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Management of hypertension in acute stroke

Expert Rev. Cardiovasc. Ther. 7(6), 637646 (2009)

Venkatesh Aiyagari and Aamir Badruddin

Author for correspondence Department of Neurology and Rehabilitation, University of Illinois at Chicago, IL 60607, USA aiyagari@uic.edu

Hypertension is commonly seen in the setting of an acute stroke. Although hypertension is the most important modiable risk factor for both ischemic and hemorrhagic stroke, the immediate management of elevated blood pressure in this setting is controversial. Questions remain to be denitively 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 denitive studies.
KEYWORDS : acute stroke blood pressure cerebral hemorrhage cerebral ischemia hypertension

Stroke is one of the leading causes of morbidity and mortality in the USA. It is well recognized that hypertension is the leading modiable risk factor for stroke and extensive research has linked hypertension and risk of stroke in multiple patient populations [1] . Epidemiological evidence suggests that a 5mm lower diastolic blood pressure (DBP) together with a 9mm lower systolic blood pressure (SBP) confers a 33% lower risk of stroke, and a 10mm lower DBP together with a 1819mm 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 56mmHg reduction in DBP reduces stroke incidence by 42% [3] . The results of the Perindopril Protection against Recurrent Stroke Study (PROGRESS) showed that, following a stroke, an average reduction in blood pressure (BP) by 9/4mmHg translates to a reduction of total stroke by 28% and a reduction of major cardiovascular events by 26% over a 4-year period [4] . However, the management of hypertension immediately after an acute stroke remains a controversial and less well-studied subject.
Cerebrovascular physiology
Normal cerebral autoregulation

pressure) of approximately 50160mmHg [5] . In this range, when the CPP decreases, the blood vessels dilate to decrease cerebrovascular resistance. The inverse is observed when the CPP increases and the arterioles constrict to increase cerebrovascular resistance (FIGURE1) . 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 stroke

The phenomenon of autoregulation can be perturbed in several ways in patients with stroke.
Effect of increased intracranial pressure

Under 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 signicant 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 hypertension

Under normal circumstances, the cerebral blood ow (CBF) of the adult brain is maintained at approximately 50ml/100g/min, despite variations in systemic BP, by a physiological regulatory mechanism termed autoregulation. The normal range for autoregulation is a cerebral perfusion pressure (CPP; the difference between the mean arterial pressure [MAP] and venous
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Patients with stroke frequently have chronic, poorly treated hypertension. The upper and lower limits of autoregulation are signicantly 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.
ISSN 1477-9072

2009 Expert Reviews Ltd

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Cerebral blood flow

Vessel diameter

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 140mmHg was noted in 63% of the patients [8] . In the International stroke trial, 17,398patients with acute stroke were studied. The mean SBP was 160.1mmHg at the time of admission and 82% of the patients enrolled had SBP greater than 140mmHg [9] . These data demonstrate that an elevated BP is common in acute stroke and its causes, effect and treatment should be addressed.
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50

Proposed mechanisms for hypertension

Cerebral perfusion pressure

pressure of approximately 50160mmHg, cerebral vessels vary in diameter to maintain a constant cerebral blood ow. Effect of cerebral ischemia

Figure1. Relationship between cerebral blood ow and cerebral perfusion pressure. Between a cerebral perfusion

In many patients, hypertension may be a reection of poorly controlled baseline hypertension contributing to the risks for stroke. However, hypertension is also noted after acute stroke in previously normotensive patients [10] . Several mechanisms have been suggested to explain the pathophysiology of this hypertensive response [11] . These are summarized in BOX1.
Natural history of hypertension

Autoregulation has been shown to be lost in the area of cerebral infarction and signicantly 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 autoregulation 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 penumbra

There is a spontaneous reduction of BP in most acute stroke patients even without any specic antihypertensive treatment. Wallace and Levy reported that patients with acute stroke had a signicant decrease in BP within 10days of the acute stroke [12] . Another study reported that a signicant decline in BP was seen within the rst few hours of the stroke onset [13] . A signicant drop in BP in patients with ischemic stroke after the blocked vessel is recanalized has also been reported [14] .
Management of hypertension in stroke subtypes
Ischemic stroke

It 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 ow between the thresholds of electrical and ion pump failure. This region of structurally viable but functionally impaired tissue has been termed the penumbra (FIGURE2) . The ability of the penumbra to survive depends not only on the degree of ow reduction, but also on the duration of reduction. This tissue is potentially salvageable with restoration of ow, but further decrease in CBF to this area might lead to irreversible neuronal death. On MRI, the area of restricted diffusion on a diffusionweighted image is often taken as a surrogate marker for the ischemic 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 oversimplication and more recent evidence suggest that the nal volume of infarction is often smaller than the volume of restricted diffusion.
Prevalence, mechanisms & natural history of hypertension after stroke
Prevalence of hypertension after acute stroke

Ischemic stroke is the most common stroke subtype, constituting 87% of all strokes. Approximately 812% of patients with ischemic stroke die within 30days and a signicant number of survivors are left with signicant disability. Hypertension is the most important modiable risk factor for stroke. The prevalence of hypertension rises from 20% at the age of 50years to 55% at the age of 80years, while the population-attributable risk of stroke from hypertension ranges from 40% at the age of 40years to 20% at the age of 80years [15] . Large, randomized trials have conrmed the signicant role of lowering BP in the primary and secondary prevention of stroke and lowering BP seems to benet not only hypertensive individuals but also patients with a normal BP after stroke [4] .
Impact of hypertension on stroke

Several studies have shown that the majority of patients presenting with acute stroke have BP values above the criteria set for diagnosis of hypertension by the Joint National Committee on
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While 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 immediate pharmacological lowering of BP in this setting and these are summarized in BOX2 . Evidence linking high BP at the onset of stroke with mortality, long-term outcome and stroke progression is conicting. A systematic review by Willmot etal. concluded that high SBP in
Expert Rev. Cardiovasc. Ther. 7(6), (2009)

Management of hypertension in acute stroke

Review

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 outcome, or a relationship between increased Penumbra 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 17,398patients with acute stroke, patients at the extremes Ischemic core of the BP range had a poor outcome. SBP of 150mmHg was found to be a balance point from which a decrease in every 10mmHg of systolic pressure was associated with 17.9% increase in mortality and an increase of every 10mmHg of SBP increased the mortality by 3.8% [9] . An increased risk of hemorrhagic transformation of the infarction with higher BPs has also been reported. However, the Expert Rev. Cardiovasc. Ther. Future Science Group (2009) risk of hemorrhagic transformation was Figure2. Cerebral infarction demonstrating the ischemic core and penumbra. independent of BP in the International Stroke Trial [9] . Hypertension has also been considered to be a risk factor for intracerebral hemorrhage of BP manipulation (11 trials lowering BP, one increasing BP) (ICH) after thrombolytic treatment. In the National Institute within 1week of an ischemic or hemorrhagic stroke was pubof Neurological Disorders and Stroke (NINDS) trial of tissue lished. The authors found insufcient evidence to evaluate plasminogen activator after ischemic stroke and the European the effects of altering BP on outcome during the acute phase Australasian Acute Stroke Study (ECASS) II trial, elevated BP of stroke [21] . was a risk factor for hemorrhagic transformation. However, There have been very few studies of BP-lowering in computer other studies have not been able to conrm this association. tomography-proven ischemic stroke patients where the sample There are also several arguments against immediate lowering of size was moderately large. These studies are summarized in TAbLE1. BP in the setting of acute cerebral ischemia. As indicated earlier, A post hoc ana lysis of NINDS tissue plasminogen activator trial BP spontaneously declines after a stroke. Cerebral ischemia can showed no difference in outcome between patients in the placebo be worsened by lowering BP in chronic hypertensives where the arm who received antihypertensive therapy compared with those autoregulatory curve is shifted to the right [19] . An ischemic area who did not [22] . The Acute Candesartan Cilexitil Evaluation with autoregulatory impairment can be converted into irreversible in Stroke Survivors (ACCESS) trial randomized 339patients ischemia if a lower BP leads to a decrease in CBF. Lowering BP with acute stroke and a BP of more than 200/110mmHg to might decrease ow distal to a vascular stenosis or promote the receive candesartan cilexitil or placebo. The trial was stopped propagation of an intraluminal thrombus. Lastly, there are several prematurely when a 47.5% reduction in mortality and cardioanecdotal case reports of worsening neurodecit in patients with vascular events was noted in the treatment group [23] . However, ischemic stroke in whom BP was acutely lowered [20] . there was no signicant difference in BP between the two groups and, hence, the benet cannot be attributed to BP reduction.
Controlled trials studying BP reduction & stroke outcomes

While the association between hypertension and outcome in ischemic stroke is debatable, in order to denitively 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 1153patients enrolled in 12 randomized, controlled trials
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Box1. Postulated causes of hypertension afterstroke.

Pre-existing hypertension White coat effect Stress of hospitalization Cushing reex Catecholamine and cortisol release Lesion of brainstem or hypothalamus Nonspecic response to brain damage
Reproduced with permission from [41].

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Box2. 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 benet 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 inblood pressure Principle of do no harm ( primum non nocere )

Thus, the currently available evidence is insufcient to provide accurate guidance on the management of BP immediately after a stroke and treatment of this condition is largely empirical. Hopefully, the results of planned large studies will provide evidence to guide the management of this common problem. Important ongoing studies in this area are summarized in TAbLE2 .
Guidelines for BP management in acute ischemic stroke

Current 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 Acute intracerebral hemorrhage below 180 mmHg and the DBP below Pros 105mmHg for 24h. The guidelines also Might lower mortality recommend withholding antihyperten Might decrease hematoma expansion sives during the acute period unless SBP exceeds 220 mmHg or DBP exceeds Might decrease cerebral edema formation 120mmHg. If BP is to be lowered, the Might be helpful for systemic reasons (e.g., associated myocardial ischemia) guidelines recommend cautious lowering Patients likely to be more compliant with antihypertensive use if treatment is initiated in the hospital of BP by 15% in the rst 24h. A class IIa Cons recommendation also notes that antihy Decreases on its own pertensive treatment should be restarted No proven benet at 24h in previously hypertensive patients There may be a zone of ischemia around an intracerebral hematoma who are neurologically stable if there are no other contraindications [26] . Chronically hypertensive patients require higher perfusion pressure due to shift of the autoregulatory curve European Stroke Organization guide Intracranial pressure may be elevated and lowering blood pressure reduces what could lines recommend lowering SBP to less than be marginal cerebral perfusion pressure 185mmHg and DBP less than 110mmHg Principle of do no harm ( primum non nocere ) prior to thrombolysis. They do not recommend acute BP-lowering in the setting of Reproduced from with permission [41] . an acute ischemic stroke but recommend The Intravenous Nimodipine West European Stroke Trial cautious lowering if the BP is extremely high (>220/120mmHg) (INWEST) randomized patients with acute strokes presenting on repeated measurements, or with severe cardiac failure, aortic within 24h of symptoms into three treatment arms. One arm dissection or hypertensive encephalopathy [27] . received placebo while the other two arms received low-dose (1mg/h) and high-dose (2mg/h) nimodipine. This trial noted Hemorrhagic stroke worsening of clinical outcomes with lower DBPs [24] . Recently, Approximately 1015% of rst-ever strokes are due to intracerethe Controlling Hypertension and Hypotension Immediately bral hemorrhage [28] . The mortality and morbidity associated with Post-Stroke Trial (CHHIPS) pilot trial results were published. this disease is quite signicant. The 30-day mortality of patients In this trial, 179patients with an acute stroke (25patients had with ICH is approximately 37%, and only 20% regain functional ICH) were randomized to treatment with placebo or antihyper- independence by 6months. In the PROGRESS trial, long-term tensives ( b -blockers or angiotensin-converting enzyme inhibi- treatment of hypertension with perindopril (an angiotensin-contors). Antihypertensive treatment appeared to be safe and there verting enzyme inhibitor) with/without indapamide (a diuretic) was a borderline signicant reduction in mortality at 90days in in patients with ICH decreased recurrent strokes by 49% over a the actively treated group [25] . mean period of 3.9years [29] .
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Management of hypertension in acute stroke

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Table1. Large completed studies on blood pressure reduction in acute stroke.

Disease
Acute ischemic stroke

Trial name
Acute Candesartan Cilexetil Evaluation in Stroke Survivors (ACCESS)

Inclusion criteria

Intervention

Results
Signicant reduction in morbidity and mortality rates at 3months, but no change in BP No difference in 3-month mortality and no safety concerns

Ref.
[23]

Randomized to treatment Initial BP >200/110, with candesartan or acute cerebral ischemia and motor paresis within placebo for 7days 72h of onset Randomized to three tiers of BP reduction (SBP: 170200, 140170 and 110140 mmHg) Randomized to SBP treatment goals of 140or180 mmHg

Intracerebral Hemorrhage SBP>200mmHg, Acute presenting within 6h intracerebral Acutely Decreasing ofonset hemorrhage Arterial Pressure Trial (ATACH) Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT) Ischemic or Continue or Stop hemorrhagic post-Stroke Antihypertensives stroke Collaborative Study (CHHIPS)
BP: Blood pressure; SBP: Systolic blood pressure.

[37]

SBP150220mmHg, presenting within 6h ofonset

Hematoma growth slightly lower in intensive treatment group, but not signicant when corrected for initial hematoma volume and time to presentation No signicant side effects or early neurological deterioration and a borderline signicant reduction in 90-day mortality in treated group

[38]

SBP>160mmHg, presenting within 36h ofsymptoms

Randomized to labetalol, lisinopril or placebo to target SBP or 145155mmHg or 15mmHg drop in SBP

[39]

Impact of hypertension on outcome after intracerebralhemorrhage

One 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 conrm this association. Similarly, there are conicting 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 218patients enrolled in a total of four clinical trials, presenting within 3h 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 expansion of the hematoma and lowering BP acutely might prevent or lessen the degree of expansion of the hematoma. Signicant hematoma expansion (>33% increase in volume) within the rst 24h is seen in approximately a third of all patients with ICH presenting within 3h of onset of symptoms [31] . It is a major cause of secondary injury after ICH and associated with clinical 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 3h of onset of symptoms, neither baseline nor peak BP was signicantly 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 hydrostatic pressure. Perihematomal edema is seen on day1 and in the 2nd and 3rd weeks after ICH [33] . However, it is unclear whether edema is responsible for clinical deterioration or worse outcomes
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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 markers 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 predictors of increased ICP in patients with ICH is not known, but is reasonable to assume that patients with signicant 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 justied. 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
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642 Inclusion criteria

Presenting with acute ischemic Phase I: candesartan cilexitil (AT1 receptor Primary: all-cause mortality and vascular mortality; Secondary: neurological recovery and antagonist) or placebo for 4weeks stroke within 72h Phase II: candesartan or ACE-inhibitor with functionalrecovery Mean BP > 120/70 mmHg BP target of < 140/85 mmHg Acute ischemic stroke within 48h of symptom onset Previous hypertension Presenting with acute ischemic Candesartan or placebo for 7days stroke within 30h Systolic BP > 140 mmHg Patients with cerebral hemorrhage presenting within24h Systolic BP > 150 mmHg Patients with cerebral hemorrhage presenting within6h Systolic BP > 150mmHg and<220mmHg Antihypertensive treatment for 2weeks Patients within 24h of acute ischemic or hemorrhagic stroke Within 24h of last dose of antihypertensive therapy Patients with hemorrhagic or ischemic stroke who show motor weakness for at least 1h Can be treated within 48h Prestroke Rankin score > 3 Patients will be randomized to receive treatment with a glyceryl trinitrate patch or to receive no patch for 7days. Patients taking antihypertensives randomized to continue or discontinue their medication for 7days Patients randomized to early intensive BPreduction or treated according to AHAguidelines Patients treated with intravenous labetalol Primary: perihematomal regional CBF; to maintain SBP < 150mmHg or according Secondary:rate of CBF decline to AHA guidelines. Perfusion CT performed 1h after treatment Primary: combination of death and dependency; Secondary: neurological deterioration, hematoma expansion, functional disability, cognitive outcome, quality of life, mortality Primary: mortality and rate of dependency at 2weeks; Secondary: neurological and functional status, discharge destination, BP at 2weeks and 6months Primary: mortality rate and Rankin score at 90days; Secondary: recurrent stroke, symptomatic deep vein thrombosis, symptomatic pulmonary embolism or symptomatic intracranial hemorrhage at 7days, major extracranial hemorrhage at 10 days, BP recorded during 7-day treatment, length of hospital stay, discharge disposition, Barthel Index, quality of life as measured by EuroQol and abbreviated mental test score at 90 days Primary: quantitative CBF (xenon CT) before and 1.5h after rst treatment; Secondary: middle cerebral artery blood ow velocity and pulsatility index (transcranial doppler), central BP, augmentation index, peripheral BP, heart rate Valsartan or placebo for 7days or untildischarge Primary: 30-day Glasgow outcome scale; Modied Rankin scale Primary: death or disability at 6months; combination of vascular death, myocardial infarction or stroke at 6months
[21] [21]

Table2. Ongoing studies of blood pressure reduction after an acute stroke.

Review

Disease

Trial name

Intervention

Outcome measures

Ref.

Acute ischemic stroke

Acute Candesartan Cilexitil Outcomes Stroke Trial (ACCOST)

Blood Pressure Lowering in Acute Stroke Trial (BLAST)

Aiyagari & Badruddin

Scandinavian Candesartan Acute Stroke Trial (SCAST)

[21]

Acute intracerebral hemorrhage

Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICHADAPT)

[21]

The Second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT 2)

[38]

Ischemic or hemorrhagic stroke

Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS)

[21]

Efcacy of Nitric Oxide in Stroke Trial (ENOS)

[40]

Telmisartan Acute Stroke Trial (TAST)

Telmisartan 80mg once a day or placebo Patients must have suffered ischemic or hemorrhagic stroke Onset date of stroke is less than 5days Systolic BP > 140mmHg.

[21]

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

AHA: American Heart Association; ACE: Angiotensin-converting enzyme; BP: Blood pressure; CBF: Cerebral blood ow; CT: Computed tomography.

Management of hypertension in acute stroke

Review

same principles apply to ICH as well. The pros and cons of lowering BP in the setting of an acute ICH are summarized in B OX2 .
Treatment of hypertension after ICH

Similar to the situation in ischemic stroke, there are no denitive studies that conclusively demonstrate the harm or benet 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 difcult to make denitive 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 efcacy trials and not powered to assess clinical outcome (summarized in TAbLE1). The CHIPPS trial has been discussed earlier. Notably, CHIPPS included 25patients 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 2weeks (modied 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 3months, 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 1824h post-ictus in patients with ICH, with a SBP of over 200mmHg presenting within 6h of symptoms. Three SBP goals (170200, 140170 and 110140mmHg) were targeted and the lower treatment targets were studied if there were no safety concerns at the higher target. In total, 58patients (18, 20 and 20 in each target group, respectively) with relatively small hematomas (mean volume<20ml) 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 difcult to achieve this degree of BP control in these patients [37] . The INTER ACT was a multicenter, randomized trial of BP reduction that enrolled patients primarily from China. Hypertensive patients (SBP 150220 mmHg) with an acute ICH within 6h of symptom onset were randomized to antihypertensive treatment to a target of 140 mmHg (intensive group; n=203) or 180mmHg (guideline group; n=201) for 7days 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 guideline group, the intensive group showed lower mean proportional hematoma growth at 24h (13.7 vs 36.3%; p=0.04). However,
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this difference was not signicant after adjustment for initial hematoma volume and time from onset of ICH to CT scan. In addition, there was no signicant difference in adverse event rate or outcome at 90days [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 efcacy of this therapeutic approach could be initiated. A few such studies are already underway (TAbLE2) .
Guidelines for BP management in cerebral hemorrhage

The American Heart Association/American Stroke Association 2007 guidelines recommend that the optimal level of a patients BP should be based on individual factors such as chronic hypertension, ICP, age, presumed cause of hemorrhage, and interval since onset. Aggressive BP reduction is recommended if SBP is greater than 200mmHg or MAP is greater than 150mmHg. If the SBP is greater than 180mmHg or MAP is greater than 130mmHg, BP management depends on the index of suspicion for increased ICP. If increased ICP is suspected, it is recommended to monitor ICP and treat BP to maintain CPP between 6080mmHg. If not, a modest reduction of BP (i.e., MAP of 110mmHg or target BP of 160/90mmHg) is recommended [26] . The European Stroke Initiative 2006 guidelines recommend an upper level of 180/105mmHg and a target of 160/100mmHg (or MAP of 120 mmHg) in hypertensive patients. In non hypertensives, an upper level of 160/95mmHg and a target of 150/90mmHg (or MAP of 110mmHg) is suggested. In patients with suspected increased ICP, a CPP of at least 6070mmHg is recommended [39] .
Choice of antihypertensive agents

In the setting of an acute ischemic stroke, it would be preferable to use an agent that has a rapid and short duration of action without signicant 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 efcacy and side-effect prole of different agents in the setting of stroke. The doses, advantages and disadvantages of these agents are summarized in BOX3.
Expert commentary

Elevated 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 treatment should have their BP controlled in accordance with published 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
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study. Recent pilot data also seem to suggest that modest acute BP-lowering after ICH and perhaps after ischemic stroke is reasonably safe; however, these ndings need to be conrmed in larger studies. Pending the completion of these studies, in the absence of other indications for BP-lowering, it is perhaps appropriate 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 view

Several studies of the management of hypertension after ischemic stroke are currently underway (TAbLE2) . The Efcacy 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 maintenance of antihypertensive medications for 7days [40] . The Scandinavian Candesartan Acute Stroke Trial (SCAST) plans to enroll 2500patients with acute stroke and SBP greater than 140 mmHg. These patients will be randomized to receiving candesartan with dose varying from 4 to 6mg/day versus placebo. The Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS) will enroll 2900patients with acute stroke and plans to study the strategies of continuation or stoppage of antihypertensive drugs [21] . Key issues

Several trials of BP reduction in patients with ICH are also being planned. INTERACT2 plans to recruit 2800patients and plans to study a primary outcome of death or dependency at 3months. ATACH2 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 signicantly help to clarify the risks and benets 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 infarction. Even for a given stroke type, there is likely to be signicant 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 ts all approach is unlikely to be benecial.
Financial & competing interests disclosure

Venkatesh Aiyagari has served as a consultant for Boehringer-Ingelheim. The authors have no other relevant afliations or nancial involvement with any organization or entity with a nancial interest in or nancial conict 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.

Hypertension is the major modiable 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 iscontroversial. 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 efcacy of blood pressure reduction in the setting of an acute stroke areneeded.

References
Papers of special note have been highlighted as: of interest of considerable interest
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Brott T, Lu M, Kothari R etal. Hypertension and its treatment in the NINDS rt-PA Stroke Trial. Stroke 29(8), 15041509 (1998). Schrader J, Luders S, Kulschewski A etal. The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 34(7), 16991703 (2003). Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 31(6), 12501255 (2000). Potter JF, Robinson TG, Ford GA etal. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebocontrolled, double-blind pilot trial. LancetNeurol. 8(1), 4856 (2009). Randomized trial assessing the effects of optimum blood pressure management after an ischemic or a hemorrhagic stroke. Adams HP Jr, del Zoppo G, Alberts MJ etal. 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 afrms the value of this guideline as an educational tool for neurologists. Stroke 38(5), 16551711 (2007).

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Early description of hematoma expansion after spontaneous intracerebral hemorrhage.

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Largest randomized trial to date of bloodpressure reduction in cerebralhemorrhage.

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Afliations
Venkatesh Aiyagari Department of Neurology and Rehabilitation, University of Illinois at Chicago, IL 60607, USA aiyagari@uic.edu Aamir Badruddin Department of Neurology and Rehabilitation, University of Illinois at Chicago, IL 60607, USA

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

ENOS Trial Investigators. Glyceryl trinitrate vs. control, and continuing vs. stopping temporarily prior antihypertensive therapy, in acute stroke: rationale and design of the Efcacy of Nitric Oxide in Stroke (ENOS) trial (ISRCTN99414122). Int. J.Stroke 1(4), 245249 (2006).

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