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. 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. These considerations have led to a 21st century updated definition of stroke. 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. Table 36.1 lists categories for the classification of ischemic and hemorrhagic stroke.
| Ischemic Stroke |
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| Silent or Unexpected Stroke |
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| Hemorrhagic Stroke |
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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. 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 high-income 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.
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. 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). 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). 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. 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). 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. 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. 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. 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.
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 than 50 years. Raised blood pressure is estimated to elevate stroke risk up to three-fold or four-fold compared with those without elevated blood pressure. 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.
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. 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. 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.
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, 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.
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). (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 others ; (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.
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. 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).
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 compromised. 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.
Blood Pressure Variability
One of the authors (PBG) has been involved in the study of blood pressure variability after acute ischemic stroke. 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.
Blood Pressure Lowering in Acute Hemorrhagic Stroke
The AHA/ASA 2015 guidance for blood pressure management in spontaneous intracerebral hemorrhage 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). 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. Another trial of blood pressure lowering in acute cerebral hemorrhage, Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) II, 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 stroke have led to the 2015 AHA/ASA guideline update recommendations for use of these devices in early stroke management. The details of the five trials are reviewed elsewhere. Key 2015 AHA/ASA guidance recommendations in relation to endovascular recanalization therapy 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.
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.
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