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637

Review

www.expert-reviews.com ISSN 1477-9072© 2009 Expert Reviews Ltd10.1586/ERC.09.45

Stroke is one of the leading causes of morbidity and mortality in the USA. It is well recognized that hypertension is the leading modifiable risk factor for stroke and extensive research has linked hypertension and risk of stroke in multiple patient populations [1]. Epidemiological evidence suggests that a 5 mm lower diastolic blood pressure (DBP) together with a 9 mm lower systolic blood pressure (SBP) confers a 33% lower risk of stroke, and a 10 mm lower DBP together with a 18–19 mm lower SBP confers more than a 50% reduction in stroke risk [2]. Combined data from well-designed, randomized trials of antihypertensive drugs have also shown that a 5–6 mmHg reduction in DBP reduces stroke incidence by 42% [3]. The results of the Perindopril Protection against Recurrent Stroke Study (PROGRESS) showed that, fol-lowing a stroke, an average reduction in blood pressure (BP) by 9/4 mmHg translates to a reduc-tion of total stroke by 28% and a reduction of major cardiovascular events by 26% over a 4-year period [4]. However, the management of hyper-tension immediately after an acute stroke remains a controversial and less well-studied subject.

Cerebrovascular physiologyNormal cerebral autoregulationUnder normal circumstances, the cerebral blood flow (CBF) of the adult brain is maintained at approximately 50 ml/100 g/min, despite varia-tions in systemic BP, by a physiological regu-latory mechanism termed autoregulation. The normal range for autoregulation is a cerebral perfusion pressure (CPP; the difference between the mean arterial pressure [MAP] and venous

pressure) of approximately 50–160 mmHg [5]. In this range, when the CPP decreases, the blood vessels dilate to decrease cerebrovascular resis-tance. The inverse is observed when the CPP increases and the arterioles constrict to increase cerebrovascular resistance (Figure 1). Above the upper limit of autoregulation, there may be ‘breakthrough’ vasodilation leading to vasogenic cerebral edema. A BP below the lower limit of autoregulation can result in a decrease in CBF and, potentially, cerebral ischemia.

Autoregulation in strokeThe phenomenon of autoregulation can be perturbed in several ways in patients with stroke.

Effect of increased intracranial pressureUnder normal circumstances, CPP is similar to the MAP. However, when intracranial pressure (ICP) is increased (i.e., patients with large cerebral hemorrhages or with large hemispheric strokes with significant edema), the CPP is the difference between the MAP and ICP and, therefore, CPP can be low even if MAP is in the normal range. Therefore, one should be cautious when lowering MAP in patients with suspected increased ICP.

Effect of chronic hypertensionPatients with stroke frequently have chronic, poorly treated hypertension. The upper and lower limits of autoregulation are significantly higher in hypertensive patients compared with normal individuals. In these patients, ‘normal’ BP may actually be a relative hypotension and lead to decrease in CBF.

Venkatesh Aiyagari† and Aamir Badruddin†Author for correspondenceDepartment of Neurology and Rehabilitation, University of Illinois at Chicago, IL 60607, USA [email protected]

Hypertension is commonly seen in the setting of an acute stroke. Although hypertension is the most important modifiable risk factor for both ischemic and hemorrhagic stroke, the immediate management of elevated blood pressure in this setting is controversial. Questions remain to be definitively answered, such as when to start lowering blood pressure, by how much to lower pressure, which pharmaceutical agents to use and whether to continue or stop previous antihypertensive medications. Recently, pilot studies have been initiated in an attempt to answer these questions and will hopefully lay the foundation for larger definitive studies.

Keywords: acute stroke • blood pressure • cerebral hemorrhage • cerebral ischemia • hypertension

Management of hypertension in acute strokeExpert Rev. Cardiovasc. Ther. 7(6), 637–646 (2009)

Expert Rev. Cardiovasc. Ther. 7(6), (2009)638

Review Aiyagari & Badruddin

Effect of cerebral ischemiaAutoregulation has been shown to be lost in the area of cerebral infarction and significantly impaired in the peri-infarct area. Any change in MAP can translate directly to a change in CBF. Several studies have shown impairment of dynamic autoregula-tion not only in the affected hemisphere but also in the unaffected hemisphere [6]. This global loss of autoregulation suggests a more systemic response to stroke rather than a focal one.

Ischemic penumbraIt has been suggested that focal cerebral ischemia leads to a central ‘core’ of severely ischemic tissue with failure of electrical activity and ionic pumps. Surrounding this core is an area of ischemic tissue with flow between the thresholds of electrical and ion pump failure. This region of structurally viable but function-ally impaired tissue has been termed the ‘penumbra’ (Figure 2). The ability of the penumbra to survive depends not only on the degree of flow reduction, but also on the duration of reduction. This tissue is potentially salvageable with restoration of flow, but further decrease in CBF to this area might lead to irreversible neuronal death.

On MRI, the area of restricted diffusion on a diffusion-weighted image is often taken as a surrogate marker for the isch-emic core, and the tissue surrounding this core with decreased perfusion, but no diffusion restriction, is taken as a surrogate for the penumbra and a marker for ‘tissue at risk’. However, this may be an oversimplification and more recent evidence suggest that the final volume of infarction is often smaller than the volume of restricted diffusion.

Prevalence, mechanisms & natural history of hypertension after strokePrevalence of hypertension after acute strokeSeveral studies have shown that the majority of patients present-ing with acute stroke have BP values above the criteria set for diagnosis of hypertension by the Joint National Committee on

Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) guidelines [7]. A study of 563,704 adult patients in the National Hospital Ambulatory Medical Care Survey showed that SBP greater than 140 mmHg was noted in 63% of the patients [8]. In the International stroke trial, 17,398 patients with acute stroke were studied. The mean SBP was 160.1 mmHg at the time of admission and 82% of the patients enrolled had SBP greater than 140 mmHg [9]. These data demonstrate that an elevated BP is common in acute stroke and its causes, effect and treatment should be addressed.

Proposed mechanisms for hypertensionIn many patients, hypertension may be a reflection of poorly con-trolled baseline hypertension contributing to the risks for stroke. However, hypertension is also noted after acute stroke in previ-ously normotensive patients [10]. Several mechanisms have been suggested to explain the pathophysiology of this hypertensive response [11]. These are summarized in Box 1.

Natural history of hypertensionThere is a spontaneous reduction of BP in most acute stroke patients even without any specific antihypertensive treatment. Wallace and Levy reported that patients with acute stroke had a significant decrease in BP within 10 days of the acute stroke [12]. Another study reported that a significant decline in BP was seen within the first few hours of the stroke onset [13]. A significant drop in BP in patients with ischemic stroke after the blocked vessel is recanalized has also been reported [14].

Management of hypertension in stroke subtypesIschemic strokeIschemic stroke is the most common stroke subtype, constitut-ing 87% of all strokes. Approximately 8–12% of patients with ischemic stroke die within 30 days and a significant number of survivors are left with significant disability. Hypertension is the most important modifiable risk factor for stroke. The prevalence of hypertension rises from 20% at the age of 50 years to 55% at the age of 80 years, while the population-attributable risk of stroke from hypertension ranges from 40% at the age of 40 years to 20% at the age of 80 years [15]. Large, randomized trials have confirmed the significant role of lowering BP in the primary and secondary prevention of stroke and lowering BP seems to benefit not only hypertensive individuals but also patients with a normal BP after stroke [4].

Impact of hypertension on strokeWhile there seems to be convincing evidence that lowering BP improves outcome in patients with stroke in the long run, the impact of lowering BP in the short term is controversial. There are several theoretical reasons both in favor and against immedi-ate pharmacological lowering of BP in this setting and these are summarized in Box 2.

Evidence linking high BP at the onset of stroke with mortal-ity, long-term outcome and stroke progression is conflicting. A systematic review by Willmot et al. concluded that high SBP in

Cerebral perfusion pressure

Cer

ebra

l blo

od

flo

w

50 150

Vessel diameter

Figure 1. Relationship between cerebral blood flow and cerebral perfusion pressure. Between a cerebral perfusion pressure of approximately 50–160 mmHg, cerebral vessels vary in diameter to maintain a constant cerebral blood flow.

www.expert-reviews.com 639

ReviewManagement of hypertension in acute stroke

acute ischemic stroke was associated with death and dependency [16]. On the other hand, other studies have shown either no relationship between increased BP and out-come, or a relationship between increased BP and better outcome [17,18]. Finally, a U-shaped curve has also been noted for the relationship between BP parameters and clinical outcome. In the International Stroke Trial, which enrolled 17,398 patients with acute stroke, patients at the extremes of the BP range had a poor outcome. SBP of 150 mmHg was found to be a balance point from which a decrease in every 10 mmHg of systolic pressure was associated with 17.9% increase in mortality and an increase of every 10 mmHg of SBP increased the mortality by 3.8% [9].

An increased risk of hemorrhagic trans-formation of the infarction with higher BPs has also been reported. However, the risk of hemorrhagic transformation was independent of BP in the International Stroke Trial [9]. Hypertension has also been considered to be a risk factor for intracerebral hemorrhage (ICH) after thrombolytic treatment. In the National Institute of Neurological Disorders and Stroke (NINDS) trial of tissue plasminogen activator after ischemic stroke and the European–Australasian Acute Stroke Study (ECASS) II trial, elevated BP was a risk factor for hemorrhagic transformation. However, other studies have not been able to confirm this association.

There are also several arguments against immediate lowering of BP in the setting of acute cerebral ischemia. As indicated earlier, BP spontaneously declines after a stroke. Cerebral ischemia can be worsened by lowering BP in chronic hypertensives where the autoregulatory curve is shifted to the right [19]. An ischemic area with autoregulatory impairment can be converted into irreversible ischemia if a lower BP leads to a decrease in CBF. Lowering BP might decrease flow distal to a vascular stenosis or promote the propagation of an intraluminal thrombus. Lastly, there are several anecdotal case reports of worsening neurodeficit in patients with ischemic stroke in whom BP was acutely lowered [20].

Controlled trials studying BP reduction & stroke outcomesWhile the association between hypertension and outcome in ischemic stroke is debatable, in order to definitively answer the question, ‘should BP be lowered acutely after an ischemic stroke?’, one needs to look at the results of large, randomized clinical trials of BP lowering in this setting. Unfortunately, no adequately powered trials have been conducted that can answer this question. However, efforts are underway to design and conduct such studies.

Several small studies have examined strategies to lower BP and their outcomes in acute stroke. A recent Cochrane review of 1153 patients enrolled in 12 randomized, controlled trials

of BP manipulation (11 trials lowering BP, one increasing BP) within 1 week of an ischemic or hemorrhagic stroke was pub-lished. The authors found insufficient evidence to evaluate the effects of altering BP on outcome during the acute phase of stroke [21].

There have been very few studies of BP-lowering in computer tomography-proven ischemic stroke patients where the sample size was moderately large. These studies are summarized in TaBle 1. A post hoc ana lysis of NINDS tissue plasminogen activator trial showed no difference in outcome between patients in the placebo arm who received antihypertensive therapy compared with those who did not [22]. The Acute Candesartan Cilexitil Evaluation in Stroke Survivors (ACCESS) trial randomized 339 patients with acute stroke and a BP of more than 200/110 mmHg to receive candesartan cilexitil or placebo. The trial was stopped prematurely when a 47.5% reduction in mortality and cardio-vascular events was noted in the treatment group [23]. However, there was no significant difference in BP between the two groups and, hence, the benefit cannot be attributed to BP reduction.

Box 1. Postulated causes of hypertension after stroke.

• Pre-existing hypertension

• White coat effect

• Stress of hospitalization

• Cushing reflex

• Catecholamine and cortisol release

• Lesion of brainstem or hypothalamus

• Nonspecific response to brain damage

Reproduced with permission from [41].

Figure 2. Cerebral infarction demonstrating the ischemic core and penumbra.

Penumbra

Ischemic core

Expert Rev. Cardiovasc. Ther. © Future Science Group (2009)



The Intravenous Nimodipine West European Stroke Trial (INWEST) randomized patients with acute strokes presenting within 24 h of symptoms into three treatment arms. One arm received placebo while the other two arms received low-dose (1 mg/h) and high-dose (2 mg/h) nimodipine. This trial noted worsening of clinical outcomes with lower DBPs [24]. Recently, the Controlling Hypertension and Hypotension Immediately Post-Stroke Trial (CHHIPS) pilot trial results were published. In this trial, 179 patients with an acute stroke (25 patients had ICH) were randomized to treatment with placebo or antihyper-tensives (b-blockers or angiotensin-converting enzyme inhibi-tors). Antihypertensive treatment appeared to be safe and there was a borderline significant reduction in mortality at 90 days in the actively treated group [25].

Thus, the currently available evidence is insufficient to provide accurate guidance on the management of BP immediately after a stroke and treatment of this con-dition is largely empirical. Hopefully, the results of planned large studies will pro-vide evidence to guide the management of this common problem. Important ongo-ing studies in this area are summarized in TaBle 2.

Guidelines for BP management in acute ischemic strokeCurrent guidelines from the American Heart Association and American Stroke Association recommend a cautious approach to lowering BP. In patients treated with thrombolytic treatment, they recommend lowering of BP to a SBP of not more than 185 mmHg and DBP no greater than 110 mmHg prior to treatment, and keeping the SBP below 180 mmHg and the DBP below 105 mmHg for 24 h. The guidelines also recommend withholding antihyperten-sives during the acute period unless SBP exceeds 220 mmHg or DBP exceeds 120 mmHg. If BP is to be lowered, the guidelines recommend cautious lowering of BP by 15% in the first 24 h. A class IIa recommendation also notes that antihy-pertensive treatment should be restarted at 24 h in previously hypertensive patients who are neurologically stable if there are no other contraindications [26].

European Stroke Organization guide-lines recommend lowering SBP to less than 185 mmHg and DBP less than 110 mmHg prior to thrombolysis. They do not recom-mend acute BP-lowering in the setting of an acute ischemic stroke but recommend

cautious lowering if the BP is extremely high (>220/120 mmHg) on repeated measurements, or with severe cardiac failure, aortic dissection or hypertensive encephalopathy [27].

Hemorrhagic strokeApproximately 10–15% of first-ever strokes are due to intracere-bral hemorrhage [28]. The mortality and morbidity associated with this disease is quite significant. The 30-day mortality of patients with ICH is approximately 37%, and only 20% regain functional independence by 6 months. In the PROGRESS trial, long-term treatment of hypertension with perindopril (an angiotensin-con-verting enzyme inhibitor) with/without indapamide (a diuretic) in patients with ICH decreased recurrent strokes by 49% over a mean period of 3.9 years [29].

Box 2. Pros and cons of acute treatment of hypertension in stroke.

Acute ischemic stroke

Pros

• Might lower mortality

• Might decrease stroke progression

• Might decrease hemorrhagic transformation (especially after tissue plasminogen activator)

• Might decrease cerebral edema formation

• Might be helpful for systemic reasons (e.g., associated myocardial ischemia)

• Patients likely to be more compliant with antihypertensive use if treatment is initiated in the hospital

Cons

• Decreases on its own

• No proven benefit

• Ongoing ischemia around the infarct (ischemic penumbra)

• Altered autoregulation due to chronic hypertension ischemia

• Large vessel stenosis might have resulted in reduction of perfusion

• Chance of propogating thrombus

• Anecdotal case reports and trial results demonstrating deterioration with decrease in blood pressure

• Principle of ‘do no harm’ (primum non nocere)

Acute intracerebral hemorrhage

Pros

• Might lower mortality

• Might decrease hematoma expansion

• Might decrease cerebral edema formation

• Might be helpful for systemic reasons (e.g., associated myocardial ischemia)

• Patients likely to be more compliant with antihypertensive use if treatment is initiated in the hospital

Cons

• Decreases on its own

• No proven benefit

• There may be a zone of ischemia around an intracerebral hematoma

• Chronically hypertensive patients require higher perfusion pressure due to shift of the autoregulatory curve

• Intracranial pressure may be elevated and lowering blood pressure reduces what could be marginal cerebral perfusion pressure

• Principle of do no harm (primum non nocere)

Reproduced from with permission [41].



Impact of hypertension on outcome after intracerebral hemorrhageOne of the arguments in favor of acutely lowering BP is the observation in some studies that high BP in the setting of acute ICH is associated with increased mortality. However, other studies have not been able to confirm this association. Similarly, there are conflicting reports on whether hypertension in the setting of acute ICH is associated with a poor clinical outcome independent of mortality. Most recently, in a pooled ana lysis of 218 patients enrolled in a total of four clinical trials, presenting within 3 h of onset of symptoms and prospectively studied, elevated BP did not predict increased mortality or poor outcome [30].

Perhaps the most compelling theoretical argument in favor of acutely lowering BP is that high BP might promote expan-sion of the hematoma and lowering BP acutely might prevent or lessen the degree of expansion of the hematoma. Significant hematoma expansion (>33% increase in volume) within the first 24 h is seen in approximately a third of all patients with ICH presenting within 3 h of onset of symptoms [31]. It is a major cause of secondary injury after ICH and associated with clini-cal deterioration and increased mortality after ICH [30]. Early observations suggested that there may be an association between hematoma expansion and acute hypertension. However, more recent observations contradict this assumption. In a study of 65 prospectively observed patients presenting within 3 h of onset of symptoms, neither baseline nor peak BP was significantly associated with hematoma expansion [32].

Another argument in favor of lowering BP is that high BP might promote edema around ICH by increasing the capillary hydro-static pressure. Perihematomal edema is seen on day 1 and in the 2nd and 3rd weeks after ICH [33]. However, it is unclear whether edema is responsible for clinical deterioration or worse outcomes

in ICH. Preliminary evidence suggest that early edema is not associated with hypertension but the association of hypertension with late edema remains to be studied in detail [34].

Other arguments for lowering BP include the presence of systemic complications that might warrant BP lowering. For example, 18% of patients with ICH have elevated serum mark-ers of cardiac injury that are associated with higher mortality [35]. Reducing BP in order to reduce after-load and improve cardiac function might be a reasonable approach in such patients.

The major argument against immediate lowering of BP is the possibility that lowering BP might lead to cerebral ischemia. There are several possible theoretical explanations for this. Patients with increased ICP in whom a normal CPP is being maintained by a high MAP will have low CPP and possibly decreased CBF if the MAP is lowered to ‘normal levels’. The exact incidence and predic-tors of increased ICP in patients with ICH is not known, but is reasonable to assume that patients with significant hydrocephalus or large hematoma volumes could have high ICP and would be at risk of developing cerebral ischemia if BP is reduced acutely. Another argument that has been put forth is that there may be a rim of ‘perihematomal ischemia’ in patients with ICH due to compression of capillaries by the blood clot. This was based on early CBF studies using single photon emission CT scans that demonstrated an area of low CBF around the hematoma. Lowering BP in this setting might lead to further secondary injury in the perihematomal region. However, more recent studies with PET and MRI scans suggest that the lowered CBF in the perihematomal region is most likely due to metabolic suppression of the tissue rather than ischemia [36]. Therefore, keeping the BP high in order to avoid exacerbation of perihematomal ischemia may not be justified.

Other arguments to avoid acute lowering of BP, such as the shifting of the autoregulatory curve in chronic hypertensives, have been discussed in the section on ischemic stroke and the

Table 1. Large completed studies on blood pressure reduction in acute stroke.

Disease Trial name Inclusion criteria Intervention Results Ref.

Acute ischemic stroke

Acute Candesartan Cilexetil Evaluation in Stroke Survivors (ACCESS)

Initial BP > 200/110, acute cerebral ischemia and motor paresis within 72 h of onset

Randomized to treatment with candesartan or placebo for 7 days

Significant reduction in morbidity and mortality rates at 3 months, but no change in BP

[23]

Acute intracerebral hemorrhage

Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ATACH)

SBP > 200 mmHg, presenting within 6 h of onset

Randomized to three tiers of BP reduction (SBP: 170–200, 140–170 and 110–140 mmHg)

No difference in 3-month mortality and no safety concerns

[37]

Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT)

SBP 150–220 mmHg, presenting within 6 h of onset

Randomized to SBP treatment goals of 140 or 180 mmHg

Hematoma growth slightly lower in intensive treatment group, but not significant when corrected for initial hematoma volume and time to presentation

[38]

Ischemic or hemorrhagic stroke

Continue or Stop post-Stroke Antihypertensives Collaborative Study (CHHIPS)

SBP > 160 mmHg, presenting within 36 h of symptoms

Randomized to labetalol, lisinopril or placebo to target SBP or 145–155 mmHg or 15 mmHg drop in SBP

No significant side effects or early neurological deterioration and a borderline significant reduction in 90-day mortality in treated group

[39]

BP: Blood pressure; SBP: Systolic blood pressure.


Review Aiyagari & BadruddinTa

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2. O

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Pati

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same principles apply to ICH as well. The pros and cons of lowering BP in the setting of an acute ICH are summarized in Box 2.

Treatment of hypertension after ICHSimilar to the situation in ischemic stroke, there are no defini-tive studies that conclusively demonstrate the harm or benefit of lowering BP acutely after an ICH. Studies have attempted to study the effect of lowering BP on mortality, clinical outcome, ICP, CPP, cerebral edema and CBF. Most of these studies are retrospective and small, and it is difficult to make definitive conclusions based on these studies. The effect of lowering BP on cerebral autoregulation in the perihematomal region has also been studied.

Recently, three pilot clinical trials on the treatment of acute hypertension after ICH (Control of Hypertension In Pregnancy Study [CHIPPS], Antihypertensive Treatment of Acute Cerebral Hemorrhage [ATACH] and Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial [INTERACT]) have been concluded and the results presented or published. All three trials were safety and efficacy trials and not powered to assess clinical outcome (summarized in TaBle 1).

The CHIPPS trial has been discussed earlier. Notably, CHIPPS included 25 patients with ICH, of whom eight were treated with placebo, nine with labetalol and nine with lisinopril. The primary end point of death or dependency at 2 weeks (modified Rankin scale score > 3) was seen in three patients in the placebo group, eight in the labetalol group and six in the lisinopril group. At 3 months, one patient each in the labetalol and lisinopril group and no patients in the placebo group had died [25].

The ATACH study was a multicenter US study that addressed the tolerability and safety of intravenous nicardipine infusion for 18–24 h post-ictus in patients with ICH, with a SBP of over 200 mmHg presenting within 6 h of symptoms. Three SBP goals (170–200, 140–170 and 110–140 mmHg) were targeted and the lower treatment targets were studied if there were no safety con-cerns at the higher target. In total, 58 patients (18, 20 and 20 in each target group, respectively) with relatively small hematomas (mean volume < 20 ml) were enrolled. There was no difference in 3-month mortality between the groups and there were no safety concerns in any tier. Of note, BP in patients assigned to the lowest tier were often above the threshold, indicating that it might be difficult to achieve this degree of BP control in these patients [37].

The INTERACT was a multicenter, randomized trial of BP reduction that enrolled patients primarily from China. Hypertensive patients (SBP 150–220 mmHg) with an acute ICH within 6 h of symptom onset were randomized to anti-hypertensive treatment to a target of 140 mmHg (intensive group; n = 203) or 180 mmHg (guideline group; n = 201) for 7 days or until hospital discharge. Most of the patients were in a good clinical grade (median Glasgow Coma Scale: 14) with small, deep ganglionic hematomas. Compared with the guide-line group, the intensive group showed lower mean proportional hematoma growth at 24 h (13.7 vs 36.3%; p = 0.04). However,

this difference was not significant after adjustment for initial hematoma volume and time from onset of ICH to CT scan. In addition, there was no significant difference in adverse event rate or outcome at 90 days [38].

While none of these trials were powered to detect a difference in clinical outcome, the results indicate that acute BP reduction in ICH may be safe and that larger studies designed to test the efficacy of this therapeutic approach could be initiated. A few such studies are already underway (TaBle 2).

Guidelines for BP management in cerebral hemorrhageThe American Heart Association/American Stroke Association 2007 guidelines recommend that “the optimal level of a patient’s BP should be based on individual factors such as chronic hyper-tension, ICP, age, presumed cause of hemorrhage, and interval since onset”. Aggressive BP reduction is recommended if SBP is greater than 200 mmHg or MAP is greater than 150 mmHg. If the SBP is greater than 180 mmHg or MAP is greater than 130 mmHg, BP management depends on the index of suspi-cion for increased ICP. If increased ICP is suspected, it is recom-mended to monitor ICP and treat BP to maintain CPP between 60–80 mmHg. If not, a modest reduction of BP (i.e., MAP of 110 mmHg or target BP of 160/90 mmHg) is recommended [26].

The European Stroke Initiative 2006 guidelines recommend an upper level of 180/105 mmHg and a target of 160/100 mmHg (or MAP of 120 mmHg) in hypertensive patients. In non-hypertensives, an upper level of 160/95 mmHg and a target of 150/90 mmHg (or MAP of 110 mmHg) is suggested. In patients with suspected increased ICP, a CPP of at least 60–70 mmHg is recommended [39].

Choice of antihypertensive agentsIn the setting of an acute ischemic stroke, it would be preferable to use an agent that has a rapid and short duration of action with-out significant neurological effects such as sedation or increase in intracranial pressure. Intravenously administered agents are preferred. In the USA, preferred agents include labetalol, hydralazine, esmolol, nicardipine, nitroglycerine, nitroprusside and enalapril. Urapidil and fenoldopam are also used in Europe. It has been suggested that vasodilators should be avoided in the setting of increased intracranial pressure. However, there are no randomized, controlled trials comparing the efficacy and side-effect profile of different agents in the setting of stroke. The doses, advantages and disadvantages of these agents are summarized in Box 3.

Expert commentaryElevated BP in the setting of an acute stroke is a very common problem. However, its management is largely empirical and not evidence based. The only area where there appears to be some consensus is that patients who have received thrombolytic treat-ment should have their BP controlled in accordance with pub-lished guidelines. However, even this recommendation is based on the BP goal used in the NINDS study and not based on true ‘level I’ evidence comparing different BP goals in a randomized



study. Recent pilot data also seem to suggest that modest acute BP-lowering after ICH and perhaps after ischemic stroke is rea-sonably safe; however, these findings need to be confirmed in larger studies. Pending the completion of these studies, in the absence of other indications for BP-lowering, it is perhaps appro-priate to take a ‘primum non nocere’ (primarily, not to harm)approach, especially for patients with acute ischemic stroke with long-standing, uncontrolled hypertension.

Five-year viewSeveral studies of the management of hypertension after ischemic stroke are currently underway (TaBle 2). The Efficacy of Nitric Oxide in Stroke (ENOS) trial plans to enroll 5000 patients to be randomized to receive transdermal nitroglycerine patch or placebo and randomization for discontinuation or main-tenance of antihypertensive medications for 7 days [40]. The Scandinavian Candesartan Acute Stroke Trial (SCAST) plans to enroll 2500 patients with acute stroke and SBP greater than 140 mmHg. These patients will be randomized to receiving candesartan with dose varying from 4 to 6 mg/day versus pla-cebo. The Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS) will enroll 2900 patients with acute stroke and plans to study the strategies of continuation or stoppage of antihypertensive drugs [21].

Several trials of BP reduction in patients with ICH are also being planned. INTERACT 2 plans to recruit 2800 patients and plans to study a primary outcome of death or dependency at 3 months. ATACH 2 is also being planned. Additionally, the COSSACS, ENOS and the Intracerebral Hemorrhage Acutely Decreasing Blood Pressure Trial – Extended (ICH ADAPT-E) are also recruiting patients with acute ICH and hypertension [21].

The results of these trials should significantly help to clarify the risks and benefits of BP-lowering in stroke. However, one should also keep in mind that stroke is a heterogenous disease and a lacunar infarct is quite different from an embolic occlusion of the trunk of the middle cerebral artery resulting in a large infarc-tion. Even for a given stroke type, there is likely to be significant variation in the collateral circulation of different patients. These factors will need to be considered in the treatment of an individual patient and a ‘one size fits all’ approach is unlikely to be beneficial.

Financial & competing interests disclosureVenkatesh Aiyagari has served as a consultant for Boehringer-Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Hypertension is the major modifiable risk factor for stroke prevention.

• Hypertension is extremely common immediately after a stroke.

• Although long-standing blood pressure control improves outcome after stroke, the immediate management of blood pressure is controversial.

• The main concern regarding the immediate lowering of blood pressure after a stroke is the possibility of exacerbating cerebral ischemia.

• Acute control of blood pressure is recommended for patients with ischemic stroke treated with thrombolytic treatment.

• Recent evidence suggest that immediate lowering of blood pressure after a cerebral hemorrhage is safe; however, an improvement in outcome has not been conclusively proven.

• Large randomized studies aimed at evaluating the safety and efficacy of blood pressure reduction in the setting of an acute stroke are needed.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

1 Pedelty L, Gorelick PB. Chronic management of blood pressure after stroke. Hypertension 44(1), 1–5 (2004).

2 MacMahon S, Peto R, Cutler J et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 335(8692), 765–774 (1990).

3 Collins R, Peto R, MacMahon S et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in

blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 335(8693), 827–838 (1990).

4 PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 358(9287), 1033–1041 (2001).

5 Urrutia VC, Wityk RJ. Blood pressure management in acute stroke. Neurol. Clin. 26(2), 565–583 (2008).

6 Immink RV, van Montfrans GA, Stam J et al. Dynamic cerebral autoregulation in acute lacunar and middle cerebral artery territory ischemic stroke. Stroke 36(12), 2595–2600 (2005).

7 Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289(19), 2560–2572 (2003).

•• Evidence-basedreportofrecommendationsformanagingchronichypertension.

8 Qureshi AI, Ezzeddine MA, Nasar A et al. Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am. J. Emerg. Med. 25(1), 32–38 (2007).

9 Leonardi-Bee J, Bath PM, Phillips SJ et al. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 33(5), 1315–1320 (2002).



• RetrospectiveanalysisoftheInternationalStrokeTrial,demonstratingaU-shapedrelationshipbetweenbloodpressureandoutcomeafterstroke.

10 Rodriguez-Yanez M, Castellanos M, Blanco M et al. New-onset hypertension and inflammatory response/poor outcome in acute ischemic stroke. Neurology 67(11), 1973–1978 (2006).

11 Qureshi AI. Acute hypertensive response in patients with stroke: pathophysiology and management. Circulation 118(2), 176–187 (2008).

12 Wallace JD, Levy LL. Blood pressure after stroke. JAMA 246(19), 2177–2180 (1981).

13 Aslanyan S, Fazekas F, Weir CJ et al. Effect of blood pressure during the acute period of ischemic stroke on stroke outcome: a tertiary analysis of the GAIN International Trial. Stroke 34(10), 2420–2425 (2003).

14 Mattle HP, Kappeler L, Arnold M et al. Blood pressure and vessel recanalization in the first hours after ischemic stroke. Stroke 36(2), 264–268 (2005).

15 Lloyd-Jones D, Adams R, Carnethon M et al. Heart disease and stroke statistics – 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119(3), 480–486 (2009).

•• ExhaustivereviewofstrokestatisticsintheUSA.

16 Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension 43(1), 18–24 (2004).

17 Britton M, Carlsson A, de Faire U. Blood pressure course in patients with acute stroke and matched controls. Stroke 17(5), 861–864 (1986).

18 Jorgensen HS, Nakayama H, Raaschou HO et al. Effect of blood pressure and diabetes on stroke in progression. Lancet 344(8916), 156–159 (1994).

19 Zazulia AR, Videen TO, Powers WJ. Symptomatic autoregulatory failure in acute ischemic stroke. Neurology 68(5), 389–390 (2007).

20 Fischberg GM, Lozano E, Rajamani K et al. Stroke precipitated by moderate blood pressure reduction. J. Emerg. Med. 19(4), 339–346 (2000).

21 Geeganage C, Bath PM. Interventions for deliberately altering blood pressure in acute stroke. Cochrane Database Syst. Rev. 4, CD000039 (2008).

•• Evidence-basedreviewoftrialsofbloodpressurereductionandelevationinthesettingofanacutestroke(ischemicandhemorrhagic).

22 Brott T, Lu M, Kothari R et al. Hypertension and its treatment in the NINDS rt-PA Stroke Trial. Stroke 29(8), 1504–1509 (1998).

23 Schrader J, Luders S, Kulschewski A et al. The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 34(7), 1699–1703 (2003).

24 Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 31(6), 1250–1255 (2000).

25 Potter JF, Robinson TG, Ford GA et al. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial. Lancet Neurol. 8(1), 48–56 (2009).

• Randomizedtrialassessingtheeffectsofoptimumbloodpressuremanagementafteranischemicorahemorrhagicstroke.

26 Adams HP Jr, del Zoppo G, Alberts MJ et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 38(5), 1655–1711 (2007).

•• GuidelinesissuedbytheAmericanStrokeAssociationregardingmanagementofacuteischemicstroke.

27 European Stroke Organisation (ESO) Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc. Dis. 25(5), 457–507 (2008).

•• GuidelinesissuedbytheEuropeanStrokeOrganizationregardingmanagementofacuteischemicstroke.

28 Broderick J, Connolly S, Feldmann E et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the

American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 38(6), 2001–2023 (2007).

•• GuidelinesissuedbytheAmericanStrokeAssociationregardingmanagementofspontaneousacutehemorrhagicstroke.

29 Chapman N, Huxley R, Anderson C et al. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial. Stroke 35(1), 116–121 (2004).

30 Davis SM, Broderick J, Hennerici M et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 66(8), 1175–1181 (2006).

31 Brott T, Broderick J, Kothari R et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 28(1), 1–5 (1997).

•• Earlydescriptionofhematomaexpansionafterspontaneousintracerebralhemorrhage.

32 Jauch EC, Lindsell CJ, Adeoye O et al. Lack of evidence for an association between hemodynamic variables and hematoma growth in spontaneous intracerebral hemorrhage. Stroke 37(8), 2061–2065 (2006).

33 Zazulia AR, Diringer MN, Derdeyn CP et al. Progression of mass effect after intracerebral hemorrhage. Stroke 30(6), 1167–1173 (1999).

34 Gebel JM Jr, Jauch EC, Brott TG et al. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke 33(11), 2636–2641 (2002).

35 Hays A, Diringer MN. Elevated troponin levels are associated with higher mortality following intracerebral hemorrhage. Neurology 66(9), 1330–1334 (2006).

36 Zazulia AR, Diringer MN, Videen TO et al. Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 21(7), 804–810 (2001).

37 Qureshi AI. Acute blood pressure management – the North American perspective. Update on Cerebral hemorrhage trials session. Presented at: The International Stroke Conference. New Orleans, LA, USA, 20 February 2008.



38 Anderson CS, Huang Y, Wang JG et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol. 7(5), 391–399 (2008).

•• Largestrandomizedtrialtodateofbloodpressurereductionincerebralhemorrhage.

39 Steiner T; European Stroke Initiative Writing Committee, Writing Committee for the EUSI Executive Committee. Recommendations for the management of intracranial haemorrhage – part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing

Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc. Dis. 22(4), 294–316 (2006).

•• GuidelinesissuedbytheEuropeanStrokeOrganizationregardingmanagementofspontaneousacutehemorrhagicstroke.

40 ENOS Trial Investigators. Glyceryl trinitrate vs. control, and continuing vs. stopping temporarily prior antihypertensive therapy, in acute stroke: rationale and design of the Efficacy of Nitric Oxide in Stroke (ENOS) trial (ISRCTN99414122). Int. J. Stroke 1(4), 245–249 (2006).

41 Feehally J, Floege J, Johnson RJ. Comprehensive Clinical Nephrology (3rd edition). Mosby, PA, USA (2007).

Affiliations• Venkatesh Aiyagari

Department of Neurology and Rehabilitation, University of Illinois at Chicago, IL 60607, USA [email protected]

• Aamir Badruddin Department of Neurology and Rehabilitation, University of Illinois at Chicago, IL 60607, USA

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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