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Hypertension and Hemorrhagic Stroke
  JOHTN
COMPLICATIONS OF HYPERTENSION
Hypertension and Hemorrhagic Stroke
Sudhir Kumar
Senior Consultant
Department of Neurology, Apollo Health City, HyderabadTelangana, India
Correspondence Author: Sudhir Kumar, Senior ConsultantDepartment of Neurology, Apollo Health City, HyderabadTelangana, India
Phone: +919866193953
e-mail: drsudhirkumar@yahoo.com
 
ABSTRACT
Hemorrhagic strokes are common and account for 20 to 30%of all strokes in India and the rest of Asia. Patients admittedwith intracerebral hemorrhage (ICH) are usually sicker, andICH is associated with worse outcomes (as compared withischemic strokes). Hypertension is the commonest risk factorfor spontaneous ICH, responsible for up to 80% of all cases ofICH, either alone or in combination with other etiological factors.Elevated blood pressure (BP) during the first few hours to daysafter ICH leads to worse outcomes (higher death and disabilityrates). This is because high BP is directly linked to hematomaexpansion and increased mass effect. Therefore, rapidlowering of BP is recommended if systolic BP > 160 mm Hg.Intravenous labetalol and nicardipine are both equally safe andeffective for this purpose. Survivors of ICH have a higher riskof developing recurrence of ICH both over the short term andover the long term. Aggressive BP lowering is recommendedin ICH survivors postdischarge from the hospital. The targetBP of < 130/80 mm Hg should be maintained in them to reducethe risk of ICH recurrence.
Keywords: Antihypertensive agents, Hematoma, Hemorrhagicstroke, Hypertension, Intracerebral hemorrhage, Labetalol,Mortality, Nicardipine, Outcome, Perindopril, Recurrence.
How to cite this article: Kumar S. Hypertension and HemorrhagicStroke. Hypertens J 2017;3(2):89-93.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Stroke is a common cause of morbidity and mortality,ranking just behind heart attacks and cancer. Strokeis classified into two types: ischemic and hemorrhagictypes. In ischemic strokes, there is blockage of bloodsupply into an artery, resulting in brain ischemia andinfarction. On the contrary, in hemorrhagic strokes, thereis rupture of blood vessel, resulting in bleeding into brainparenchyma and damage to brain tissue. Hypertension isthe commonest risk factor for nontraumatic hemorrhagicstrokes and brain hemorrhage. Other risk factors for hemorrhagicstroke include rupture of an aneurysm, bleeding diathesis, use of anticoagulants and antiplatelet agents,drug abuse, such as cocaine, etc. The current reviewarticle focuses on the relationship between hypertensionand hemorrhagic strokes, especially role of hypertensionin causing hemorrhagic stroke, clinical features of hypertensivebrain hemorrhage, and management of hypertensionin patients with hemorrhagic strokes.

 
Hypertension as a Causative Factor
in Hemorrhagic Strokes


Hypertension has been consistently found as a majorrisk factor in causing hemorrhagic strokes. In a systemicreview, all 14 studies (11 case-control and 3 cohortstudies) showed a positive correlation between hypertensionand hemorrhagic strokes.1 The overall odds ratio ofhemorrhagic strokes among hypertensive patients was3.68. The risk of developing ICH increases with increasingseverity of hypertension. Leppala et al2 found anadjusted relative risk (RRadjusted) of 2.20 for systolic BP of140 to 159 mm Hg and 3.78 for ≥160 mm Hg comparedwith ≤139 mm Hg. In another study, Suh et al3 found anRR of 2.2 for high normal BP, 5.3 for stage 1 hypertension,10.4 for stage 2 hypertension, and 33 for stage 3 hypertension.These two cohort studies clearly showed that thehigher the degree of hypertension, the higher is the riskof developing ICH.

In a recent study, possible etiologies of ICH wereprospectively investigated in 439 patients.4 Hypertensionwas found as an etiology (definite, probable, or possible)in about 80% of the patients. The next most common etiologywas cerebral amyloid angiopathy (in only 30% ofpatients). The incidence of hypertension increases withage; therefore, hypertension as a risk factor for ICH ismore common in older people. On the contrary, hypertensionis not a significant risk factor leading to spontaneousICH in children. In a recent study, the commonest causeof spontaneous ICH in children was arteriovenous malformation(63% of patients), and hypertension was foundin just 1 out of 70 patients.5

There are specific mechanisms by which hypertensioncauses ICH. A high intraluminal pressure in theintracerebral arteries leads to extensive alterations in thesmooth muscle wall and endothelium functions. Thesechanges can take the form of hyalinosis, lipohyalinosis(or focal necrosis), and Charcot-Bouchard aneurysms.These degenerative changes in the smooth muscle cellsand endothelium predispose to ICH.6

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Locations of Hypertensive ICH

Intracerebral hemorrhage caused due to hypertensiontends to affect specific areas of brain. In a study on 100patients with hypertensive ICH, the commonest site ofbleed was found to be the basal ganglia (55%), followedby thalamus (26%), cerebral hemispheres (11%), brainstem(8%), and cerebellum (7%).7 In another older case series,Weiner and Cooper8 reported somewhat similar figures.In their series, the locations of hypertensive ICH were asfollows: 65% were in the basal ganglia, 15% were in thesubcortical white matter, 10% were in the cerebellum,and 10% were located in the pons.

The reason why hypertensive ICH affects the deeperstructures more is because of hemodynamic injury tothe perforating arteries, which arise directly from themajor arteries and enter the brain at right angles. Corticalvessels have a thicker smooth muscle layer in thetunica media, which protects them from the effects ofhypertension.8 Perforating arteries on the contrary havethinner walls and are more prone to the effects of highBP. The arteries affected include lenticulostriate arteries,thalamoperforate arteries, paramedian branches of thebasilar artery, and superior and anterior inferior cerebellararteries. These arteries supply to basal ganglia, thalamus,pons, and cerebellum respectively, thus explainingthe propensity of these areas of brain to be affected moreby severe hypertension.

Effects of Hypertension on Acute ICH

Presence of hypertension influences the short-term andlong-term outcomes in patients with ICH. HypertensionrelatedICH tends to have a higher risk of hematomaexpansion, as compared with amyloid angiopathy-relatedICH cases. In a recent study, significant hematomaexpansion was defined as an absolute increase in theICH volume >12.5 mL or >50% within 48 hours of onset.9This study found that significant hematoma expansionoccurred in about 45% of hypertensive patients, as comparedwith only 19% of amyloid angiopathy-related ICHpatients (odds ratio: 3.081, p = 0.004).

Hematoma expansion is frequently associated withearly neurological deterioration in patients with ICH. Ina recent study, neurological deterioration within the firsthour (hyperacute) and within 1 to 24 hours (acute) afterthe onset of ICH was strongly associated with hematomaexpansion (odds ratio of 3.6 and 7.6 for hyperacute andacute cases respectively).10 In this study, patients withneurological deterioration had worse modified Rankinscores (5 vs 3; p < 0.001).

Cerebral edema and perihematomal edema (edema inbrain tissue surrounding the hematoma) are independentpredictors of poor functional outcome in patients with hypertensive ICH. These lead to increased mass effect andneurological deterioration in patients with ICH. In a recentstudy, rate of perihematomal edema expansion at 24 hourspredicted a higher mortality (odds ratio 2.97) and poormodified Rankin Scale scores (odds ratio 2.21) at 90 days.11Intensive BP lowering within the first 24 hours after theonset of ICH has been shown to reduce cerebral edema andperihematomal edema, leading to better outcomes.12
 
First day mean arterial pressure (MAP) is directlylinked to the chance of survival. In a study conducted inFinland, MAP was correlated with chances of survivalin 282 patients with supratentorial ICH.13 In this study,the MAPs varied between 66.7 and 203.3 mm Hg, andthe cutoff points of the MAP quartiles were 118, 132, and145 mm Hg. Patients in the first three quartiles had a fairoutcome, with 28-day survival rates of 71, 65, and 60%respectively. In contrast, only 33% of patients in the fourthquartile survived for 28 days (p = 0.001). This study alsofound that comatose/unconscious patients had a higherMAP, as compared with conscious patients. However, atevery level of consciousness (alert, somnolent, or unconscious),the proportion of patients dying during 28 daysincreased from the first to the fourth MAP quartile.

Blood Pressure Control in the Acute
Phase of ICH


Blood pressure lowering is the single most importantpredictor of better outcome in patients with hypertensiveICH. In hypertensive ICH, we aim for faster and tighterBP lowering in the acute phase. This is in contrast to acuteischemic stroke, where BP lowering is not considered inthe acute phase. This is because lowering of BP may reducecerebral perfusion pressure, leading to further ischemiaand brain damage in patients with acute ischemic stroke.

In a recently conducted study (interact 2), rapid BPlowering in patients with ICH resulted in better functionaloutcomes.14 In this study, about 2,800 patients withspontaneous ICH (within the previous 6 hours) withelevated systolic BP were assigned to two groups: (1)intensive treatment to lower BP to systolic level of < 140mm Hg within 1 hour; and (2) guideline-recommendedtreatment with a target systolic BP < 180 mm Hg. Thechoice of antihypertensive agent and the dose was leftto the treating physician. The group receiving intensivetherapy had a significantly lower modified Rankinscores at 90 days (odds ratio 0.87, p = 0.04), as comparedwith guideline-recommended treatment. Intensive BPloweringgroup also had better physical and mentalhealth-related quality of life on EQ-5D scale. So, this studyindicated improved functional outcomes with intensivelowering of BP. Mortality rates, however, did not differbetween the two groups (11.9% in intensive loweringgroup vs 12% in guideline-recommended group).
 
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In another recently concluded study (ATACH-2),1,000 patients with ICH (volume < 60 cm3) and Glasgowcoma scale score of 5 or more with high systolic BPwere assigned to intensive treatment (target systolic BP110-139 mm Hg) or standard treatment (target systolicBP 140-179 mm Hg).15 Intravenous nicardipine wasadministered within 4.5 hours of symptom onset toachieve the target systolic BP. There was no differencebetween the two groups in terms of death or disability at90 days (38.7% in intensive treatment group versus 37.7%in standard treatment group).

In a Scandinavian study, the effect of BP loweringwith candesartan was assessed in 274 patients with ICH(SCAST trial).16 Patients with systolic BP >140 mm Hgreceived candesartan or placebo for 7 days. There wasno difference between treatment and placebo groupswith respect to the risk of vascular events (death, stroke,or myocardial infarction). Functional outcome tended tobe worse in candesartan-treated group.

In another study (CHHIPS trial), patients with ICHor cerebral infarction, with systolic BP > 160 mm Hg,were randomly assigned to treatment with lisinopril,labetalol, or placebo, within 36 hours of symptom onset.17Lisinopril and labetalol were found to be safe and effectiveBP-lowering agents in acute stroke including ICH.Three-month mortality was halved in active treatmentgroup (9.7% in active treatment group vs 20.3% in placebogroup). The main drawback of this study was the smallsample size and including patients with both ischemicand hemorrhagic strokes.

Many patients are already on antihypertensive medicationswhen they suffer from ICH. One study assessedwhether it is advisable to continue or stop the ongoingantihypertensive medications in such patients [Continueor Stop Post-Stroke Antihypertensives CollaborativeStudy (COSSACS) trial].18 A total of 379 patients wereassigned to "continue" and 384 were assigned to "stop"preexisting antihypertensive medications for 2 weeks.This study found that continuation of antihypertensivedrugs did not reduce 2-week death, or dependency,cardiovascular event rate, or mortality at 6 months. Thedrawback of this study was that it was underpowereddue to early termination of the trial.

This point-whether to continue or withhold thepreexisting antihypertensive medications within thefirst few days after the onset of ICH-was assessed inanother recently published study-ENOS trial.19 About4,000 patients were enrolled and randomized to receive7-day treatment of transdermal glyceryl trinitrate (5 mgper day) or no glyceryl trinitrate. Further, about 1,000were asked to continue their preexisting antihypertensivemedications, and about 1,000 were asked to stop theirpreexisting antihypertensive medications. Significantly lower BP was seen in groups receiving glyceryl trinitrateas well as those continuing their preexisting antihypertensivemedications; however, no improvement infunctional outcome was noted in either of the groups.This study concluded that there is no evidence to supportcontinuing prestroke antihypertensive drugs in first fewdays after ICH.

 
Guidelines of the AHA/American Stroke
Association for the Management of
Hypertension in Acute Spontaneous ICH20
  • For ICH patients presenting with systolic BP between150 and 220 mm Hg and without contraindication toacute BP treatment, acute lowering of systolic BP to140 mm Hg is safe (Class I; Level of Evidence A) andcan be effective for improving functional outcome(Class IIa; Level of Evidence B).
  • For ICH patients presenting with systolic BP >220 mm Hg, it may be reasonable to consider aggressivereduction of BP with a continuous intravenousinfusion and frequent BP monitoring (Class IIb; Levelof Evidence C).

Role of Hypertension in causing Recurrence of
Hemorrhagic Stroke


Patients with hypertensive ICH have a high risk of recurrence.In a recently published study from Denmark, 15,270patients diagnosed with primary ICH were followed upfor 5 years.21 The recurrence of ICH was noted in 8.9%patients after 1 year and 13.7% after 5 years. Surgicaltreatment and renal insufficiency were associated withincreased recurrence risks of ICH (RR 1.64 and 1.72respectively), whereas treatment with antihypertensivemedications was associated with reduced risk of ICHrecurrence (RR 0.84). This study concluded that patientswith ICH warrant an aggressive management of hypertensionto prevent short-term and long-term recurrenceof ICH, especially in those treated surgically for primaryICH and patients with renal insufficiency.

In another single-center study from Boston (USA),1145 patients with ICH were followed up at regular intervalsfor a median duration of 36.8 months (minimum 9.8months).22 Recurrence of ICH was noted in 102 of 505(20%) survivors in lobar ICH, and 44 of 640 (6.9%) survivorsof non-lobar ICH. The recurrence rate of both lobarand nonlobar ICH was found to be higher in patients withinadequate control of BP. Therefore, stricter BP control isneeded in ICH survivors to prevent its recurrence.

Choice of Antihypertensive Agent in Acute ICH

There is a lack of published data regarding the specificantihypertensive agent to be used in the setting of acute ICH. In a recent survey conducted in Japan, most neurologistsand neurosurgeons preferred using intravenousnicardipine for lowering BP in patients with acute ICH.23In a recent study, the efficacy and safety of nicardipineand labetalol infusion were compared.24 Eighty-onepatients with ICH or subarachnoid hemorrhage, whoreceived either nicardipine or labetalol infusion or acombination of both for BP control, were included foranalysis. Both the agents were found to be equally safeand effective for BP control in ICH during the initialadmission hours.

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Choice of Antihypertensive Agent in Patients
with ICH after Discharge


It is clear that patients with ICH have a high risk ofrecurrence of ICH over the short term as well as longterm. Therefore, BP control is of paramount importance.Antihypertensive medication should be started at theearliest, and all patients at discharge from hospital mustbe on antihypertensive agents. There is no specific antihypertensiveagent that is preferentially used in thispopulation. The choice depends on other factors, suchas age and comorbid conditions (diabetes mellitus, renalinsufficiency, cardiac disease, etc) and can be decided asin general population with hypertension.

In progress trial, perindopril-based lowering of BPreduced the risk of ICH recurrence by 46% over a meanfollow-up of 3.9 years.25

The latest American Heart Association/AmericanStroke Association guidelines recommend a target BP of< 130/80 mm Hg after ICH, in order to reduce the risk of ICHrecurrence. In SPS3 trial, the rate of ICH was reduced by63% in the lower target group (systolic BP < 130 mm Hg).26

CONCLUSION

Hypertension is an important risk factor for incident aswell as recurrent hemorrhagic stroke. Elevated BP in theacute phase of ICH is associated with worse functionaland neurological outcomes. Rapid lowering of BP isneeded if systolic BP > 180 mm Hg in the early periodafter ICH. Aggressive control with antihypertensivemedications is needed for long-term duration to reducethe risk of ICH recurrence.

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