake remains high and potassium intake quite low in silent on the issue of defining hypertension but chose instead
the United States. to focus on defining BP thresholds for initiating or modify-
Other dietary factors may affect the risk of stroke, but the ing therapy.220 Hypertension is a major risk factor for both
evidence is insufficient to make specific recommendations.182 cerebral infarction and ICH. The relationship between BP and
In Asian countries, a low intake of animal protein, saturated stroke risk is strong, continuous, graded, consistent, indepen-
fat, and cholesterol has been associated with a decreased risk dent, predictive, and etiologically significant.221 Throughout
of stroke,212 but such relationships have been less apparent in the usual range of BPs, including the nonhypertensive range,
Western countries.213 A recent prospective study214 showed the higher the BP is, the greater the risk of stroke.222
that higher intake of red meat was associated with a higher The prevalence of hypertension has plateaued over the
risk of stroke, but a higher intake of poultry was associated past decade. On the basis of national survey data from 1999
Meschia et al Guidelines for the Primary Prevention of Stroke 3765
to 2000 and 2007 to 2008, the prevalence of hypertension in In a separate meta-analysis of 13 trials involving 80 594
the United States remained stable at 29%.223,224 Hypertension individuals, among those either with prevalent atherosclerotic
control has also improved over the past 25 years, with control disease or at high risk for developing it, angiotensin-convert-
rates of 27.3% measured in 1988 to 1994 and 50.1% measured ing enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor
in 2007 to 2008. The improved control is likely attributable to blocker (ARB) therapy reduced the risk of a composite primary
heightened awareness and treatment. Awareness of hyperten- outcome including stroke by 11%, without variability by base-
sion among US residents significantly increased from 69% in line BP.233 There was also a significant reduction in fatal and
1988 to 1994 to 81% in 2007 to 2008, and treatment improved nonfatal strokes (OR, 0.91; 95% CI, 0.86–0.97). Non–ACEI/
from 54% to 73% over the same period. Despite the improve- ARB therapies were allowed, but meta-regression analyses
ments, however, rates of control were lower among Hispanics provided evidence that the benefits were not due solely to BP
compared with whites and among those 18 to 39 years of age reductions during the trial. Several other meta-analyses have
compared with older individuals. evaluated whether specific classes of antihypertensive agents
BP, particularly SBP, rises with increasing age in both chil- offer protection against stroke beyond their BP-lowering
dren225 and adults.226 Individuals who are normotensive at 55 effects.230,234–237 In one of these meta-analyses evaluating differ-
years of age have a 90% lifetime risk for developing hyperten- ent classes of agents used as first-line therapy in subjects with
sion.227 More than two thirds of people ≥65 years of age are a baseline BP >140/90 mm Hg, thiazide diuretics (RR, 0.63;
hypertensive.221 95% CI, 0.57–0.71), β-blockers (RR, 0.83; 95% CI, 0.72–
Because the risk of stroke increases progressively with 0.97), ACEIs (RR, 0.65; 95% CI, 0.52–0.82), and calcium
increasing BP and because many individuals have a BP level channel blockers (RR, 0.58; 95% CI, 0.41–0.84) each reduced
below current drug treatment thresholds,220 nondrug or life- the risk of stroke compared with placebo or no treatment.236
style approaches are recommended as a means of reducing Compared with thiazides, β-blockers, ACEIs, and ARBs, cal-
BP in nonhypertensive individuals with an elevated BP (ie, cium channel blockers appear to have a slightly greater effect
pre-hypertension: 120 to 139 mm Hg SBP or 80 to 89 mm Hg on reducing the risk of stroke, although the effect is not seen
DBP).228 Pharmacological treatment of prehypertension for other cardiovascular outcomes and was of small magnitude
appears to reduce the risk of stroke. In a meta-analysis of 16 (8% relative reduction in risk).235 One meta-analysis found that
trials involving 70 664 prehypertensive patients, prehyperten- diuretic therapy was superior to ACEI therapy,230 and another
sive patients randomized to active antihypertensive treatment found that calcium channel blockers were superior to ACEIs.237
had a consistent and statistically significant 22% reduction Another found that β-blockers were less effective in reducing
in the risk of stroke compared with those taking placebo stroke risk than calcium channel blockers (RR, 1.24; 95%
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on other outcomes and in all subgroups of patients remain stroke risk reduction of treatments focused on reducing intra-
unclear. Among 11 trials with 42 572 participants, the RR of individual variability in BP and nocturnal BP changes seem
stroke for those whose SBP was <130 mm Hg was 0.80 (95% warranted.
CI, 0.70–0.92). The effect was greater among those with car- Controlling isolated systolic hypertension (SBP ≥160
diovascular risk factors but without established CVD.245 This mm Hg and DBP <90 mm Hg) in the elderly is also impor-
benefit of intensive BP lowering may be more specific to tant. The Systolic Hypertension in Europe (Syst-Eur) Trial
stroke than to other cardiovascular outcomes, at least among randomized 4695 patients with isolated systolic hypertension
certain subgroups of patients. Among patients with diabetes to active treatment with a calcium channel blocker or placebo
mellitus at high cardiovascular risk enrolled in the ACCORD and found a 42% (95% CI, 18–60; P=0.02) risk reduction in
Blood Pressure Trial, more intensive BP control (SBP the actively treated group.257 The Systolic Hypertension in the
<120 mm Hg) compared with standard control (<140 mm Hg) Elderly Program (SHEP) Trial found a 36% reduction (95%
led to a significant reduction in risk of stroke, a prespecified sec- CI, 18–50; P=0.003) in the incidence of stroke from a diuretic-
ondary outcome (HR, 0.59; 95% CI, 0.39–0.89).246,247 However, based regimen.258 In the Hypertension in the Very Elderly
there was no effect on either the primary composite outcome (HYVET) trial, investigators randomized 3845 patients ≥80
or overall mortality. This absence of benefit on nonstroke out- years of age with SBP ≥160 mm Hg to placebo or indap-
comes was not attributable to obesity because effects were simi- amide, with perindopril or placebo added as needed to target
lar across levels of obesity. A meta-analysis of 31 trials with a BP <150/80 mm Hg. After 2 years, there was a reduction in
73 913 individuals with diabetes mellitus demonstrated that SBP of 15 mm Hg, associated with a 30% reduction in risk of
more intensive BP reduction significantly reduced the risk of stroke (P=0.06), a 39% reduction in fatal stroke (P=0.046),
stroke but not MI.248 For every 5-mm Hg reduction in SBP, the and a 21% reduction in overall mortality (P=0.02).257 No trial
risk of stroke decreased by 13% (95% CI, 5–20). In a secondary has focused on individuals with lesser degrees of isolated sys-
analysis of the Losartan Intervention for Endpoint Reduction tolic hypertension (SBP=140–159 mm Hg; DBP <90 mm Hg).
in Hypertension (LIFE) trial, however, among 9193 hyperten- The most recent National Heart, Lung, and Blood Institute–
sive patients with left ventricular hypertrophy by ECG criteria, appointed panel provides an evidence-based approach to pharma-
achieving intensive BP control to <130 mm Hg was not associ- cological treatment of hypertension.220 The report focuses on age
ated with a reduction in stroke after multivariable adjustment, as a guide for therapeutic targets, with recommendations to lower
and there was a significant increase in all-cause mortality (HR, BP pharmacologically to a target of <150/90 mm Hg for patients
1.37; 95% CI, 1.10–1.71).249 The target for BP reduction, there- >60 years of age and target a BP of <140/90mm Hg for younger
fore, may differ by patient characteristics and comorbidities. patients. However, these recommendations differ from the 2014
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Pharmacogenomics may contribute to improving individu- science advisory on high BP control endorsed by the AHA,
alized selection of antihypertensive medications for stroke ACC, and Centers for Disease Control and Prevention in which
prevention. For example, in genetic studies ancillary to the more aggressive BP targets are recommended (<140/90 mm Hg)
Antihypertensive and Lipid Lowering to Prevent Heart Attack regardless of age.218 There is concern that raising the SBP thresh-
Trial (ALLHAT), individuals with the stromelysin (matrix old from 140 to 150 mm Hg might reverse some of the gains that
metalloproteinase-3) genotype 6A/6A had higher stroke rates have been achieved in reducing stroke by tighter BP control. For
on lisinopril than on chlorthalidone, and those with the 5A/6A patients with diabetes mellitus who are at least 18 years of age,
genotype had lower stroke rates on lisinopril.250 The 5A/5A the panel originally appointed by the National Heart, Lung, and
homozygotes had the lowest stroke rates compared with those Blood Institute to review the evidence on treatment of hyperten-
taking chlorthalidone (HR for interaction=0.51; 95% CI, 0.31– sion recommends initiating pharmacologic treatment to lower BP
0.85). The effect was not seen for other medications. Carriers at SBP of ≥140 mm Hg or DBP of ≥90 mm Hg and to treat to a
of mutations of the fibrinogen-β gene also had a lower risk goal SBP of <140 mm Hg and a goal DBP <90 mm Hg.220
of stroke on lisinopril compared with amlodipine than those The International Society on Hypertension in Blacks
who were homozygous for the usual allele, potentially because revised its recommendations for managing BP in this at-risk
ACEIs lower fibrinogen levels and this effect is more clinically population in 2010.259 In the absence of target-organ damage,
important among those with mutations associated with higher the target should be <135/85 mm Hg; in the presence of tar-
fibrinogen levels.251 The role of genetic testing in hypertension get-organ damage, the target should be <130/80 mm Hg. For
management remains undefined at present, however. patients who are within 10 mm Hg above target, monotherapy
Recent evidence suggests that intraindividual variability in with diuretic or calcium channel blocker is preferred, and for
BP may confer risk beyond that caused by mean elevations patients >15/10 mm Hg above target, 2-drug therapy is pre-
in BP alone.252 There is further observational evidence that ferred either with a calcium channel blocker plus renin-angio-
calcium channel blockers may have benefits in reducing BP tensin system blocker or, in edematous or volume-overloaded
variability that are not present with β-blockers and that these states, with a thiazide diuretic plus a renin-angiotensin system
benefits may provide additional benefits in stroke risk reduc- blocker. Largely on the basis of a prespecified subgroup analy-
tion.253,254 Twenty-four–hour ambulatory BP monitoring pro- sis of the ALLHAT trial, the National Heart, Lung, and Blood
vides additional insight into risk of stroke and cardiovascular Institute panel originally appointed to address hypertension
events. Measurements of nocturnal BP changes (“reverse dip- management recommend that in the general black population,
ping” or “extreme dipping”) and the ratio of nocturnal to day- including those with diabetes mellitus, initial antihypertensive
time BPs may provide data about risk beyond that provided therapy should include a thiazide-type diuretic or a calcium
by mean 24-hour SBP.255,256 Further study of the benefits on channel blocker.220
Meschia et al Guidelines for the Primary Prevention of Stroke 3767
Population-wide approaches to reducing BP have also Obesity and Body Fat Distribution
been advocated as more effective than approaches focused on Stroke, along with hypertension, heart disease, and diabetes
screening individual patients for the presence of hypertension mellitus, is associated with being overweight or obese. The
and treating them.235,260 Because the benefits of BP reduction prevalence of obesity in the United States has tripled for chil-
can be seen across the range of measurements in the popula- dren and doubled for adults since 1980.262 Only in the last
tion, with and without pre-existing CVD, it may be reason- 3 years has a leveling off been seen.263–265 Increasing public
able to provide BP-lowering medications to all patients above awareness and government initiatives have placed this public
a certain age (eg, 60 years of age).235 Similarly, on the basis of health issue in the forefront.
observational data from 19 cohorts with 177 025 participants According to the National Center for Health Statistics data
showing lower salt intake to be associated with a lower risk from the Department of Health and Human Services, in 2009
of stroke and other cardiovascular outcomes, population-wide and 2010, the prevalence of obesity was 35.7% among adults
reductions in salt intake may be advocated as a way to reduce and 16.9% among children, with a higher prevalence in adults
stroke risk.194 Self-measured BP monitoring is recommended >60 years of age and adolescents.263–265 Among the race/eth-
because with or without additional support such monitoring nic groups surveyed in the United States, age-adjusted rates
lowers BP compared with usual care.261 of obesity indicate the highest rates in non-Hispanic blacks
(49.5%), followed by Mexican Americans (40.45%) and then
Hypertension: Summary and Gaps all Hispanics (39.1%), with the lowest rate being among non-
Hypertension remains the most important, well-documented Hispanic whites (34.3%).263–265
modifiable stroke risk factor, and treatment of hypertension is A patient’s body mass index (BMI), defined as weight in
among the most effective strategies for preventing both isch- kilograms divided by the square of the height in meters, is used
emic and hemorrhagic stroke. Across age groups, including to distinguish overweight (BMI, 25 to 29 kg/m2) from obesity
adults ≥80 years of age, the benefit of hypertension treatment (BMI >30 kg/m2) and morbid obesity (BMI >40 kg/m2).266 Men
in preventing stroke is clear. Reduction in BP is generally presenting with a waist circumference of >102 cm (40 in) and
more important than the specific agents used to achieve this women with a waist circumference >88 cm (35 in) are catego-
goal. Optimal BP targets for reducing stroke risk are uncer- rized as having abdominal obesity.267 Abdominal obesity can also
tain. Although the benefits of BP reduction on stroke risk be measured as the waist-to-hip ratio. For every 0.01 increase in
continue to be seen at progressively lower pressures, adverse waist-to-hip ratio, there is a 5% increase in risk of CVD.268
effects on mortality and other outcomes may limit the lower Abdominal body fat has proved to be a stronger predictor of
level to which BP targets can be pushed, particularly among stroke risk than BMI.269,270 In contrast, another study reported
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certain subgroups of patients such as patients with diabetes that in men only BMI was significantly associated with stroke,
mellitus. Future studies are needed to determine the effects of whereas for women it was waist-to-hip ratio.271 Adiposity, how-
treating BP variability beyond the effects of treatment of mean ever, correlated with risk of ischemic heart disease for both sexes.
BP levels. Hypertension remains undertreated in the commu- When fat distribution measured by dual-energy x-ray absorpti-
nity, and additional programs to improve treatment adherence ometry in relation to incidence of stroke was studied, there was
need to be developed, tested, and implemented. Both person- a significant association in both men and women between stroke
alized approaches to pharmacotherapy based on pharmacoge- and abdominal fat mass. This association, however, was not
netics and population-level approaches to reducing BP require independent of diabetes mellitus, smoking, and hypertension.272
further study. Mounting evidence shows a graded positive relationship
between stroke and obesity independent of age, lifestyle, or
Hypertension: Recommendations other cardiovascular risk factors. Prospective studies of the
relationship between weight (or measures of adiposity) and
1. Regular BP screening and appropriate treatment of incident stroke indicate that in the BMI range of 25 to 50 kg/
patients with hypertension, including lifestyle modi- m2 there was a 40% increased stroke mortality with each 5-kg/
fication and pharmacological therapy, are recom- m2 increase in BMI. However, in the BMI range of 15 to 24 kg/
mended (Class I; Level of Evidence A). m2, there was no relationship between BMI and mortality.273
2. Annual screening for high BP and health-promoting A meta-analysis of data from 25 studies involving >2.2
lifestyle modification are recommended for patients
million people and >30 000 events found an RR for ischemic
with prehypertension (SBP of 120 to 139 mm Hg or
stroke of 1.22 (95% CI, 1.05–1.41) for overweight people and
DBP of 80 to 89 mm Hg) (Class I; Level of Evidence A).
1.64 (95% CI, 1.36–1.99) for obese people.274 For hemor-
3. Patients who have hypertension should be treated
with antihypertensive drugs to a target BP of <140/90 rhagic stroke, the RR was 1.01 (95% CI, 0.88–1.17) for over-
mm Hg (Class I; Level of Evidence A). weight people and 1.24 (95% CI, 0.99–1.54) for obese people.
4. Successful reduction of BP is more important in This meta-analysis showed an increased risk of ischemic
reducing stroke risk than the choice of a specific stroke compared with normal-weight individuals of 22% in
agent, and treatment should be individualized on the overweight individuals and 64% in obese individuals. When
basis of other patient characteristics and medication diabetes mellitus, hypertension, dyslipidemia, and other con-
tolerance (Class I; Level of Evidence A). founders were taken into account, there was no significant
5. Self-measured BP monitoring is recommended to increase in the incidence of hemorrhagic stroke. These find-
improve BP control. (Class I; Level of Evidence A). ings have been subsequently borne out in a Chinese study of
3768 Stroke December 2014
27 000 patients.275 In Japan, a meta-analysis of 44 000 patients adult Americans had diabetes mellitus.283 Moreover, the preva-
found a positive correlation in both sexes of elevated BMI lence of prediabetes among Americans >65 years of age tested
with both ischemic and hemorrhagic events.276 ARIC exam- in 2005 through 2008 was estimated to be 50%.283
ined a population of 13 000 black and white participants and Diabetes mellitus is an independent risk factor for stroke.284
found that obesity was a risk factor for ischemic stroke inde- Diabetes mellitus more than doubles the risk for stroke, and
pendently of race.277 Adjustments for covariates in all these ≈20% of patients with diabetes mellitus will die of stroke.
studies significantly reduced these associations. Duration of diabetes mellitus also increases the risk of non-
The effects of stroke risk and weight reduction have not hemorrhagic stroke (by 3%/y of diabetes duration).284 For
been studied extensively. A Swedish study that followed 4000 those with prediabetes, fasting hyperglycemia is associated
patients over 10 to 20 years, comparing individuals with weight with stroke.285 In a study of 43 933 men (mean age, 44.3±9.9
loss through bariatric surgery and obese subjects receiving usual years) free of known CVD and diabetes mellitus at baseline
care, showed significant reductions in diabetes mellitus, MI, and between 1971 and 2002, a total of 595 stroke events (156
stroke.278 Thirty-six thousand Swedish subjects followed for >13 fatal and 456 nonfatal strokes) occurred. Age-adjusted fatal,
years again showed a significant decrease in stroke incidence
nonfatal, and total stroke event rates per 10 000 person-years
when more than 3 healthy lifestyle goals, including normal
for normal fasting plasma glucose (80–109 mg/dL), impaired
weight, were met.279 The Sibutramine Cardiovascular Outcomes
fasting glucose (110–125 mg/dL), and undiagnosed diabetes
(SCOUT) trial followed up 10 000 patients with CVD or type 2
mellitus (≥126 mg/dL) were 2.1, 3.4, and 4.0 (Ptrend=0.002);
diabetes mellitus and found that even modest weight loss reduced
10.3, 11.8, and 18.0 (Ptrend=0.008); and 8.2, 9.6, and 12.4
cardiovascular mortality in the following 4 to 5 years.280 Reduction
in body weight improves control of hypertension. A meta-analysis (Ptrend=0.008), respectively.285
of 25 trials showed mean SBP and DBP reductions of 4.4 and 3.6 In the Greater Cincinnati/Northern Kentucky Stroke Study,
mm Hg, respectively, with a 5.1-kg weight loss.281 ischemic stroke patients with diabetes mellitus were younger,
The US Preventive Services Task Force currently recom- more likely to be black, and more likely to have hypertension,
mends that all adults be screened for obesity and that patients MI, and high cholesterol than patients without diabetes mel-
with a BMI of ≥30 kg/m2 be referred for intensive multicom- litus.286 Age-specific incidence rates and rate ratios showed that
ponent behavioral interventions for weight loss.282 diabetes mellitus increased ischemic stroke incidence for all ages
but that the risk was most prominent before 55 years of age in
Obesity and Body Fat Distribution: Summary blacks and before 65 years of age in whites. Although Mexican
and Gaps Americans had a substantially greater incidence rate for the com-
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Although there is ample evidence that increased weight is associ- bination of ischemic stroke and ICH than non-Hispanic whites,40
ated with an increased incidence of stroke, with stronger associa- there is insufficient evidence that the presence of diabetes mel-
tions for ischemic events, many questions remain unanswered. litus or other forms of glucose intolerance influenced this rate. In
There is no clear and compelling evidence that weight loss in the Strong Heart Study (SHS), 6.8% of 4549 Native American
isolation reduces the risk of stroke because of the difficulty in participants 45 to 74 years of age at baseline without prior stroke
isolating the effects of weight loss as a single contributing fac- had a first stroke over 12 to 15 years, and diabetes mellitus and
tor rather than as a component contributing to better control of impaired glucose tolerance increased the HR to 2.05.43
hypertension, diabetes mellitus, metabolic syndrome, and other In NOMAS, which included 3298 stroke-free community
stroke risk factors. It remains to be determined whether the dis- residents, 572 reported a history of diabetes mellitus, and 59%
parities among studies stem from choosing BMI, waist-to-hip (n=338) had elevated fasting blood glucose.287 Those subjects
ratio, or waist circumference as the measure of obesity. with an elevated fasting glucose had an increased stroke risk
(HR, 2.7; 95% CI, 2.0–3.8), but those with a fasting blood
Obesity and Body Fat Distribution: glucose level of <126 mg/dL were not at increased risk.
Recommendations Stroke risk can be reduced in patients with diabetes mellitus.
In the Steno-2 Study, 160 patients with type 2 diabetes mellitus
1. Among overweight (BMI=25 to 29 kg/m2) and obese and persistent microalbuminuria were assigned to receive either
(BMI >30 kg/m2) individuals, weight reduction is intensive therapy, including behavioral risk factor modification
recommended for lowering BP (Class I; Level of and the use of a statin, an ACEI, an ARB, or an antiplatelet drug
Evidence A). as appropriate, or conventional therapy with a mean treatment
2. Among overweight (BMI=25 to 29 kg/m2) and obese
period of 7.8 years.288 Patients were subsequently followed up for
(BMI >30 kg/m2) individuals, weight reduction is rec-
an average of 5.5 years. The primary end point was time to death
ommended for reducing the risk of stroke (Class I;
Level of Evidence B). resulting from any cause. The risk of cardiovascular events was
reduced by 60% (HR, 0.41; 95% CI, 0.25–0.67; P<0.001) with
intensive versus conventional therapy, and strokes were reduced
Diabetes Mellitus from 30 to 6. In addition, intensive therapy was associated with
People with diabetes mellitus have both an increased suscepti- a 57% lower risk of death from cardiovascular causes (HR, 0.43;
bility to atherosclerosis and an increased prevalence of athero- 95% CI, 0.19–0.94; P=0.04). Eighteen of the 30 strokes were
genic risk factors, notably hypertension and abnormal blood fatal in the conventional group, and all 6 were fatal in the inten-
lipids. In 2010, an estimated 20.7 million adults or 8.2% of sive group.
Meschia et al Guidelines for the Primary Prevention of Stroke 3769
In the Euro Heart Survey on Diabetes and the Heart, 3488 can be accomplished with good adherence but with more fre-
patients were enrolled, 59% without and 41% with diabetes quent episodes of severe hypoglycemia.297 Although glyce-
mellitus.289 Evidence-based medicine was defined as the com- mia was similar between the groups over a mean 17 years of
bined use of renin-angiotensin-aldosterone system inhibitors, follow-up in the Diabetes Control and Complications Trial/
β-adrenergic receptor blockers, antiplatelet agents, and statins. Epidemiology of Diabetes Interventions and Complications
In patients with diabetes mellitus, the use of evidence-based (DCCT/EDIC) study, intensive treatment reduced the risk of
medicine (RR, 0.37; 95% CI, 0.20–0.67; P=0.001) had an any CVD event by 42% (95% CI, 9–63; P=0.02) and the com-
independent protective effect on 1-year mortality and on car- bined risk nonfatal MI, stroke, or death from CVD events by
diovascular events (RR, 0.61; 95% CI, 0.40–0.91; P=0.015) 57% (95% CI, 12–79; P=0.02).298 The decrease in glycated
compared with those without diabetes mellitus. Although hemoglobin was associated with the positive effects of inten-
stroke rates were not changed, there was an ≈50% reduction sive treatment on the overall risk of CVD. There were too few
in cerebrovascular revascularization procedures. strokes, however, to evaluate the effect of improved glycemia
during the trial, and as with type 2 diabetes mellitus, there
Glycemic Control remains no evidence that tight glycemic control reduces risk
The effect of previous randomization of the UK Prospective of stroke.
Diabetes Study (UKPDS)290 to either conventional therapy Despite the lack of convincing support from any individual
(dietary restriction) or intensive therapy (either sulfonylurea clinical trial for intensified glycemic control to reduce stroke
or insulin or, in overweight patients, metformin) for glucose incidence in patients with diabetes mellitus, a recent meta-
control was assessed in an open-label extension study. In post- analysis provided some supportive evidence in a subgroup of
trial monitoring, 3277 patients were asked to attend UKPDS patients with diabetes mellitus. From 649 identified studies,
clinics annually for 5 years; however, there were no attempts the authors identified 9 relevant trials, which provided data
to maintain their previously assigned therapies.291 A reduction for 59 197 patients and 2037 stroke events.299 Overall, inten-
in MI and all-cause mortality was found; however, stroke inci- sive control of glucose compared with usual care had no effect
dence was not affected by assignment to either sulfonylurea/ on incident stroke (RR, 0.96; 95% CI, 0.88–1.06; P=0.445);
insulin or metformin treatment. however, in a stratified analyses, a beneficial effect was seen
Three major recent trials have evaluated the effects of in patients with diabetes mellitus and a BMI >30 kg/m2 (RR,
reduced glycemia on CVD events in patients with type 2 dia- 0.86; 95% CI, 0.75–0.99; P=0.041).
betes mellitus. The ACCORD recruited 10 251 patients (mean
age, 62 years) with a mean glycated hemoglobin of 8.1%.292 Diabetes Mellitus and Hypertension
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Participants were then randomized to receive intensive (gly- More aggressive lowering of BP in patients with diabetes mel-
cated hemoglobin goal, <6.0%) or standard (goal, 7.0%–7.9%) litus and hypertension reduces stroke incidence.300 In addition
therapy. The study was stopped earlier than planned because to comparing the effects of more intensive glycemic control
of an increase in all-cause mortality in the intensive therapy and standard care on the complications of type 2 diabetes
group with no difference in the numbers of fatal and nonfatal mellitus, the UKPDS found that tight BP control (mean BP,
strokes. The Action in Diabetes and Vascular Disease: Preterax 144/82 mm Hg) resulted in a 44% reduction (95% CI, 11–65;
and Diamacron MR Controlled Evaluation (ADVANCE) Trial P=0.013) in the risk of stroke compared with more liberal
included 11 140 patients (mean age, 66.6 years) with type 2 control (mean BP, 154/87 mm Hg).301 There was also a nonsta-
diabetes mellitus and used a number of strategies to reduce tistically significant 22% (RR, 0.78; 95% CI, 0.45–1.34) risk
glycemia in an intensive treatment group.293 Mean glycated reduction with antihypertensive treatment in subjects with dia-
hemoglobin levels were 6.5% versus 7.4% at 5 years, with betes mellitus in SHEP.302 In UKPDS, 884 patients with type
no effect of more intensive therapy on the risk of CVD events 2 diabetes mellitus who attended annual UKPDS clinics for 5
or on the risk of nonfatal strokes between groups. In another years after study completion were evaluated.303 Differences in
study, 1791 US veterans (Veterans Affairs Diabetes Trial) with BP between the 2 groups, standard of care and more aggres-
an average duration of diabetes mellitus of >10 years (mean sive BP lowering, disappeared within 2 years. There was a
age, 60.4 years) were randomized to a regimen to decrease nonsignificant trend toward reduction in stroke with more
glycated hemoglobin by 1.5% or standard care.294 After 5.6 intensive BP control (RR, 0.77; 95% CI, 0.55–1.07; P=0.12).
years, the mean levels of glycated hemoglobin were 6.9% Continued efforts to maintain BP targets might have led to
versus 8.4%, with no difference in the number of macrovas- maintenance of the benefit.
cular events, including stroke, between the 2 groups.295 From The Heart Outcomes Prevention Evaluation (HOPE) study
the available clinical trial results, there is no evidence that compared the addition of an ACEI to the current medical regi-
reduced glycemia decreases the short-term risk of macrovas- men in high-risk patients. The substudy of 3577 patients with
cular events, including stroke, in patients with type 2 diabetes diabetes mellitus with a previous cardiovascular event or an
mellitus. A glycated hemoglobin goal of <7.0% has been rec- additional cardiovascular risk factor (total population, 9541
ommended by the American Diabetes Association to prevent participants) showed a reduction in the ACEI group in the
long-term microangiopathic complications in patients with primary combined outcome of MI, stroke, and cardiovascular
type 2 diabetes mellitus.296 Whether control to this level also death by 25% (95% CI, 12–36; P=0.0004) and stroke by 33%
reduces the long-term risk of stroke requires further study. In (95% CI, 10–50; P=0.0074).304 Whether these benefits repre-
patients with recent-onset type I diabetes mellitus, intensive sent a specific effect of the ACEI or were simply the result of
diabetes therapy aimed at achieving near-normal glycemia BP lowering remains unclear. The LIFE study compared the
3770 Stroke December 2014
effects of an ARB with a β-adrenergic receptor blocker in 9193 Two recent meta-analyses investigated the effect of BP
people with essential hypertension (160–200/95–115 mm Hg) lowering in patients with type 2 diabetes mellitus. The first
and electrocardiographically determined left ventricular hyper- included 37 760 patients with type 2 diabetes mellitus or
trophy over 4 years.305 BP reductions were similar for each impaired fasting glucose/impaired glucose tolerance with
group. The 2 regimens were compared among the subgroup achieved SBP of ≤135 versus ≤140 mm Hg, and the follow-up
of 1195 people who also had diabetes mellitus in a prespeci- was at least 1 year.310 Intensive BP control was associated with
fied analysis.306 There was a 24% reduction (RR, 0.76; 95% a 10% reduction in all-cause mortality (OR, 0.90; 95% CI,
CI, 0.58–0.98) in major vascular events and a nonsignificant 0.83–0.98) and a 17% reduction in stroke, but there was a 20%
21% reduction (RR, 0.79; 95% CI, 0.55–1.14) in stroke among increase in serious adverse effects. Meta-regression analysis
those treated with the ARB. showed continued risk reduction for stroke to a SBP of <120
The ADVANCE Trial also determined whether a fixed mm Hg. However, at levels of <130 mm Hg, there was a 40%
combination of perindopril and indapamide or matching pla- increase in serious adverse events with no benefit for other
cebo in 11 140 patients with type 2 diabetes mellitus would outcomes.
decrease major macrovascular and microvascular events.307 In the second meta-analysis, 73 913 patients with diabetes
After 4.3 years of follow-up, subjects assigned to the com- mellitus (295 652 patient-years of exposure) were randomized
bination had a mean reduction in BP of 5.6/2.2 mm Hg. The in 31 intervention trials.248 Overall, more aggressive treatment
risk of a composite of major macrovascular and microvascu- reduced stroke incidence by 9% (P=0.006), and lower versus
lar events was reduced by 9% (HR, 0.91; 95% CI, 0.83–1.00; less aggressive BP control reduced the risk of stroke by 31%
P=0.04), but there was no reduction in the incidence of major (RR, 0.61; 95% CI, 0.48–0.79). In a meta-regression analy-
macrovascular events, including stroke. sis, the risk of stroke decreased by 13% (95% CI, 0.05–0.20;
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), P=0.002) for each 5-mm Hg reduction in SBP and by 11.5%
the effects of 2 antihypertensive treatment strategies (amlodipine (95% CI, 0.05–0.17; P<0.001) for each 2-mm Hg reduction
with the addition of perindopril as required [amlodipine-based] in DBP.
or atenolol with addition of thiazide as required [atenolol-
based]) for the prevention of major cardiovascular events were Lipid-Altering Therapy and Diabetes Mellitus
compared in 5137 patients with diabetes mellitus.308 The target Although secondary subgroup analyses of some studies did not
BP was <130/80 mm Hg. The trial was terminated early because find a benefit of statins in patients with diabetes mellitus,311,312
of reductions in mortality and stroke with the amlodipine-based the Medical Research Council/British Heart Foundation Heart
regimen. In patients with diabetes mellitus, the amlodipine- Protection Study (HPS) found that the addition of a statin to
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based therapy reduced the incidence of total cardiovascular existing treatments in high-risk patients resulted in a 24%
events and procedures compared with the atenolol-based regi- reduction (95% CI, 19–28) in the rate of major CVD events.313
men (HR, 0.86; 95% CI, 0.76–0.98; P=0.026), including a 25% A 22% reduction (95% CI, 13–30) in major vascular events
reduction (P=0.017) in fatal and nonfatal strokes. (regardless of the presence of known coronary heart disease
The open-label ACCORD trial randomized trial 4733 par- or cholesterol levels) and a 24% reduction (95% CI, 6–39;
ticipants to 1 of 2 groups with different treatment goals: SBP P=0.01) in strokes were found among 5963 diabetic individu-
<120 mm Hg as the more intensive goal and SBP <140 mm Hg als treated with the statin in addition to best medical care.314
as the less intensive goal. Randomization to the more intensive The Collaborative Atorvastatin Diabetes Study (CARDS)
goal did not reduce the rate of the composite outcome of fatal reported that in patients with type 2 diabetes mellitus, at least
and nonfatal major CVD events (HR, 0.88; 95% CI, 0.73–1.06; 1 additional risk factor (retinopathy, albuminuria, current
P=0.20). Stroke was a prespecified secondary end point occur- smoking, or hypertension), and an LDL cholesterol level <160
ring at annual rates of 0.32% (more intensive) and 0.53% (less mg/dL but without a history of CVD, treatment with a statin
intensive) treatment (HR, 0.59; 95% CI, 0.39–0.89; P=0.01).247 resulted in a 48% reduction (95% CI, 11–69) in stroke.315
In the Avoiding Cardiovascular Events in Combination In a post hoc analysis of the Treating to New Targets (TNT)
Therapy in Patients Living with Systolic Hypertension study, the effects of intensive lowering of LDL cholesterol
(ACCOMPLISH) trial, 11 506 patients (6746 with diabetes with high-dose (80 mg daily) versus low-dose (10 mg daily)
mellitus) with hypertension were randomized to treatment atorvastatin on CVD events were compared for patients with
with benazepril plus amlodipine or benazepril plus hydro- coronary heart disease and diabetes mellitus.316 After a median
chlorothiazide.309 The primary end point was the composite follow-up of 4.9 years, higher-dose treatment was associated
of death resulting from CVD, nonfatal MI, nonfatal stroke, with a 40% reduction in the time to a CVD event (HR, 0.69;
hospitalization for angina, resuscitated cardiac arrest, and cor- 95% CI, 0.48–0.98; P=0.037).
onary revascularization. The trial was terminated early after a Clinical trials with a statin or any other single intervention
mean follow-up of 36 months when there were 552 primary in patients with high CVD risk, including the presence of dia-
outcome events in the benazepril/amlodipine group (9.6%) betes mellitus, are often insufficiently powered to determine
and 679 in the benazepril/hydrochlorothiazide group (11.8%), an effect on incident stroke. In 2008, data from 18 686 indi-
an absolute risk reduction of 2.2% (HR, 0.80; 95% CI, 0.72– viduals with diabetes mellitus (1466 with type 1 and 17 220
0.90; P<0.001). There was, however, no difference in stroke with type 2 diabetes mellitus) were assessed to determine the
between the groups. Of the participants in the ACCOMPLISH impact of a 1.0-mmol/l (≈40-mg/dL) reduction in LDL choles-
trial with diabetes mellitus, the primary outcome results were terol.317 During a mean follow-up of 4.3 years, there were 3247
similar. major cardiovascular events with a 9% proportional reduction
Meschia et al Guidelines for the Primary Prevention of Stroke 3771
in all-cause mortality per 1-mmol/L LDL cholesterol reduction Several large primary prevention trials have included subgroup
(RR, 0.91; 95% CI, 0.82–1.01; P=0.02) and a 13% reduction in analyses of patients with diabetes mellitus. The Antithrombotic
vascular death (RR, 0.87; 95% CI, 0.76–1.00; P=0.008). There Trialists’ Collaboration meta-analysis of 287 randomized trials
were also reductions in MI or coronary death (RR, 0.78; 95% reported effects of antiplatelet therapy (mainly aspirin) versus
CI, 0.69–0.87; P<0.0001) and stroke (RR, 0.79; 95% CI, 0.67– control in 135 000 patients.322 There was a nonsignificant 7%
0.93; P=0.0002). A subgroup analysis was carried out from reduction in serious vascular events, including stroke, in the
the Department of Veterans Affairs High-Density Lipoprotein subgroup of 5126 patients with diabetes mellitus.
Intervention Trial (VA-HIT) in which subjects received either A meta-analysis covering the interval between 1950 and 2011
gemfibrozil (1200 mg/d) or placebo for 5.1 years.318 Compared included 7 studies in patients with diabetes mellitus without
with those with normal fasting plasma glucose, the risk for previous CVD and helps to shed new light on this controversial
major cardiovascular events was higher in subjects with either topic.323 A total of 11 618 participants were included in the anal-
known (HR, 1.87; 95% CI, 1.44–2.43; P=0.001) or newly ysis. The overall relative risk for major cardiovascular events
diagnosed (HR, 1.72; 95% CI, 1.10–2.68; P=0.02) diabetes was 0.91 (95% CI, 0.82–1.00), but an effect on stroke incidence
mellitus. Gemfibrozil treatment did not affect the risk of stroke was not found (RR, 0.84; 95% CI, 0.64–1.11). Because hyper-
among subjects without diabetes mellitus, but treatment was glycemia reduces platelet sensitivity to aspirin,324 an important
associated with a 40% reduction in stroke in those with diabe- consideration in patients with diabetes mellitus is aspirin dose.
tes mellitus (HR, 0.60; 95% CI, 0.37–0.99; P= 0.046). In another meta-analysis, there was no evidence that aspirin dose
The FIELD study assessed the effect of fenofibrate on car- explained the lack of an aspirin effect on cardiovascular and
diovascular events in 9795 subjects 50 to 75 years of age with stroke mortality in patients with diabetes mellitus.325 However,
type 2 diabetes mellitus who were not taking a statin therapy the systematic review identified an important gap in random-
at study entry.319 The study population included 2131 people ized, controlled trials for using anywhere between 101 to 325
with and 7664 people without previous CVD. Over 5 years, mg aspirin daily in patients with diabetes mellitus.
5.9% of patients (n=288) on placebo and 5.2% (n=256) on
fenofibrate had a coronary event (P=0.16). There was a 24% Diabetes: Summary and Gaps
(RR, 0.76; 95% CI, 0.62–0.94; P=0.010) reduction in nonfatal A comprehensive program that includes tight control of hyper-
MI. There was no effect on stroke with fenofibrate. A higher tension with ACEI or ARB treatment reduces the risk of stroke
rate of statin therapy initiation occurred in patients allocated in people with diabetes mellitus. Glycemic control reduces
to placebo, which might have masked a treatment effect. The microvascular complications, but there remains no evidence that
ACCORD trial randomized 5518 patients with type 2 diabetes improved glycemic control reduces the risk of incident stroke.
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mellitus who were being treated with open-label simvastatin Adequately powered studies show that treatment of patients with
to double-blind treatment with fenofibrate or placebo.177 There diabetes mellitus with a statin decreases the risk of a first stroke.
was no effect of added fenofibrate on the primary outcome Although a subgroup analysis of VA-HIT suggests that gemfi-
(first occurrence of nonfatal MI, nonfatal stroke, or death brozil reduces stroke in men with diabetes mellitus and dyslip-
from cardiovascular causes [HR, 0.92; 95% CI, 0.79–1.08; idemia, a fibrate effect was not seen in FIELD, and ACCORD
P=0.32]) and no effect on any secondary outcome, including found no benefit of adding fenofibrate to statin. However, the
stroke (HR, 1.05; 95% CI, 0.71–1.56; P=0.80). subgroup analysis from fibrate trials suggests a benefit of fibrates
A recent meta-analysis examining the effects of fibrates on in patients with diabetes mellitus and a BMI >30 kg/m2.
stroke in 37 791 patients included some patients with diabetes
mellitus.320 Overall, fibrate therapy was not associated with a Diabetes: Recommendations
significant reduction on the risk of stroke (RR, 1.02; 95% CI,
0.90–1.16; P=0.78). However, a subgroup analysis suggested 1. Control of BP in accordance with an AHA/ACC/
that fibrate therapy reduced fatal stroke (RR, 0.49; 95% CI, CDC Advisory218 to a target of <140/90 mm Hg is rec-
0.26–0.93; P=0.03) in patients with diabetes mellitus, CVD, ommended in patients with type 1 or type 2 diabetes
or stroke. mellitus (Class I; Level of Evidence A).
2. Treatment of adults with diabetes mellitus with a
Diabetes Mellitus, Aspirin, and Stroke statin, especially those with additional risk factors, is
The benefit of aspirin in the primary prevention of cardiovascu- recommended to lower the risk of first stroke (Class
lar events, including stroke in patients with diabetes mellitus, I; Level of Evidence A).
remains unclear. A recent study at 163 institutions throughout 3. The usefulness of aspirin for primary stroke prevention
Japan enrolled 2539 patients with type 2 diabetes mellitus and for patients with diabetes mellitus but low 10-year risk
no history of atherosclerotic vascular disease.321 Patients were of CVD is unclear (Class IIb; Level of Evidence B).
assigned to receive low-dose aspirin (81 or 100 mg/d) or no 4. Adding a fibrate to a statin in people with diabetes
mellitus is not useful for decreasing stroke risk (Class
aspirin. Over 4.37 years, a total of 154 atherosclerotic vascu-
III; Level of Evidence B).
lar events occurred (68 in the aspirin group [13.6 per 1000
person-years] and 86 in the nonaspirin group [17.0 per 1000
person-years; HR, 0.80; 95% CI, 0.58–1.10; P=0.16]). Only a Cigarette Smoking
single fatal stroke occurred in the aspirin group, but 5 strokes Virtually every multivariable assessment of stroke risk factors
occurred in the nonaspirin group; thus, the study was insuf- (eg, Framingham,16 CHS,326 and the Honolulu Heart Study327) has
ficiently powered to detect an effect on stroke. identified cigarette smoking as a potent risk factor for ischemic
3772 Stroke December 2014
stroke, associated with an approximate doubling of risk. Data a reduction in strokes despite a decrease in risk of MI when
from studies largely conducted in older age groups also pro- it enacted a comprehensive smoking ban in enclosed work-
vide evidence of a dose-response relationship, and this has been spaces, restaurants, and construction sites.353
extended to young women from an ethnically diverse cohort.328 Smoking likely contributes to increased stroke risk through
Smoking is also associated with a 2- to 4-fold increased risk for both short-term effects on the risk of thrombus generation in ath-
SAH.329–332 The data for ICH (apart from SAH), however, are erosclerotic arteries and long-term effects related to increased
inconsistent. A multicenter case-control study found an adjusted atherosclerosis.354 Smoking as little as a single cigarette increases
OR of 1.58 (95% CI, 1.02–2.44)333 for ICH, and analyses from heart rate, mean BP, and cardiac index and decreases arterial dis-
the Physicians’ Health Study332 and WHS331 also found such an tensibility.355,356 Beyond the immediate effects of smoking, both
association, but other studies, including a pooled analysis of the active and passive exposure to cigarette smoke is associated with
ARIC and CHS cohorts, found no relationship between smoking the development of atherosclerosis.357 In addition to placing indi-
and ICH risk.135,334–336 A meta-analysis of 32 studies estimated viduals at increased risk for both thrombotic and embolic stroke,
the RR for ischemic stroke to be 1.9 (95% CI, 1.7–2.2) for cigarette smoking approximately triples the risk of cryptogenic
smokers versus nonsmokers, the RR for SAH to be 2.9 (95% CI, stroke among individuals with a low atherosclerotic burden and
2.5–3.5), and the RR for ICH to be 0.74 (95% CI, 0.56–0.98).335 no evidence of a cardiac source of emboli.358,359
The annual number of stroke deaths attributed to smoking Although the most effective preventive measures are to never
in the United States is estimated to be between 21 400 (with- smoke and to minimize exposure to environmental tobacco
out adjustment for potential confounding factors) and 17 800 smoke, risk is reduced with smoking cessation. Smoking cessa-
(after adjustment), which suggests that smoking contributes to tion is associated with a rapid reduction in the risk of stroke and
12% to 14% of all stroke deaths.337 From data available from other cardiovascular events to a level that approaches, but does
the National Health Interview Survey and death certificate not reach, that of those who never smoked.354,360–362
data for 2000 through 2004, the Centers for Disease Control Although sustained smoking cessation is difficult to
and Prevention estimated that smoking resulted in an annual achieve, effective behavioral and pharmacological treatments
average of 61 616 stroke deaths among men and 97 681 stroke for nicotine dependence are available.363–365 Comprehensive
deaths among women.338 reviews and recommendations for smoking cessation are pro-
Cigarette smoking may potentiate the effects of other stroke vided in the 2008 Surgeon General’s report,363 the 2008 update
risk factors, including SBP339 and OCs.340,341 For example, a from the Public Health Service,366 and the 2009 affirmation of
synergistic effect exists between the use of OCs and smoking these recommendations from the US Preventive Services Task
on the risk of cerebral infarction. With nonsmoking, non-OC Force.367 The combination of counseling and medications is
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users serving as the reference group, the odds of cerebral infarc- more effective than either therapy alone.367
tion were 1.3 times greater (95% CI, 0.7–2.1) for women who With regard to specific pharmacotherapy, in a meta-anal-
smoked but did not use OCs, 2.1 times greater (95% CI, 1.0– ysis current to January 2012, nicotine replacement therapy,
4.5) for nonsmoking OC users, and 7.2 times greater (95% CI, bupropion, and varenicline were all superior to inert control
3.2–16.1) for OC users who smoked.340 There was also a syn- medications, but varenicline was superior to each of the other
ergistic effect of smoking and OC use on hemorrhagic stroke active interventions in direct comparisons.368 Emerging evi-
risk. With nonsmoking, non-OC users as the reference group, dence suggests that varenicline may be more cost-effective
the odds of hemorrhagic stroke were 1.6 times greater (95% CI, than nicotine replacement therapy.369
1.2–2.0) for women who smoked but did not use OCs, 1.5 times
greater (95% CI, 1.1–2.1) for nonsmoking OC users, and 3.7 Cigarette Smoking: Summary and Gaps
times greater (95% CI, 2.4–5.7) for OC users who smoked.341 Cigarette smoking increases the risk of ischemic stroke and
Exposure to environmental tobacco smoke (also referred SAH, but the data on ICH are inconclusive. Epidemiological
to as passive or second-hand smoke) is an established risk studies show a reduction in stroke risk with smoking cessation
factor for heart disease.342,343 Exposure to environmental and with community-wide smoking bans. Although effective
tobacco smoke may also be a risk factor for stroke, with a programs to facilitate smoking cessation exist, data show-
risk approaching the doubling found for active smoking,344–349 ing that participation in these programs leads to a long-term
although 1 study found no association.350 Because the dose reduction in stroke are lacking.
of exposure to environmental tobacco smoke is substantially
lower than for active smoking, the magnitude of the risk
associated with environmental tobacco smoke is surpris- Cigarette Smoking: Recommendations
ing. This apparent lack of a dose-response relationship may 1. Counseling, in combination with drug therapy using
be explained in part by physiological studies suggesting a nicotine replacement, bupropion, or varenicline, is
tobacco smoke exposure threshold rather than a linear dose- recommended for active smokers to assist in quitting
response relationship.351 Recent studies of the effects of smok- smoking (Class I; Level of Evidence A).
ing bans in communities have also shown that these bans are 2. Abstention from cigarette smoking is recommended
associated with a reduction in the risk of stroke. After Arizona for patients who have never smoked on the basis of
enacted a statewide ban on smoking in most indoor public epidemiological studies showing a consistent and
places. including workspaces, restaurants, and bars, there was overwhelming relationship between smoking and
a 14% reduction in strokes in counties that had not previously both ischemic stroke and SAH (Class I; Level of
had a ban in place.352 A study of New York State did not find Evidence B).
Meschia et al Guidelines for the Primary Prevention of Stroke 3773
3. Community-wide or statewide bans on smoking in Table 3. Stroke Risk Stratification Schemes for Patients
public spaces are reasonable for reducing the risk of With Atrial Fibrillation
stroke and MI (Class IIa; Level of Evidence B).
CHADS2378 CHA2DS2-VASc379
Scoring system Scoring system
Atrial Fibrillation Congestive heart failure–1 point Congestive heart failure–1 point
AF, even in the absence of cardiac valvular disease, is associ- Hypertension–1 point Hypertension–1 point
Age ≥75 y–1 point Age 65–74 y–1 point
ated with a 4- to 5-fold increased risk of ischemic stroke result-
Diabetes mellitus–1 point ≥75 y–2 points
ing from embolism of stasis-induced thrombi forming in the Stroke/TIA–2 points Diabetes mellitus–1 point
left atrial appendage (LAA).370 About 2.3 million Americans Risk scores range: 0–6 points Stroke/TIA–2 points
have either sustained or paroxysmal AF.370 Embolism of Levels of risk for thromboembolic Vascular disease (eg, peripheral
appendage thrombi associated with AF accounts for ≈10% of stroke artery disease, myocardial
all ischemic strokes and an even higher fraction in the very Low risk for stroke=0 points infarction, aortic plaque)–1 point
elderly in the United States.371 The absolute stroke rate aver- Moderate risk=1 point Female sex–1 point
High risk ≥2 points Risk scores range: 0–9 points
ages ≈3.5%/y for 70-year-old individuals with AF, but the risk
Levels of risk for thromboembolic
varies 20-fold among patients, depending on age and other stroke
clinical features (see below).372,373 AF is also an independent Low risk=0 points
predictor of increased mortality.374 Paroxysmal AF increases Moderate risk=1 point
stroke risk similar to sustained AF.375 High risk ≥2 points
There is an important opportunity for primary stroke pre- ACCP treatment guidelines based on HAS-BLED381
vention in patients with AF because the dysrhythmia is diag- estimated risk for thromboembolic
nosed before stroke in many patients. However, a substantial stroke380
minority of AF-related stroke occurs in patients without a Low risk: no therapy Hypertension–1 point
prior diagnosis of the condition. Studies of active screening Moderate risk: OAC Abnormal renal function–1 point
of patients >65 years of age for AF in primary care settings High risk: OAC Abnormal liver function–1 point
Prior stroke–1 point
show that pulse assessment by trained personnel increases the Prior major bleeding or bleeding
detection of undiagnosed AF.376,377 Systematic pulse assess- predisposition–1 point
ment during routine clinic visits followed by 12-lead ECG in INR in therapeutic range <60%
those with an irregular pulse resulted in a 60% increase in the of time–1 point
detection of AF.376 Age >65 y–1 point
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Most of these analyses stratifying risk of future bleeding have possibility of a small but consistent increased risk of MI or
not focused on intracranial hemorrhages, the category of major acute coronary syndrome versus the risk observed in various
bleeding with the greatest long-term effect on quality of life. control arms of these studies (OR, 1.33; 95% CI, 1.03–1.71;
Another limitation of prediction scales for hemorrhage is that P=0.03).393 Finally, analyses of multiple patient subgroups,
several of their components such as age and hypertension are categorized by nationality,394 CHADS2 score,395 and the pres-
also risks for cardioembolic stroke. ence or absence of prior TIA/stroke, have not found evidence
for differences in the risk/benefit profile for dabigatran. In
Selecting Treatment to Reduce Stroke Risk in Patients the subgroup of patients ≥75 years of age,396 dabigatran 150
With AF mg was associated with increased gastrointestinal hemor-
Adjusted-dose warfarin has generally been the treatment of rhage relative to warfarin (OR, 1.79; 95% CI, 1.35–2.37) but
choice for patients at high risk for cardioembolic stroke and reduced ICH (OR, 0.42; 95% CI, 0.25–0.70).
acceptably low risk of hemorrhagic complications, particu- The Rivaroxaban Versus Warfarin in Nonvalvular Atrial
larly intracranial hemorrhage. Treatment with adjusted-dose Fibrillation (ROCKET AF) Trial397 randomized 14 264 patients
warfarin (target INR, 2 to 3) robustly protects against stroke with nonvalvular AF to rivaroxaban 20 mg/d or adjusted-dose
(RR reduction, 64%; 95% CI, 49–74), virtually eliminating warfarin (target INR, 2 to 3). A CHADS2 score of ≥2 was
the excess risk of ischemic stroke associated with AF if the required, yielding a mean score for enrolled subjects of 3.5,
intensity of anticoagulation is adequate and reducing all-cause which was higher than in the RE-LY and ARISTOTLE trials;
mortality by 26% (95% CI, 3–23).385 In addition, anticoagu- more than half of the participants had a stroke, TIA, or sys-
lation reduces stroke severity and poststroke mortality.386–388 temic embolism before enrollment. Over a median follow-up
Compared with aspirin, adjusted-dose warfarin reduces stroke of 707 days, the primary end point of ischemic and hemor-
by 39% (95% CI, 22–52).385,389 rhagic stroke and systemic embolism in patients as actually
Three newer oral anticoagulants have been approved in the treated (the prespecified analysis plan for efficacy in this
United States for stroke prevention in patients with nonvalvu- study) occurred in 1.7%/y in those receiving rivaroxaban and
lar AF: the direct thrombin inhibitor dabigatran (dosed at 150 2.2%/y in those on warfarin (HR, 0.79; 95% CI, 0.66–0.96;
mg twice daily in patients with creatinine clearance ≥30 mL/ P<0.001 for noninferiority; analyzed by intention to treat, HR,
min) and the direct factor Xa inhibitors rivaroxaban (20 mg 0.88; 95% CI, 0.74–1.03; P<0.001 for noninferiority; P=0.12
once daily for patients with creatinine clearance ≥50 mL/min) for superiority). The primary safety end point of major or
and apixaban (5 mg twice daily for patients with no more than nonmajor bleeding occurred in 14.9% of patients per year in
1 of the following characteristics: age ≥80 years, serum creati- those receiving rivaroxaban and 14.5% in those on warfarin
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nine ≥1.5 mg/dL, or body weight ≤60 kg). Clinical trial data (HR, 1.03; 95% CI, 0.96–1.11; P=0.44). ICH (0.5% versus
and other information for these agents were recently reviewed 0.7%; HR, 0.67; 95% CI, 0.47–0.93) and fatal bleeding (0.2%
in an AHA/American Stroke Association science advisory390 versus 0.5%; HR, 0.50; 95% CI, 0.31–0.79), however, were
and are briefly summarized here. reduced on rivaroxaban relative to warfarin. Subsequent sub-
The Randomized Evaluation of Long-Term Anticoagulant group analysis of the 6796 subjects without previous stroke
Therapy (RE-LY) trial391 randomized 18 113 patients to dabi- or TIA398 found rivaroxaban to have borderline superiority to
gatran 150 mg or 110 mg twice daily or adjusted-dose war- warfarin in intention-to-treat analysis of efficacy (HR, 0.77;
farin (target INR, 2 to 3). The study enrolled patients with 95% CI, 0.58–1.01), supporting its use in primary prevention.
and without a history of prior stroke but with overall mod- Other subgroup analyses397 found no differences in the effec-
erate to high risk of stroke (mean CHADS2 score, 2.1) and tiveness of rivaroxaban according to age, sex, CHADS2 score,
excluded patients who had stroke within 14 days (6 months or the presence of moderate renal insufficiency399 (creatinine
for severe stroke), increased bleeding risk, creatinine clear- clearance, 30 to 49 mL/min; these subjects were randomized
ance <30 mL/min, or active liver disease. The primary out- to rivaroxaban 15 rather than 20 mg/d). Important concerns
come of stroke or systemic embolism during the mean 2-year have been raised about the interpretation of ROCKET AF,
follow-up occurred at a rate of 1.7%/y in the warfarin (INR, most notably the relatively poor management of warfarin
2 to 3) group compared with 1.11%/y in the 150 mg dabi- (mean time in therapeutic range, 55%) and the relatively high
gatran group (RR=0.66 versus warfarin; 95% CI, 0.53–0.82; number of outcomes (stroke or systemic embolism) beyond
P<0.001 for superiority). Intracranial hemorrhage rates were the 2-day monitoring period after drug cessation.400
strikingly lower with 150 mg dabigatran relative to adjusted- Apixaban has been studied in 2 phase III trials. The
dose warfarin (0.30%/y versus 0.74%/y; RR, 0.40; 95% CI, Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in
0.27–0.60). However, the overall rates of major bleeding were Atrial Fibrillation Patients Who Have Failed or Are Unsuitable
not different between the groups (3.11%/y versus 3.36%/y; for Vitamin K Antagonist Treatment (AVERROES) trial401
P=0.31), and gastrointestinal bleeding was more frequent compared apixaban 5 mg twice daily with aspirin 81 to 324
on 150 mg dabigatran (1.51%/y versus 1.12%/y; RR, 1.50; mg daily in 5599 subjects with nonvalvular AF unsuitable
95% CI, 1.19–1.89). MI was also increased in the 150 mg for warfarin therapy. The Apixaban for Reduction in Stroke
dabigatran group (0.74%/y versus 0.53%/y; RR, 1.38; 95% and Other Thromboembolic Events in Atrial Fibrillation
CI, 1.00–1.91),392 although this difference was no longer sig- (ARISTOTLE) trial402 compared the same dose of apixaban
nificant when silent MIs or unstable angina, cardiac arrest, with adjusted-dose warfarin (target INR, 2 to 3) among 18 201
and cardiac death were included.391 Meta-analysis of 7 trials patients with nonvalvular AF. Subjects in each study had at
of dabigatran use for various indications has supported the least 1 additional risk factor for stroke (prior stroke or TIA,
Meschia et al Guidelines for the Primary Prevention of Stroke 3775
age ≥75 years, hypertension, diabetes mellitus, heart failure, than warfarin. Most notably, each appears to confer lower risk
or peripheral artery disease). A reduced dose of apixaban 2.5 than adjusted-dose warfarin for ICH, arguably the strongest
mg twice daily was used in both studies for subjects with at determinant of long-term safety for anticoagulation (Table 4).
least 2 of the following: ≥80 years, body mass ≤60 kg, or These agents also raise important concerns, however,
serum creatinine ≥1.5 mg/dL. AVERROES was terminated including substantial cost to the healthcare system, renal
after a mean follow-up of 1.1 years when an interim analy- clearance, short half-lives, general unavailability of a moni-
sis found apixaban to be markedly superior to aspirin for the toring test to ensure compliance, and lack of a specific agent
prevention of stroke or systemic embolism (1.6%/y versus to reverse their anticoagulant effects.412 Although a dabigatran
3.7%/y; HR, 0.45; 95% CI, 0.32–0.62) with similar rates of dose of 75 mg twice daily was approved for patients with
major bleeding (1.4%/y versus 1.2%/y). Germane to primary creatinine clearance of 15 to 30 mL/min, such subjects were
prevention, apixaban was also superior to aspirin in subjects in fact excluded from RE-LY and have not been extensively
without prior TIA or stroke (HR, 0.51; 95% CI, 0.35–0.74).403 studied. The short half-lives of the newer anticoagulants raise
Over a median 1.8 years of follow-up in ARISTOTLE, the the possibility of increased risk of cardioembolism if doses are
primary outcome occurred in 1.27%/y in the apixaban group missed, a concern heightened by the relatively large number of
(analyzed as intention to treat) and 1.60%/y in the warfarin events in ROCKET AF occurring between 2 and 7 days after
group (HR, 0.79; 95% CI, 0.66–0.95; P<0.001 for nonin- discontinuation of rivaroxaban.400 In assessments of the lack
feriority; P=0.01 for superiority). Much of the difference of reversing agent for the newer anticoagulants, it is important
between the groups could be attributed to a reduction in ICH to consider that even warfarin-related ICH mortality rates are
in the apixaban group (0.24%/y versus 0.47%/y); the differ- extremely high despite the availability of reversing agents.413
ences in ischemic or uncertain type of stroke were minimal An analysis of ICH events occurring on dabigatran 150 mg
(0.97%/y versus 1.05%/y). Major bleeding events were simi- twice daily and adjusted-dose warfarin in RE-LY found no
larly less frequent on apixaban (2.13%/y versus 3.09%/y; difference in mortality (35% versus 36%) and, because of the
HR, 0.69; 95% CI, 0.60–0.80). Subgroup analysis404 found lower overall risk of bleeding with dabigatran, significantly
a similar magnitude effect for primary prevention of stroke fewer deaths caused by ICH (13 versus 32; P<0.01).
or systemic embolism in subjects without prior stroke or TIA In studies of antiplatelet agents for nonvalvular AF, aspirin
(1.01%/y versus 1.23%/y; HR, 0.82; 95% CI, 0.65–1.03), with offers modest protection against stroke (RR reduction, 22%;
the sharpest difference again in risk of ICH (0.29%/y versus 95% CI, 6–35).385 No convincing data favor 1 dose of aspi-
0.65%/y; HR, 0.44; 95% CI, 0.30–0.66). Another secondary rin (50–325 mg daily) over another. Two randomized trials
analysis found consistent efficacy of apixaban in subjects assessed the potential role of the combination of clopidogrel
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with impaired renal function (estimated glomerular filtra- (75 mg daily) plus aspirin (75–100 mg daily) for prevent-
tion rate <80 mL/min) and significantly greater reduction in ing stroke in patients with AF. The AF Clopidogrel Trial
major bleeding among those with more advanced dysfunction With Irbesartan for Prevention of Vascular Events (ACTIVE)
(estimated glomerular filtration rate ≤50 mL/min).405 Because investigators compared this combination antiplatelet regi-
of the clustering of stroke observed after discontinuation of men with adjusted-dose warfarin (target INR, 2 to 3) in AF
apixaban, a black box warning was required for this agent (as patients with 1 additional risk factor for stroke in ACTIVE W
for rivaroxaban), indicating that coverage with another antico- and found a reduction in stroke risk with warfarin compared
agulant should be strongly considered at the time of cessation with the dual antiplatelet regimen (RR reduction, 40%; 95%
unless there is pathological bleeding. CI, 18–56; P=0.001) and no significant difference in risk of
Early analyses406-409 suggest that the newer oral anticoagu- major bleeding.385,414 ACTIVE A compared the combination
lants can be cost-effective, particularly for patients at high risk of clopidogrel and aspirin with aspirin alone in AF patients
of cardioembolism or hemorrhage. A Markov decision model who were deemed unsuitable for warfarin anticoagulation
using data from RE-LY, for example, found that dabigatran and who had at least 1 additional risk factor for stroke (≈25%
150 mg twice daily provided 0.36 additional quality-adjusted
life-years at a cost of $9000,407 representing an incremental Table 4. Odds ratios of intracranial hemorrhage relative to
cost-effectiveness ratio ($25 000 per quality-adjusted life-year) warfarin with an INR of 2.0 to 3.0
that is within the range tolerated by many healthcare systems.
These analyses are based on only a single trial of dabigatran, Drug Dose(s) OR (95% CI) Reference
however, and similar evaluations have yet to be performed for Apixaban 5 mg twice daily 0.42 (0.30 to 0.58) Granger402
rivaroxaban and apixaban. The cost-effectiveness of newer 2.5 or 5 mg 0.17 (0.01 to 4.30) Ogawa321
anticoagulants relative to adjusted-dose warfarin is predicted to twice daily
be sensitive to the cost of the medications, the risk for cardio- Dabigatran 110 to 150 mg 0.36 (0.26 to 0.49) Connolly392
embolism or hemorrhage (cost-effectiveness improving with twice daily
increasing risk), and the quality of INR control on warfarin. Rivaroxaban 20 mg daily 0.65 (0.46 to 0.92) Patel397
There are many factors to consider in the selection of an 15 mg daily 0.50 (0.17 to 1.46) Hori394
anticoagulant for patients with nonvalvular AF. The newer
CI indicates confidence interval; INR, international normalized ratio; and
agents offer clearly attractive features such as fixed dose, lack OR, odds ratio. Adapted with permission from Chatterjee et al.411 Copyright
of required blood monitoring, absence of known interaction © 2013, American Medical Association. All rights reserved. Authorization for
with the immune complexes associated with heparin-induced this adaptation has been obtained both from the owner of the copyright in the
thrombocytopenia,410 and fewer identified drug interactions original work and from the owner of copyright in the translation or adaptation.
3776 Stroke December 2014
were deemed unsuitable because of concern for warfarin- appears sufficient to tip the balance away from anticoagula-
associated bleeding).415 Dual antiplatelet therapy resulted in tion in nonvalvular AF is a history of lobar ICH suggestive
a significant reduction in all strokes (including parenchy- of cerebral amyloid angiopathy.419 Other risks for ICH such
mal ICH) over treatment with aspirin alone (RR reduction, as certain genetic profiles or the presence of asymptomatic
28%; 95% CI, 17–38; P=0.0002) but also resulted in a sig- cerebral microbleeds on neuroimaging do not currently appear
nificant increase in major bleeding (RR increase, 57%; 95% sufficient by themselves to outweigh the benefits of antico-
CI, 29–92; P<0.001). Overall and in absolute terms, major agulation in patients at average risk of cardioembolism.420
vascular events (the study primary end point) were decreased For patients treated with adjusted-dose warfarin, the initial
0.8%/y, but major hemorrhages increased 0.7%/y (RR for 3-month period is a particularly high-risk period for bleeding421
major vascular events and major hemorrhages, 0.97; 95% and requires especially close anticoagulation monitoring. ICH
CI, 0.89–1.06; P=0.54). Disabling/fatal stroke, however, was is the most devastating complication of anticoagulation, but
decreased by dual antiplatelet therapy (RR reduction, 26%; the absolute increase in risk is small for INR ≤3.5.387 Treatment
95% CI, 11–38; P=0.001). A post hoc analysis of randomized of hypertension in AF patients reduces the risk of both ICH
trial data that used relative weighting of events suggested a and ischemic stroke and hence has dual benefits for antico-
modest net benefit from the combination of aspirin and clopi- agulated patients with AF.422–424 A consensus statement on the
dogrel over aspirin alone.416 delivery of optimal anticoagulant care (focusing primarily on
Recommendations for the selection of antithrombotic warfarin) has been published.425 The combined use of warfa-
therapy for patients with nonvalvular AF have had to adjust rin with antiplatelet therapy increases the risk of intracranial
for 2 emerging trends: a decreasing rate of stroke for any and extracranial hemorrhage.426 Because adjusted-dose warfa-
given CHADS2 risk category,417 possibly related to improv- rin (target INR, 2 to 3) appears to offer protection against MI
ing control of other stroke risk factors, and the appearance of comparable to that provided by aspirin in AF patients,427 the
the newer oral anticoagulants with a lower risk of ICH. These addition of aspirin is not recommended for most patients with
2 trends tend to have opposing effects on the tipping point AF and stable coronary artery disease.428,429 There are meager
at which the benefits of anticoagulation outweigh its risks: data on the type and duration of optimal antiplatelet therapy
A lower stroke risk argues for more limited use of antico- when combined with warfarin in AF patients with recent
agulation, and safer agents argue for more extensive use.418 coronary angioplasty and stenting.430,431 The combination of
On the basis of the decreasing risk of AF-related stroke, the clopidogrel, aspirin, and warfarin has been suggested for at
2012 American College of Chest Physicians evidence-based least 1 month after placement of bare metal coronary stents in
practice guidelines380 suggested that patients with nonrheu- patients with AF.432 Because drug-eluting stents require even
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matic AF at low stroke risk (ie, CHADS2=0) be treated with more prolonged antiplatelet therapy, bare metal stents are gen-
no therapy rather than any antithrombotic agent (American erally preferred for AF patients taking warfarin.433,434 A lower
College of Chest Physicians grade 2B; ie, weak recommenda- target INR of 2.0 to 2.5 has been recommended in patients
tion, moderate evidence); for those patients preferring anti- requiring warfarin, aspirin, and clopidogrel after percutane-
thrombotic treatment, aspirin rather than anticoagulation was ous coronary intervention during the period of combined anti-
recommended (grade 2B). These guidelines also favored oral platelet and anticoagulant therapy.435
anticoagulation rather than antiplatelet therapy for those at Closure of the LAA has been evaluated as an alternative
moderate risk (ie, CHADS2=1; grade 2B) and for those at high approach to stroke prevention in nonvalvular AF.436 In a trial
risk (ie, CHADS2 ≥2; American College of Chest Physicians of 707 subjects randomized 2:1 to percutaneous LAA closure
grade 1B, ie strong recommendation, moderate evidence) and with the WATCHMAN device (in which patients were treated
the use of dabigatran (the only approved newer anticoagulant with warfarin for at least 45 days after device placement, then
when the guidelines were formulated) rather than warfarin as aspirin plus clopidogrel from echocardiographically demon-
oral anticoagulant (grade 2B). For patients in these groups strated closure of the LAA until 6 months after placement,
who select antiplatelet rather than anticoagulant therapy, the then aspirin alone) versus adjusted-dose warfarin (target
guidelines recommended combination aspirin plus clopido- INR, 2 to 3), LAA closure was noninferior to warfarin for
grel rather than aspirin alone (grade 2B). Of these clinical sce- preventing the primary outcome of ischemic or hemorrhagic
narios, the greatest uncertainty surrounds the management of stroke, cardiac or unexplained death, or systemic embolism
patients at moderate risk (CHADS2=1). A large cohort study during the mean 18-month follow-up (RR, 0.62; 95% CI,
did not find net clinical benefit of warfarin for AF patients 0.35–1.25; P<0.001 for noninferiority). Hemorrhagic stroke
with a CHADS2 score of 1,417 and a decision-analysis model was less frequent in the LAA closure group (RR, 0.09; 95%
predicted that anticoagulation would be beneficial in this CI, 0–0.45), but ischemic stroke was insignificantly more
group only when the lower risk of ICH associated with the frequent (RR, 1.34; 95% CI, 0.60–4.29), in part because of
newer agents was assumed.418 procedure-related strokes (occurring in 5 of the 449 patients
Most guidelines have not explicitly incorporated risk for in whom LAA closure was attempted, including 2 with long-
anticoagulant-related hemorrhagic complications, largely term residual deficits). At 1588 patient-years of follow-up,
because of the paucity of precise data on the risk of bleeding. the rate of the primary efficacy end point of stroke, systemic
Some of the risks for hemorrhage are also risks for cardio- embolism, and cardiovascular death was not inferior for the
embolism and thus do not necessarily argue against antico- WATCHMAN device compared with warfarin.437 Although
agulation. Age >75 years, for example, is a factor favoring this approach appears promising, there are substantial reasons
rather than opposing anticoagulation.377 One bleeding risk that for proceeding cautiously with this treatment, including the
Meschia et al Guidelines for the Primary Prevention of Stroke 3777
relatively modest power of the trial, the exclusion of subjects 2. For patients with nonvalvular AF, a CHA2DS2-VASc
with firm contraindications to anticoagulation (who would score of ≥2, and acceptably low risk for hemorrhagic
otherwise appear to be ideal candidates for LAA closure), and complications, oral anticoagulants are recommended
the lack of comparison to the newer, potentially more effec- (Class I). Options include warfarin (INR, 2.0 to 3.0)
tive oral anticoagulants. Other potential nonpharmacological (Level of Evidence A), dabigatran (Level of Evidence
approaches such as therapeutic cardioversion and rhythm con- B), apixaban (Level of Evidence B), and rivaroxaban
trol do not reduce stroke risk.438 Intervals of asymptomatic AF (Level of Evidence B). The selection of antithrombotic
also persist after apparently successful radiofrequency abla- agent should be individualized on the basis of patient
tion,439 suggesting a persistent need for antithrombotic treat- risk factors (particularly risk for intracranial hemor-
ment after this procedure. rhage), cost, tolerability, patient preference, potential
for drug interactions, and other clinical characteris-
Several randomized, clinical trials have consistently shown
tics, including the time that the INR is in therapeutic
that rhythm control does not protect against stroke relative
range for patients taking warfarin.
to rate control.438,440–442 For patients with AF of ≥48 hours or
3. Active screening for AF in the primary care setting
when duration is unknown, it is recommended that patients in patients >65 years of age by pulse assessment fol-
receive warfarin to an INR of 2.0 to 3.0 for 3 weeks before lowed by ECG as indicated can be useful (Class IIa;
and 4 weeks after chemical or electrical cardioversion.443 Level of Evidence B).
Subgroup analyses of ROCKET AF444 and RE-LY445 sug- 4. For patients with nonvalvular AF and CHA2DS2-
gest that protection from cardioembolism around the time of VASc score of 0, it is reasonable to omit antithrom-
cardioversion appears to be comparable for warfarin and the botic therapy (Class IIa; Level of Evidence B).
novel oral anticoagulants. 5. For patients with nonvalvular AF, a CHA2DS2-VASc
score of 1, and an acceptably low risk for hemor-
AF: Summary and Gaps rhagic complication, no antithrombotic therapy,
AF is a prevalent, potent, and treatable risk factor for embolic anticoagulant therapy, or aspirin therapy may be
stroke. Knowing which treatment offers the optimal balance considered (Class IIb; Level of Evidence C). The selec-
of benefits and risks for a particular patient remains challeng- tion of antithrombotic agent should be individual-
ing, however. Complicating the decision is that the field is ized on the basis of patient risk factors (particularly
rapidly changing, with ongoing changes in the epidemiology risk for intracranial hemorrhage), cost, tolerability,
patient preference, potential for drug interactions,
of AF-related stroke, improvements in the ability to predict
and other clinical characteristics, including the time
risk of stroke and hemorrhage, and a growing armamentarium
that the INR is in the therapeutic range for patients
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fraction <40%.447–449 Systemic embolism occurs in ≈11% of thromboembolic event (Class IIb; Level of Evidence B).458
patients with left ventricular thrombus.450 In the Warfarin, Based on the more recent WARCEF trial,457 this recommenda-
Aspirin Reinfarction Study, (WARIS II), warfarin, combined tion is upgraded in this document to state that anticoagulants
with aspirin or given alone, compared with aspirin alone or antiplatelet agents are reasonable for patients with heart
reduced the risk of thromboembolic stroke but was associated failure who do not have AF or a previous thromboembolic
with a greater risk of bleeding.451 A meta-analysis of 14 trials event (Class IIa; Level of Evidence B).
comprising 25 307 patients with an acute coronary syndrome
reported that aspirin plus warfarin, in which the achieved INR Valvular Heart Disease
was 2.0 to 3.0, compared with aspirin alone reduced the risk The risk of embolic stroke is increased in patients with rheu-
of death, nonfatal MI, and nonfatal thromboembolic stroke matic mitral valve disease, even in the absence of AF, and
but doubled the risk of major bleeding.452 A meta-analysis of in patients with prosthetic heart valves. Rheumatic carditis
24 542 patients in 10 randomized trials that evaluated the effi- is the most common cause of mitral stenosis. Studies from
cacy of warfarin after acute MI found a stroke incidence over the middle part of the last century found an annual incidence
5 years of 2.4%. In this meta-analysis, warfarin decreased the of systemic embolism among patients with rheumatic mitral
risk of stroke (OR, 0.75; 95% CI, 0.63–0.89) but increased valve disease of 1.5% to 4.7% (reviewed by Whitlock et al459).
the risk of bleeding. The 2013 ACCF/AHA guideline for the Thrombus and subsequent embolism may be more likely to
management of ST-segment–elevation MI (STEMI) states that occur in large left atria. The ACCF/AHA guidelines for the
anticoagulant therapy with a vitamin K antagonist is reason- management of valvular heart disease recommend anticoag-
able for patients with STEMI and asymptomatic left ventricu- ulation in patients with mitral stenosis and a prior embolic
lar mural thrombi (Class IIa; Level of Evidence C) and that event, even in sinus rhythm (Class I; Level of Evidence B),
anticoagulant therapy may be considered for patients with and in patients with mitral stenosis with left atrial thrombus
STEMI and anterior apical akinesis or dyskinesis (Class IIb; (Class I; Level of Evidence B).460 Reports on the association of
Level of Evidence C).453 embolic stroke with mitral valve prolapse have been inconsis-
tent.461–463 A population-based study of patients from Olmsted
Cardiomyopathy County, Minnesota, found an increased RR of stroke or TIA
The incidence of stroke in patients with cardiomyopathy and among patients with mitral valve prolapse who were initially
sinus rhythm is ≈1 per 100 patient-years.454–456 The Warfarin/ in sinus rhythm (RR, 2.2; 95% CI, 1.5–3.2).464 Independent
Aspirin Study in Heart Failure (WASH) randomized patients factors associated with stroke included older age, mitral valve
with heart failure, reduced left ventricular systolic function, thickening, and the development of AF. The ACCF/AHA
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and no other indications for anticoagulant therapy to warfarin, guidelines for the management of valvular heart disease rec-
aspirin, or no treatment.454 There was no difference between ommend aspirin therapy for patients with mitral valve pro-
groups in the primary composite cardiovascular end point, lapse who experience TIAs (Class I; Level of Evidence C) and
which included stroke. The Warfarin and Antiplatelet Therapy warfarin for these patients with a history of stroke and mitral
in Chronic Heart Failure (WATCH) trial randomized patients regurgitation, AF, or left atrial thrombus (Class I; Level of
with heart failure, reduced left ventricular systolic function, Evidence C).460 The risk of stroke is also increased in patients
and sinus rhythm to warfarin, clopidogrel, or aspirin. The with mitral annular calcification. There was an increased risk
study was terminated early because of slow enrollment. There of stroke (RR, 2.1; 95% CI, 1.2–3.6) among participants in
was no difference in the composite primary end point of death, the Framingham study who had mitral annular calcification.465
nonfatal MI, or nonfatal stroke, but warfarin was associated Risk of stroke was associated with the severity of mitral
with fewer nonfatal strokes than aspirin or clopidogrel.455 The annular calcification. Similarly, in the SHS, a cohort study
Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction of American Indians, stroke incidence was increased among
(WARCEF) trial randomized 2305 patients with reduced left those with mitral annular calcification (RR, 3.1; 95% CI, 1.8–
ventricular ejection fraction and sinus rhythm to warfarin or 5.2).466 In contrast, in the multiethnic NOMAS, mitral annular
aspirin and followed them up for up to 6 years.457 There was calcification was associated with an increased risk of MI and
no difference in the primary composite outcome of ischemic vascular death but not ischemic stroke.467 There is no evidence
stroke, ICH, or death resulting from any cause (HR, 0.93; that anticoagulant therapy reduces the risk of stroke in patients
95% CI, 0.79–1.10), but there was a significant reduction in with mitral annular calcification. Calcific aortic stenosis is an
the rate of ischemic stroke with warfarin compared with aspi- uncommon cause of embolic stroke, unless disrupted by val-
rin (0.72 versus 1.36 events per 100 patient-years; HR, 0.52; vuloplasty, transcatheter aortic valve replacement, or open
95% CI, 0.33–0.82). The rate of major hemorrhage, however, surgical aortic valve replacement.468
was greater in the warfarin than in the aspirin group. The 2009 Prosthetic heart valves can serve as a source of thrombo-
ACCF/AHA guideline for the diagnosis and management of embolism. The risk of embolic stroke is greater in patients
heart failure in adults states that the usefulness of anticoagula- with mechanical valves than bioprosthetic valves. The annual
tion is not well established in patients with heart failure who incidence of thromboembolism in patients with bioprosthetic
do not have AF or a previous thromboembolic event.458 The valves and sinus rhythm is ≈0.7% (reviewed by Bonow et al460).
American College of Chest Physicians guidelines on anti- Among patients with bioprosthetic valves, the risk of embo-
thrombotic therapy and prevention of thrombosis state that lism is greatest within the first 3 months after implantation
the usefulness of anticoagulation is not well established in and is higher with mitral than aortic bioprosthetic valves.469
patients with heart failure who do not have AF or a previous ACCF/AHA guidelines for the management of patients with
Meschia et al Guidelines for the Primary Prevention of Stroke 3779
valvular heart disease recommend aspirin after aortic or mitral and may be a source of an embolic stroke.480 Anticoagulant
valve replacement with a bioprosthesis in patients with no risk therapy is indicated for patients with nonbacterial thrombotic
factors (ie, AF, previous thromboembolism, left ventricular endocarditis and systemic embolism.459
dysfunction, and hypercoagulable condition) and warfarin
(INR, 2.0 to 3.0) after aortic or mitral valve replacement with PFO and ASAs
a bioprosthesis in patients with additional risk factors (Class I; A PFO is present in ≈15% to 25% of the adult population,
Level of Evidence C). During the first 3 months after aortic or and ASA occurs in 1% to 4%. A PFO serves as a right-to-
mitral valve replacement with a bioprosthesis, the guidelines left conduit for paradoxical emboli originating in the veins,
indicate that it is reasonable to give warfarin to achieve an whereas ASA may be a nidus for thrombus formation. PFO
INR of 2.0 to 3.0 (Class IIa; Level of Evidence C). and ASA have been associated with stroke in many, but not
In the first 3 months after bioprosthetic valve implantation, all, studies.481–487 In the Patent Foramen Ovale in Cryptogenic
aspirin is recommended for aortic valves; the combination of Stroke Study (PICSS), a PFO was detected by transesopha-
aspirin and clopidogrel is recommended if the aortic valve is geal echocardiography more often in patients with crypto-
transcatheter; and vitamin K antagonist therapy with a target genic stroke than in those with known causes of stroke (39.2%
INR of 2.5 is recommended for mitral valves. After 3 months, versus 29.9%, respectively).482 Another study also found that
aspirin is recommended.459 the prevalence of PFO was greater among patients with cryp-
A meta-analysis of 46 studies comprising 13 088 patients who togenic stroke than among those with known causes of stroke,
received mechanical mitral or aortic valve prostheses reported including patients <55 years of age (OR, 4.70; 95% CI, 1.89–
an incidence of valve thrombosis or embolism in the absence of 11.68; P<0.001) and patients ≥55 years of age (OR, 2.92; 95%
antithrombotic therapy of 8.6 per 100 patient-years (95% CI, CI, 1.70–5.01).488 A meta-analysis of case-control studies of
7.0–10.4). Risk of embolism was lower in patients with tilting patients who have had an ischemic stroke found that among
disk and bileaflet valves than in those with caged ball valves patients ≤55 years of age there are significant associations
(no longer used).470 Antithrombotic therapy with a vitamin K with PFO (OR, 3.10; 95% CI, 2.29–4.21), ASA (OR, 6.14;
antagonist reduced the risk of thromboembolic events to 1.8 per 95% CI, 2.47–15.22), and PFO plus ASA (OR, 15.59; 95%
100 patient-years (95% CI, 1.7–1.9). Even among anticoagu- CI, 2.83–85.87).486 In patients >55 years of age, the associa-
lated patients, the risk of embolism is higher among those with tion with PFO was not significant (OR, 1.27; 95% CI, 0.80–
mechanical mitral valves than mechanical aortic valves.471,472 2.01), although it was for ASA (OR, 3.43; 95% CI, 1.89–6.22)
ACC/AHA guidelines for the management of patients with val- and for PFO plus ASA (OR, 5.09; 95% CI, 1.25–20.74). In
vular heart disease recommend warfarin (INR, 2.0 to 3.0) after a population-based study from Olmstead County, Minnesota,
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aortic valve replacement with bileaflet mechanical or Medtronic in which the mean participant age was 66.9±13.3 years, PFO
Hall prostheses in patients with no risk factors (Class I; Level was not associated with increased risk of stroke (HR, 1.46;
of Evidence B), warfarin (INR, 2.5 to 3.5) in patients with risk 95% CI, 0.74–2.88), whereas there was an association with
factors (Class I; Level of Evidence B), and warfarin (INR, 2.5 ASA (HR, 3.72; 95% CI, 0.88–15.71).489 In the multiethnic
to 3.5) after mitral valve replacement with any mechanical NOMAS, in which the mean age was 68.7±10.0 years, PFO
valve (Class IIa; Level of Evidence C).460 The addition of low- was not associated with increased risk of stroke (HR, 1.64;
dose aspirin to warfarin is recommended for all patients with 95% CI, 0.87–3.09), nor was the coexistence of PFO and ASA
mechanical valves (Class IIa; Level of Evidence C). (HR, 1.25; 95% CI, 0.17–9.24).483 Another study examining the
The novel oral anticoagulants (factor Xa inhibitors and direct characteristics of PFO observed larger PFOs, longer tunnels,
thrombin inhibitors) are not indicated for the prevention of and a greater frequency of ASA in patients with stroke than in
thromboembolism associated with mechanical heart valves. The those without stroke.490 One study of patients with cryptogenic
randomized, phase II study to evaluate the safety and pharmaco- stroke found that the risk of recurrent stroke was 2.3% (95%
kinetics of oral dabigatran etexilate in patients after heart valve CI, 0.3–4.3) among patients with PFO alone, 0% in those with
replacement (RE-ALIGN) trial showed an increase in thrombo- ASA alone, 15.2% (95% CI, 1.8–28.6) in patients with both
embolic and bleeding complications with dabigatran compared PFO and ASA, and 4.2% (95% CI, 1.8–6.6) in patients with
to warfarin in patients with mechanical heart valves.473 neither.491 Further analyses from NOMAS with longer follow-
About 20% to 40% of patients with endocarditis suf- up also failed to find evidence for an increased risk of first
fer embolic events, the majority of which affect the central stroke with PFO (adjusted HR, 1.10; 95% CI, 0.64–1.91) and
nervous system.474,475 The rate of embolic events decreases provided further evidence that PFO is not associated with sub-
rapidly after the initiation of antibiotic therapy.476–478 The clinical cerebrovascular disease.492
risk of embolic stroke is associated with the size of the veg- No study has examined treatments to prevent initial strokes
etation, involvement of the mitral valve, and infection by in patients with PFO or ASA. Accordingly, given the uncer-
Staphylococcus aureus.475,476,479 Anticoagulant therapy does tainties and relatively low risk of initial stroke caused by PFO
not reduce the risk of embolic stroke and may increase the or ASA and the potential risk of antithrombotic therapy or
risk of cerebral hemorrhage.474 Anticoagulant therapy should invasive treatments, no treatment is recommended for the pri-
not be used to treat patients with infective endocarditis unless mary prevention of stroke in people with PFO or ASA. Several
indicated for other cardiovascular conditions.459 Nonbacterial studies have examined the treatment of PFO with antithrom-
thrombotic endocarditis, also known as marantic endocardi- botic therapy or percutaneous closure devices in patients with
tis, is associated with malignant neoplasms, antiphospholipid cryptogenic stroke, but a discussion of secondary prevention
antibodies (aPLs), and systemic lupus erythematosus (SLE) exceeds the scope of this document.482,493–495
3780 Stroke December 2014
Atheroembolism from aortic plaques is also a cause of stroke 6. Aspirin is reasonable after aortic or mitral valve
associated with cardiac surgery.505,506,508 There are no prospec- replacement with a bioprosthesis (Class IIa; Level of
tive, randomized trials examining the efficacy of medical ther- Evidence B).
apy to reduce the risk of stroke caused by embolic events from 7. It is reasonable to give warfarin to achieve an INR
large thoracic aortic plaques. One nonrandomized study found of 2.0 to 3.0 during the first 3 months after aortic or
that warfarin reduced the risk of recurrent stroke in patients with mitral valve replacement with a bioprosthesis (Class
IIa; Level of Evidence C).
mobile thoracic atheroma detected by transesophageal echo-
8. Anticoagulants or antiplatelet agents are reasonable
cardiography.509 In another nonrandomized study, patients with
for patients with heart failure who do not have AF or
aortic plaques >4 mm thick treated with oral anticoagulants had
a previous thromboembolic event (Class IIa; Level of
fewer stroke and peripheral embolic events than those treated Evidence A).
with antiplatelet therapy.510 A retrospective analysis of patients 9. Vitamin K antagonist therapy is reasonable for
with severe thoracic aortic plaque found that statin therapy (OR, patients with STEMI and asymptomatic left ventric-
0.3; 95% CI, 0.2–0.6), but not warfarin (OR, 0.7; 95% CI, 0.4– ular mural thrombi (Class IIa; Level of Evidence C).
1.2) or antiplatelet therapy (OR, 1.4; 95% CI, 0.8–2.4), reduced 10. Anticoagulation may be considered for asymptom-
the risk of stroke, TIA, and peripheral emboli.511 atic patients with severe mitral stenosis and left atrial
dimension ≥55 mm by echocardiography (Class IIb;
Other Cardiac Conditions: Summary and Gaps Level of Evidence B).
Cardiac conditions, including MI, cardiomyopathy, valvular 11. Anticoagulation may be considered for patients with
heart disease, PFO and ASAs, cardiac tumors, and aortic ath- severe mitral stenosis, an enlarged left atrium, and
erosclerosis, are associated with an increased risk for stroke. spontaneous contrast on echocardiography (Class
IIb; Level of Evidence C).
Therapies to prevent stroke in many of these conditions are
12. Anticoagulant therapy may be considered for
based on well-reasoned consensus of opinion, but random-
patients with STEMI and anterior apical akinesis or
ized, prospective trials to support these decisions are often
dyskinesis (Class IIb; Level of Evidence C).
lacking. For example, therapy with a vitamin K antagonist 13. Antithrombotic treatment and catheter-based closure
is reasonable for patients with STEMI and left ventricular are not recommended in patients with PFO for primary
mural thrombi, but clinical trials could inform the duration of prevention of stroke (Class III; Level of Evidence C).
treatment. Prospective trials are lacking to determine whether
antithrombotic therapy is useful for the primary prevention *Risk factors include AF, previous thromboembolism, left ventricular dys-
of stroke in patients with mitral valve prolapse and mitral function, and hypercoagulable condition.
Meschia et al Guidelines for the Primary Prevention of Stroke 3781
Asymptomatic Carotid Artery Stenosis nephrogenic systemic fibrosis in patients with renal dysfunc-
Atherosclerotic stenosis in the extracranial internal carotid tion. When concordant, the combination of duplex ultrasound
artery or carotid bulb has been associated with an increased and MRA is more accurate than either test alone.521 Computed
risk of stroke. What follows is a summary of recommendations tomographic angiography is another means of identifying and
for managing asymptomatic patients with carotid atheroscle- measuring stenosis of the extracranial carotid artery.522 Like
rotic stenosis. Further details are available in an earlier guide- MRA, it has the advantage of being able to evaluate the intra-
line endorsed by the AHA that is dedicated to this topic.512 cranial circulation. Disadvantages of computed tomographic
Previous randomized trials have shown that prophylac- angiography include radiation exposure and the need for intra-
tic carotid endarterectomy (CEA) in appropriately selected venous injection of contrast material. Atherosclerotic calcifi-
patients with carotid stenosis results in a relative risk reduc- cation may confound accurate measurement of stenosis with
tion of stroke of 53% and an absolute 5-year risk reduction of computed tomographic angiography.
6% compared with patients treated by medical management A variety of vascular risk factors reviewed in this guideline
alone.513–515 However, since these trials were performed, medi- are associated with carotid atherosclerosis.523,524 Carotid bruit
cal management has improved. The question has been raised can reflect an underlying carotid stenosis. However, the sen-
if invasive treatment of carotid bifurcation disease remains an sitivity for detecting carotid stenosis is low. In NOMAS, aus-
effective way to reduce stroke risk compared to contemporary cultation had a sensitivity of 56% and a specificity of 98%.525
medical management alone.
Endarterectomy for Asymptomatic Carotid Stenosis
Assessment of Carotid Stenosis The first study with >1000 patients comparing CEA plus
A hemodynamically significant carotid stenosis produces a best medical therapy to medical therapy alone was the
pressure drop across the lesion, a flow reduction distal to the Asymptomatic Carotid Atherosclerosis Study (ACAS).513 The
lesion, or both. This generally corresponds to a 60% diameter- primary outcome was the composite of any stroke or death
reducing stenosis as reflected by catheter angiography as mea- occurring in the perioperative period and ipsilateral cerebral
sured with the North American method. This method was first infarction thereafter. During follow-up after 34 centers random-
described in publications from the Joint Study of Extracranial ized 1662 patients, the Data and Safety Monitoring Committee
Arterial Occlusive Disease of the 1960s516 and has been used called a halt to the trial because of a clear benefit in favor of
in multiple trials carried out in North America. This method CEA. Patients randomized to surgery had contrast angiography
measures the minimal residual lumen at the level of the stenotic showing diameter-reducing lesions of ≥60% using the North
lesion compared with the diameter of the more distal internal American method of measurement. Both treatment groups
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carotid artery where the walls of the artery first become paral- received what at the time was considered best medical man-
lel. It uses the following formula: stenosis=(1−N/D)×100%, agement. The aggregate risk over 5 years for ipsilateral stroke,
where N is the diameter at point of maximum stenosis and D any perioperative stroke, and death was 5.1% for the surgical
is the diameter of the arterial segment distal to the stenosis patients and 11% for the medical patients (RR reduction, 53%;
where the arterial walls first become parallel. This method is 95% CI, 22–72). The 30-day stroke morbidity and all-cause
in contrast to the European method, which estimates stenosis mortality for CEA was 2.3%, which included a 1.2% stroke
of the internal carotid bulb. complication rate for catheter angiography. It was suggested
Because the randomized trials of CEA for symptomatic and that the complications of angiography should be considered
asymptomatic disease in North America used catheter angiog- part of the risk of surgery because an angiogram would not
raphy, this has become the gold standard against which other have been performed if surgery were not contemplated. It
imaging technologies are compared. Historically, catheter should be noted that ACAS was conducted at a time when best
angiography carried an ≈1% risk of causing a stroke in patients medical management was limited to control of BP, the control
with atherosclerotic disease.513,517–519 The complication rate of diabetes mellitus, and the use of daily aspirin. The value of
has been dropping over the past several years, and the perma- statins and newer antiplatelet drugs had not been established.
nent stroke complication rate is <0.2%.519 Duplex ultrasound The Asymptomatic Carotid Surgery Trial (ACST), carried
is the noninvasive method of screening the extracranial carotid out primarily in European centers,514 included 3120 patients
artery for an atherosclerotic stenosis with the lowest cost and with asymptomatic carotid stenoses of ≥70%, as measured by
risk. Although there can be considerable variation in the accu- duplex ultrasonography. Subjects were randomized to imme-
racy of duplex scanning among laboratories,520 certification diate CEA versus indefinite deferral of the operation. The
programs are available that set standards for levels of perfor- trial used end points that were different from those used in
mance and accuracy. Duplex ultrasound may be insensitive to ACAS (perioperative stroke, MI or death, and nonperiopera-
differentiating high-grade stenosis from complete occlusion. tive stroke). The net 5-year risks were 6.4% in the immediate
MR angiography (MRA), with and without contrast, is also surgery group and 11.8% in the deferred surgery group for
used as a noninvasive method for evaluating arterial anatomy any stroke or perioperative death (net gain, 5.4%; 95% CI,
and has the advantage of providing images of both the cer- 3.0–7.8; P<0.0001). In subgroup analysis, the benefits of CEA
vical and intracranial portions of the carotid artery and its were confined to patients <75 years of age.
proximal intracranial branches. MRA may overestimate the The National Institute of Neurological Disorders and Stroke–
degree of stenosis, and as with duplex ultrasound, there may sponsored Carotid Revascularization of Primary Prevention of
be errors when high-grade stenosis is differentiated from com- Stroke (CREST-2) trial will be comparing centrally managed,
plete occlusion. MR contrast material may cause debilitating intensive medical therapy with or without CEA.526
3782 Stroke December 2014
Careful screening of surgeons participating in clinical trials either CEA or CAS.535 Asymptomatic patients could be
might lead to results that cannot be generalized to the com- included if they had a stenosis of ≥60% on angiography, ≥70%
munity. This is particularly evident when the complications on ultrasonography, or ≥80% on computed tomographic angi-
from angiography are removed from the surgical group. When ography or MRA if the stenosis on ultrasonography was 50%
this is done, the 30-day rate of stroke and death for CEA in to 69%. Randomization was stratified according to symptom
ACAS was 1.54%.517 The perioperative complication rate in status. The primary end point was a composite of stroke, MI,
ACST was 3.1%. or death resulting from any cause during the periprocedural
The results of CEA for asymptomatic patients were exam- period or any ipsilateral stroke within 4 years after random-
ined in the National Hospital Discharge Database for 2003 ization. There was no difference in the estimated 4-year
and 2004.527 The rate of the combination of stroke and death occurrence of the composite primary end point between stent-
for CEA was 1.16%. This compares favorably with the rate ing (7.2%) and endarterectomy (6.8%; HR, 1.11; 95% CI,
of the combination of stroke and death for carotid artery 0.81–1.51; P=0.51), with no significant heterogeneity based
stent/angioplasty during the same interval, which was 2.24%. on symptom status. CREST demonstrated an interaction of
These estimates, however, are based on administrative data age on the primary end point, with age >70 years showing
and are limited to the procedural hospitalization. A 10-state a significant benefit for CEA over CAS. CAS had a higher
survey of 30-day complication rates after CEA performed periprocedural stroke/death rate for patients >64 years of
in asymptomatic patients a few years earlier found rates that age.529 Patient age may be among the factors to consider when
varied from 1.4% (Georgia) to 6.0% (Oklahoma).528 Thus, it choosing between the 2 procedures. The periprocedural rate
would appear the perioperative complication rates for CEA of stroke was higher with CAS than with CEA (4.1% versus
found in the ACAS trial could be similar or better in the com- 2.3%; P=0.01), and the periprocedural rate of MI was lower
munity; however, in at least some areas, rates may be higher. with CAS than with CEA (1.1% versus 2.3%; P=0.03). In
More recently, complication rates from the CREST trial were the periprocedural period, point estimates for the rates of any
reported.529 CEA in asymptomatic patients carried a com- stroke or death among asymptomatic patients were low (2.5%
bined risk of stroke and death of 1.4%. Additionally, a registry in CAS versus 1.4% for CEA; HR, 1.88; 95% CI, 0.79–4.42;
maintained by the Society for Vascular Surgery documented P=0.15). The overall estimated 4-year rate of any periproce-
a 30-day postoperative combined rate of stroke and death of dural stroke or death or postprocedural ipsilateral stroke, how-
1.35%.530 This rate among unselected surgeons was compa- ever, was higher with stenting compared with endarterectomy
rable to the rate seen among surgeons selected to participate (HR, 1.50; 95% CI, 1.05–2.15; P=0.03). Although the trial
in a trial. was not powered to evaluate symptomatic and asymptom-
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is time-consuming to perform and has not received uniform Asymptomatic Carotid Stenosis: Recommendations
acceptance. Additionally, the effect of intensive medical ther-
apy on high-intensity transient signals has not been adequately 1. Patients with asymptomatic carotid stenosis should
assessed. Another method of study uses plaque analysis in a be prescribed daily aspirin and a statin. Patients
computerized algorithm using B-mode insonation of the carotid should also be screened for other treatable risk fac-
plaque. Population screening for asymptomatic carotid artery tors for stroke, and appropriate medical therapies
and lifestyle changes should be instituted (Class I;
stenosis is not recommended by the US Preventive Services
Level of Evidence C).
Task Force, which found “no direct evidence that screening
2. In patients who are to undergo CEA, aspirin is rec-
adults with duplex ultrasonography for asymptomatic stenosis
ommended perioperatively and postoperatively
reduces stroke.”540 Screening for other risk factors is addressed unless contraindicated (Class I; Level of Evidence C).
in relevant sections of this guideline. 3. It is reasonable to consider performing CEA in
asymptomatic patients who have >70% stenosis of
Asymptomatic Carotid Stenosis: Summary the internal carotid artery if the risk of periopera-
and Gaps tive stroke, MI, and death is low (<3%). However, its
Medical therapy has advanced since clinical trials have been effectiveness compared with contemporary best med-
completed comparing endarterectomy plus best medical ther- ical management alone is not well established (Class
apy with best medical therapy alone in patients with an asymp- IIa; Level of Evidence A).
tomatic carotid artery stenosis.541 Recent studies suggest that 4. It is reasonable to repeat duplex ultrasonography
the annual rate of stroke in medically treated patients with an annually by a qualified technologist in a certified
asymptomatic carotid artery stenosis has fallen to ≤1%.541–543 In laboratory to assess the progression or regression of
the ACST, the rate of absolute benefit from CEA per year was disease and response to therapeutic interventions in
lower in patients on lipid-lowering therapy (0.6%/y) compared patients with atherosclerotic stenosis >50% (Class
with patients not on lipid lowering therapy (1.5%/y).544 ACST IIa; Level of Evidence C).
had no explicit targets for LDL, and intensive targets (eg, LDL 5. Prophylactic CAS might be considered in highly
<70 mg/dL) may further reduce the benefit of revascularization. selected patients with asymptomatic carotid stenosis
Statin therapy is appropriate for patients with asymptomatic (minimum, 60% by angiography, 70% by validated
carotid stenosis, whether or not they undergo revascularization. Doppler ultrasound), but its effectiveness compared
Interventional therapy has also advanced, particularly with medical therapy alone in this situation is not
in terms of perioperative management and device design. well established (Class IIb; Level of Evidence B).
6. In asymptomatic patients at high risk of complica-
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risk for ischemic stroke is not known, the association is well trial MRI-guided prophylactic transfusion, found that regular
established. The risk of stroke during childhood in those with blood transfusion significantly reduced the incidence of the
SCD is 1%/y, but patients with TCD evidence of high cere- recurrence of cerebral infarction in children with sickle cell
bral blood flow velocities (time-averaged mean velocity >200 anemia.567 In a cohort of 67 patients with indication for cervi-
cm/s) have stroke rates >10%/y.551,552 Retrospective analysis cal internal carotid artery MRA, 15% of patients had occlu-
of the Stroke Prevention Trial in Sickle Cell Anemia (STOP) sions or stenoses.568 The role of cervical MRA in stroke risk
data suggested that velocity >170 cm/s in the anterior cerebral prediction remains undefined.
artery is associated with increased stroke risk after controlling Additional clinical features identify children at risk for devel-
for the middle cerebral artery/internal carotid artery veloci- oping elevated TCD velocities and stroke. G6PD deficiency,
ties.553 TCD surveillance of children with SCD remains the absence of α-thalassemia (OR, 6.45; 95% CI, 2.21–18.87;
gold standard for stroke risk prediction, and its increased use P=0.001), hemoglobin levels (OR, 0.63 per 1 g/dL; 95% CI,
coincides with a decrease in stroke among the pediatric SCD 0.41–0.97; P=0.038), and lactate dehydrogenase levels (OR,
population.554,555 1.001 per 1 IU/L; 95% CI, 1.000–1.002; P=0.047) are inde-
The optimal frequency of screening to detect patients at pendent risk factors for abnormally high velocities.569 This con-
high risk has not been determined. The STOP study, which firmed a previously reported protective effect of α-thalassemia570
compared periodic blood transfusion with standard care in and found for the first time that G6PD deficiency and hemolysis
130 children with SCD, used time-averaged means of the independently increased the risk of abnormal TCD.571 Another
maximum velocity. Additionally, peak systolic velocity may study found independent effects of hemoglobin and aspartate
be used, in which case a measurement of 250 cm/s is used as a transaminase levels on TCD velocities, whereas age had an
threshold for prophylactic transfusion.556 In general, younger unclear association.572 Several recent studies of children with
children and those with relatively high cerebral blood flow SCD identified increased lactate dehydrogenase concentrations
velocities should be monitored more frequently because of a and baseline reticulocyte counts to be predictive of stroke573,574
higher risk of conversion to abnormal velocities in younger and elevated plasma glial fibrillary acidic protein concentra-
patients and in those with TCD velocities closer to 200 cm/s.557 tions to be predictive of cognitive impairment, suggesting sub-
Despite strong evidence of its value, overall TCD screening clinical injury.575 Markers of systemic inflammation such as
rates continue to be suboptimal as a result of patient and pro- interleukin-1β also have been associated with stroke risk.576 A
vider factors.558,559 The National Institutes of Health and the future process that integrates blood biomarkers and TCD blood
American Academy of Pediatrics recommend annual TCD flow findings may identify children at greatest risk.
screening from 2 to 16 years of age.560,561 Other genetic factors also affect stroke risk in patients with
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Few studies have been done to determine whether TCD SCD. A study evaluated 108 SNPs in 39 candidate genes in
also predicts stroke in adults with SCD. One study comparing 1398 individuals with SCD using bayesian networks and
TCD velocities in SCD adults with those of healthy control found that 31 SNPs in 12 genes interact with fetal hemoglobin
subjects found that velocities in SCD adults were lower than to modulate the risk of stroke.577 This network of interactions
those found in children, higher than in healthy control sub- includes 3 genes in the transforming growth factor-β pathway
jects, and negatively correlated with the hematocrit in both and selectin P, which is associated with stroke in the general
SCD groups.562 Another study found no examples of high TCD population. The model was validated in a different population,
(>200 cm/s) in adults with SCD. The mean velocity was 110 predicting the occurrence of stroke in 114 individuals with
cm/s, which is higher than in normal adults but lower than in 98.2% accuracy.577 STOP data were used to confirm previous
children with SCD.563 At present, there are no validated TCD findings of associations between the tumor necrosis factor
criteria for predicting stroke in adults with SCD. (−308) G/A, IL4R 503 S/P, and ADRB2 27 Q/E polymor-
Although TCD remains the most extensively validated stroke phisms and risk of large-vessel stroke in SCD.578 Consistent
prediction tool, other clinical characteristics are also associated with prior findings, the tumor necrosis factor (−308) GG
with increased risk of stroke. One study found that nocturnal genotype increased the risk of large-vessel disease by >3-fold
desaturation predicted neurological events in 95 patients with (OR, 3.27; 95% CI, 1.6–6.9; P=0.006). Unadjusted analyses
SCD (median age, 7.7 years; range, 1 to 23 years) followed also showed a previously unidentified association between the
up for a median of 6 years.564 There were 7 strokes among 19 leukotriene C4-synthase (−444) A/C variant and risk of large-
individuals with events. Mean overnight oxygen saturation vessel stroke.578 The Stroke With Transfusions Changing to
and TCD independently predicted events.564 Nocturnal oxygen Hydroxyurea (SWiTCH) study found that of the 38 candidate
desaturation appears to place children at risk for developing SNPs in 22 genes studied, 5 polymorphisms had significant
executive dysfunction, which was not associated with MRI- influence on stroke risk; SNPs in the ANXA2, TGFBR3, and
demonstrable infarcts.565 There is no proven therapy for the TEK genes were associated with increased stroke risk, and
cognitive impairment associated with nocturnal desaturation. α-thalassemia and an SNP in the ADCY9 gene were linked
MRI has also been used to identify children with SCD who to decreased stroke risk.579 The SIT Trial found that 2 varia-
are at high risk of stroke. The Cooperative Study of Sickle tions in the G6PD gene that are linked to reduced enzymatic
Cell Disease, which preceded the use of TCD-based monitor- function, rs1050828 and rs1050829, were associated with vas-
ing, found that 8.1% of children with an asymptomatic MRI culopathy in male participants with SCD (OR, 2.78; 95% CI,
lesion versus 0.5% of those with a normal MRI had a stroke 1.04–7.42; P=0.04).580 Further validation of these findings is
during the ensuing 5 years.566 The Silent Cerebral Infarct required before these genetic variations can be used for stroke
Multicenter Clinical Trial (SIT), a randomized, controlled risk prediction.
Meschia et al Guidelines for the Primary Prevention of Stroke 3785
Periodic red cell transfusion is the only intervention proven correlated with the maximal baseline TCD value.588 Most
in randomized trials to prevent stroke in patients with SCD. recently, the phase III Pediatric Hydroxyurea Clinical Trial
STOP randomized children with SCD who had abnormal (BABY HUG) demonstrated significantly lower increases in
high-risk TCD profiles to either standard care, which included TCD velocities in the hydroxyurea group, but neurocognitive
episodic transfusion as needed for pain, or periodic red cell testing of the infants was not statistically different between
transfusion an average of 14 times per year for >2 years groups.589 The SWiTCH study, a phase III noninferiority trial
with a target reduction of hemoglobin S from a baseline of comparing standard treatment (transfusions/chelation) with
>90% to <30%. The risk of stroke was reduced from 10%/y alternative treatment (hydroxyurea/phlebotomy) for chil-
to <1%/y.552 Unless exchange methods in which blood is dren with SCA, stroke, and iron overload,579 was stopped for
removed from the patient with each transfusion are used, long- safety reasons when adjudication documented no strokes in
term transfusion results in iron toxicity that requires treatment patients on transfusions/chelation but a 10% stroke rate in
with chelation.581 In STOP, there was no evidence of transfu- patients on hydroxyurea/phlebotomy. Hydroxyurea therapy
sion-related infection, but iron overload and alloimmunization for stroke prevention is promising for primary stroke preven-
remain important transfusion risks.582 To address these risks, tion but requires additional study. Results from the ongo-
STOP II tested whether long-term transfusions for primary ing Transcranial Doppler With Transfusions Changing to
stroke prevention could be safely discontinued after at least Hydroxyurea (TWiTCH) trial may provide greater insight into
30 months (range, 30–91 months) in children who had not the benefit of hydroxyurea in stroke prevention.
had an overt stroke and who had reversion to low-risk TCD Bone marrow transplantation is usually entertained after
velocities (time-averaged mean velocity in middle cerebral or stroke, but TCD and other indexes of cerebral vasculopathy
internal carotid artery, <170 cm/s) with long-term transfusion have also been used as an indication for myeloablative stem-
therapy. The study end point was the first occurrence of rever- cell transplantation. One study of 55 patients with a median
sion of TCD to abnormal confirmed by ≥2 TCDs with mean follow-up of 6 years found overall and event-free survival
velocities of ≥200 cm/s or stroke. The study was terminated rates of 93% and 85%, respectively. No new ischemic lesions
earlier than planned when an interim analysis showed worse were reported, and TCD velocities decreased.590 In a study of
outcomes with discontinuation of transfusion therapy. Eight 55 children who underwent bone marrow transplantation for
children (≈20%) tolerated removal from long-term transfusion severe SCD, 16 patients without prior stroke and unremark-
therapy, but there was a high TCD reversion rate and a small able MRI before bone marrow transplantation had no clinical
risk of stroke despite frequent TCD surveillance.583,584 Further or silent stroke on follow-up, and the 10 patients with prior
analyses from STOP II also demonstrated increased rates of silent ischemia had no further events.591 Bone marrow trans-
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silent infarcts on MRI in the discontinuation group (27.5% plantation is promising for primary stroke prevention but
versus 8.1%; P=0.03).585 Primary stroke prevention for chil- requires additional study.
dren with SCD remains centered on red cell transfusions. No trial has been done on the primary prevention of stroke
Therapies other than transfusion such as hydroxyurea or in adults with SCD. Improvements in care have increased
bone marrow transplantation that reduce the number of pain- life expectancy in people with SCD, and it is anticipated that
ful crises have an uncertain effect on organ damage, including stroke prophylaxis in older patients with SCD will pose an
stroke. Of the 127 children with SCD enrolled in the Belgian increasing challenge in the future.
Hydroxyurea SCD registry, 72 patients were evaluated by
TCD. Of these 72, 34 were found at risk of stroke, and only SCD: Summary and Gaps
1 had a cerebrovascular event after a follow-up of 96 patient- Significant progress has been achieved in the primary pre-
years, suggesting a benefit of hydroxyurea in stroke preven- vention of stroke in children with SCD. TCD can be used
tion.586 A study of 291 children with SCD included clinical to identify children who are at high risk of stroke and who
and imaging follow-up of 35 children with abnormal TCDs benefit from transfusion therapy. Although the optimal
who were placed on transfusion therapy (median follow- screening interval has not been established, TCD remains
up, 4.4 years). Of 13 patients with normalized velocities on the most extensively validated method for risk assessment.
transfusion, 10 had normal MRAs, and transfusion therapy Improvements in prediction may come from incorporating
was replaced with hydroxyurea. Four of these 10 patients additional predictors such as anterior cerebral artery velocity,
redeveloped high velocities, so only 6 remained transfusion blood biomarkers, variations in several genes, and nocturnal
free.569 In another study, the adjusted mean change in TCD oxygen saturation. On the basis of STOP II, even those whose
velocities was −13.0 cm/s (95% CI, −20.19 to −5.92) in a risk of stroke decreases with transfusion therapy on the basis
hydroxyurea-treated group and 4.72 cm/s (95% CI, −3.24 to of TCD criteria have an ≈50% probability of reverting to high
12.69) in control subjects (P<0.001).587 In a study of 59 initiat- risk or having a stroke if transfusion therapy is discontinued.
ing hydroxyurea therapy for severe vaso-occlusive complica- Alternative methods of maintenance therapy that are safer
tions who had pretreatment baseline TCD measurements, 37 than transfusion need to be developed because studies show
had increased time-averaged maximum velocities ≥140 cm/s the need for ongoing active treatment despite TCD normaliza-
and were enrolled in a trial with TCD velocities measured at tion and the risk of iron toxicity with repeated transfusions.
maximum tolerated dose and 1 year later.588 At the hydroxy- Predictive methods other than TCD (eg, MRI techniques)
urea maximum tolerated dose (mean±SD=27.9 ± 2.7 mg/kg need to be systematically compared and combined with TCD
per day), decreases were observed in bilateral middle cerebral to further refine the estimation of stroke risk in individuals.
artery velocities. The magnitude of the TCD velocity decline Hydroxyurea may be beneficial when red cell transfusions are
3786 Stroke December 2014
not feasible but should not be considered as a substitute for on possible alternative forms of birth control other than OCs
transfusion. Data on risk of stroke and prevention options in in women with migraine may lower the risk of stroke, but this
adults with SCD are needed, and a stroke prevention strategy recommendation should be placed in the context of overall
for adults needs to be developed. Future stroke prevention tri- health implications of such a change.
als are needed for adults with SCD. The WHS, a primary prevention trial of women ≥45 years
of age and free of CVD at enrollment, continues to inform the
SCD: Recommendations association between women with migraine and stroke. After a
mean follow-up of 11.9 years, multivariable-adjusted analysis
1. TCD screening for children with SCD is indicated found that high migraine frequency (more than weekly) had
starting at 2 years of age and continuing annually to an increased association with ischemic stroke (HR, 2.77; 95%
16 years of age (Class I; Level of Evidence B). CI, 1.03–7.46) but not in lower frequencies.596 When migraine
2. Transfusion therapy (target reduction of hemoglobin aura status was taken into account, a significant association of
S, <30%) is effective for reducing stroke risk in those migraine frequency was found only in the migraine with aura
children at elevated risk (Class I; Level of Evidence B). group (HR, 4.25; 95% CI, 1.36–13.29).596 From this analysis,
3. Although the optimal screening interval has not been
increased frequency of attacks in migraine with aura appears
established, it is reasonable for younger children and
to increase the risk for ischemic stroke. However, caution in
those with borderline abnormal TCD velocities to be
overly interpreting these results is needed because the incident
screened more frequently to detect the development
of high-risk TCD indications for intervention (Class numbers for these subgroup analyses were small. In a separate
IIa; Level of Evidence B). analysis of the WHS, the association of migraine with aura
4. Pending further studies, continued transfusion, even and ischemic stroke was found to be more pronounced in the
in those whose TCD velocities revert to normal, is absence (HR, 3.27; 95% CI, 1.93–5.51) than in the presence
probably indicated (Class IIa; Level of Evidence B). (HR, 0.91; 95% CI, 0.43–1.93) of nausea/vomiting.597 Overall,
5. In children at high risk for stroke who are unable or the WHS found that increased frequency in patients with
unwilling to be treated with periodic red cell transfu- migraine with aura increases ischemic stroke risk and that this
sion, it might be reasonable to consider hydroxyurea increased risk is more pronounced in the absence of typical
or bone marrow transplantation (Class IIb; Level of migraine features.
Evidence B). The WHS also investigated the association between
6. MRI and MRA criteria for selection of children for migraines and ICH. Although there was no increased risk of
primary stroke prevention with transfusion have ICH in those who reported any history of migraine compared
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not been established, and these tests are not recom- with those without a history of migraine (HR, 0.98; 95% CI,
mended in place of TCD for this purpose (Class III; 0.56–1.71), there was an increased risk for ICH in women
Level of Evidence B). with active migraine with aura (HR, 2.25; 95% CI, 1.11–
4.54).598 The age-adjusted increased risk was stronger for ICH
Less Well-Documented or Potentially (HR, 2.78; 95% CI, 1.09–7.07) and for fatal events (HR, 3.56;
95% CI, 1.23–10.31).598 From this study, it is estimated that 4
Modifiable Risk Factors
additional ICH events are attributable to migraine with aura
Migraine per 10 000 women per year.598 Women who reported active
Migraine headache has been most consistently associated with migraine without aura had no increased risk for ICH. This
stroke in young women, especially those with migraine with increase in risk for ICH for women with migraine with aura,
aura.592 A meta-analysis of 21 studies (13 case-control and 8 but not for women with migraine without aura, was similar to
cohort) reported an overall pooled RR of 2.04 (95% CI, 1.72– the increased risk found with ischemic strokes.
2.43).593 The risk was greater in migraine with aura (pooled The association of migraine in middle-aged to late-life
adjusted OR for 7 studies, 2.51; 95% CI, 1.52–4.14) com- infarct-like lesions on imaging was studied in a Reykjavik,
pared with the association of ischemic stroke and migraine Iceland, population-based cohort.599 After multivariable
without aura (pooled adjusted OR for 6 studies, 1.29; 95% adjustment, midlife migraine with aura had an increased risk
CI, 0.81–2.06).593 A second meta-analysis of 9 studies (6 case- of late-life infarct-like lesions (OR, 1.4; 95% CI, 1.1–1.8).599
control and 3 cohort) reported a pooled RR of 1.73 (95% CI, This was particularly reflected by an association with cerebel-
1.31–2.29) between any migraine and ischemic stroke.594 This lar lesions in women (OR, 1.9; 95% CI, 1.4–2.6), but not in
study also found a significantly higher risk of stroke among men, with migraine with aura (OR, 1.0; 95% CI, 0.6–1.8).599
individuals with migraine with aura (RR, 2.16; 95% CI, Migraine without aura and nonmigraine headache were not
1.53–3.03) compared with individuals with migraine with- associated with an increased risk.599 Therefore, similar to the
out aura (RR, 1.23; 95% CI, 0.90–1.69; meta-regression for risk for ischemic stroke found in women with migraine with
aura status, P=0.02).594 Furthermore, there was a significant aura in the WHS, in this Icelandic population, women with
risk among women (RR, 2.08, 95% CI, 1.13–3.84) but not migraine with aura had an increased risk for late-life isch-
among men (RR, 1.37; 95% CI, 0.89–2.11). Age <45 years, emic lesions as seen on brain MRI; however, this association
especially in women (RR, 3.65; 95% CI, 2.21–6.04), smoking was not appreciated in men or in those with migraine with-
(RR, 9.03; 95% CI, 4.22–19.34), and OC use (RR, 7.02; 95% out aura or nonmigraine headaches. Overall, the Icelandic
CI, 1.51–32.68) further increased the risk.594 Both meta-anal- study is in agreement with the previous studies, including the
yses are in general agreement with prior studies.595 Counseling Cerebral Abnormalities in Migraine, an Epidemiological Risk
Meschia et al Guidelines for the Primary Prevention of Stroke 3787
Analysis (MRI CAMERA) study, which found that, on the benefit of PFO closure on the cessation of migraine headaches
basis of MRI, migraineurs with aura had higher prevalence (primary outcome; 3 of 74 versus 3 of 73; P=0.51).610 There is
of subclinical infarcts in the posterior circulation (OR, 13.7; much controversy concerning the results of this trial,611 and it
95% CI, 1.7–112), with female migraineurs at an indepen- was not designed to evaluate the primary prevention of stroke
dent increased risk of white matter lesions (OR, 2.1; 95% CI, in patients with migraines with aura. Furthermore, recent
1.0–4.1).600,601 The mechanism and relevance of the migraine– studies have found a lack of association between migraine and
brain lesion association are unclear. In 1 cohort study based PFO in a large population-based study among elderly indi-
on MRA, there was a significant association between anatomi- viduals,612 in a hospital-based case-control study,613 and in a
cal variants of the circle of Willis and both migraines with- recent meta-analysis,614 placing some doubt on whether PFO
out aura (OR, 2.4; 95% CI, 1.5–3.9) and migraines with aura has a causal role in migraines.
(OR, 3.2; 95% CI, 1.6–4.1).602 Unilateral posterior variants In terms of primary prevention of stroke in patients with
with basilar hypoplasia were statistically associated only with migraine, aspirin reduced risk of ischemic stroke (RR, 0.76;
migraines with aura (OR, 9.2; 95% CI, 2.3–37.2).602 However, 95% CI, 0.63–0.93) but not other clinical atherothrombotic
there was no statistical association between the presence of end points in the WHS group.615 In subgroup analyses, the pro-
circle of Willis variants and ischemic lesions on MRI (OR, tective effect of aspirin on ischemic stroke was similar among
1.5; 95% CI, 0.68–1.94), or with infratentorial lacunar lesions women with or without migraines.615 However, women with
(OR, 1.58; 95% CI, 0.48–5.24).602 The relationship between migraine with aura on aspirin had an increased risk of MI (RR,
these vascular anatomical variants in migraineurs to ischemic 3.72; 95% CI, 1.39–9.95), primarily women with history of
strokes is unclear. smoking or hypertension.615 The clinical significance of this
Once considered a disease of cerebral blood vessels, recent increased risk for this subgroup is unclear because of small
experimental and clinical data have indicated that migraine numbers.
results from a complex interaction of several converging
pathogenic factors. These include disturbance of cortical
excitability, cortical spreading depression, meningeal inflam-
Migraine: Summary and Gaps
Migraine headache, particularly migraine with aura, appears
mation, and activation of the trigeminovascular system.603
to be associated with stroke in women <55 years of age, but
However, factors contributing to the increased risk of stroke
the mechanisms linking these 2 conditions remain unclear.
with migraine remain elusive. Clinical-epidemiological stud-
The stroke risk of migraine in men appears to be less estab-
ies have suggested several mechanisms. In 1 prospective
lished. Randomized trial evidence that migraine prophylaxis
study of patients <55 years of age, hypercoagulable states
decreases stroke risk is lacking. The significance of deep white
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(3) HDL cholesterol <40 mg/dL for men and <50 mg/dL for screened for entry into the Diabetes Reduction Assessment
women; (4) BP ≥130/≥85 mm Hg; and (5) fasting glucose with Ramipril and Rosiglitazone Medication (DREAM) trial
≥110 mg/dL.616 A modified criterion for fasting glucose was from 21 different countries, 8000 subjects were normoglyce-
published in 2004.617 The International Diabetes Foundation mic, 8427 had impaired fasting glucose or impaired glucose
(IDF) then modified the definition by requiring inclusion of a tolerance, and 2563 had newly diagnosed type 2 diabetes mel-
waist circumference >88 cm for men and >80 cm in women litus.640 Among all subjects, an 18-mg/dL increase in fasting
plus 2 of the other National Cholesterol Education Program– plasma glucose or a 45-mg/dL increase in the 2-hour glucose
Adult Treatment Panel III criteria.618 In 2009, a harmonized after an oral glucose tolerance test was associated with an
definition was proposed wherein an identical set of thresholds increase in cardiovascular events, including stroke or death
was used for all components except waist circumference, an (HR, 1.17; 95% CI, 1.13–1.22). The relationships between
area in which further evidence for the relationship to CVD other individual components of the metabolic syndrome and
events was felt to be required.619 In the interim, the Harmonized stroke risk, including elevated BP, are reviewed in other sec-
Definition Work Group suggested that national or regional cut tions of this guideline.
points for waist circumference should be used. Thus, because The metabolic syndrome is a predictor of CVD and vascular
the waist circumference and risk for CVD and diabetes melli- death; however, this risk does not appear to be any larger than
tus vary around the world, the National Cholesterol Education the sum of the components of the syndrome.626,641 A similar lack
Program–Adult Treatment Panel III, IDF, and harmonized def- of greater predictability is true for the metabolic syndrome and
initions all make a provision for an ethnic/racial/geographic stroke.642 This lack of relationship may be because of sample
modification of waist circumference.620 Obesity and sedentary size or a small number of stroke events. The National Health and
lifestyle, in addition to other genetic or acquired factors, seem Nutrition Examination Survey, among 10 357 subjects,643 the
to interact to produce the metabolic syndrome.621 Screening prevalence of metabolic syndrome was higher in people with
for the syndrome requires no more than a routine physical self-reported history of stroke (43.5%) than in those with no
examination and routine blood tests.622 history of stroke or myocardial infarct (22.8%; P≤0.001). The
Obesity, discussed separately, is an important component metabolic syndrome was independently associated with stroke
of the metabolic syndrome and is associated with major health history in all ethnic groups and in both sexes (OR, 2.16; 95% CI,
risk factors (such as diabetes mellitus, hypertension, and dys- 0.48–3.16). The association between metabolic syndrome and
lipidemia), poor health status, and, when extreme, lower life stroke has been confirmed in other populations, including those
expectancy.623–625 The visceral adiposity characteristic of the enriched with elderly subjects, and the frequency of the meta-
metabolic syndrome is associated with insulin resistance, bolic syndrome was notably higher in patients with a history of
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inflammation, diabetes mellitus, and other metabolic and nonhemorrhagic stroke269,643–646 but also in Korean patients with
cardiovascular derangements.626 Visceral adipocytes provoke spontaneous ICH.645 The adjusted RRs for ischemic stroke asso-
insulin resistance by promoting extensive lipolysis and release ciated with the metabolic syndrome in prospective studies has
of fatty acids into the splanchnic circulation. Leptin, plasmin- ranged between 2.10 and 2.47, and an HR as high as 5.15 has
ogen activator inhibitor-1, tumor necrosis factor-α, and other been reported.647–653 This predictive capacity does not appear to
proinflammatory cytokines, in addition to reduced production be influenced by the definition used for the metabolic syndrome
and release of adiponectin by adipocytes, have all been impli- and showed no significant variation across sex, age, or ethnic
cated in this pathophysiological process.626 groups. Yet, in the Stroke Prevention by Aggressive Reduction
The metabolic syndrome is highly prevalent in the United in Cholesterol Levels (SPARCL) trial, the 642 subjects with
States.626 Applying the harmonized definition of the meta- the metabolic syndrome and a previous stroke or TIA did not
bolic syndrome to data from the National Health and Nutrition experience an increased risk of stroke.654 Although many stud-
Examination (2003 through 2006) in up to 3461 participants ≥20 ies have used >1 definition of the metabolic syndrome to assess
years of age with a waist circumference threshold of ≥102 cm the risk for stroke, the harmonized definition may prove to be
for men and ≥88 cm for women, the age-adjusted prevalence superior in establishing the relationship.655,656
of metabolic syndrome was 34.3% among all adults, 36.1% There are essentially no trial data that have addressed the
among men, and 32.4% among women.627 With the use of race- effects of treatment on cardiovascular morbidity and mortal-
or ethnicity-specific IDF criteria for waist circumference, the ity in patients with the metabolic syndrome. In the JUPITER
age-adjusted prevalence was 38.5% for all participants, 41.9% Trial, 17 802 healthy men and women with LDL cholesterol
for men, and 35.0% for women. Prevalence increased with age, levels <130 mg/dL and hs-CRP levels ≥2.0 mg/L were ran-
with the highest prevalence in subjects between 60 to 69 years domized to receive rosuvastatin 20 mg daily or placebo and
of age. Prevalence was lower among black men than white or followed up for the occurrence of the combined primary end
Mexican American men and lower among white women than point of MI, stroke, arterial revascularization, hospitalization
among black or Mexican American women. Mostly attributable for unstable angina, or death resulting from cardiovascular
to the obligatory use of a lower waist circumference for the IDF, causes.657 The rates were reduced by a hazard ratio of 0.56
the IDF definition led to higher estimates of prevalence in all (95% CI, 0.46–0.69) for the primary end point, 0.46 (95% CI,
demographic groups, especially among Mexican American men. 0.30–0.70) for MI, and 0.52 (95% CI, 0.34–0.79) for stroke.
Hyperinsulinemia/insulin resistance is an important marker Patients with or without the metabolic syndrome had similar
of the metabolic syndrome; however, results concerning a reductions in CVD events. The TNT study included 10 001
relationship between glucose intolerance and stroke risk patients with clinically evident coronary heart disease.658
are conflicting.628–639 In 18 990 men and women who were Treating to an LDL cholesterol substantially <100 mg/dL
Meschia et al Guidelines for the Primary Prevention of Stroke 3789
with a high dose of a high-potency statin reduced both stroke hypercoagulability, reduced cerebral blood flow,694 and an
and cardiovascular events by an additional 20% to 25% com- increased risk of AF.662,668,695–698 Studies show an increased
pared with a lower dose. Of these subjects, 5584 patients with risk for stroke in hypertensive patients who consume alco-
the metabolic syndrome were randomly assigned to high- or hol, as well as poor BP control in heavy drinkers with
low-dose statin.659 As expected, the higher dose led to greater hypertension.
reductions in LDL cholesterol (73 versus 99 mg/dL at 3 A study of 43 685 men from the Health Professionals
months). Regardless of treatment assignment, more patients Follow-Up Study and 71 243 women from the Nurses’ Health
with the metabolic syndrome (11.3%) had a major cardio- Study showed that alcohol intake had a J-shaped associa-
vascular event than those without the metabolic syndrome tion for risk of stroke.667 A lower risk for stroke was found
(8.0%, HR, 1.44; 95% CI, 1.26–1.64; P<0.0001). At a median in women who were light drinkers, but women who drank
follow-up of 4.9 years, major cardiovascular events occurred ≥ 30 g alcohol per day had a 40% increased risk for stroke
in 13% patients receiving the low-dose statin compared with (RR, 1.41; 95% CI, 1.07–1.88 for ischemic stroke; RR, 1.40;
9.5% receiving the higher dose (HR, 0.71; 95% CI, 0.61–0.84; 95% CI, 0.86–2.28 for ICH). There was a similar but nonsig-
P<0.0001), and cardiovascular events were reduced by 26% nificant pattern for men. In the WHS,699 alcohol consumption
(HR, 0.74; 95% CI, 0.59–0.93; P=0.011). was not associated with risk for stroke, even for ≥10.5 drinks
per week. However, a recent meta-analysis showed a higher
Metabolic Syndrome: Summary and Gaps mortality risk for women compared with men who drank >3
Individual components of the metabolic syndrome are associ- drinks per day.700
ated with an increased risk of ischemic stroke and should be A prospective study of Chinese men701 supports the associa-
treated as appropriate. The specific risk of stroke in people tion between heavy alcohol and risk for stroke. A 22% increase
with the metabolic syndrome appears to be higher but remains in stroke occurred for those consuming at least 21 drinks per
uncertain, as is the effect of treatment of the syndrome. week, whereas consumption of 1 to 6 drinks per week was
associated with the lowest risk. In a meta-analysis of 35 obser-
vational studies,678 consumption of 60 g alcohol per day was
Metabolic Syndrome: Recommendations associated with a 64% increased risk for all stroke (RR, 1.64;
1. Management of individual components of the meta- 95% CI, 1.39–1.93), a 69% increase for ischemic stroke (RR,
bolic syndrome is recommended, including lifestyle 1.69; 95% CI, 1.34–2.15), and more than doubling for hemor-
measures (ie, exercise, appropriate weight loss, rhagic stroke (RR, 2.18; 95% CI, 1.48–3.20). Consumption
proper diet) and pharmacotherapy (ie, medications of <12 g/d was associated with a reduced risk of total (RR,
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for BP lowering, lipid lowering, glycemic control, and 0.83; 95% CI, 0.75–0.91) and ischemic (RR, 0.80; 95% CI,
antiplatelet therapy), as endorsed in other sections of 0.67–0.96) stroke, with consumption of 12 to 24 g/d associ-
this guideline. (Refer to relevant sections for Class ated with a lower risk of ischemic stroke (RR, 0.72; 95% CI,
and Levels of Evidence for each recommendation.) 0.57–0.91). A systematic review of triggers of ischemic stroke
showed a significant association between ischemic stroke and
alcohol abuse of >40 to 60 g within the preceding 24 hours
Alcohol Consumption (OR, 2.66; 95% CI, 1.54–4.61) or >150 g within the previous
The National Institute on Alcohol Abuse and Alcoholism week (OR, 2.47; 95% CI, 1.52–4.02).702
defines heavy drinking for a man as >4 drinks in any single
day or >14 drinks per week and defines heavy drinking for a Alcohol Consumption: Summary and Gaps
woman as >3 drinks any single day and >7 drinks per week.660 In observational studies, light to moderate alcohol consump-
A standard drink is defined as 12 fl oz of regular beer, 5 fl oz tion is associated with reduced risk of total and ischemic
of table wine, or a 1.5–fl oz shot of 80-proof spirits. Heavy stroke, whereas heavier alcohol consumption increases stroke
alcohol consumption can lead to multiple medical compli- risk. Prospective, randomized, clinical trials showing that
cations, including stroke. Heavy alcohol consumption is a reduction of heavy alcohol consumption reduces risk or that
risk factor for all types of stroke.661–665 Most studies suggest light alcohol consumption is beneficial are lacking and are
a J-shaped association between alcohol consumption and the ethically untenable because it is well established that alcohol
risk of total and ischemic stroke, with a protective effect in dependence is a major health problem.
light (<151 g/wk) or moderate (151 to 300 g/wk) drinkers and
an elevated risk with heavy (>300 g/wk) alcohol consump-
tion.661,662,666–676 In contrast, a linear association exists between Alcohol Consumption: Recommendations
alcohol consumption and the risk of ICH.330,334,677,678 In a pro- 1. Reduction or elimination of alcohol consumption in
spective cohort study of 540 patients with spontaneous ICH,679 heavy drinkers through established screening and
heavy alcohol intake was associated with ICH at a young age counseling strategies as described in the 2004 US
(median age, 60 versus 74 years in nonabusers; P<0.001). Preventive Services Task Force update is recom-
Light-to-moderate alcohol consumption is associated mended703 (Class I; Level of Evidence A).
with higher levels of HDL cholesterol,680,681 reduced plate- 2. For individuals who choose to drink alcohol, con-
let aggregation,682,683 lower fibrinogen concentrations,684 and sumption of ≤2 drinks per day for men and ≤1 drink
increased insulin sensitivity and glucose metabolism.685,686 per day for nonpregnant women might be reason-
Heavy alcohol consumption can result in hypertension,687–693 able704,705 (Class IIb; Level of Evidence B).
3790 Stroke December 2014
1.48–2.79). Amphetamine abuse was associated with a higher prospective studies that included 8435 participants identified
risk of fatal ICH (OR, 2.63; 95% CI, 1.07–6.50). In a retro- an OR for incident stroke risk of 2.24 (95% CI, 1.57–3.19).734
spective analysis of patients with ICH, patients with cocaine- This meta-analysis also found that increased stroke risk is
associated ICH had worse functional outcomes and an almost associated with increasing sleep apnea severity with an OR of
3-fold greater risk of death during the acute hospitalization 1.35 (95% CI, 1.25–1.45) for every 10-unit increase in AHI. A
than patients with cocaine-negative ICH.727 study of 50 men with sleep apnea and 15 obese male control
Long-term treatment strategies, including medication, subjects found that silent brain infarctions on MRI were more
psychological counseling, and community-based programs, common among patients with moderate to severe sleep apnea
are effective in the management of drug dependency.706,728 than among control subjects or patients with mild sleep apnea
According to the US Preventive Services Task Force, there (25% versus 7.7% versus 6.7%, respectively; P<0.05).735
is insufficient evidence to assess the balance of benefits and Although alternative therapeutic strategies exist, the main-
harms of screening adolescents, adults, and pregnant women stay of sleep apnea treatment is continuous positive airway
for illicit drug use. Although standardized questionnaires to pressure (CPAP), which improves a variety of clinical out-
screen individuals for drug use/misuse have been shown to be comes (eg, daytime sleepiness).730,736 No randomized trial has
valid and reliable, there is insufficient evidence to assess the evaluated the effectiveness of CPAP on primary stroke preven-
clinical utility of these instruments when applied widely in tion. The existing longitudinal cohort data indicate that CPAP
primary care settings.729 treatment is associated with a reduction in cardiovascular risk
among patients with sleep apnea compared with patients who
Drug Abuse: Summary and Gaps are not treated with CPAP even after adjustment for vascular
Several drugs of abuse are associated with ischemic and hem- risk factors and that this finding is most robust for patients
orrhagic stroke. There are no controlled trials demonstrating a with the most severe sleep apnea.737–739 For example, a study of
reduction in stroke risk with abstinence. 264 healthy subjects, 403 untreated patients with sleep apnea,
and 372 patients with CPAP treatment for 10 years739 had a
combined vascular event end point that included fatal or non-
Drug Abuse: Recommendation
fatal stroke or MI or acute coronary syndrome requiring car-
1. Referral to an appropriate therapeutic program is diac intervention. In this cohort, severe untreated sleep apnea
reasonable for patients who abuse drugs that have was associated with a 3-fold increased risk of vascular events
been associated with stroke, including cocaine, (adjusted OR, 2.87; 95% CI, 1.17–7.51 for cardiovascular
khat, and amphetamines (Class IIa; Level of death; OR, 3.17; 95% CI, 1.12–7.52 for nonfatal cardiovascu-
Evidence C). lar events), but patients with treated sleep apnea had vascular
Meschia et al Guidelines for the Primary Prevention of Stroke 3791
event risks that were similar to those of patients with mild a significant proportion of patients.758 Patients who are con-
untreated sleep apnea and healthy subjects. A cardiovascular sidered to be high risk on the basis of this screening should be
end-point benefit was observed with CPAP treatment among referred for polysomnography.730
364 patients receiving CPAP compared with 85 untreated
patients.738 The adjusted HR was 0.34 (95% CI, 0.20–0.58) for Sleep-Disordered Breathing: Summary and Gaps
CPAP treatment. Sleep apnea independently contributes to risk of stroke, and
Although no randomized, controlled trials have been pub- increasing sleep apnea severity is associated with increas-
lished on primary prevention, several randomized, controlled ing risk. No prospective, randomized trial has evaluated the
trials and cohort studies have evaluated the effectiveness of effectiveness of sleep apnea treatment for primary stroke
CPAP among patients with stroke and TIA (These data are
prevention.
reviewed in detail in the AHA secondary stroke prevention
guidelines).740 Among these secondary prevention studies,
the one with the longest follow-up studied 189 patients after Sleep-Disordered Breathing: Recommendations
stroke with sleep apnea for 7 years, finding that patients who
1. Because of its association with stroke risk, screening
did not use CPAP had a much higher recurrent stroke rate than
for sleep apnea through a detailed history, includ-
patients who used CPAP (32% versus 14%; P=0.021) and a ing structured questionnaires such as the Epworth
higher adjusted incidence of nonfatal vascular events (HR, Sleepiness Scale and Berlin Questionnaire, physical
2.87; 95% CI, 1.11–7.71).741 The number needed to treat to examination, and, if indicated, polysomnography
prevent 1 new vascular event was 4.9 patients (95% CI, 2–19). may be considered (Class IIb; Level of Evidence C).
Adherence to CPAP can be measured directly by CPAP 2. Treatment of sleep apnea to reduce the risk of stroke
machines in hours per night used and proportion of nights used. may be reasonable, although its effectiveness for pri-
The reported CPAP adherence has varied considerably across mary prevention of stroke is unknown (Class IIb;
studies and across populations, with mixed data about differ- Level of Evidence C).
ences in adherence related to differences in CPAP mode (eg,
autotitrating versus fixed pressure) or humidification use.742–746
Cognitive-behavioral interventions appear to improve CPAP Hyperhomocysteinemia
adherence.747 Several studies have sought to identify predic- Homocysteine is an amino acid derived from the metabolism
tors of CPAP adherence, and results have varied across stud- of the essential amino acid methionine. Increased plasma lev-
ies. In general, however, patients who are most symptomatic els of homocysteine are often a consequence of reduced enzy-
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(eg, excessive daytime sleepiness) are most likely to adhere to matic activity in its metabolic pathways. This may be caused
treatment in the long term.745 A CPAP use study among 1155 by genetic defects in the enzymes involved in homocysteine
patients with sleep apnea found that 68% were continuing to metabolism such as deficiencies of cystathionine β-synthase
use the CPAP after 5 years of follow-up.748 and methylenetetrahydrofolate reductase (MTHFR), involved
Patients with sleep apnea often have concomitant stroke in the transsulfuration and remethylation pathways, respec-
risk factors, including hypertension, AF, diabetes mellitus, tively, or by a thermolabile variant of MTHFR that results from
obesity, and hyperlipidemia, and several studies have dem- a point mutation in which cytosine is replaced by thymidine
onstrated the importance of adjusting for these factors when at position 677 (MTHFR C677T).759 Hyperhomocysteinemia
examining the relationship between sleep apnea and risk of also is caused by nutritional deficiencies of pyridoxine (vita-
stroke.733,734 Given the robust relationship between sleep apnea min B6), a cofactor of cystathionine β-synthase, and of folic
and hypertension,749–751 numerous studies have specifically acid and cobalamin (vitamin B12), cofactors of MTHFR.760
examined the degree to which CPAP treatment is associated Decreased renal clearance of homocysteine in patients with
with improvements in BP. Several meta-analyses suggest that chronic renal failure may contribute to hyperhomocysteinemia.
the difference in SBP that can be expected with CPAP ranges Elevated levels of plasma homocysteine are associated
from a decrease of 1.4 to 7.2 mm Hg,736,752–754 with most of the with 2- to 3-fold increased risk for atherosclerotic vascu-
estimates closer to the lower end of this range. lar disease, including stroke.761–767 Carotid IMT and carotid
Despite being highly prevalent, as many as 70% to 80% of artery stenosis are increased in people with elevated homo-
patients with sleep apnea are neither diagnosed nor treated.755 cysteine levels.768–770 In the Study of Health Assessment and
The American Academy of Sleep Medicine730 advocates Risk in Ethnic Groups (SHARE), a cross-sectional study of
screening high-risk patients for symptoms of sleep apnea. South Asian Chinese and white Canadians, plasma homocys-
High-risk populations include those with risk factors for teine >11.7 μmol/L, but not MTHFR C677T, was associated
stroke (eg, AF, refractory hypertension) and patients with with increased carotid IMT.771 Several recent investigations
stroke. The recommended screening includes a sleep his- found that the relationship between homocysteine levels
tory (eg, snoring, witnessed apneas, daytime sleepiness), an and carotid IMT was eliminated after adjustment for other
evaluation of conditions that may occur as a consequence of cardiovascular risk factors or renal function.772,773 One meta-
sleep apnea (eg, motor vehicle accidents, stroke), and physi- analysis of epidemiological studies found a 19% (95% CI,
cal examination (eg, BMI ≥35 kg/m2, neck circumference 5–31) reduction in odds of stroke per 25% lower homo-
>17 in for men or 16 in for women). The Epworth Sleepiness cysteine concentration after adjustment for smoking, SBP,
Scale756 and Berlin Questionnaire757 are tools for screening and cholesterol.774 Another meta-analysis found that for
for sleep apnea. However, most clinical screening tests miss each 5-μmol/L increase in homocysteine, the odds of stroke
3792 Stroke December 2014
increased by 59% (95% CI, 29–96), and for each 3-μmol/L reduced stroke risk (RR, 0.93; 95% CI, 0.86–1.00). A some-
decrease in homocysteine, the odds of stroke decreased by what stronger reduction in stroke (RR, 0.89; 95% CI, 0.79–
24% (95% CI, 15–33).775 A further line of evidence support- 0.99) was noted in a different subgroup analysis790 restricted
ing a causal role for homocysteine in a stroke is a meta-anal- to 35325 participants who did not have stroke as a qualifying
ysis of 29 studies comparing the MTHFR C677T genotype event for inclusion in the trial.
between 4454 stroke patients and 7586 control subjects. This The effect of folic acid therapy has also been studied in
“mendelian randomization” approach found increased stroke patients with chronic renal disease and hyperhomocystein-
in those with the TT genotype (OR for stroke, 1.26; 95% CI, emia, but the results of these studies are inconsistent.791–793 In
1.11–1.43) without significant between-study heterogeneity the Atherosclerosis and Folic Acid Supplementation Trial, a
or evidence of publication bias.776 placebo-controlled study of 315 patients with chronic renal
The B complex vitamins pyridoxine (B6), cobalamin (B12), failure, folic acid supplementation did not reduce the compos-
and folic acid lower homocysteine levels. Folic acid intake is ite risk of cardiovascular events, with fewer treated patients
associated with reduced risk of ischemic stroke in some epide- having strokes (RR reduction, 0.55; 95% CI, 0.01–0.80).793,794
miological studies but not in others.777–780 In a clinical trial of Similarly, in the HOPE 2 study of patients with established
healthy adults without diabetes mellitus and CVD, B complex vascular disease or diabetes mellitus, combination therapy
vitamin supplementation compared with placebo decreased with vitamin B6, vitamin B12, and folic acid lowered plasma
carotid IMT in the group of participants whose baseline plasma homocysteine levels; did not affect the composite end point
homocysteine was ≥9.1 μmol/L but not in those whose homo- of cardiovascular death, MI, or stroke; but did reduce the risk
cysteine levels were lower.781 A meta-analysis of 10 random- of stroke by 25% (RR, 0.75, 95% CI, 0.59–0.97).795 A sub-
ized trials of folic acid similarly found that treatment decreased sequent exploratory analysis found no heterogeneity in the
IMT but with substantial heterogeneity resulting from larger effect on stroke based on whether or not the subjects had a
effects at higher baseline IMTs or with greater reductions in prior history of stroke or TIA (P for interaction=0.88).796
homocysteine.782 A substudy of the Vitamins to Prevent Stroke
(VITATOPS) trial, however, reported that B complex vitamins Hyperhomocysteinemia: Summary and Gaps
did not slow the progression of carotid IMT.783 Hyperhomocysteinemia is associated with an increased risk
Most trials of patients with established atherosclerotic vas- of stroke. Trials that have examined the effect of homocys-
cular disease have found no benefit of homocysteine lower- teine-lowering therapy with B complex vitamins on the risk
ing by B complex vitamin therapy on clinical cardiovascular of stroke are inconsistent. Stroke reduction generally was
end points. In the Vitamin Intervention for Stroke Prevention found in trials in which the duration of treatment exceeded
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(VISP) trial, therapy with high doses of vitamin B6, vitamin 3 years, the decrease in plasma homocysteine concentration
B12, and folic acid did not affect the risk of recurrent isch- was >20%, the region where patients were recruited did not
emic stroke compared with a low-dose formulation of these fortify diet with folate, and the participants had no prior
B complex vitamins. In 2 Norwegian trials, 1 trial of patients history of stroke. Better understanding of the mechanisms
with MI and the other of patients with coronary artery disease through which homocysteine causes atherosclerosis may
or aortic stenosis, B complex vitamins did not reduce mortal- enable identification of more targeted and effective therapies
ity or cardiovascular events, including stroke.784,785 Similarly, to reduce the risk of stroke in patients with elevated homo-
in the Women’s Antioxidant and Folic Acid Cardiovascular cysteine levels.
Study (WAFACS), these B complex vitamins did not alter the
risk of stroke in women with established CVD or ≥3 risk fac-
tors.786 Most recently, the VITATOPS trial,787 in which 8164 Hyperhomocysteinemia: Recommendation
subjects with recent stroke or TIA were randomized to vitamin 1. The use of the B complex vitamins, cobalamin (B12),
B6, vitamin B12, and folic acid versus placebo and followed up pyridoxine (B6), and folic acid might be considered
for a median of 3.4 years, found no effect of B vitamin supple- for the prevention of ischemic stroke in patients with
mentation on risk of stroke (HR, 0.92; 95% CI, 0.81–1.06). hyperhomocysteinemia, but its effectiveness is not
Interestingly, a post hoc analysis restricted to the 1463 sub- well established (Class IIb; Level of Evidence B).
jects in VITATOPS not taking antiplatelet medication788 found
a reduced risk of stroke in the B vitamin group (HR, 0.6; 95%
CI, 0.50–0.95) and a significant interaction between anti- Elevated Lp(a)
platelet use and assignment to B vitamins. It remains unclear Lp(a) is an LDL particle in which apolipoprotein B-100 is
whether the effectiveness of B vitamin treatment within the covalently linked to the glycoprotein apoprotein(a). The
no-antiplatelet subgroup represents biological modification of structure and chemical properties of this lipoprotein particle
the effects of homocysteine by antiplatelet drugs, intergroup are similar to those of LDL. Lp(a) contributes to athero-
differences between patients on and off antiplatelet therapy genesis in experimental models797 and is associated with an
(such as the greater proportion of patients with hemorrhagic or increased risk for coronary artery disease.798,799 Apoprotein(a)
cardioembolic strokes among those not taking antiplatelets), also has structural homology to plasminogen but does not
or a spurious result of secondary analysis. A meta-analysis of possess its enzymatic activity. Thus, it may inhibit fibrino-
folic acid supplementation in 26 randomized, controlled tri- lysis, binding to the catalytic complex of plasminogen, tis-
als enrolling 58 804 participants789 found no effect on the risk sue plasminogen activator, and fibrin, thereby contributing
of CVD (RR, 0.98; 95% CI, 0.95–1.02) but a trend toward to thrombosis.797,800
Meschia et al Guidelines for the Primary Prevention of Stroke 3793
HDL cholesterol slightly improved the prediction of cardio- mine whether aCL was a risk factor for ischemic stroke and
vascular events and would reclassify ≈4% of individuals to a venous thrombosis in healthy adult men.818 This was a nested,
≥20% predicted risk of having a cardiovascular event within case-control study in a prospective cohort with 60.2 months
10 years and therefore needing statin treatment according to of follow-up. At entry into the study, 68% of 22 071 partici-
Adult Treatment Panel III guidelines.810 pants submitted plasma samples. A control was matched by
A meta-analysis of observational studies reported an asso- age, smoking history, and length of follow-up to each of the
ciation of elevated Lp(a) with first childhood arterial ischemic 100 patients with ischemic stroke and the 90 patients with
stroke (OR, 6.53; 95% CI, 4.46–9.55).811 More recently, ele- deep vein thrombosis or pulmonary embolus. The aCL titers
vated Lp(a) was also associated with recurrent arterial isch- were higher in cases with deep vein thrombosis or pulmonary
emic stroke in children.812 embolus than in matched controls (P=0.01). People with aCL
Niacin decreases Lp(a) levels.813 In a meta-analysis of sec- titers above the 95th percentile had an RR for developing deep
ondary prevention trials including a total of 9959 subjects, vein thrombosis or pulmonary embolus of 5.3 (95% CI, 1.55–
niacin treatment yielded relative odds reductions of 34% of 18.3; P=0.01). Although an aCL level above the 95th percen-
any CVD event (P=0.007).173 However, no significant effect tile was an important risk factor for deep vein thrombosis or
of niacin on stroke was observed. pulmonary embolus, there was no effect on stroke (an RR of 2
for ischemic stroke could not, however, be excluded because
of low power).
Lp(a): Summary and Gaps
The Honolulu Heart Study was a nested case-control study
Elevated Lp(a) is associated with a higher risk of stroke.
examining aCL as a risk factor for ischemic stroke and MI.819
Although niacin lowers Lp(a), randomized trials have not
The study used stored frozen sera obtained from subjects in
showed that niacin supplementation lowers the risk of stroke.
the Honolulu Heart Program who were followed for up to 20
years. aCL (β2 glycoprotein-I [β2GPI] dependent) was tested
Elevated Lp(a): Recommendations in 259 men who developed ischemic stroke, 374 men who
1. The use of niacin, which lowers Lp(a), might be developed MI, and a control group of 1360 men who remained
reasonable for the prevention of ischemic stroke in free of both conditions. aCL was significantly associated with
patients with high Lp(a), but its effectiveness is not both incident ischemic stroke and MI. Men with a positive
well established (Class IIb; Level of Evidence B). aCL had higher risk of stroke relative to men with negative
2. The clinical benefit of using Lp(a) in stroke risk pre- aCL (OR, 2.2 [95% CI, 1.5–3.4] at 15 years and OR, 1.5 [95%
diction is not well established (Class IIb; Level of CI, 1.0–2.3] at 20 years). These data suggest that aCL is an
Evidence B). important predictor of future stroke and MI in men.
3794 Stroke December 2014
The Framingham Offspring Cohort Study, a longitudinal Willebrand factor small polymorphism in intron 2, tissue-type
observational study, used an ELISA to measure aCL from stored plasminogen activator −7351 C/T, thrombotic thrombocyto-
frozen sera. This study found an association between aCL titers penic purpura, and heparin-induced thrombocytopenia.826 The
and ischemic stroke or TIA, but only in women.820 Overall, majority of case-control studies have not found an association
although elevated aCL titers may be commonly found in isch- between arterial stroke and other hereditary hypercoagulable
emic stroke patients, the strength of the association between states such as factor V Leiden or prothrombin 20210 muta-
elevated aCL titers and stroke origin or risk is uncertain. tions or deficiencies of protein C, protein S, or antithrom-
The shortcoming of many studies evaluating aCL in stroke bin III.98,99 One study suggests that hypercoagulable states
patients such as the Framingham Offspring Cohort study has may be more frequent in stroke patients with PFO compared
been the use of the aCL ELISA, a test with low sensitivity. The with those without PFO. That study found no difference in the
assay for anti-β2GPI antibodies, a cofactor for antiphospho- prevalence of either the factor V Leiden mutation or the pro-
lipid binding, may be more specific for thrombosis, including thrombin 20210 mutation in patients with cryptogenic strokes
stroke and MI.819,821 Only a few studies have investigated β2GPI compared with control subjects. The prevalence of the pro-
in the absence of SLE. 819,821,822 Because most studies involved thrombin 20210 mutation alone (OR, 10.09; 95% CI, 1.09–
patients with SLE, lupus anticoagulant, or aCL, it is difficult to 109) was higher in those with cryptogenic stroke and PFO
establish the value of anti-β2GPI as an independent risk factor. versus those without PFO,827 suggesting a greater thrombotic
Therefore, the clinical significance of these antibodies requires risk in the setting of PFO than in either condition alone. The
further investigation.821 A prospective, observational study was presumed stroke mechanism is paradoxical embolism related
performed to establish the incidence of first-time thromboem- to venous rather than arterial thrombosis. Similarly, a familial
bolic events in subjects with a high-risk aPL profile (positive cohort study found that the prothrombin 20210 mutation was
lupus anticoagulant, positive aCL, and positive β2GPI).823 The a mild risk factor for venous thromboembolism but was not
incidence of first thromboembolus was 5.3% annually com- found to increase the risk of arterial thromboembolic events.828
pared with an annual rate of 1.9% in a study from the same Prothrombotic abnormalities have been identified in 20%
group looking at subjects with only a single positive aPL test.824 to 50% of children with acute ischemic stroke and 33% to
Forty percent of thromboembolic events were stroke or TIA, 99% of children with cerebral sinus venous thrombosis.829 In
and aspirin did not affect the incidence. children with arterial ischemic stroke, emerging associations
include an increased frequency of factor V Leiden mutation,
Acquired Hypercoagulable State: Treatment for Primary
Prevention of Stroke elevated Lp(a), protein C deficiency, and aPL.
Adequately powered, controlled studies evaluating treatment The 2 most common genetic causes of thrombophilia are
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thrombophilia compared with no screening were evaluated. lipoprotein-associated phospholipase A2 and stroke risk.837-840
Selective screening based on prior venous thromboembolism In addition to numerous epidemiological studies and random-
history was more cost-effective than universal screening. ized, clinical trials with coronary disease end points, several
epidemiological studies have identified associations between hs-
Inherited Hypercoagulable State: Treatment for Primary
Prevention of Stroke CRP and stroke, including the Physician’s Health Study, 841 the
There is very little evidence to guide the management of WHS,842 and the Framingham Heart Study.843 The RRs between
asymptomatic people with thrombophilia. A systematic the highest tertiles/quartiles and the lowest tertile/quartiles range
review of prospective observational studies indicated that from 1.5 to 2.0. The association persists after adjustment for
most venous thromboembolic events occurred during periods multiple risk factors. However, hs-CRP is also associated with
of high risk such as surgery, trauma, or pregnancy.834 These similar increases in mortality from several cancers and lung
studies and expert opinion suggest that antithrombotic pro- diseases,844 indicating that its association with cardiovascular
phylaxis during these periods would be likely to be effec- risk is not specific. On the basis of multiple prospective studies,
tive.829,834 However, the effect of prophylaxis on the incidence hs-CRP was recommended for measurement limited to people
of stroke or TIA in these subjects is not known. with moderate risk for coronary disease (10% to 20% 10-year
risk using the Framingham Risk Score) as an adjunct to global
risk assessment to help guide the aggressiveness of risk factor
Hypercoagulability: Summary and Gaps interventions.835 Recent evidence indicates that elevated plasma
Inherited and acquired hypercoagulable states are associated
levels of YKL-40, a product of lipid-laden macrophages, are
with venous thrombosis, but their association with arterial
associated with an increased risk of ischemic stroke indepen-
cerebral infarction is uncertain. Young women with isch-
dently of hs-CRP levels.845 The JUPITER study, a randomized
emic stroke have a higher prevalence of aPL. The majority of
trial of a statin versus placebo, was performed in people free of
case-control studies have not found an association between
CVD with otherwise normal LDL cholesterol levels (≤130 mg/
acquired or hereditary hypercoagulable states and stroke in
dL) but with hs-CRP levels >2 mg/dL. The trial found a reduc-
other patient populations. The relationship between the pres-
tion in cardiovascular end points, including stroke (RR, 0.52;
ence of PFO and thrombophilia deserves further study because
95% CI, 0.34–0.79), in the statin-treated patients.160 The study
it may affect primary and secondary stroke prevention strate-
design did not include similarly treated subjects with lower lev-
gies. Large prospective studies should be undertaken to refine
els of hs-CRP. No data are available to determine the potential
the risks and to establish the associations of thrombophilias
effects of other treatments such as aspirin in this population.
with venous thromboembolism and first ischemic stroke.
Monitoring of hs-CRP has not been evaluated in randomized
Although the pathogenic role of prothrombotic abnormalities
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of multiple infections, or infectious burden, rather than single 5.39–5.77) per 1000 person-years for aspirin users compared
organisms, may be associated with risk of stroke and carotid with 3.60 (95% CI, 3.48–3.72) per 1000 person-years for
atherosclerosis.859,860 Unfortunately, several randomized trials of nonusers (incidence rate ratio, 1.55; 95% CI, 1.48–1.63).872
antibiotic therapy have failed to find any benefit in the preven- A meta-analysis of 9 clinical trials including 50 868 subjects
tion of cardiovascular end points, including stroke.861,862 found no overall benefit of aspirin for the primary preven-
A final issue in the role of infection and inflammation in tion of stroke (OR, 0.919; 95% CI, 0.828–1.021; P=0.116),
stroke relates to acute infectious diseases (such as influenza). with no heterogeneity among trials.873 Similarly, a second
Possible mechanisms include the induction of procoagulant meta-analysis of 9 trials with 100 076 subjects found that
acute-phase reactants (such as fibrinogen) or destabiliza- aspirin reduced the risk of ischemic stroke (RR, 0.86; 95%
tion of atherosclerotic plaques. Hospitalization for infection CI, 0.75–0.98), but this benefit was offset by an increase in
appears to be a short-term risk factor for stroke,863 although hemorrhagic stroke (RR, 1.36; 95% CI, 1.01–1.82), again
it is unclear what, if any, management implications this has with no heterogeneity among trials.874 A third meta-analysis
for patients. An increase in cardiovascular deaths has long had similar results (risk of stroke, 0.20%/y versus 0.21%/y,
been observed in association with influenza.864,865 A retrospec- P=0.4; hemorrhagic stroke, 0.04%/y versus 0.03%/y, P=0.05;
tive study found that treatment with an antiviral agent within other stroke, 0.16%/y versus 0.18%/y, P=0.08, aspirin versus
2 days of an influenza diagnosis was associated with a 28% control, respectively).875 Taken together, these results reflect
reduction (HR, 0.72; 95% CI, 0.62–0.82) in the risk of stroke risk but no benefit of aspirin for the prevention of a first stroke
or TIA over the ensuing 6 months.866 One case-control study867 in the general population. The US Preventive Services Task
and 1 cohort study868 of influenza vaccination demonstrate a Force recommends aspirin at a dose of 75 mg/d to prevent
reduced risk of stroke associated with vaccination. A pro- MI (but not stroke) in men 45 to 79 years of age and to pre-
spective study in Taiwan found that influenza vaccination of vent stroke in women 55 to 79 years of age on the basis of
people >65 years of age was associated with lower all-cause their vascular risk and the chances of serious gastrointestinal
mortality, including a 65% reduction in stroke (HR, 0.35; 95% hemorrhage.876 The US Preventive Services Task Force further
CI, 0.27–0.45).869 However, because of the risk of bias, ran- notes that the 10-year level of cardiovascular risk for which
domized trials have been advocated.870 Although all people at the benefit exceeds bleeding risk varies from 3% to 11%,
increased risk of complications from influenza should receive depending on age and sex. The most recent AHA guideline
influenza vaccinations on the basis of evidence including ran- for the primary prevention of CVD and stroke also recom-
domized trials, influenza vaccination is recommended by the mends aspirin for primary cardiovascular prevention in those
AHA/ACC for the secondary prevention of CVD. There have with a 10-year coronary heart risk ≥10%.877 There is no evi-
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been no recommendations for influenza vaccination in the dence that antiplatelet medications reduce the risk of stroke in
primary prevention of stroke. No studies have identified any the general population at low risk.878–880 Although stroke was
increase in the risk of stroke after influenza vaccinations.871 not analyzed as a separate end point, lack of aspirin use was
independently associated with a 16% higher risk of cardiovas-
Inflammation and Infection: Recommendations cular events (HR, 1.16; 95% CI, 1.03–1.31) among healthy
male physicians ≥65 years of age.881 The benefit of aspirin for
1. Patients with chronic inflammatory disease such as primary prevention of stroke is therefore limited to selected
RA or SLE should be considered at increased risk of subgroups of patients. Several relevant trials further inform
stroke (Class I; Level of Evidence B). the use of aspirin and other antiplatelet agents for the preven-
2. Annual influenza vaccination can be useful in lower- tion of a first stroke.
ing stroke risk in patients at risk of stroke (Class IIa; The Japanese Primary Prevention of Atherosclerosis With
Level of Evidence B). Aspirin for Diabetes (JPAD) Trial randomized 2539 patients
3. Measurement of inflammatory markers such as hs-
with type 2 diabetes mellitus but without a history of atheroscle-
CRP or lipoprotein-associated phospholipase A2 in
rotic disease (including stroke) to either low-dose aspirin (81 or
patients without CVD may be considered to iden-
100 mg/d) or no aspirin.321 The primary outcome was the occur-
tify patients who may be at increased risk of stroke,
although their usefulness in routine clinical practice is rence of atherosclerotic events (fatal or nonfatal ischemic heart
not well established (Class IIb; Level of Evidence B). disease, fatal or nonfatal stroke, and peripheral arterial disease).
4. Treatment of patients with hs-CRP >2.0 mg/dL with There was no effect of aspirin on the primary end point (HR,
a statin to decrease stroke risk might be considered 0.80; 95% CI, 0.58–1.10; P=0.16) and no effect on cerebrovas-
(Class IIb; Level of Evidence B). cular events (2.2% with aspirin versus 2.5% with no aspirin;
5. Treatment with antibiotics for chronic infections as a HR, 0.84; 95% CI, 0.53–1.32; P=0.44). There was no difference
means to prevent stroke is not recommended (Class in the combined rates of hemorrhagic stroke and severe gastro-
III; Level of Evidence A). intestinal bleeding. A subgroup analysis of the JPAD trial noted
that aspirin therapy lowered the rate of cerebrovascular events
in patients with diabetes mellitus with uncontrolled hyperten-
Antiplatelet Agents for Primary Prevention sion (SBP ≥140 mm Hg and/or DBP ≥90 mm Hg) compared
of Stroke with those with controlled BP (HR, 1.64; 95% CI, 0.83–3.29),
Aspirin use is associated with an increased risk of gastrointes- although the 95% CI includes the possibility of no benefit.882
tinal bleeding. For example, 1 observational study found that The Prevention of Progression of Arterial Disease and
the overall hemorrhagic event incidence was 5.58 (95% CI, Diabetes (POPADAD) trial was a randomized, double-blind,
Meschia et al Guidelines for the Primary Prevention of Stroke 3797
placebo-controlled trial including 1276 adults with type 1 or 2 0.02%/y; number needed to treat, 5000). Gastrointestinal hem-
diabetes mellitus and an ankle-brachial index of ≤0.99 but no orrhage requiring transfusion was more frequent in the aspirin
symptomatic CVD who were randomized in a 2-by-2 factorial group (RR, 1.40; 95% CI, 1.07–1.83; P=0.02). The average
design to 100 mg aspirin or placebo plus antioxidants or placebo gastrointestinal hemorrhage rates were 0.06%/y for aspirin and
daily.883 The study had 2 primary end points: (1) death resulting 0.05%/y for placebo (absolute risk increase, 0.01%/y; num-
from coronary heart disease or stroke, nonfatal MI or stroke, ber needed to harm, 10 000). The most consistent benefit for
or amputation above the ankle for critical limb ischemia and aspirin was in women ≥65 years of age at study entry, among
(2) death resulting from coronary heart disease or stroke. There whom the risk of major cardiovascular events was reduced
was no interaction between aspirin and antioxidant. There was by 26% (RR, 0.74; 95% CI, 0.59–0.92; P=0.008), including
no effect of aspirin on the composite primary end points (HR, a 30% reduction in the risk of ischemic stroke (RR, 0.70; 95%
0.98; 95% CI, 0.76–1.26; P=0.86) or on death resulting from CI, 0.49–1.00; P=0.05); however, there was only a trend in the
coronary heart disease or stroke (HR, 1.23; 95% CI, 0.79–1.93; reduction of the overall risk of all types of stroke (RR, 0.78;
P=0.36). There was no effect of aspirin on fatal stroke (HR, 95% CI, 0.57–1.08; P=0.13), likely related to an increase in the
0.89; 95% CI, 0.34–2.30; P=0.80) or nonfatal stroke (HR, risk of brain hemorrhages. Subgroup analyses showed a reduc-
0.71; 95% CI, 0.44–1.14; P=0.15). There was no difference tion in stroke for those women with a history of hypertension
in the risk of gastrointestinal hemorrhage (HR, 0.90; 95% CI, (RR, 0.76; 95% CI, 0.59–0.98; P=0.04), hyperlipidemia (RR,
0.53–1.52; P=0.69). The lack of increased bleeding risk with 0.62; 95% CI, 0.47–0.83; P=0.001), or diabetes mellitus (RR,
aspirin in those with diabetes mellitus was also found in the 0.46; 95% CI, 0.25–0.85; P=0.01) or having a 10-year cardio-
observational study cited above (incidence rate ratio for aspirin vascular risk ≥10% (RR, 0.54; 95% CI, 0.30–0.98; P=0.04). A
users versus nonusers, 1.09; 95% CI, 0.97–1.22).872 Diabetes further post hoc subgroup WHS analysis found that the over-
mellitus was independently associated with an increased risk all effect of aspirin was not modified in women with migraine
of major bleeding regardless of aspirin use (RR, 1.36; 95% CI, (with or without aura), but aspirin use was associated with an
1.28–1.44). A meta-analysis of 7 trials (11 618 subjects) of the increased risk of MI in those with migraine with aura (RR,
effects of aspirin in patients with diabetes mellitus found a treat- 3.72; 95% CI, 1.39–9.95), an unexpected finding that may have
ment-associated 9% reduction in major cardiovascular events been attributable to chance.615 The AHA evidence-based guide-
(RR, 0.91; 95% CI, 0.82–1.00) but found no significant reduc- lines for CVD prevention in women also endorse the use of
tion in stroke (RR, 0.84; 95% CI, 0.64–1.11).323 Four additional aspirin in high-risk women, unless contraindicated, in women
meta-analyses also found no reduction in stroke with aspirin in ≥65 years of age if BP is controlled and benefit for ischemic
subjects with diabetes mellitus.884–887 stroke and MI prevention outweighs the risk of gastrointesti-
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A focused, multisociety position paper on the primary nal bleeding and hemorrhagic stroke, as well as in women <65
prevention of cardiovascular events in people with diabetes years of age when benefit for ischemic stroke prevention is
mellitus considered these and other studies and recommended likely to outweigh complications.890
low-dose aspirin for adults with diabetes mellitus who have There are several other subpopulations for whom aspirin
a 10-year cardiovascular risk >10% (men >50 years of age might be helpful in reducing risk of stroke. Patients with a
and women >60 years of age who have at least 1 additional reduced ankle-brachial index are at higher risk of vascular
major risk factor such as smoking, hypertension, dyslipid- events. One trial evaluated the benefit of aspirin in a screened
emia, a family history of premature CVD, or albuminuria) and general population cohort with a low ankle-brachial index.891
who are not at high risk of aspirin-related bleeding complica- There was no benefit of aspirin in reducing the rate of fatal
tions.888 It was further recommended that aspirin not be used or nonfatal coronary events, stroke, or revascularization pro-
for cardiovascular prevention among those with diabetes mel- cedures (HR, 1.03; 95% CI, 0.84–1.27). One meta-analysis
litus at low risk and that aspirin might be considered for those evaluated cilostazol versus placebo in 3782, 1187, and 705
at intermediate (10-year risk in the 5%–10% range) risk. patients with peripheral artery disease, cerebrovascular dis-
Relatively few women were enrolled in the primary preven- ease, and coronary stenting, respectively.892 The incidence
tion trials that showed a benefit of aspirin in the prevention of vascular events was lower in the cilostazol group com-
of coronary heart events but no reduction in stroke. The WHS pared with the placebo group (RR, 0.86; 95% CI, 0.74–0.99;
randomized 39 876 initially asymptomatic women ≥45 years P=0.038), including a lower incidence of cerebrovascular
of age to receive 100 mg aspirin on alternate days or placebo events (RR, 0.58; 95% CI, 0.43–0.78; P<0.001), with no
and followed them up for 10 years for a first major vascular increase in serious bleeding complications (RR, 1.00; 95% CI,
event (nonfatal MI, nonfatal stroke, or cardiovascular death).889 0.66–1.51; P=0.996). The primary and secondary prevention
Unlike data from earlier studies that included mainly men, this populations were not analyzed separately; however, there was
study found a nonsignificant 9% reduction (RR, 0.91; 95% no statistical heterogeneity among the trials.
CI, 0.80–1.03; P=0.13) for the combined primary end point In a subgroup analysis of the Hypertension Optimal
among women but a 17% reduction in the risk of stroke (RR, Treatment (HOT) trial, subjects with renal failure (estimated
0.83; 95% CI 0.69–0.99; P=0.04). This was based on a 24% glomerular filtration rate <45 mL/min/1.73 m2) had a reduction
reduction in the risk of ischemic stroke (RR, 0.76; 95% CI, in stroke risk with aspirin (HR, 0.21; 95% CI, 0.06–0.75).893 In
0.63–0.93; P=0.009) and a nonsignificant increase in the risk addition, total mortality was reduced by half (HR, 0.51; 95%
of hemorrhagic stroke (RR, 1.24; 95% CI, 0.82–1.87; P=0.31). CI, 0.27–0.94) and cardiovascular mortality by 64% (HR, 0.36;
The overall average stroke rates were 0.11%/y in aspirin- 95% CI, 0.14–0.90). These results, however, were based on a
treated women and 0.13%/y in placebo-treated women (RR, post hoc analysis. Given the small number of participants with
3798 Stroke December 2014
stage 4 or 5 chronic kidney disease (estimated glomerular fil- Primary Prevention in the Emergency
tration rate <30 mL/min/1.73 m2) in the HOT trial, the RRs and Department
benefits of aspirin in this population are not known. Emergency departments (EDs) in the United States are the default
safety net for millions of Americans,894 yet at a time when more
Antiplatelet Agents and Aspirin: Summary and more Americans use EDs for emergency and primary care, the
and Gaps number of EDs across the United States continues to decline.895 By
Previous guideline statements endorse the use of aspirin for definition, EDs provide immediate access to healthcare providers
cardiac but not stroke prophylaxis among asymptomatic men trained in emergency care and allow access to advanced tech-
whose risk is sufficiently high for the benefits to outweigh nologies and medical specialists for patients with diverse medi-
the risks associated with treatment.876 These recommenda- cal conditions. EDs are equipped to evaluate and manage acute
tions were based on a reduction of coronary events in men and life-threatening illness yet are increasingly called on to provide
reduction of stroke in women. services typically associated with primary care. For many patients
There remains little evidence (aside from cilostazol in those who use the ED for the majority of their healthcare services, the
with peripheral artery disease) supporting the use of antiplate- ED may serve as an important location to provide health promo-
let therapy other than aspirin and cilostazol for primary stroke tion and disease prevention services, including stroke.
prevention because of the lack of relevant trials. In addition to addressing the primary reason for the ED visit,
the ED encounter may serve to reinforce healthy living, to per-
form primary disease identification and prevention, to provide
Antiplatelet Agents and Aspirin: Recommendations: early disease detection (secondary prevention), to encourage
1. The use of aspirin for cardiovascular (including but and facilitate compliance with disease management, and to refer
not specific to stroke) prophylaxis is reasonable for patients to primary care providers for continued management of
people whose risk is sufficiently high (10-year risk existing disease (tertiary prevention).896,897 With the growing num-
>10%) for the benefits to outweigh the risks associ- bers of Americans using the ED for primary care, especially socio-
ated with treatment. A cardiovascular risk calcula- economically at-risk populations, the ED may present a unique
tor to assist in estimating 10-year risk can be found opportunity to reduce cerebrovascular disease and CVD.898
online at http://my.americanheart.org/cvriskcalcula- Enthusiasm to use the ED as a site for initiating primary and
tor (Class IIa; Level of Evidence A). secondary preventative services, however, must be tempered
2. Aspirin (81 mg daily or 100 mg every other day) can by the higher cost of providing care in this setting and per-
be useful for the prevention of a first stroke among formance pressures on the ED personnel to decrease length of
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women, including those with diabetes mellitus, whose stay, rates of patients who leave without treatment, overall wait
risk is sufficiently high for the benefits to outweigh times, and resource use.896,899 Although the list of potentially
the risks associated with treatment (Class IIa; Level
modifiable stroke risk factors as reviewed in this guideline is
of Evidence B).
extensive, not all are amenable to assessment and initiation of
3. Aspirin might be considered for the prevention of a first
stroke in people with chronic kidney disease (ie, esti- preventive strategies in the ED.896 Aside from resource avail-
mated glomerular filtration rate <45 mL/min/1.73 m2) ability, to effectively initiate primary preventive strategies, ED
(Class IIb; Level of Evidence C). This recommenda- personnel must know the risk factors for various diseases, in
tion does not apply to severe kidney disease (stage 4 this case stroke; must understand the appropriate diagnostic
or 5; estimated glomerular filtration rate <30 mL/ evaluations and definitions for the risk factors; must be aware
min/1.73 m2). of recommendations for appropriate interventions; and must be
4. Cilostazol may be reasonable for the prevention of a able to arrange primary care follow-up to assess the effect of
first stroke in people with peripheral arterial disease initiated preventive interventions. Adding delivery of primary
(Class IIb; Level of Evidence B). care and primary prevention to the growing list of mandated
5. Aspirin is not useful for preventing a first stroke in interventions delivered in the ED setting will require engaging
low-risk individuals (Class III; Level of Evidence A). and enabling already largely receptive ED professionals.900
6. Aspirin is not useful for preventing a first stroke in ED visits serve as opportunities to screen and potentially
people with diabetes mellitus in the absence of other treat patients with asymptomatic hypertension. The prevalence
high-risk conditions (Class III; Level of Evidence A). of asymptomatic hypertension in patients presenting to the ED
7. Aspirin is not useful for preventing a first stroke in may be as high as 1 in 20.901 Although patients are asymptom-
people with diabetes mellitus and asymptomatic
atic, many have target-organ injury; an ED cohort of blacks with
peripheral artery disease (defined as asymptomatic
elevated BP in the ED found that 90% had subclinical hyper-
in the presence of an ankle brachial index ≤0.99)
(Class III; Level of Evidence B). tensive heart disease.902 In ED patients with newly identified
8. The use of aspirin for other specific situations (eg, AF, hypertension or chronically untreated hypertension, performing
carotid artery stenosis) is discussed in the relevant screening tests in the ED for target-organ damage and tests for
sections of this statement. identifiable causes of hypertension in selected patents is appro-
9. As a result of a lack of relevant clinical trials, anti- priate. Most asymptomatic patients will not require acute BP
platelet regimens other than aspirin and cilostazol reduction or long-term antihypertensive medication initiation in
are not recommended for the prevention of a first the ED. For most newly diagnosed hypertensive patients, the ED
stroke (Class III; Level of Evidence C). encounter can serve as a means of arranging appropriate referral
Meschia et al Guidelines for the Primary Prevention of Stroke 3799
to outpatient primary care, coupled with counseling on lifestyle Alcohol consumption is a major contributor to many ED
modifications, although this is inconsistently performed.221,903 visits. In response to the epidemic of alcohol-related inju-
ED personnel can identify patients with a history of hyperten- ries and illnesses, numerous ED-based interventions have
sion but nonadherence to their medication regimen who need been investigated.918,919 The American College of Emergency
to resume their previous medications. ED screening for hyper- Physicians developed a brief alcohol use intervention bro-
tension is feasible and cost-effective. Once hypertensive patients chure that does not require significant resources to produce
are identified, ED personnel can educate on and encourage or distribute but, by itself, was found to be only marginally
healthy lifestyles to address their hypertension and the impor- effective in the absence of referral for cessation counseling.920
tance of outpatient follow-up, in accordance with the current More interactive ED interventions require more resources but
Joint National Committee 8 outpatient guidelines.219,896,904 are more likely to produce enduring benefits.921 Integrating
The incidence of diabetes mellitus has more than doubled health promotion into the curriculum of emergency medicine
over the last 2 decades, and millions with the condition remain training programs will help overcome existing nihilism of
undiagnosed. On the basis of screening hemoglobin A1c and many practicing emergency physicians related to the benefit
fasting plasma glucose, the National Health and Nutrition of alcohol interventions.922
Examination Survey estimated the prevalence of undiagnosed Nutrition, physical activity, and drug abuse are potential
diabetes mellitus in the US population to be 2.8%.905 Similar lifestyle targets for behavioral interventions aimed at pri-
to hypertension, there is an even higher prevalence of undi- mary stroke prevention. Of these issues, only the feasibility
agnosed diabetes mellitus in the ED patient population.905 and efficacy of substance abuse screening and intervention
Although point-of-care glucose and hemoglobin A1c testing have been studied in the adult ED setting, although an obe-
of ED patients may be feasible, it remains to be determined sity screening study in a pediatric ED was recently reported,
whether such screening is cost-effective.906 Unselected screen- with more than half of the children being overweight or
ing by capillary blood glucose or hemoglobin A1c measure- obese.923 Obesity contributes to medical conditions fre-
ment is not currently recommended by emergency medicine quently seen in the ED and may complicate medical inter-
societies or other healthcare agencies, but emergency physi- ventions. Many physicians are reluctant to discuss issues
cians support improved recognition and referral for hyper- related to a patient’s weight, and patients are not always
glycemia.896,905,907,908 Patients with known diabetes mellitus receptive to the discussion.924 No study has investigated the
commonly use EDs for acute care of complications related to use of the ED as a site for nutritional and dietary counseling.
diabetes mellitus, and many present with poor glycemic con- Overall, although emergency physicians recognize the need
trol. These encounters provide another opportunity to encour- for health promotion, few actually practice routine screening
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age medication compliance, dietary management, lifestyle and counseling of emergency patients, and many are skepti-
modification, and outpatient follow-up. cal of the effect of ED health promotion.924
Despite decades of public health interventions, cigarette Aside from education on individual risk factors and overall
smoking remains a leading cause of preventable deaths in the healthy lifestyle promotion, the ED can serve as an effective
United States, accounting for 1 of every 5 deaths each year.909 location to educate patients about stroke signs and symptoms
Recognizing this continuing problem, the American College of and the need to seek immediate medical attention. A pilot
Emergency Physicians recommends ED interventions aimed study of stroke education using educational videos was per-
at smoking cessation.910 Numerous studies have demonstrated formed using printed stroke education materials and one-on-
that the ED represents a promising site for smoking cessa- one counseling.925 Compared with a control group that did
tion interventions through self-service kiosks and culturally not receive any intervention, the intervention group demon-
appropriate literature, brief interventions, and referrals to out- strated better stroke awareness immediately after the program,
patient treatment.911,912 With the high prevalence of smoking- but by 3 months after intervention, although statistically still
related illnesses leading to ED visits, these episodes provide more knowledgeable than the control group, test scores had
outstanding “teachable moments” to encourage cessation. declined, highlighting the need for reinforcement. The inter-
The use of oral antithrombotic agents for the prevention vention did not affect rates of smoking or positive changes in
of stroke in patients with nonvalvular AF remains a corner- diet and physical activity. The ED can be part of a broader sys-
stone of stroke prevention.390,913 The US National Hospital tem to educate and reinforce these key messages.
Ambulatory Medical Care Survey revealed an 88% increase in Health care, in particular emergency care, is undergoing
US ED visits for AF, and visits for AF are likely to increase.914 dramatic changes. The increasing demands for emergent and
Despite ample evidence supporting anticoagulation in selected primary care will strain the capacity of many EDs to provide
patients with AF, ≈12% to 34% of patients with AF presenting even basic emergency care to acutely ill patients. To effectively
in the ED are eligible for warfarin but are either undertreated incorporate preventive services into routine ED practice, a care-
or untreated.915,916 The ED represents an important location to ful review of feasibility and cost-effectiveness is required of
identify patients with new-onset AF, to initiate anticoagula- each intervention, again assuming that sufficient resources are
tion depending on comorbidities, and to plan for the initial available.896 Effective primary, secondary, and tertiary stroke
management. Similar to patients with known hypertension prevention can occur in EDs, but significant healthcare organi-
and diabetes mellitus, for patients with known AF, their ED zational changes are required.926 These changes must address
encounters provide opportunities to promote behaviors to current limitations of health promotion training for healthcare
improve compliance with medication and to ensure access to providers, program funding, resource availability, and opportu-
outpatient care.917 nities for timely referral for longitudinal care.
3800 Stroke December 2014
Primary Prevention in the ED: Summary and Gaps care is delivered, including delegation of preventive services to
The ED may serve as an important location to provide health nonphysician staff (eg, nurses or pharmacists), the use of group
promotion and disease prevention services, especially during visits, or the implementation of clinics devoted to screening and
these unique teachable moments, through screening, brief inter- preventive services.943,945–948 Quality improvement efforts that
vention, and referral for treatment. This opportunity to identify include activities that focus on the system, the provider, and
risk factors for stroke and to begin primary prevention requires the patient, as well as the coordination of services across these
further study into resource use, efficacy, effectiveness, and cost. domains, are often the most effective.949 Studies examining the
effectiveness of stroke education programs have generally iden-
Primary Prevention in the ED: Recommendations tified a modest effect on patient knowledge, risk perception, or
health beliefs.944–947 However, studies have demonstrated the
1. ED-based smoking cessation programs and interven- effectiveness of tailored patient self-management programs to
tions are recommended (Class I; Level of Evidence B). improve vascular risk factor control.950,951 Integrated healthcare
2. Identification of AF and evaluation for anticoagula- systems that have focused on improving the quality of vascu-
tion in the ED are recommended (Class I; Level of lar prevention have demonstrated improvements in a variety of
Evidence B). stroke risk factors at the facility or system level.952,953 Achieving
3. ED population screening for hypertension is reason- sustained improvements in the quality of vascular prevention
able (Class IIa; Level of Evidence C). care at the system level may require multidimensional interven-
4. When a patient is identified as having a drug or alco- tions, including implementation of electronic medical record
hol abuse problem, ED referral to an appropriate
systems, ongoing performance measurement, change in the cul-
therapeutic program is reasonable (Class IIa; Level
ture, and alignment of economic incentives.953,954 Stroke preven-
of Evidence C).
tion services are most cost-effective for populations at increased
5. The effectiveness of screening, brief intervention, and
referral for treatment of diabetes mellitus and life- risk (eg, patients >50 years of age).955
style stroke risk factors (obesity, alcohol/substance
abuse, sedentary lifestyle) in the ED setting is not Preventive Health Services: Summary and Gaps
established (Class IIb; Level of Evidence C). Although stroke risk factor quality of care is improving, sub-
stantial gaps in primary stroke prevention care exist. The
existing literature includes prospective trials and observa-
tional cohorts that demonstrate the effectiveness of a vari-
Strategies to Improve Preventive Vascular ety of approaches to delivering vascular prevention services.
Health Services
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Obesity and body fat Among overweight (body mass index=25 to 29 kg/m2) and obese (body mass index >30 kg/m2) Overweight and obesity have now
distribution cont'd individuals, weight reduction is recommended for reducing the risk of stroke (Class I; Level been defined on the basis
of Evidence B). of body mass index, and the
recommendation has been
upgraded from IIa to I
Diabetes mellitus Control of blood pressure in accordance with an AHA/ACC/CDC advisory to a target of <140/90 Reworded to reference AHA/ACC/
mm Hg is recommended in patients with type 1 or type 2 diabetes mellitus (Class I; Level of CDC advisory
Evidence A).
The usefulness of aspirin for primary stroke prevention for patients with diabetes mellitus but Deleted the phrase “however,
low 10-y risk of cardiovascular disease is unclear (Class IIb; Level of Evidence B). administering aspirin may be
reasonable”
Cigarette smoking Counseling in combination with drug therapy using nicotine replacement, bupropion, or Reworded and LOE changed
varenicline is recommended for active smokers to assist in quitting smoking from B to A
(Class I; Level of Evidence A).
Community-wide or statewide bans on smoking in public spaces are reasonable for reducing the New recommendation
risk of stroke and myocardial infarction (Class IIa; Level of Evidence B).
Atrial fibrillation For patients with valvular atrial fibrillation at high risk for stroke, defined as a CHA2DS2- New recommendation
VASc score of ≥2, and acceptably low risk for hemorrhagic complications, chronic oral
anticoagulant therapy with warfarin at a target INR of 2.0 to 3.0 is recommended
(Class I; Level of Evidence A).
For patients with nonvalvular atrial fibrillation, a CHA2DS2-VASc score of ≥2, and acceptably New recommendation
low risk for hemorrhagic complications, oral anticoagulants are recommended (Class I).
Options include warfarin (INR, 2.0 to 3.0) (Level of Evidence A), dabigatran (Level of Evidence
B), apixaban (Level of Evidence B), and rivaroxaban (Level of Evidence B). The selection of
antithrombotic agent should be individualized on the basis of patient risk factors (particularly
risk for intracranial hemorrhage), cost, tolerability, patient preference, potential for drug
interactions, and other clinical characteristics, including time INR is in therapeutic range for
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Other cardiac Surgical intervention is recommended for symptomatic fibroelastomas and for fibroelastomas New recommendation
conditions cont'd that are >1 cm or appear mobile, even if asymptomatic (Class I; Level of Evidence C)
Aspirin is reasonable after aortic or mitral valve replacement with a bioprosthesis New recommendation
(Class IIa; Level of Evidence C).
It is reasonable to give warfarin to achieve an INR of 2.0–3.0 during the first 3 mo after aortic or New recommendation
mitral valve replacement with a bioprosthesis (Class IIa; Level of Evidence C).
Anticoagulants or antiplatelet agents are reasonable for patients with heart failure who do not New recommendation
have atrial fibrillation or a previous thromboembolic event (Class IIa; Level of Evidence A).
Vitamin K antagonist therapy is reasonable for patients with ST-segment–elevation myocardial The level of evidence has been
infarction and asymptomatic left ventricular mural thrombi (Class IIa; Level of Evidence C). downgraded from A to C, but
the recommendation grade is
the same
Anticoagulation may be considered for asymptomatic patients with severe mitral stenosis and New recommendation
left atrial dimension ≥55 mm by echocardiography (Class IIb; Level of Evidence B).
Anticoagulation may be considered for patients with severe mitral stenosis, an enlarged left New recommendation
atrium, and spontaneous contrast on echocardiography (Class IIb; Level of Evidence C).
Anticoagulant therapy may be considered for patients with ST-segment–elevation myocardial New recommendation
infarction and anterior apical akinesis or dyskinesis (Class IIb; Level of Evidence C).
Antithrombotic treatment and catheter-based closure are not recommended in patients with New recommendation
patent foramen ovale for primary prevention of stroke (Class III; Level of Evidence C).
Asymptomatic carotid Patients with asymptomatic carotid stenosis should be prescribed daily aspirin and a statin. New recommendation. The use of
stenosis Patients should also be screened for other treatable risk factors for stroke, and appropriate aspirin and statin therapy was
medical therapies and lifestyle changes should be instituted (Class I; Level of Evidence C). implied but not explicitly stated
except in the perioperative and
postoperative context in the
prior guidelines.
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Migraine cont'd Closure of patent foramen ovale is not indicated for preventing stroke in patients with migraine New recommendation
(Class III; Level of Evidence B).
Drug abuse Referral to an appropriate therapeutic program is reasonable for patients who abuse drugs that Wording slightly revised to
have been associated with stroke, including cocaine, khat, and amphetamines (Class IIa; specifically list drugs associated
Level of Evidence C). with stroke
Sleep-disordered Because of its association with stroke risk, screening for sleep apnea through a detailed history, Wording slightly revised to include
breathing including structured questionnaires such as the Epworth Sleepiness Scale and Berlin polysomnography and use
Questionnaire, physical examination, and, if indicated, polysomnography may be considered of specific questionnaires.
(Class IIb; Level of Evidence C). Recommendation class and LOE
have been downgraded.
Elevated lipoprotein(a) The clinical benefit of using lipoprotein(a) in stroke risk prediction is not well established New recommendation
(Class IIb; Level of Evidence B).
Inflammation and Treatment of patients with high-sensitivity C-reactive protein >2.0 mg/dL with a statin to The revised recommendation now
infection decrease stroke risk might be considered (Class IIb; Level of Evidence B). defines elevated high-sensitivity
C-reactive protein as >2.0 mg/
dL in the context of considering
statin initiation
Antiplatelet agents The use of aspirin for cardiovascular (including but not specific to stroke) prophylaxis is Reworded to include cardiovascular
and aspirin reasonable for people whose risk is sufficiently high (10-y risk >10%) for the benefits to risk calculator and link; changed
outweigh the risks associated with treatment. A cardiovascular risk calculator to assist in from Class I to IIa
estimating 10-y risk can be found online at http://my.americanheart.org/cvriskcalculator
(Class IIa; Level of Evidence A).
Aspirin might be considered for the prevention of a first stroke in people with chronic kidney New recommendation
disease (ie, estimated glomerular filtration rate <45 mL·min−1·1.73 m−2) (Class IIb; Level of
Evidence C). This recommendation does not apply to severe kidney disease (stage 4 or 5;
estimated glomerular filtration rate <30 mL·min−1·1.73 m−2).
Cilostazol may be reasonable for the prevention of a first stroke in people with peripheral arterial New recommendation
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As health professionals, we must ensure that progress in pre- effects on patient-centered outcomes such as preventing stroke
venting stroke does not lead to complacency. We must acknowl- and not merely demonstrate favorable effects on surrogates
edge that several recommendations remain vague because of such as expanding lumens or closing holes. The control groups
suboptimal clinical trial evidence or, even more concerning, of old that showed the benefits of CEA for asymptomatic
may be out of date and therefore irrelevant. Diet and exercise stenosis would be seen as grossly undertreated medically by
are notoriously challenging to study with the same rigor as contemporary standards. It would be important to see if revas-
drugs or devices. It is easier to convince a patient to take a cularization remains relevant in a modern context.
pill than to radically change his or her lifestyle. Nonetheless,
Acknowledgments
we must expect the same standards of evidence for lifestyle
We thank medical librarians Ann Farrell at Mayo Clinic Rochester
interventions. Devices such as stents for carotid stenosis and and Tara Brigham at Mayo Clinic Florida for assistance with a sys-
occluders for PFO should be required to demonstrate favorable tematic review of the medical literature.
Meschia et al Guidelines for the Primary Prevention of Stroke 3805
Disclosures
Writing Group Disclosures
Other Speakers’
Writing Group Research Research Bureau/ Ownership
Member Employment Grant Support Honoraria Expert Witness Interest Consultant/Advisory Board Other
James F. Mayo Clinic NINDS† None None None None None None
Meschia
Cheryl Bushnell Wake Forest World Federation None None None None None None
University Baptist of Neurology†
Medical Center
Bernadette New York University, NIH† None None None None None None
Boden-Albala Global Institute of
Public Health
Lynne T. Rush University NIH† None None None None Nurse Practitioner Advisory None
Braun Medical Center Board*; UpToDate*
Dawn M. Department of Department of None None None None None None
Bravata Veteran Affairs Veteran Affairs†;
NIH/NHLBI†
Seemant University of Miami None None None None None Abbott Vascular*; None
Chaturvedi Miller School of Boehringer-Ingelheim*;
Medicine Thornhill Research*
W.L. Gore*
Mark A. Brigham and Medtronic†; NIH† None None None None AstraZeneca†; None
Creager Women’s Hospital Baxter Healthcare*;
Merck (via TIMI Group)*;
Novartis*; Takeda*
Robert H. University of Colorado None None None None None Amarin*; Amylin*; Genetech*; None
Eckel at Denver Janssen, Johnson & Johnson*;
Lilly*; Novo Nordisk*;
Downloaded from http://ahajournals.org by on August 29, 2018
Regulus*; Sanofi-Aventis*
Mitchell S.V. Columbia University BMS/Sanofi†; None None Merck Organon None BMS-Pfizer Pharmaceutical None
Elkind diaDexus, Inc† (Nuvaring Partnership*;
NIH† and stroke)†; Janssen*;
Novartis Daiichi Sankyo*;
(aliskiren and Biogen IDEC*
stroke)*
Myriam University of Texas None None None None None None None
Fornage Health Science Center
at Houston
Larry B. Duke University None None Pfizer* None None Daiichi Sankyo* None
Goldstein
Steven M. Massachusetts NIH/NINDS† None None None None None None
Greenberg General Hospital
Susanna E. Columbia University None None None None None None None
Horvath
Costantino Weill Cornell None None None None None None None
Iadecola Medical College
Edward C. Medical University NIH/NINDS† None None None None None None
Jauch of South Carolina
Wesley S. University of California None None None None None None None
Moore at Los Angeles
John A. Wake Forest School None None None None None None None
Wilson of Medicine
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the
Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person
receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of
the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding
definition.
*Modest.
†Significant.
3806 Stroke December 2014
Reviewer Disclosures
Other
Research Speakers’ Bureau/ Expert Ownership Consultant/Advisory
Reviewer Employment Research Grant Support Honoraria Witness Interest Board Other
Kevin M. Cockroft Penn State Hershey None None None None None Covidien Neurovascular* None
Medical Center
Karen L. Furie Rhode Island None None None None None None None
Hospital
David M Greer Yale University None None None None None None None
Millie NYU Langone None None None None None American Association None
Hepburn-Smith Medical Center of NeuroScience Nurses
(member of the Board
of Directors)*; National
Aphasia Association
(Board of Directors)*
Steven J. Kittner University of 1U01NS069208 The Stroke None None None None None None
Maryland Genetics Network (SiGN)
Study is an NINDS-funded
international consortium
to study the genetics
of ischemic stroke and
ischemic stroke
subtypes†; R01NS069763
Ethnic/Racial Variations of
Intracerebral Hemorrhage
(ERICH) is an NINDS-funded
study of the risk factors for
intracerebral hemorrhage
occurrence and outcome*
Tatjana Rundek University of None None None None None None None
Miami
Downloaded from http://ahajournals.org by on August 29, 2018
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure
Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during
any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more
of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.
†Significant.
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