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Introduction
Stroke is the leading cause of physical and cognitive disability in the United States and the fourth leading cause of death.[1–3] Strokes occur across all continents, age groups, and socioeconomic groups, but are much more common in those over age 65.[4]
Although the term “stroke” is generally understood to reflect a sudden and abrupt onset of neurological symptoms and signs that correspond to an underlying vascular etiology, only in recent years has the definition been updated to reflect trends in neuroimaging and histopathology. Stroke is defined as an episode of loss of neurological function due to a focal infarction of the brain, spinal cord, or retina, [5] This term includes ischemic stroke and all types of intracerebral hemorrhage (ICH), including subdural hemorrhage (SDH) and subarachnoid hemorrhage (SAH).
In the 1960s, the term “transient ischemic attack” (TIA) came into use, to separate patients who had brief and self-limited neurological symptoms from those who had more prolonged neurological deficits. The definition of TIA was updated in 2009 to reflect that TIA is a transient episode of neurological dysfunction caused by focal ischemia of the brain, spinal cord, or retina without acute infarction.[6] These updated definitions highlight the importance of a tissue-based diagnosis of infarction, rather than a purely clinical diagnosis, for both stroke and TIA.
Epidemiology
There are approximately 800,000 strokes annually in the United States. Half of these occur in people who are 75 or older,[2] while only 34% of hospitalized patients with stroke are under age 65.[6] In the United States alone, there are approximately 7 million stroke survivors, and this number is likely to increase due to a combination of an increasingly aging population and declining stroke mortality.[7] The cost of caring for stroke patients in the United States alone is estimated at $38.6 billion annually.[1]
There has been a decrease in the incidence of stroke since 1987, with the biggest decline occurring in patients above age 65.[2] Between 2000 and 2010, the relative rates of stroke death fell by 35.8%, while the actual number of stroke deaths fell by almost 23%.[2] While there are likely many reasons for this change, one factor is the improved management of modifiable vascular risk factors. However, despite the improvement in overall stroke incidence, mortality continues unchanged in the older population. The higher mortality in the elderly may be driven partly by early withdrawal of care,[8] as well as the increased use of advance directives in hospitalized patients over the last decade.[8–10]
Stroke types
Stroke is a heterogeneous disorder with many causes.[5] Management of the stroke itself and prevention of future strokes relies on establishing the mechanism of the stroke and reducing triggers for stroke recurrence.
Approximately 85% of all strokes are ischemic strokes, and 15% of all strokes are hemorrhagic strokes (including intracerebral, subarachnoid, and subdural hemorrhages). Hemorrhagic strokes are more likely to be fatal than ischemic strokes.[11]
Efforts to understand causes of stroke have led to two major classification systems for ischemic stroke. Although not interchangeable, both classification systems have been validated, particularly in categorizing stroke into large vessel, small vessel, and cardioembolic.[12] The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is outlined in Table 16.1.[13] The Causative Classification of Stroke System (CSS) is an online database that uses an evidence-based algorithm that provides both causative and phenotypic stroke subtypes (css.mgh.harvard.edu).[14]
Transient ischemic attack
Approximately 240,000 adults experience a TIA in the United States every year, and evidence suggests a very high risk for adverse events afterward. TIAs are stroke-events that resolve spontaneously, without persistent neurological dysfunction or magnetic resonance imaging (MRI) evidence for infarction.[15,16]
The diagnosis of stroke and TIA has shifted from a time-based to a tissue-based diagnosis, requiring imaging for confirmation. Early on after the symptom onset, computerized tomography (CT) scanning does not usually reveal ischemic changes, but is very sensitive to identification of hemorrhagic stroke. CT scan is still recommended as the first imaging modality in the acute presentation of symptoms suggestive of stroke and TIA. MRI is more sensitive to identification of ischemic brain tissue,[17] but it is not always feasible, particularly in the elderly population, due to unstable clinical symptoms, claustrophobia, or presence of pacemakers or other devices, among other factors.
In one population-based study, the risk for ischemic stroke during the six months following a TIA was 17%,[18] with the highest risk of recurrent TIA or stroke occurring in the first two days (6%). These data have been reproduced in several studies, suggesting the TIA be considered the “unstable angina” of the brain. TIA events represent an opportunity to identify risk factors, such as intermittent atrial fibrillation. Modification of risk factors will reduce future risk for recurrent TIA or stroke.
Risk stratification for TIA
After the initial presentation with TIA symptoms, the ABCD2 criteria (Table 16.2) can be used in the clinical setting to identify patients at high risk for stroke, using clinical data obtained at the time of the initial clinical assessment.[15, 17, 19] The ABCD2 criteria can also be useful in identifying patients likely to require hospitalization rather than an expedited outpatient evaluation, due to elevated risk for stroke in the near future. For example, a total ABCD2 score of 6–7 is associated with an 8% risk for stroke in the 48 hours after the TIA.
| Criteria | Details | Points |
|---|---|---|
| Age | More than 60 years | 1 |
| Blood pressure | More than 140/90 at initial presentation | 1 |
| Clinical features | Weakness | 21 |
| Aphasia/speech disruption | ||
| Duration of episode | 10–59 minutes | 12 |
| 60 minutes or more | ||
| Diabetes | History of diabetes | 1 |
It is reasonable to hospitalize patients who present with symptoms suggestive of TIA, if they present within 72 hours of the TIA event and any of the following criteria are present:
1. ABCD2 score of 3 or higher
2. ABCD2 score of 0–2 and uncertainty that diagnostic workup can be completed within two days as an outpatient
3. ABCD2 score of 0–2 and other evidence that indicates the patient’s event was caused by focal ischemia
Risk factors for stroke and TIA
Stroke and TIA are known to be associated with risk factors that often overlap for atherosclerosis and heart disease and are typically described in two categories: “modifiable” risk factors (those risk factors that may be altered with some intervention) and “nonmodifiable” risk factors (those risk factors which cannot be altered with medication or simple intervention) (see Table 16.3). Since 25% of all strokes are recurrent, identifying the underlying cause for the stroke, and associated modifiable risk factors, may provide opportunities to reduce the risk for future stroke events.
| Modifiable | Nonmodifiable |
|---|---|
| Atrial fibrillation | Older age |
| Hypertension | Gender |
| Heart disease | Genetics (e.g., ethnicity, sickle cell disease) |
| Hyperlipidemia | |
| Diabetes | |
| Obesity | |
| Tobacco use | |
| Alcohol abuse | |
Less well identified:
|
Identification and management of modifiable risk factors is a key factor in stroke prevention and is discussed in detail later in this chapter.
Of the nonmodifiable risk factors, age is the most important. Stroke affects people over the age of 65 more so than any other group.[20] Gender and genetics are the other two significant nonmodifiable risk factors, with notable racial and ethnic disparities in stroke incidence and outcome. Socioeconomic factors also affect stroke risk and are not easily modifiable.
There is a higher incidence of stroke in African-American men in the United States; they also have poorer outcomes after stroke.[7] Similar disparities have been found in ethnic minorities in Europe.[21] There is a higher rate of major cardiovascular events in low-income countries and rural communities despite the fact that these countries have a lower risk-factor burden. Additionally, case fatality rates after major cardiovascular events are highest in low-income countries and rural areas, although the risk-factor burden is higher in urban communities than in the rural communities.[4]
Sickle cell disease (SCD) is associated with increased ischemic stroke risk in children and young adults. As longevity increases for those who have sickle cell disease, the risk for stroke increases again after age 29; however, there is very little data on the treatment of older adults with SCD, with most data extrapolated from the pediatric experience.[22, 23]
Hemorrhagic stroke
Hemorrhagic strokes represent a heterogeneous group of conditions, including intracerebral, subarachnoid, subdural, epidural, and intraventricular hemorrhage.
Risk factors for hemorrhagic stroke
Trauma is a major risk factor for hemorrhagic strokes of all types, more so in elderly and frail patients because of their high rate of falls.
Hypertension increases the risk for spontaneous intracerebral hemorrhage. However, hypertension treatment itself presents a challenge in the elderly patient and requires careful weighing of risk and benefit, as antihypertensive medications increase the risk of falls in elderly patients.[24, 25]
In contrast to these long-term data regarding stroke risk, reducing blood pressure aggressively in the setting of acute intracerebral hemorrhage has been considered an opportunity to reduce hematoma size, but there remains no clear association with improved neurological function or outcomes.[11]
Another risk factor for hemorrhagic stroke in the elderly is medications, particularly anticoagulants and antiplatelet drugs.
Stroke prevention
Prevention of stroke is the key element in preventing stroke-related disability and should focus on the modifiable risk factors, previously discussed and outlined in Table 16.3. Almost a quarter of all strokes are recurrent strokes and are associated with twice the probability of death as well as increased cardiovascular complications compared to first-ever stroke.[26]
A reasonable strategy for the clinical management of patients presenting with TIA or stroke is to try to identify the stroke type and subtype, followed by a careful analysis of their individual risk factors, a process referred to as risk stratification (as described in the section on TIA). This allows for targeted opportunities to reduce modifiable risk factors.[27] (See Table 16.3.)
In addition to obtaining a detailed clinical history, a baseline assessment of blood pressure (BP) at the time of hospital discharge is important, since BP is elevated initially after stroke and may return to normal within a few days of the stroke. Screening fasting lipid profile and glucose at the time of the event is also reasonable. A drug history is also important since anticoagulants and antiplatelet drugs are associated with elevated risk for hemorrhagic stroke, and atypical antipsychotics are associated with increased ischemic stroke risk.[28]
For some risk factors, such as hyperhomocysteneimia, which may be associated with increased risk for ischemic stroke, there is no recommendation for routine screening. Furthermore, it remains unclear whether reducing the levels of homocysteine with supplementation of folate, vitamin B6, and vitamin B12 reduces future stroke risk.[27]
High levels of chronic stress, depressive symptoms, and higher levels of hostility are associated with higher stroke and TIA risk, independent of other risk factors. Assessing for depression and stress in elderly patients may provide additional opportunities for reducing risk factor burden.[29, 30]
Atrial fibrillation
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 1%–2% of the general population, with an increased prevalence with age. The prevalence of atrial fibrillation in those over age 65 is 5%, and 10% in people over 80 years of age.[31–33] Factors associated with atrial fibrillation include age, hypertension, diabetes, cardiomyopathy, chronic obstructive pulmonary disease, obesity, and sleep apnea, most of which overlap with other vascular and stroke risk factors, as outlined in Table 16.3.
Cryptogenic stroke is defined as ischemic stroke of undetermined cause and accounts for approximately 20%–40% of ischemic strokes. Atrial fibrillation can be intermittent and asymptomatic, thus creating a challenge for diagnosis. Although AF is identified in about 15% of strokes,[31] it is suspected in older patients with cryptogenic stroke. The importance of identifying the presence of AF in cryptogenic stroke is self-evident, given the risk associated with anticoagulation therapy. Particularly in elderly patients, anticoagulation is not indicated for secondary stroke prevention unless there is clear evidence for AF. In addition, strokes in patients with AF are associated with higher morbidity and mortality than those without AF.[32, 33]
The use of prolonged cardiac monitoring increases the likelihood of finding AF and should be considered within six months of a cryptogenic stroke or TIA in patients over age 65.[27, 34, 35] There are many strategies and devices to detect paroxysmal AF. Although the mode and duration of enhanced electrocardiogram (ECG) monitoring remains under investigation, noninvasive ambulatory ECG monitoring for 30 days increases the detection of paroxysmal atrial fibrillation by a factor of 5, as compared to standard 24-hour ECG monitoring.[36, 37]
The risk for stroke related to paroxysmal AF appears to be similar to the risk with chronic AF and atrial flutter. Nonvalvular AF confers an increased stroke risk of two to seven times that of patients without AF, whereas rheumatic AF confers a risk up to 17 times higher than in those without the disease and five times higher than nonvalvular AF.
The decision to consider anticoagulant or antithrombotic treatment to reduce stroke risk should be balanced against the risk of bleeding, cost of monitoring, and difficulty of monitoring therapy.
Risk stratification provides an estimate of stroke risk without anticoagulants. The CHADS2 score is an acronym for five clinical factors (congestive heart failure, hypertension, age 75 or older, diabetes, and prior stroke or TIA), the presence of which counts as one point, except for stroke or TIA, that count as two points. Patients with a CHADS2 score of 0 are considered low risk for recurrent stroke, and those with scores of 2 or higher are considered high risk for stroke.
The CHA2DS2-VASc score adds female gender, additional age strata, and vascular disease. This enhanced score performs similarly to the CHADS2 score, but considers all women and people aged 65–74 at intermediate risk for stroke, and therefore leads to a larger percentage of patients being considered for anticoagulation therapy.[33]
Antincoagulants
Timing of anticoagulation initiation
Timing of anticoagulation is another important clinical consideration. Although anticoagulants are usually initiated within 14 days after the onset of the neurological symptoms, this may be delayed if there is a concern for hemorrhagic transformation of the ischemic infarct (such as with large infarct size, hemorrhagic transformation on imaging, uncontrolled hypertension, or tendency to hemorrhage).
Selection of an anticoagulant
The selection of an anticoagulant is very individualized, with recent data suggesting that newer anticoagulants are probably as safe as warfarin in the elderly.[38] Combining oral anticoagulation with antiplatelet therapy is not recommended for stroke or TIA prevention, although this combination may be appropriate for other cardiovascular indications.[27] A more detailed discussion of anticoagulants follows later in this chapter. For those patients unable to take oral anticoagulants, aspirin alone is recommended, with the addition of clopidogrel in some patients.[27]
Use of anticoagulants
Overall, the newer anticoagulants appear to be equal in efficacy to conventional therapy and do not cause excess bleeding.[32,39] In particular, the risk for intracranial hemorrhage, which is related to age, is reduced by the new anticoagulants relative to warfarin, making newer agents particularly attractive for older patients. In addition, warfarin remains the only oral anticoagulant that can be reversed, if necessary.
Vitamin K antagonists: warfarin
Vitamin K antagonists, such as warfarin, have been used for many years and reduce stroke risk by 68% and overall mortality by 33%, with the recommended target international normalized ratio (INR) of 2.0–3.0.[33] However, warfarin carries significant potential for drug–drug interactions, and dietary interactions create a significant burden for monitoring and dose adjustment. However, a major advantage of warfarin is in the potential for reversibility using fresh frozen plasma (FFP), Vitamin K and, more recently prothrombin complex concentrates (PCCs). This is particularly important in the setting of emergency management of patients with bleeding complications or the need for intervention that may require reversing anticoagulation effects.[40] RFVIIa is not recommended as a solo agent to reverse anticoagulation, although it can shorten the measured INR.[40]
Direct thrombin inhibitors: dabigatran
Dabigatran is the only oral direct thrombin inhibitor available since ximelagatran was withdrawn from the market due to hepatotoxicity. It features twice daily dosing that does not require coagulation monitoring, lower rates of ischemic stroke, and a lower intracranial hemorrhage risk.[33] Issues that remain under review are overall cost and risk for use in those with renal insufficiency (a major factor in the older adult population), who require lower-dose therapy. Furthermore, as previously outlined, there is no known agent that allows reversibility of anticoagulation effects, particularly in the emergency management of older adults.
Oral factor Xa agents
Rivaroxaban and apixaban directly inhibit factor Xa, which is the enzyme that converts prothrombin to active thrombin (similar to low-molecular-weight heparin). There are other agents under development, including edoxaban and betrixaban, with pending efficacy data at the time of writing. These drugs do not require monitoring, but require lower dosing in patients with renal insufficiency. Unlike warfarin, this drug does not have a known antidote or agent for reversibility of anticoagulation effects.
Antiplatelet therapy
Antiplatelet agents are effective in stroke risk reduction, with aspirin conferring approximately 20% reduction in stroke risk but associated with slightly increased bleeding risk. There is debate regarding the optimal dosing of aspirin, but it generally ranges between 81 mg and 325 mg. There is a lack of evidence indicating superior efficacy with higher doses.
As described earlier in the chapter, there may be a role for using aspirin or other antiplatelet agents along with full-dose warfarin in some patients with indications such as atrial fibrillation and coronary artery disease or coronary stenting. However, antiplatelet and anticoagulant agents are among the most frequent cause of adverse drug-event-related hospitalizations.[41] Dual antiplatelet therapy combining the use of aspirin and clopidogrel has been associated with slightly increased risk for hemorrhagic complications, although there appears to be benefit to the early use of this combination after an ischemic stroke or TIA, particularly in patients with carotid disease TIA.[42–44]
Blood pressure for risk modification
Normalizing blood pressure (BP) is an important factor in long-term risk reduction for stroke and other vascular diseases. However, following an acute ischemic stroke, 80% of patients will have elevated BP with a spontaneous return to baseline within days, and the timing and degree of BP lowering after acute stroke, particularly hemorrhagic stroke, remains under investigation.[45] The benefit must be weighed against the risk of recurrent falls in those over the age of 70 associated with antihypertensive medications in all classes.[24, 25]
Current guidelines recommend the initiation of BP therapy for previously untreated patients with ischemic stroke or TIA who, after the first several days, have an established systolic blood pressure of 140 mmHg or higher or diastolic blood pressure of 90 or higher. The benefit of reducing BP lower than that is of unclear benefit and may be risky in older adults. In patients with an established diagnosis of hypertension, BP therapy should be re-initiated after the first few days, although the BP target is not clear. The routine use of beta blockers to lower stroke recurrence for secondary prevention has not been demonstrated to be effective.[46]
Myocardial infarction and cardiomyopathy in stroke
Stroke following acute anterior myocardial infarction is more frequently associated with anterior apical akinesis or dyskinesia on echocardiography, left ventricular mural thrombus, or anterior or apical wall-motion abnormalities with a left ventricular ejection fraction of less than 40%. In these patients, anticoagulation (or low-molecular-weight heparin) for three months may be reasonable to prevent recurrence of ischemic stroke or TIA.
Valvular heart disease
In patients with rheumatic mitral valve disease and AF who present with stroke or TIA, long-term anticoagulation is indicated, with INR target 2.5. In the absence of AF but with no evidence for another cause of symptoms such as carotid disease, long-term use of anticoagulation is reasonable rather than antiplatelet therapy. If the ischemic stroke or TIA occurs in the setting of appropriate anticoagulation, adding aspirin is reasonable. Antiplatelets are also recommended for those who do not have an indication for anticoagulation, including mitral valve prolapse.
Patent foramen ovale
The presence of patent foramen ovale (PFO) is associated with higher risk for stroke, although closure of PFO in young (less than 65 years of age) patients with stroke or TIA has not been associated with improved outcomes. The use of antiplatelets is reasonable unless there is evidence for venous thromboembolism, in which case either anticoagulation or an inferior vena cava filter may be reasonable. In patients with PFO and deep venous thrombosis (DVT), closure may be considered, depending on risk for recurrent DVT.[47]
Mechanical closure
Embolization from the left atrial appendage remains a concern, although closure of the appendage using devices remains under investigation.
Lipid lowering
Current American Heart Association (AHA) guidelines recommend the initiation of statin therapy for patients with recent stroke or TIA whose LCL-C is greater than 100 mg/dL. However, most studies of lipid lowering have either not been validated in the elderly, or their use is predicated upon long-term use with questionable translation of benefit to an elderly population.[48, 49] The use of statins in elderly people, in particular, presents a significantly increased burden of liver enzyme abnormalities,[50] myalgias, and concerns about adverse cognitive effects.[51, 52]
Glycemic control and stroke
All patients who present with TIA or stroke should be screened for diabetes.[27] Increased glucose levels within 24 hours of hypertensive spontaneous intracerebral hemorrhage correlate with poorer outcomes.[53] Diagnosis of diabetes or pre-diabetes following acute ischemic stroke is associated with poor long-term outcomes and a higher risk for recurrent stroke.[54, 55]
Obesity and physical inactivity
All patients with stroke or TIA should have a body mass index (BMI) calculation. Obesity is an increasing problem across all age groups, although weight fluctuations appear to be greater in the older adult.[56] Physical inactivity and poor nutrition remain a major concern in older people, often compounded by comorbid and social conditions, and may impact recovery after stroke.
Carotid disease
Carotid revascularization in symptomatic carotid stenosis should be considered for all patients to reduce stroke risk. Carotid endarterectomy (CEA) and carotid artery stenting (CAS) have been found equally effective carotid revascularization procedures.
Although there are several factors when selecting a procedure, it is clear that only operators with established periprocedural stroke and mortality rates of less than 6% should perform the procedures for symptomatic patients. Both surgeons and interventionalists need to be rigorously trained to minimize the pitfalls of learning curve on outcomes of patients undergoing either procedure.
The North American Symptomatic Carotid Endarterectomy Trial (NASCET) demonstrated that patients older than 75 years of age benefited more from CEA than younger patients, due to high risk for ipsilateral stroke in the medical therapy arm.[57] However, medical therapy has changed outcomes in the intervening time since the NASCET publication in 2001.
The Carotid Revascularization Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis (CREST) trial discontinued enrollment of patients over the age of 80 due to the higher rate of complications associated with this age group.[58] A recent meta-analysis suggests that carotid artery stenting carries an increased risk for stroke in older adults, while mortality (at least in the short term) is equivalent to younger patients. CAS should only be considered in older adults if the risk for surgery is very high or unacceptable.[59, 60] Carotid endarterectomy is associated with increased mortality but similar stroke outcomes when compared to younger patients.[61]
Routine long-term follow-up imaging of the extracranial carotid circulation with carotid duplex ultrasonography is not recommended.
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