- Email: [email protected]
Cerebrovascular Disease
36
Cerebrovascular Disease Philip B. Gorelick, Jiangyong Min, and Muhammad U. Farooq
A NEW DEFINITION OF STROKE, 335
MANAGEMENT OF CHRONIC STROKE, 337
BRIEF OVERVIEW OF STROKE EPIDEMIOLOGY, 335
BLOOD PRESSURE MANAGEMENT FOR SELECT RECURRENT STROKE PREVENTION CONDITIONS, 338
TREATMENT OF ACUTE ISCHEMIC STROKE, 336
REFERENCES, 339
SUMMARY, 339
Raised blood pressure has been referred to as the crown jewel of stroke prevention, and blood pressure lowering has been the focus of substantial study in acute stroke and recurrent stroke prevention as a means to improve outcomes. In this chapter we discuss hypertension and stroke within the context of acute and chronic stroke management. To provide a framework for subsequent discussion of acute and chronic stroke management, we begin this chapter with the definition of stroke and a brief overview of stroke epidemiology.
A NEW DEFINITION OF STROKE Stroke has traditionally been defined based on the presence of neurological signs and symptoms and time course. The occurrence of focal neurological signs or symptoms caused by cerebrovascular disease and lasting more than 24 hours has been previously defined as stroke, whereas transient ischemic attack (TIA) has been defined as having the same clinical features as stroke but the neurological sign or symptom duration is transient lasting up to 24 hours.1 The definitions of stroke and TIA have been criticized as being arbitrary and importantly do not take into account the underlying mechanism or etiology. In cerebrovascular disease, elucidation of stroke mechanism is the primary basis for administration of specific chronic preventative therapy and acute treatment.2 These considerations have led to a 21st century updated definition of stroke.3 The updated definition takes into account not only focal neurological signs or symptoms of the brain, spinal cord or retina injury, but also incorporates consideration of brain tissue status or evidence of stroke based on modern neuroimaging such as magnetic resonance imaging (MRI). In the case of TIA, it is estimated that up to 30% to 40% of persons will have evidence of correlative prior or acute cerebral ischemia on neuroimaging study. In addition, the new definition of stroke takes into account silent or unexpected strokes which may manifest as small deep infarcts, white matter disease (leukoaraiosis), and cerebral microbleeds.3 Table 36.1 lists categories for the classification of ischemic and hemorrhagic stroke.1,4,5
BRIEF OVERVIEW OF STROKE EPIDEMIOLOGY The Prospective Urban Rural Epidemiologic (PURE) cohort study was carried out among greater than 150,000 adults in 17 high-income, middle-income, and low-income countries on 5 continents. The PURE study was designed to answer questions about cardiovascular disease mortality, incidence, and risks.6 In PURE, age-adjusted and sex-adjusted case fatality rates for stroke were highest among low-income countries followed in descending order by medium-income and highincome countries. Overall, although risk factor burden was lowest in low-income countries, rates of major cardiovascular disease and mortality were much higher in low-than high-income countries. High-income countries had a high burden of risks, but better control of these risks and more
frequent administration of pharmacologic treatments and revascularization procedures may explain these disparities in outcome.6 In the Global Burden of Disease Study 2013 (GBD 2013) among 306 diseases and injuries in 188 countries, stroke ranked as the second leading cause of disability-adjusted life years (DALYs) behind ischemic heart disease.7 In addition, GBD 2013 showed a greater than three times increase in burden of stroke (4.85 million stroke deaths, 91.4 million DALYs) in developing countries compared with high-income countries (1.6 million deaths, 21.5 million DALYs).8 Overall, there were approximately 25.7 million stroke survivors (71% with ischemic stroke), 6.5 million stroke deaths (51% from ischemic stroke), 113 million DALYs attributed to stroke (58% ischemic stroke), and 10.3 million persons with new strokes (67% ischemic).8 There was substantially greater reduction of stroke mortality rates in developed compared with developing countries. In summary, stroke-associated rates are on the rise and are being driven by the stroke burden in low-income countries. These observations provide a potential opportunity to better prevent stroke and implement more sophisticated acute care systems in developing regions.9 One of us (PBG) was involved in the development of a prototype Internet-based, worldwide survey of diagnostic and treatment capacitance for stroke in developing countries (Chile, Georgia, Nigeria, Qatar, India, Lithuania, Kazakhstan, Indonesia, Brazil and Bangladesh).10 We found a significant correlation between income and access or affordability to a number of stroke diagnostics and treatments.
Hypertension and Risk for Stroke Blood pressure is a factor associated with a continuous risk of stroke.11,12 We no longer think of stroke risk with raised blood pressure as a threshold effect. Lawes et al. showed in cohort studies that for each 10 mm Hg lower systolic blood pressure, there was a reduction of stroke of about one-third in persons aged 60 to 79 years, and this association was continuous down to at least a blood pressure level of 115/75 mm Hg.13 Furthermore, the relationship held according to sex, region, stroke subtype, and for fatal and nonfatal events. In randomized controlled trials, a 10 mm Hg reduction in systolic blood pressure was associated with a reduction of stroke risk by about one-third.13 The authors emphasized that there were greater benefits of larger blood pressure lowering and maintenance of blood pressure lowering on stroke reduction, and challenged the importance of choice of initial blood pressure lowering agent.13 Systolic blood pressure has become the main target for stroke and cardiovascular disease prevention. Because systolic blood pressure continues to rise with age and diastolic blood pressure increases until about age 50 years and falls thereafter when stroke and other cardiovascular disease begins to substantially increase, systolic blood pressure is the major target of intervention, especially for those older
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TABLE 36.1 Categories for Classification of Stroke of the VI Brain, Spinal Cord, and Retina Ischemic Stroke
1. Large artery atherosclerotic extracranial or intracranial occlusive disease 2. Embolism (cardio-aortic, artery-to-artery) 3. Small artery occlusion (lacunar) 4. Uncommon causes of stroke (e.g., arterial dissection, cardiac, or arterial surgery and interventions) 5. Undetermined causes (cryptogenic): when there is suspicion of an embolism, for example, but no obvious source is identified; or incomplete evaluation 6. Unclassified (e.g., more than one possible mechanism)
Silent or Unexpected Stroke
1. Small deep infarction 2. White matter disease (leukoaraiosis) 3. Cerebral microbleeds 4. Enlarged perivascular spaces
Hemorrhagic Stroke
1. Intraparenchymal hemorrhage (hypertensive and nonhypertensive [e.g., anticoagulant or illicit drug induced]) 2. Subarachnoid hemorrhage
than 50 years.14 Raised blood pressure is estimated to elevate stroke risk up to three-fold or four-fold compared with those without elevated blood pressure.11 Based on a meta-analysis of individual patient data, blood pressure lowering is associated with a similar relative protection at all levels of baseline cardiovascular risk; however, there is greater absolute risk reduction as baseline risk increases.15 As noted above, a substantial number of observational epidemiological studies link hypertension to stroke, and numerous clinical trials show the benefit of blood pressure lowering on stroke incidence or recurrence. In addition, population attributable risk (PAR) calculations place hypertension as the most important remediable factor as it explains the highest percentage of stroke risk. The PAR for hypertension in stroke is in the 25% to almost 50% range.12,16 In the INTERSTROKE Study, a large case-control design, there were participants from 22 countries of different geographic regions, and it was shown that 10 risk factors were associated with 90% of stroke risk.17 The PAR for hypertension in relation to stroke was 34.6%. Overall, the relative risk or estimate of relative risk of hypertension for stroke is in the three-fold to nine-fold range.18
TREATMENT OF ACUTE ISCHEMIC STROKE As previously mentioned in this chapter, the classification of stroke includes a number of major ischemic subtypes as well as the two major hemorrhagic subtypes: subarachnoid hemorrhage and intraparenchymal hemorrhage. Because the scope and depth of the topic on the management of acute stroke is so broad, we will largely limit our discussion in this chapter to management of acute ischemic stroke,19,20 but will also review select clinical trials that address blood pressure reduction in hemorrhagic stroke. For reviews of the management of subarachnoid hemorrhage and intraparenchymal hemorrhage, the reader is referred to authoritative sources found elsewhere.21-23
Blood Pressure Lowering in Acute Ischemic Stroke According to the American Heart Association(AHA)/ American Stroke Association (ASA) 2013 guidelines for the early management of acute ischemic stroke, the following evidence-based blood pressure guidance is recommended (evidence rating by Class and Level are in parenthesis).19 (1) For patients eligible to receive intravenous tissue plasminogen activator (tPA), blood pressure should be lowered
to less than 185/110 mm Hg (class I, Level of Evidence [LOE] B) and maintained before initiation of thrombolytic therapy; (2) After intravenous tPA administration, blood pressure should be maintained below 180/105 mm Hg for at least 24 hours after tPA treatment; (3) For recanalization procedures and until additional scientific study information becomes available, the recommendations just mentioned should be followed for interventional recanalization procedures including intraarterial fibrinolysis (class I, LOE C); (4) For patients with substantially raised blood pressure and who are not undergoing intravenous tPA or recanalization procedures, it is reasonable to lower blood pressure by around 15% during the first 24 hours after stroke onset. Guidance further indicates that blood pressure lowering medication should be withheld unless systolic blood pressure is greater than 220 mm Hg or diastolic is greater than 120 mm Hg (class I, LOE C), or there is a compelling indication to otherwise treat blood pressure (e.g., heart failure). Initial blood pressure lowering medications may include intravenous labetalol, nicardipine, or others19; (5) Administration of antihypertensive therapy within 24 hours of stroke is relatively safe. It is reasonable to restart blood pressure lowering agents 24 hours after stroke onset for persons with preexistent hypertension and who are neurologically stable (class IIa, LOE B); and (6) For patients not undergoing acute reperfusion strategies data regarding blood pressure lowering in acute ischemic stroke are inconclusive or conflicting, and the benefit of such treatment is not well established (class IIb, LOE C). It has been argued that in acute ischemic stroke too substantial blood pressure lowering could lead to extension of brain infarction in an already ischemic brain hemisphere with penumbral compromise, yet too high a blood pressure might potentiate brain edema, hemorrhagic transformation, and worsening of neurological outcome.24,25
Updated Trial Findings Since the publication of the AHA/ASA 2013 guidelines for early management of acute ischemic stroke, several new major studies addressing blood pressure control have been published. The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) was a multicenter, randomized controlled study organized to test whether moderate blood pressure lowering within 48 hours of onset of acute ischemic stroke could reduce death and major disability at 14 days or at hospital discharge.26 Patients were in their early sixties, were randomized within approximately 15 hours of stroke onset, had mild acute stroke impairment on neurological exam, and had entry blood pressures of about 167/97 mm Hg. Intravenous angiotensin-converting enzyme inhibitors were first-line treatment. Within 24 hours, blood pressure targets were met as mean systolic blood pressure (SBP) was lowered by 12.7% in the active treatment group and by 7.2% in the control group. By day 7 the corresponding group blood pressures were 137.3 mm Hg and 146.5 mm Hg, respectively. However, there was no difference in the primary (death and major disability at 14 days or discharge) or secondary (death and major disability at 3 months) outcomes between the intensive and less intensive blood pressure lowering groups. In the Efficacy of Nitric Oxide in Stroke (ENOS) trial, therapy with transdermal glyceryl trinitrate for 7 days and given within 48 hours of ischemic or hemorrhagic stroke onset was compared with control. Active blood pressure lowering therapy significantly reduced blood pressure and was safe, but it did not improve functional outcome based on the modified Rankin Scale (mRS).27 The above mentioned studies and others, with the exception of the Scandinavian Candesartan Acute Stroke Trial (SCAST) (there was a signal of poor outcome based on the mRS), suggest that blood pressure lowering in acute stroke is generally safe but secondary outcomes might be
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Blood Pressure Variability One of the authors (PBG) has been involved in the study of blood pressure variability after acute ischemic stroke.33,34 Blood pressure variability after acute ischemic stroke has been associated with neurological deterioration, and thus, serves as a target for possible intervention to improve outcomes and requires further study.32
Blood Pressure Lowering in Acute Hemorrhagic Stroke The AHA/ASA 2015 guidance for blood pressure management in spontaneous intracerebral hemorrhage21 recommends: (1) Acute systolic blood pressure lowering to 140 mm Hg as a safe strategy in patients with systolic blood pressure between 150 and 220 mm Hg (class I, LOE A). In addition, this management strategy can be effective for improving functional outcome (class IIa, LOE B); and (2) For patients with systolic blood pressure higher than 220 mm Hg, aggressive reduction of blood pressure with continuous intravenous infusion therapy and frequent blood pressure monitoring may be reasonable (class IIb, LOE C). A key consideration in the development of the above recommendations for blood pressure lowering for spontaneous intracerebral hemorrhage was the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2).35 In this trial, where intensive blood pressure lowering (a target of <140 mm Hg SBP) was compared with guideline treatment (a target of <180 mm Hg systolic blood pressure), the primary outcome (death or severe disability at 90 days) was not significantly reduced with intensive treatment. However, an ordinal analysis of the mRS showed improved functional outcome with intensive blood pressure lowering.35 Another trial of blood pressure lowering in acute cerebral hemorrhage, Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) II,36 was recently halted prematurely, but the results have not been published.
2015 Guidance for Early Management of Patients With Acute Ischemic Stroke in Relation to Endovascular Treatment Five major clinical trials of predominantly stent retrievers deployed for recanalization of large cerebral arteries in acute ischemic stroke37-41 have led to the 2015 AHA/ASA guideline update recommendations for use of these devices in early stroke management.20 The details of the five trials are reviewed elsewhere.20 Key 2015 AHA/ASA guidance recommendations in relation to endovascular recanalization therapy20 include: (1) Use of intravenous tPA as a first step for eligible patients being considered for intraarterial endovascular therapy (class I, LOE A); and (2) Endovascular therapy with a stent retriever should be deployed in patients according to the following criteria (class I, LOE A): A. Prestroke mRS score of 0 or 1; B. Administration of intravenous tPA within 4.5 hours of stroke onset; C. For causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); D. 18 years of age or older; E. National Institutes of Health Stroke Scale score of 6 or greater; F. ASPECTS (a grading scale for acute ischemic change on computed tomography [CT] head study) score of 6 or greater; and G. Endovascular treatment can be initiated (groin puncture) within 6 hours of stroke symptom onset. Other recommendations from this guidance statement are discussed elsewhere.20
TABLE 36.2 General Treatment Recommendations for Early 36 Management of Acute Ischemic Stroke 1. Airway and ventilator support if airway compromise 2. Maintain oxygen saturation >94% (supplemental oxygen is not indicated in nonhypoxic patients) 3. Antipyretic therapy if fever occurs 4. Raised blood pressure (see text) 5. Avoid hypoglycemia and if hyperglycemic, treat to a glucose level of 140-180 mg/dL 6. Swallow evaluation to assess for aspiration potential 7. Subcutaneous anticoagulant therapy to prevent deep vein thrombosis in immobilized patients 8. Avoid indwelling bladder catheter 9. Utilize a standardized stroke order set 10. Management of acute edema or seizures (see reference 19 for details) (From Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947.)
General Treatment Recommendations for Early Acute Ischemic Stroke Management Table 36.2 lists select other general treatment recommendations for the management of early acute ischemic stroke.19
MANAGEMENT OF CHRONIC STROKE Persons who have experienced ischemic stroke or TIA are at high risk for recurrent stroke.1 Of the total number of strokes occurring in the United States each year, recurrent ones make up almost 25%. It is estimated that the annual risk of a future ischemic stroke after an initial stroke or TIA is approximately 3% to 4%.42 Given this annualized average rate of stroke recurrence over time, there is a higher risk early on (i.e., in the first year) compared with later epochs. Furthermore, as time passes, the risk of a major coronary events heightens. Thus, it is important to be aware of coronary risk in stroke patients (and vice versa). Recurrent stroke risk will vary according to stroke subtype, age, comorbid conditions, and adherence to preventive therapy.42 Hypertension is recognized as a risk for early and late recurrent stroke.43 Traditionally, hypertension has not been well controlled in a number of recurrent stroke prevention trials up until more recently when it was shown that lifestyle coaching and a concerted effort to monitor and treat blood pressure is a highly efficacious strategy.44 It has been observed that 7-day, 30-day, and 90-day recurrent stroke rates are higher for atherosclerotic and cardiac embolic stroke subtypes compared with lacunar stroke.45 Thus, proper definition of stroke subtype has prognostic significance and also dictates the therapeutic approach as we shall learn in the following sections. In a single center observational study inadequate blood pressure control was linked to higher recurrence of both lobar and nonlobar intraparenchymal hemorrhage, suggesting the need for additional clinical trial study of blood pressure control in brain hemorrhage survivors.46 Also, in a retrospective cohort study carried out at 19 German tertiary care centers among persons with oral anticoagulation-associated intraparenchymal hemorrhage, rapid reversal of an elevated international normalized ratio (INR) and SBP lowering to less than 160 mm Hg within 4 hours was associated with lower rates of hematoma enlargement.47 Furthermore, return to oral anticoagulant therapy was linked to a lower risk of subsequent ischemic events.47
Management of Blood Pressure for Recurrent Stroke Prevention The 2014 AHA/ASA guidance statement for recurrent stroke prevention recommends the following in relation to blood
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compromised.28-31 Thus, there has been a call to hold blood pressure lowering therapy in acute ischemic stroke patients until they are considered to be medically and neurologically stable, and therefore have suitable oral or enteral access.32
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pressure management42: (1) Although initiation of blood VI pressure lowering therapy after stroke for persons with blood pressure less than 140/90 mm Hg is of uncertain benefit (class IIb, LOE C), blood pressure therapy may be initiated within several days after stroke for those with a blood pressure of 140 or 90 mm Hg or greater (class I, LOE B); (2) Resumption of blood pressure lowering therapy to prevent recurrent stroke and other vascular events is indicated for those with a history of hypertension (class I, LOE A); (3) It is reasonable to aim for a target blood pressure less than 140/90 mm Hg (class IIa, LOE B), and it is reasonable to target a systolic blood pressure less than 130 mm Hg in patients with recent symptomatic lacunar infarction (class IIb, LOE B); (4) Lifestyle modifications (salt restriction, weight loss, diet rich in fruits and vegetables and low-fat dairy products, regular physical exercise, and limited alcohol consumption) are a reasonable component of a blood pressure lowering therapy regimen (class IIa, LOE C); (5) The optimal drug treatment regimen remains uncertain; however, diuretics or a diuretic plus angiotensin-converting enzyme inhibitor are considered useful (class I, LOE A); and (6) Specific blood pressure lowering agents should be chosen based on pharmacologic properties, mechanism of action, and patient characteristics (e.g., presence of diabetes mellitus, heart failure, renal disease) (class IIa, LOE B).
Select Trial Data Influencing Blood Pressure Lowering Recommendations for Recurrent Ischemic Stroke Prevention Two trials stand out as having a major influence on the above guidance for recurrent stroke prevention in relation to blood pressure management: Perindopril Protection Against Recurrent Stroke Study (PROGRESS) and Secondary Prevention of Small Subcortical Strokes (SPS3). PROGRESS featured the angiotensin-converting enzyme inhibitor, perindopril, with or without the diuretic, indapamide, versus placebo in a large trial designed to include persons with stroke or TIA in the past 5 years.48 Active treatment reduced blood pressure by 9/4 mm Hg. Overall, there was a statistically significant 28% relative risk reduction in recurrent stroke and a 50% reduction of recurrent intracerebral hemorrhage favoring the perindopril-based treatment arm. Perindopril alone achieved a blood pressure lowering effect of 5/3 mm Hg and did not achieve statistically significant stroke reduction results. With greater blood pressure lowering (12/5 mm Hg with combination therapy), there was greater reduction of key study endpoints. SPS3 was a randomized open-label trial of MRI brain that defined symptomatic lacunar infarcts.49 SBP lowering treatment targets were set for two comparator groups: less than 130 mm Hg versus 130 to 149 mm Hg. The primary endpoint, similar to PROGRESS, was reduction of all-cause stroke. The higher intensity blood pressure treatment group achieved a mean systolic SBP of 127 mm Hg, whereas the less intense treatment group achieved an SBP of 138 mm Hg after 1 year. There was no statistically significant advantage of intensive blood pressure lowering on all stroke; fatal stroke; or the composite of myocardial infarction or vascular death. However, intracerebral hemorrhage was significantly reduced (63% relative reduction; p = 0.03). Intensive blood pressure lowering therapy was deemed to be safe. Blood pressure lowering medications were prescribed at the discretion of the study team and were provided by the local site formulary. Meta-analysis of randomized controlled trials in recurrent stroke prevention has shown a reduction of recurrent stroke with blood pressure lowering of 29% and a reduction of cardiovascular events by 31%.50 However, there was no advantage for reduction of myocardial infarction or all-cause mortality.50
TABLE 36.3 Management of Select Risks or Cerebrovascular Conditions After Ischemic Stroke or Transient Ischemic Attack 1. Lipids: statin therapy with intensive lipid lowering properties and lifestyle modification if low-density lipoprotein cholesterol 100 or more mg/dL and atherosclerotic stroke . Symptomatic extracranial carotid artery stenosis: 2 A. Less than 50% carotid artery stenosis: medical management B. Between 50% and 69% carotid artery stenosis: individualize medical or medical management plus carotid endarterectomy based on patient characteristics, age, and comorbidities C. Between 70% and 99% carotid artery stenosis: carotid endarterectomy plus medical management D. Carotid artery stenting: if the carotid artery lumen is reduced by more than 70% through noninvasive imaging or more than 50% through catheter conventional cerebral angiography and direct surgical access to carotid artery is difficult (e.g., high carotid bifurcation), medical comorbidities increase risk of direct surgery, or there are local circumstances (history of neck radiation, prior carotid endarterectomy) making endarterectomy difficult . Large artery intracranial atherosclerosis: 3 A. Extracranial to intracranial bypass is not recommended B. Aggressive medical management including but not limited to a highpotency statin therapy and a blood pressure target of more than 140/90 mm Hg if 50% to 99% stenosis C. If 70% to 99% stenosis: clopidogrel 75 mg per day plus aspirin for 90 days followed by antiplatelet monotherapy D. Intracranial stenting is not recommended for routine use 4. Nonvalvular atrial fibrillation: A. If cause of stroke uncertain, 30-day continuous cardiac rhythm monitoring B. Warfarin, apixaban, dabigatran or rivaroxaban (reasonable choice)a C. If oral anticoagulation is contraindicated, consider aspirin alone or aspirin plus clopidogrel . Antiplatelet therapy (if no indication for oral anticoagulation): 5 A. Aspirin 50 to 325 mg per day or aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily or clopidogrel 75 mg per day B. Aspirin plus clopidogrel may be considered within 24 hours of minor ischemic stroke or transient ischemic attack for 90 days followed by antiplatelet monotherapy, otherwise aspirin plus clopidogrel is not indicated unless there is some other compelling indication (e.g., coronary artery stent) aEdoxaban
was approved for this indication after the publication of this statement. (From Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160-2236.)
Management of Select Risks or Cerebrovascular Conditions After Ischemic Stroke or Transient Ischemic Attack Management of select risks or cerebrovascular conditions for recurrent stroke prevention are listed in Table 36.3 in accordance with the AHA/ASA 2014 guidance statement.42
BLOOD PRESSURE MANAGEMENT FOR SELECT RECURRENT STROKE PREVENTION CONDITIONS Preservation of Cognition and Blood Pressure Cognitive impairment is common after stroke, and up to about one-third of these persons may have significant cognitive impairment. In addition, it has been estimated that midlife raised blood pressure may account for 5% and 8% of Alzheimer disease (AD) worldwide and in the U.S., respectively, and the relative risk of raised blood pressure on AD is about 1.6.51 In a 2011 AHA/ASA evidence review and guidance statement it was concluded that in patients with stroke, blood pressure lowering is effective for reducing dementia after stroke (class I, LOE B); there is reasonable evidence that lowering blood pressure in middle-aged and young elderly people may prevent
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High-Grade Occlusive Large Artery Disease Reduction of stroke risk is highly dependent on blood pressure lowering, especially in the case of hemorrhagic stroke.57 However, when it comes to recurrent ischemic stroke prevention there may be a “J”-shaped curve as demonstrated by Ovbiagele et al. in the Prevention Regimen for Effectively Preventing Second Strokes (PRoFESS) study, whereby systolic blood pressure levels during follow-up in the very low–normal (<120 mm Hg), high (140 to <150 mm Hg), or very high (≥150 mm Hg) range were associated with increased risk of recurrent stroke.58 Furthermore, when there is high-grade symptomatic intracranial occlusive cerebrovascular disease, it has been shown that patients with misery perfusion based on positron emission tomography (PET) had an increased risk of ipsilateral stroke when systolic blood pressure was less than 130 mm Hg.59 In the Carotid Occlusion Surgery Study (COSS) among a limited sample size in a nonprimary analysis, there was benefit for stroke reduction in patients who had blood pressure 130/85 or less mm Hg versus more than 130/85 mm Hg, carotid artery occlusion, and increased oxygen extraction on PET study.60 In a nonprimary analysis of the WarfarinAspirin Symptomatic Intracranial Disease Study (WASID), systolic blood pressure 160 or higher mm Hg was associated with the highest ipsilateral recurrent stroke rates compared with lower blood pressure levels.61 The above data may be interpreted to suggest a blood pressure in the range of 130 to 139/80 to 85 mm Hg as a reasonable target when there is highgrade large artery occlusive disease.
SUMMARY Blood pressure above 140/90 mm Hg is an important and modifiable risk factor for first and recurrent stroke. Blood pressure lowering in acute ischemic stroke is generally safe but has not been shown to reduce early death or disability, and concern has been raised that such therapy may worsen functional outcomes. In relation to hemorrhagic stroke, acute intensive blood pressure lowering (i.e., a target < 140 mm Hg systolic) has not been shown to reduce death or severe disability, but may improve functional outcome. In select conditions, blood pressure lowering has not been conclusively shown to reduce risk of cognitive impairment or decline, and persons with large artery occlusion may benefit from lowering of blood pressure but too high or too low a blood pressure may lead to an increased risk of recurrent stroke. Table 36.4 lists blood pressure targets for stroke prevention and acute stroke management based on the guidance statements reviewed in this chapter and the authors’ experience.
TABLE 36.4 Blood Pressure Targets for Stroke Prevention and Acute Stroke Management The following blood pressure targets may be reasonable for stroke prevention: 1. For recurrent stroke/transient ischemic attack (TIA) prevention in general: aim for a blood pressure target less than 140/90 mm Hg (target range: 130 to 139/80 to 85 mm Hg) 2. If a lacunar infarction: consider aiming for a systolic blood pressure target less than 130 mm Hg 3. Caution must be considered when lowering blood pressure when there is symptomatic high-grade or total occlusion of large cerebral arteries such as the carotid, basilar, and middle cerebral (M1): in the absence of positron emission tomography scan guidance, it is reasonable to aim for a blood pressure target less than 140/90 mm Hg (target range: 130 to 139/80 to 85 mm Hg) 4. Although a J-shaped blood pressure lowering curve may not be a major consideration for first stroke prevention, such may exist for recurrent stroke prevention: aim for a blood pressure target less than 140/90 mm Hg (target range: 130 to 139/80 to 85 mm Hg) The following blood pressure targets may be reasonable for acute stroke treatment: 1. For acute ischemic stroke and intravenous tissue plasminogen activator (tPA) administration or intraarterial recanalization procedures: aim for a blood pressure less than 185/110 mm Hg and maintain the blood pressure at less than 180/105 mm Hg for 24 hours after intravenous tPA therapy 2. For acute ischemic stroke without intravenous tPA administration or intraarterial recanalization procedure: unless there is a compelling indication (e.g., heart failure), blood pressure lowering may be withheld up to a systolic level of 220 mm Hg or a diastolic of 120 mm Hg 3. For acute intraparenchymal hemorrhage: aim for a systolic blood pressure of 140 mm Hg
References 1. Gorelick PB, Ruland S. Cerebrovascular disease. Disease-a-Month. 2010;56:33-100. 2. Gorelick PB, Farooq MU. Stroke: an emphasis on guidelines. Lancet Neurol. 2015;14:2-3. 3. Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century. A statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2013;44:2064-2089. 4. Kim BJ, Kim JS. Ischemic stroke subtype classification: an Asian viewpoint. J Stroke (Korea). 2014;16:8-17. 5. Ay H, Benner T, Arsava M, et al. A computerized algorithm for etiologic classification of ischemic stroke. The causative classification of stroke system. Stroke. 2007;38:2979-2984. 6. Yusuf S, Rangarajan S, Teo K, et al. Cardiovascular risk and events in 17 low-, middle-, and high-income countries. N Engl J Med. 2014;371:818-827. 7. GBD 2013 DALYs and HALE Collaborators, Murray CJL, Barber RM, et al. Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiologic transition. Lancet. 2015;386:2145-2191. 8. Feigin VL, Krishnamurthi RV, Parmar P, et al. Update on the global burden of ischemic and hemorrhagic stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology. 2015;45:161-176. 9. Norrving B, Davis SM, Feigin VL, et al. Stroke prevention worldwide-what could make it work? Neuroepidemiology. 2015;45:215-220. 10. Aiyagari V, Pandey D, Testai FD, et al. A prototype worldwide survey of diagnostic and treatment modalities for stroke. J Stroke Cerebral Dis. 2015;24:2909–2296. 11. Gorelick PB. New horizons for stroke prevention; PROGRESS and HOPE. Lancet Neurol. 2002;1:149-156. 12. Gorelick PB. The future of stroke prevention by risk factor modification. In: Fisher M (ed): Handbook of Clinical Neurology. New York: Stroke Part III, Elsevier; 2009. 13. Lawes CMM, Bennett DA, Feigin VL, et al. Blood pressure and stroke. An overview of published reviews. Stroke. 2004;35:1024-1033. 14. Williams B, Lindholm LH, Sever P. Systolic pressure is all that matters. Lancet. 2008;371:2219-2221. 15. The Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet. 2014;384:591-598. 16. Gorelick PB. Stroke prevention. An opportunity for efficient utilization of health care resources during the coming decade. Stroke. 1994;25:220-224. 17. O’Donnell MJ, Xavier D, Lui L, et al. Risk factors for ischemic and intracerebral hemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376:112-123. 18. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke. A guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2011;42:517-584. 19. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947. 20. Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:3020-3035. 21. Hemphill JC III, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032-2060.
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dementia in late life (class IIa, LOE B); and the usefulness of blood pressure lowering in persons older than 80 years for the prevention of dementia is unconfirmed (class IIb, LOE B).52 Uncertainty exists about the value of blood pressure lowering for preservation of cognitive function because there have been disparate study methodology, missed opportunities for study in many cardiovascular trials, a number of studies that suggest that blood pressure lowering may be useful and others that have shown no benefit, lack of long-term clinical trial data beginning in middle life or earlier, and adequate study of the phenomenon that higher blood pressure (to some degree) may be better for preservation of cognitive function in the very old.53-55 Thus, it may turn out that blood pressure control may have different effects on cognition based on absolute age.53 Furthermore, control of multiple cardiovascular risks including blood pressure may be needed to achieve successful cognitive preservation.56 Currently and given the equipoise in relation to blood pressure control and maintenance of cognitive vitality, we recommend following blood pressure control parameters in the AHA/ASA 2011 guidance statement.52
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VI
22. Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43:1711-1737. 23. Steiner T, Juvela S, Unterberg A, et al. European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid hemorrhage. Cerebrovasc Dis. 2013;35:93-112. 24. Gorelick PB, Aiyagari V. The management of hypertension for acute stroke: what is the blood pressure goal? Curr Cardiol Rep. 2013;15:366. 25. Aiyagari V, Gorelick PB. Management of blood pressure for acute and recurrent stroke. Stroke. 2009;40:2251-2256. 26. He J, Zhang Y, Xu T, et al. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke. The CATIS randomized clinical trial. JAMA. 2014;311:479-489. 27. The ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomized controlled trial. Lancet. 2015;385:617-628. 28. Sandset EC, Bath PMW, Boysen G, et al. on behalf of the SCAST Study Group. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomized, placebo-controlled, double-blind trial. Lancet. 2011;371:741-750. 29. Robinson TG, Potter JF, Ford GA, et al. Effects of antihypertensive treatment after acute strokein the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomized, open, blinded-endpoint trial. Lancet Neurol. 2010;9:767-775. 30. Potter J, Mistri A, Brodie F, et al. Controlling hypertension and hypotension immediately post stroke (CHHIPS)—a randomized controlled trial. Health Technol Assess. 2009;13:1-73. 31. Bath PMW, Martin RH, Palesch Y, et al. Effect of telmisartan on functional outcome, recurrence, and blood pressure in patients with acute mild ischemic stroke. A PRoFESS subgroup analysis. Stroke. 2009;40:3541-3546. 32. Gorelick PB. Should blood pressure be lowered in acute ischemic stroke? The CATIS Trial. J Am Soc Hypertens. 2015;9:331-333. 33. Kang J, Ko Y, Park JH, et al. Effect of blood pressure on 3-month functional outcome in the subacute stage of ischemic stroke. Neurology. 2012;79:2018-2024. 34. Chung J-W, Kim N, Kang J, et al. Blood pressure variability and the development of early neurological deterioration following acute ischemic stroke. J Hypertension. 2015;33: 2099–2021. 35. Anderson C, Heeley E, Huang Y, et al. Rapid blood pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368:2355-2365. 36. Qureshi AI, Palesch YY. Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATTACH) II: design, methods, and rationale. Neurocrit Care. 2011;15:559-576. 37. Berkheimer OA, Fransen PS, Beumer D, et al. A randomized trial of inta-arterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11-20. 38. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019-1030. 39. Saver JL, Goyal M, Bonafe A, et al. Stent retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285-2295. 40. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion imaging selection. N Engl J Med. 2015;372:1009-1018. 41. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296-2306.
42. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160-2236. 43. Weimar C, Diener H-C, Alberts MJ, et al. The Essen Stroke Risk Score predicts recurrent cardiovascular events. A validation within the REduction of Atherothrombosis for Continued Health (REACH) registry. Stroke. 2009;40:350-354. 44. Towfighi A, Markovic D, Ovbiagele B. Consistency of blood pressure control after ischemic stroke. Prevalence and prognosis. Stroke. 2014;45:1313-1317. 45. Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology. 2004;62:569-573. 46. Biffi A, Anderson CD, Battey TWK, et al. Association between blood pressure control and risk of recurrent intracerebral hemorrhage. JAMA. 2015;314:904-912. 47. Kuramatsu JB, Berner ST, Schellinger PD, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA. 2015;313:824-826. 48. PROGRESS Collaborative Group. Randomized trial of perindopril-based blood-pressurelowering regimen among 6,105 individuals with previous stroke or transient ischemic attack. Lancet. 2001;358:1033-1041. 49. The SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomized trial. Lancet. 2013;382:507-515. 50. Boan AD, Lackland DT, Ovbiagele B. Lowering of blood pressure for recurrent stroke prevention. Stroke. 2014;45:2506-2513. 51. Gorelick PB, Nyenhuis D. ASH Position Paper. Blood pressure and treatment of persons with hypertension as it relates to cognitive outcomes including executive function. J Am Soc Hypertens. 2012;6:309-315. 52. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2011;42:2672-2713. 53. Gorelick PB. Blood pressure and the prevention of cognitive impairment. JAMA Neurol. 2014;71:1211-1213. 54. Williamson JD, Launer LJ, Bryan RN, et al. Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels: a randomized clinical trial. JAMA Intern Med. 2014;174:324-333. 55. Peters R, Beckett N, Forette F, et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008;7:683-689. 56. Ngandu T, Lehitsalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomized controlled trial. Lancet. 2015;385:2255-2263. 57. Chrysant SG. Current status of aggressive blood pressure control. World J Cardiol. 2011;3:65-71. 58. Ovbiagele B, Diener H-C, Yusuf S, et al. Level of systolic blood pressure within the normal range and risk of recurrent stroke. JAMA. 2011;306:2137-2144. 59. Yamauchi H, Kagawa S, Kishibe Y, et al. Misery perfusion, blood pressure control, and 5-year stroke risk in symptomatic major cerebral artery disease. Stroke. 2015;46:265-268. 60. Powers WJ, Clarke WR, Grubb RL Jr, et al. Lower stroke risk with lower blood pressure in hemodynamic cerebral ischemia. Neurology. 2014;82:1027-1032. 61. Turan TN, Cotsonis G, Lynn MJ, et al. Relationship between blood pressure and stroke recurrence in patients with intracranial arterial stenosis. Circulation. 2007;115:2969-2975.
Cerebrovascular Disease Philip B. Gorelick, Jiangyong Min, and Muhammad U. Farooq
A NEW DEFINITION OF STROKE, 335
MANAGEMENT OF CHRONIC STROKE, 337
BRIEF OVERVIEW OF STROKE EPIDEMIOLOGY, 335
BLOOD PRESSURE MANAGEMENT FOR SELECT RECURRENT STROKE PREVENTION CONDITIONS, 338
TREATMENT OF ACUTE ISCHEMIC STROKE, 336
REFERENCES, 339
SUMMARY, 339
Raised blood pressure has been referred to as the crown jewel of stroke prevention, and blood pressure lowering has been the focus of substantial study in acute stroke and recurrent stroke prevention as a means to improve outcomes. In this chapter we discuss hypertension and stroke within the context of acute and chronic stroke management. To provide a framework for subsequent discussion of acute and chronic stroke management, we begin this chapter with the definition of stroke and a brief overview of stroke epidemiology.
A NEW DEFINITION OF STROKE Stroke has traditionally been defined based on the presence of neurological signs and symptoms and time course. The occurrence of focal neurological signs or symptoms caused by cerebrovascular disease and lasting more than 24 hours has been previously defined as stroke, whereas transient ischemic attack (TIA) has been defined as having the same clinical features as stroke but the neurological sign or symptom duration is transient lasting up to 24 hours.1 The definitions of stroke and TIA have been criticized as being arbitrary and importantly do not take into account the underlying mechanism or etiology. In cerebrovascular disease, elucidation of stroke mechanism is the primary basis for administration of specific chronic preventative therapy and acute treatment.2 These considerations have led to a 21st century updated definition of stroke.3 The updated definition takes into account not only focal neurological signs or symptoms of the brain, spinal cord or retina injury, but also incorporates consideration of brain tissue status or evidence of stroke based on modern neuroimaging such as magnetic resonance imaging (MRI). In the case of TIA, it is estimated that up to 30% to 40% of persons will have evidence of correlative prior or acute cerebral ischemia on neuroimaging study. In addition, the new definition of stroke takes into account silent or unexpected strokes which may manifest as small deep infarcts, white matter disease (leukoaraiosis), and cerebral microbleeds.3 Table 36.1 lists categories for the classification of ischemic and hemorrhagic stroke.1,4,5
BRIEF OVERVIEW OF STROKE EPIDEMIOLOGY The Prospective Urban Rural Epidemiologic (PURE) cohort study was carried out among greater than 150,000 adults in 17 high-income, middle-income, and low-income countries on 5 continents. The PURE study was designed to answer questions about cardiovascular disease mortality, incidence, and risks.6 In PURE, age-adjusted and sex-adjusted case fatality rates for stroke were highest among low-income countries followed in descending order by medium-income and highincome countries. Overall, although risk factor burden was lowest in low-income countries, rates of major cardiovascular disease and mortality were much higher in low-than high-income countries. High-income countries had a high burden of risks, but better control of these risks and more
frequent administration of pharmacologic treatments and revascularization procedures may explain these disparities in outcome.6 In the Global Burden of Disease Study 2013 (GBD 2013) among 306 diseases and injuries in 188 countries, stroke ranked as the second leading cause of disability-adjusted life years (DALYs) behind ischemic heart disease.7 In addition, GBD 2013 showed a greater than three times increase in burden of stroke (4.85 million stroke deaths, 91.4 million DALYs) in developing countries compared with high-income countries (1.6 million deaths, 21.5 million DALYs).8 Overall, there were approximately 25.7 million stroke survivors (71% with ischemic stroke), 6.5 million stroke deaths (51% from ischemic stroke), 113 million DALYs attributed to stroke (58% ischemic stroke), and 10.3 million persons with new strokes (67% ischemic).8 There was substantially greater reduction of stroke mortality rates in developed compared with developing countries. In summary, stroke-associated rates are on the rise and are being driven by the stroke burden in low-income countries. These observations provide a potential opportunity to better prevent stroke and implement more sophisticated acute care systems in developing regions.9 One of us (PBG) was involved in the development of a prototype Internet-based, worldwide survey of diagnostic and treatment capacitance for stroke in developing countries (Chile, Georgia, Nigeria, Qatar, India, Lithuania, Kazakhstan, Indonesia, Brazil and Bangladesh).10 We found a significant correlation between income and access or affordability to a number of stroke diagnostics and treatments.
Hypertension and Risk for Stroke Blood pressure is a factor associated with a continuous risk of stroke.11,12 We no longer think of stroke risk with raised blood pressure as a threshold effect. Lawes et al. showed in cohort studies that for each 10 mm Hg lower systolic blood pressure, there was a reduction of stroke of about one-third in persons aged 60 to 79 years, and this association was continuous down to at least a blood pressure level of 115/75 mm Hg.13 Furthermore, the relationship held according to sex, region, stroke subtype, and for fatal and nonfatal events. In randomized controlled trials, a 10 mm Hg reduction in systolic blood pressure was associated with a reduction of stroke risk by about one-third.13 The authors emphasized that there were greater benefits of larger blood pressure lowering and maintenance of blood pressure lowering on stroke reduction, and challenged the importance of choice of initial blood pressure lowering agent.13 Systolic blood pressure has become the main target for stroke and cardiovascular disease prevention. Because systolic blood pressure continues to rise with age and diastolic blood pressure increases until about age 50 years and falls thereafter when stroke and other cardiovascular disease begins to substantially increase, systolic blood pressure is the major target of intervention, especially for those older
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TABLE 36.1 Categories for Classification of Stroke of the VI Brain, Spinal Cord, and Retina Ischemic Stroke
1. Large artery atherosclerotic extracranial or intracranial occlusive disease 2. Embolism (cardio-aortic, artery-to-artery) 3. Small artery occlusion (lacunar) 4. Uncommon causes of stroke (e.g., arterial dissection, cardiac, or arterial surgery and interventions) 5. Undetermined causes (cryptogenic): when there is suspicion of an embolism, for example, but no obvious source is identified; or incomplete evaluation 6. Unclassified (e.g., more than one possible mechanism)
Silent or Unexpected Stroke
1. Small deep infarction 2. White matter disease (leukoaraiosis) 3. Cerebral microbleeds 4. Enlarged perivascular spaces
Hemorrhagic Stroke
1. Intraparenchymal hemorrhage (hypertensive and nonhypertensive [e.g., anticoagulant or illicit drug induced]) 2. Subarachnoid hemorrhage
than 50 years.14 Raised blood pressure is estimated to elevate stroke risk up to three-fold or four-fold compared with those without elevated blood pressure.11 Based on a meta-analysis of individual patient data, blood pressure lowering is associated with a similar relative protection at all levels of baseline cardiovascular risk; however, there is greater absolute risk reduction as baseline risk increases.15 As noted above, a substantial number of observational epidemiological studies link hypertension to stroke, and numerous clinical trials show the benefit of blood pressure lowering on stroke incidence or recurrence. In addition, population attributable risk (PAR) calculations place hypertension as the most important remediable factor as it explains the highest percentage of stroke risk. The PAR for hypertension in stroke is in the 25% to almost 50% range.12,16 In the INTERSTROKE Study, a large case-control design, there were participants from 22 countries of different geographic regions, and it was shown that 10 risk factors were associated with 90% of stroke risk.17 The PAR for hypertension in relation to stroke was 34.6%. Overall, the relative risk or estimate of relative risk of hypertension for stroke is in the three-fold to nine-fold range.18
TREATMENT OF ACUTE ISCHEMIC STROKE As previously mentioned in this chapter, the classification of stroke includes a number of major ischemic subtypes as well as the two major hemorrhagic subtypes: subarachnoid hemorrhage and intraparenchymal hemorrhage. Because the scope and depth of the topic on the management of acute stroke is so broad, we will largely limit our discussion in this chapter to management of acute ischemic stroke,19,20 but will also review select clinical trials that address blood pressure reduction in hemorrhagic stroke. For reviews of the management of subarachnoid hemorrhage and intraparenchymal hemorrhage, the reader is referred to authoritative sources found elsewhere.21-23
Blood Pressure Lowering in Acute Ischemic Stroke According to the American Heart Association(AHA)/ American Stroke Association (ASA) 2013 guidelines for the early management of acute ischemic stroke, the following evidence-based blood pressure guidance is recommended (evidence rating by Class and Level are in parenthesis).19 (1) For patients eligible to receive intravenous tissue plasminogen activator (tPA), blood pressure should be lowered
to less than 185/110 mm Hg (class I, Level of Evidence [LOE] B) and maintained before initiation of thrombolytic therapy; (2) After intravenous tPA administration, blood pressure should be maintained below 180/105 mm Hg for at least 24 hours after tPA treatment; (3) For recanalization procedures and until additional scientific study information becomes available, the recommendations just mentioned should be followed for interventional recanalization procedures including intraarterial fibrinolysis (class I, LOE C); (4) For patients with substantially raised blood pressure and who are not undergoing intravenous tPA or recanalization procedures, it is reasonable to lower blood pressure by around 15% during the first 24 hours after stroke onset. Guidance further indicates that blood pressure lowering medication should be withheld unless systolic blood pressure is greater than 220 mm Hg or diastolic is greater than 120 mm Hg (class I, LOE C), or there is a compelling indication to otherwise treat blood pressure (e.g., heart failure). Initial blood pressure lowering medications may include intravenous labetalol, nicardipine, or others19; (5) Administration of antihypertensive therapy within 24 hours of stroke is relatively safe. It is reasonable to restart blood pressure lowering agents 24 hours after stroke onset for persons with preexistent hypertension and who are neurologically stable (class IIa, LOE B); and (6) For patients not undergoing acute reperfusion strategies data regarding blood pressure lowering in acute ischemic stroke are inconclusive or conflicting, and the benefit of such treatment is not well established (class IIb, LOE C). It has been argued that in acute ischemic stroke too substantial blood pressure lowering could lead to extension of brain infarction in an already ischemic brain hemisphere with penumbral compromise, yet too high a blood pressure might potentiate brain edema, hemorrhagic transformation, and worsening of neurological outcome.24,25
Updated Trial Findings Since the publication of the AHA/ASA 2013 guidelines for early management of acute ischemic stroke, several new major studies addressing blood pressure control have been published. The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) was a multicenter, randomized controlled study organized to test whether moderate blood pressure lowering within 48 hours of onset of acute ischemic stroke could reduce death and major disability at 14 days or at hospital discharge.26 Patients were in their early sixties, were randomized within approximately 15 hours of stroke onset, had mild acute stroke impairment on neurological exam, and had entry blood pressures of about 167/97 mm Hg. Intravenous angiotensin-converting enzyme inhibitors were first-line treatment. Within 24 hours, blood pressure targets were met as mean systolic blood pressure (SBP) was lowered by 12.7% in the active treatment group and by 7.2% in the control group. By day 7 the corresponding group blood pressures were 137.3 mm Hg and 146.5 mm Hg, respectively. However, there was no difference in the primary (death and major disability at 14 days or discharge) or secondary (death and major disability at 3 months) outcomes between the intensive and less intensive blood pressure lowering groups. In the Efficacy of Nitric Oxide in Stroke (ENOS) trial, therapy with transdermal glyceryl trinitrate for 7 days and given within 48 hours of ischemic or hemorrhagic stroke onset was compared with control. Active blood pressure lowering therapy significantly reduced blood pressure and was safe, but it did not improve functional outcome based on the modified Rankin Scale (mRS).27 The above mentioned studies and others, with the exception of the Scandinavian Candesartan Acute Stroke Trial (SCAST) (there was a signal of poor outcome based on the mRS), suggest that blood pressure lowering in acute stroke is generally safe but secondary outcomes might be
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Blood Pressure Variability One of the authors (PBG) has been involved in the study of blood pressure variability after acute ischemic stroke.33,34 Blood pressure variability after acute ischemic stroke has been associated with neurological deterioration, and thus, serves as a target for possible intervention to improve outcomes and requires further study.32
Blood Pressure Lowering in Acute Hemorrhagic Stroke The AHA/ASA 2015 guidance for blood pressure management in spontaneous intracerebral hemorrhage21 recommends: (1) Acute systolic blood pressure lowering to 140 mm Hg as a safe strategy in patients with systolic blood pressure between 150 and 220 mm Hg (class I, LOE A). In addition, this management strategy can be effective for improving functional outcome (class IIa, LOE B); and (2) For patients with systolic blood pressure higher than 220 mm Hg, aggressive reduction of blood pressure with continuous intravenous infusion therapy and frequent blood pressure monitoring may be reasonable (class IIb, LOE C). A key consideration in the development of the above recommendations for blood pressure lowering for spontaneous intracerebral hemorrhage was the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2).35 In this trial, where intensive blood pressure lowering (a target of <140 mm Hg SBP) was compared with guideline treatment (a target of <180 mm Hg systolic blood pressure), the primary outcome (death or severe disability at 90 days) was not significantly reduced with intensive treatment. However, an ordinal analysis of the mRS showed improved functional outcome with intensive blood pressure lowering.35 Another trial of blood pressure lowering in acute cerebral hemorrhage, Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) II,36 was recently halted prematurely, but the results have not been published.
2015 Guidance for Early Management of Patients With Acute Ischemic Stroke in Relation to Endovascular Treatment Five major clinical trials of predominantly stent retrievers deployed for recanalization of large cerebral arteries in acute ischemic stroke37-41 have led to the 2015 AHA/ASA guideline update recommendations for use of these devices in early stroke management.20 The details of the five trials are reviewed elsewhere.20 Key 2015 AHA/ASA guidance recommendations in relation to endovascular recanalization therapy20 include: (1) Use of intravenous tPA as a first step for eligible patients being considered for intraarterial endovascular therapy (class I, LOE A); and (2) Endovascular therapy with a stent retriever should be deployed in patients according to the following criteria (class I, LOE A): A. Prestroke mRS score of 0 or 1; B. Administration of intravenous tPA within 4.5 hours of stroke onset; C. For causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); D. 18 years of age or older; E. National Institutes of Health Stroke Scale score of 6 or greater; F. ASPECTS (a grading scale for acute ischemic change on computed tomography [CT] head study) score of 6 or greater; and G. Endovascular treatment can be initiated (groin puncture) within 6 hours of stroke symptom onset. Other recommendations from this guidance statement are discussed elsewhere.20
TABLE 36.2 General Treatment Recommendations for Early 36 Management of Acute Ischemic Stroke 1. Airway and ventilator support if airway compromise 2. Maintain oxygen saturation >94% (supplemental oxygen is not indicated in nonhypoxic patients) 3. Antipyretic therapy if fever occurs 4. Raised blood pressure (see text) 5. Avoid hypoglycemia and if hyperglycemic, treat to a glucose level of 140-180 mg/dL 6. Swallow evaluation to assess for aspiration potential 7. Subcutaneous anticoagulant therapy to prevent deep vein thrombosis in immobilized patients 8. Avoid indwelling bladder catheter 9. Utilize a standardized stroke order set 10. Management of acute edema or seizures (see reference 19 for details) (From Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947.)
General Treatment Recommendations for Early Acute Ischemic Stroke Management Table 36.2 lists select other general treatment recommendations for the management of early acute ischemic stroke.19
MANAGEMENT OF CHRONIC STROKE Persons who have experienced ischemic stroke or TIA are at high risk for recurrent stroke.1 Of the total number of strokes occurring in the United States each year, recurrent ones make up almost 25%. It is estimated that the annual risk of a future ischemic stroke after an initial stroke or TIA is approximately 3% to 4%.42 Given this annualized average rate of stroke recurrence over time, there is a higher risk early on (i.e., in the first year) compared with later epochs. Furthermore, as time passes, the risk of a major coronary events heightens. Thus, it is important to be aware of coronary risk in stroke patients (and vice versa). Recurrent stroke risk will vary according to stroke subtype, age, comorbid conditions, and adherence to preventive therapy.42 Hypertension is recognized as a risk for early and late recurrent stroke.43 Traditionally, hypertension has not been well controlled in a number of recurrent stroke prevention trials up until more recently when it was shown that lifestyle coaching and a concerted effort to monitor and treat blood pressure is a highly efficacious strategy.44 It has been observed that 7-day, 30-day, and 90-day recurrent stroke rates are higher for atherosclerotic and cardiac embolic stroke subtypes compared with lacunar stroke.45 Thus, proper definition of stroke subtype has prognostic significance and also dictates the therapeutic approach as we shall learn in the following sections. In a single center observational study inadequate blood pressure control was linked to higher recurrence of both lobar and nonlobar intraparenchymal hemorrhage, suggesting the need for additional clinical trial study of blood pressure control in brain hemorrhage survivors.46 Also, in a retrospective cohort study carried out at 19 German tertiary care centers among persons with oral anticoagulation-associated intraparenchymal hemorrhage, rapid reversal of an elevated international normalized ratio (INR) and SBP lowering to less than 160 mm Hg within 4 hours was associated with lower rates of hematoma enlargement.47 Furthermore, return to oral anticoagulant therapy was linked to a lower risk of subsequent ischemic events.47
Management of Blood Pressure for Recurrent Stroke Prevention The 2014 AHA/ASA guidance statement for recurrent stroke prevention recommends the following in relation to blood
Cerebrovascular Disease
compromised.28-31 Thus, there has been a call to hold blood pressure lowering therapy in acute ischemic stroke patients until they are considered to be medically and neurologically stable, and therefore have suitable oral or enteral access.32
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pressure management42: (1) Although initiation of blood VI pressure lowering therapy after stroke for persons with blood pressure less than 140/90 mm Hg is of uncertain benefit (class IIb, LOE C), blood pressure therapy may be initiated within several days after stroke for those with a blood pressure of 140 or 90 mm Hg or greater (class I, LOE B); (2) Resumption of blood pressure lowering therapy to prevent recurrent stroke and other vascular events is indicated for those with a history of hypertension (class I, LOE A); (3) It is reasonable to aim for a target blood pressure less than 140/90 mm Hg (class IIa, LOE B), and it is reasonable to target a systolic blood pressure less than 130 mm Hg in patients with recent symptomatic lacunar infarction (class IIb, LOE B); (4) Lifestyle modifications (salt restriction, weight loss, diet rich in fruits and vegetables and low-fat dairy products, regular physical exercise, and limited alcohol consumption) are a reasonable component of a blood pressure lowering therapy regimen (class IIa, LOE C); (5) The optimal drug treatment regimen remains uncertain; however, diuretics or a diuretic plus angiotensin-converting enzyme inhibitor are considered useful (class I, LOE A); and (6) Specific blood pressure lowering agents should be chosen based on pharmacologic properties, mechanism of action, and patient characteristics (e.g., presence of diabetes mellitus, heart failure, renal disease) (class IIa, LOE B).
Select Trial Data Influencing Blood Pressure Lowering Recommendations for Recurrent Ischemic Stroke Prevention Two trials stand out as having a major influence on the above guidance for recurrent stroke prevention in relation to blood pressure management: Perindopril Protection Against Recurrent Stroke Study (PROGRESS) and Secondary Prevention of Small Subcortical Strokes (SPS3). PROGRESS featured the angiotensin-converting enzyme inhibitor, perindopril, with or without the diuretic, indapamide, versus placebo in a large trial designed to include persons with stroke or TIA in the past 5 years.48 Active treatment reduced blood pressure by 9/4 mm Hg. Overall, there was a statistically significant 28% relative risk reduction in recurrent stroke and a 50% reduction of recurrent intracerebral hemorrhage favoring the perindopril-based treatment arm. Perindopril alone achieved a blood pressure lowering effect of 5/3 mm Hg and did not achieve statistically significant stroke reduction results. With greater blood pressure lowering (12/5 mm Hg with combination therapy), there was greater reduction of key study endpoints. SPS3 was a randomized open-label trial of MRI brain that defined symptomatic lacunar infarcts.49 SBP lowering treatment targets were set for two comparator groups: less than 130 mm Hg versus 130 to 149 mm Hg. The primary endpoint, similar to PROGRESS, was reduction of all-cause stroke. The higher intensity blood pressure treatment group achieved a mean systolic SBP of 127 mm Hg, whereas the less intense treatment group achieved an SBP of 138 mm Hg after 1 year. There was no statistically significant advantage of intensive blood pressure lowering on all stroke; fatal stroke; or the composite of myocardial infarction or vascular death. However, intracerebral hemorrhage was significantly reduced (63% relative reduction; p = 0.03). Intensive blood pressure lowering therapy was deemed to be safe. Blood pressure lowering medications were prescribed at the discretion of the study team and were provided by the local site formulary. Meta-analysis of randomized controlled trials in recurrent stroke prevention has shown a reduction of recurrent stroke with blood pressure lowering of 29% and a reduction of cardiovascular events by 31%.50 However, there was no advantage for reduction of myocardial infarction or all-cause mortality.50
TABLE 36.3 Management of Select Risks or Cerebrovascular Conditions After Ischemic Stroke or Transient Ischemic Attack 1. Lipids: statin therapy with intensive lipid lowering properties and lifestyle modification if low-density lipoprotein cholesterol 100 or more mg/dL and atherosclerotic stroke . Symptomatic extracranial carotid artery stenosis: 2 A. Less than 50% carotid artery stenosis: medical management B. Between 50% and 69% carotid artery stenosis: individualize medical or medical management plus carotid endarterectomy based on patient characteristics, age, and comorbidities C. Between 70% and 99% carotid artery stenosis: carotid endarterectomy plus medical management D. Carotid artery stenting: if the carotid artery lumen is reduced by more than 70% through noninvasive imaging or more than 50% through catheter conventional cerebral angiography and direct surgical access to carotid artery is difficult (e.g., high carotid bifurcation), medical comorbidities increase risk of direct surgery, or there are local circumstances (history of neck radiation, prior carotid endarterectomy) making endarterectomy difficult . Large artery intracranial atherosclerosis: 3 A. Extracranial to intracranial bypass is not recommended B. Aggressive medical management including but not limited to a highpotency statin therapy and a blood pressure target of more than 140/90 mm Hg if 50% to 99% stenosis C. If 70% to 99% stenosis: clopidogrel 75 mg per day plus aspirin for 90 days followed by antiplatelet monotherapy D. Intracranial stenting is not recommended for routine use 4. Nonvalvular atrial fibrillation: A. If cause of stroke uncertain, 30-day continuous cardiac rhythm monitoring B. Warfarin, apixaban, dabigatran or rivaroxaban (reasonable choice)a C. If oral anticoagulation is contraindicated, consider aspirin alone or aspirin plus clopidogrel . Antiplatelet therapy (if no indication for oral anticoagulation): 5 A. Aspirin 50 to 325 mg per day or aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily or clopidogrel 75 mg per day B. Aspirin plus clopidogrel may be considered within 24 hours of minor ischemic stroke or transient ischemic attack for 90 days followed by antiplatelet monotherapy, otherwise aspirin plus clopidogrel is not indicated unless there is some other compelling indication (e.g., coronary artery stent) aEdoxaban
was approved for this indication after the publication of this statement. (From Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160-2236.)
Management of Select Risks or Cerebrovascular Conditions After Ischemic Stroke or Transient Ischemic Attack Management of select risks or cerebrovascular conditions for recurrent stroke prevention are listed in Table 36.3 in accordance with the AHA/ASA 2014 guidance statement.42
BLOOD PRESSURE MANAGEMENT FOR SELECT RECURRENT STROKE PREVENTION CONDITIONS Preservation of Cognition and Blood Pressure Cognitive impairment is common after stroke, and up to about one-third of these persons may have significant cognitive impairment. In addition, it has been estimated that midlife raised blood pressure may account for 5% and 8% of Alzheimer disease (AD) worldwide and in the U.S., respectively, and the relative risk of raised blood pressure on AD is about 1.6.51 In a 2011 AHA/ASA evidence review and guidance statement it was concluded that in patients with stroke, blood pressure lowering is effective for reducing dementia after stroke (class I, LOE B); there is reasonable evidence that lowering blood pressure in middle-aged and young elderly people may prevent
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High-Grade Occlusive Large Artery Disease Reduction of stroke risk is highly dependent on blood pressure lowering, especially in the case of hemorrhagic stroke.57 However, when it comes to recurrent ischemic stroke prevention there may be a “J”-shaped curve as demonstrated by Ovbiagele et al. in the Prevention Regimen for Effectively Preventing Second Strokes (PRoFESS) study, whereby systolic blood pressure levels during follow-up in the very low–normal (<120 mm Hg), high (140 to <150 mm Hg), or very high (≥150 mm Hg) range were associated with increased risk of recurrent stroke.58 Furthermore, when there is high-grade symptomatic intracranial occlusive cerebrovascular disease, it has been shown that patients with misery perfusion based on positron emission tomography (PET) had an increased risk of ipsilateral stroke when systolic blood pressure was less than 130 mm Hg.59 In the Carotid Occlusion Surgery Study (COSS) among a limited sample size in a nonprimary analysis, there was benefit for stroke reduction in patients who had blood pressure 130/85 or less mm Hg versus more than 130/85 mm Hg, carotid artery occlusion, and increased oxygen extraction on PET study.60 In a nonprimary analysis of the WarfarinAspirin Symptomatic Intracranial Disease Study (WASID), systolic blood pressure 160 or higher mm Hg was associated with the highest ipsilateral recurrent stroke rates compared with lower blood pressure levels.61 The above data may be interpreted to suggest a blood pressure in the range of 130 to 139/80 to 85 mm Hg as a reasonable target when there is highgrade large artery occlusive disease.
SUMMARY Blood pressure above 140/90 mm Hg is an important and modifiable risk factor for first and recurrent stroke. Blood pressure lowering in acute ischemic stroke is generally safe but has not been shown to reduce early death or disability, and concern has been raised that such therapy may worsen functional outcomes. In relation to hemorrhagic stroke, acute intensive blood pressure lowering (i.e., a target < 140 mm Hg systolic) has not been shown to reduce death or severe disability, but may improve functional outcome. In select conditions, blood pressure lowering has not been conclusively shown to reduce risk of cognitive impairment or decline, and persons with large artery occlusion may benefit from lowering of blood pressure but too high or too low a blood pressure may lead to an increased risk of recurrent stroke. Table 36.4 lists blood pressure targets for stroke prevention and acute stroke management based on the guidance statements reviewed in this chapter and the authors’ experience.
TABLE 36.4 Blood Pressure Targets for Stroke Prevention and Acute Stroke Management The following blood pressure targets may be reasonable for stroke prevention: 1. For recurrent stroke/transient ischemic attack (TIA) prevention in general: aim for a blood pressure target less than 140/90 mm Hg (target range: 130 to 139/80 to 85 mm Hg) 2. If a lacunar infarction: consider aiming for a systolic blood pressure target less than 130 mm Hg 3. Caution must be considered when lowering blood pressure when there is symptomatic high-grade or total occlusion of large cerebral arteries such as the carotid, basilar, and middle cerebral (M1): in the absence of positron emission tomography scan guidance, it is reasonable to aim for a blood pressure target less than 140/90 mm Hg (target range: 130 to 139/80 to 85 mm Hg) 4. Although a J-shaped blood pressure lowering curve may not be a major consideration for first stroke prevention, such may exist for recurrent stroke prevention: aim for a blood pressure target less than 140/90 mm Hg (target range: 130 to 139/80 to 85 mm Hg) The following blood pressure targets may be reasonable for acute stroke treatment: 1. For acute ischemic stroke and intravenous tissue plasminogen activator (tPA) administration or intraarterial recanalization procedures: aim for a blood pressure less than 185/110 mm Hg and maintain the blood pressure at less than 180/105 mm Hg for 24 hours after intravenous tPA therapy 2. For acute ischemic stroke without intravenous tPA administration or intraarterial recanalization procedure: unless there is a compelling indication (e.g., heart failure), blood pressure lowering may be withheld up to a systolic level of 220 mm Hg or a diastolic of 120 mm Hg 3. For acute intraparenchymal hemorrhage: aim for a systolic blood pressure of 140 mm Hg
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dementia in late life (class IIa, LOE B); and the usefulness of blood pressure lowering in persons older than 80 years for the prevention of dementia is unconfirmed (class IIb, LOE B).52 Uncertainty exists about the value of blood pressure lowering for preservation of cognitive function because there have been disparate study methodology, missed opportunities for study in many cardiovascular trials, a number of studies that suggest that blood pressure lowering may be useful and others that have shown no benefit, lack of long-term clinical trial data beginning in middle life or earlier, and adequate study of the phenomenon that higher blood pressure (to some degree) may be better for preservation of cognitive function in the very old.53-55 Thus, it may turn out that blood pressure control may have different effects on cognition based on absolute age.53 Furthermore, control of multiple cardiovascular risks including blood pressure may be needed to achieve successful cognitive preservation.56 Currently and given the equipoise in relation to blood pressure control and maintenance of cognitive vitality, we recommend following blood pressure control parameters in the AHA/ASA 2011 guidance statement.52
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