The role of blood pressure lowering before and after strokeGeoffrey A. Donnana, Stephen M. Davisb and Amanda Thrifta
Elevated blood pressure is one of the most potent risk factors
Acute Candesartan Cilexetil Evaluation in Stroke Survivors
for first ever and recurrent stroke as well as influencing early
outcome after acute stroke. There have been a number of
significant randomized controlled trials which may influence
Losartan Intervention for Endpoint Reduction to Hypertension
management in each of these three categories.
Ongoing Telmisartan Alone and in Combination with Ramipril
Perindopril Protection against Recurrent Stroke Study
For primary prevention, the recent information from the Heart
Study on Cognition and Prognosis in the Elderly
Outcomes Prevention Evaluation, Losartan Intervention for
Telmisartan Randomized Assessment Study in ACE Intolerant
Endpoint Reduction to Hypertension, Study on Cognition andPrognosis in the Elderly and Australian National Blood Pressure
Study support the view that blood pressure lowering protects
against stroke regardless of baseline blood pressure level. There is some evidence that blockade of the angiotensin systemmay give additional protection. For secondary prevention,
evidence from the Perindopril Protection against Recurrent
Hypertension and increasing age are the most powerful
Stroke Study shows that blood pressure lowering with
risk factors for stroke [1]. Fortunately, blood pressure
perindopril based therapy reduces fatal or non-fatal stroke
levels are modifiable and reductions in levels in clinical
events, again in hypertensive or normotensive individuals. There
trials have resulted in reductions in fatal and non-fatal
is uncertainty about blood pressure lowering in acute stroke,
stroke [2–5]. Risk factor modification, predominantly
although presentation of the recent Acute Candesartan Cilexetil
blood pressure lowering, has probably been responsible
Evaluation in Stroke Survivors trial in which there was significant
for reductions in stroke mortality in western countries
protection against vascular events using candesartan suggests
over the last 50 years, although this is debated [6].
that further studies should be undertaken. Summary
The relationship between blood pressure levels and first
Blood pressure lowering for primary prevention of stroke should
ever stroke risk appears to be log-linear [2,7] (Fig. 1).
be undertaken using a variety of therapeutic agents. For
The same relationship exists for recurrent stroke [8].
secondary stroke prevention perindopril based therapy should
This has been shown in a number of populations [7–9]
be used based on current evidence. Uncertainty still exists as to
and, in general, for a 10 mm rise in approximate mean
whether blood pressure lowering in the acute stroke setting is
usual blood pressure about a 30% increase in stroke risk
occurs [2,7]. Even greater risk increases for the sameblood pressure changes may be seen for primary
When discussing risk factor modification by lowering
Curr Opin Neurol 16:81–86. # 2003 Lippincott Williams & Wilkins.
blood pressure, it is convenient to distinguish primaryfrom secondary prevention and both of these from acute
aNational Stroke Research Institute, Austin & Repatriation Medical Centre, University
stroke management [10]. We define primary stroke
of Melbourne, West Heidelberg, and bDepartment of Neurology, Royal MelbourneHospital, Parkville, Victoria, Australia
prevention as risk factor modification for any individualor group of individuals in whom no clinical cerebrovas-
Correspondence to Geoffrey A. Donnan, National Stroke Research Institute, Austin &
cular event has yet occurred. Secondary prevention may
Repatriation Medical Centre, University of Melbourne, Level 1, NeurosciencesBuilding, Gate 10 Banksia St, West Heidelberg, Victoria, Australia 3081
occur some time after transient ischaemic attacks, or
Tel: +61 3 9496 2699; fax: +61 3 9496 2650; e-mail: [email protected]
clinically evident stroke. Acute stroke management may
Current Opinion in Neurology 2003, 16:81–86
be defined arbitrarily as from any time immediately afterthe onset of stroke (minutes or hours) up to about 2weeks.
Accrual of knowledge concerning stroke preventionusing blood pressure lowering strategies has acceleratedover the last few decades, particularly for primaryprevention and, latterly, for secondary prevention
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Figure 1. The relative risks of stroke for five categories of blood
undertaken [4]. From this, there was clear evidence
that either ACE inhibitors or calcium channel blockersversus placebo led to significant relevant risk reduc-
tions for stroke (about 70% for ACE inhibitors and
40% for calcium channel blockers). For major cardi-
ovascular events, relative risk reductions were 21%
and 18% respectively. This confirmed the lesser effect
for cardiac than for cerebral events. When moreintense regimes were compared with less intense
regimes, again stroke was protected more significantly(20%) than cardiac disease (8%). While there was
fairly strong evidence that both ACE inhibitors and
placebo, there was much weaker evidence that there
was any real difference between drug regimens or
Approximate mean usual blood pressure(estimated from later remeasurementsin the Framingham study)
There have been a number of more recent studies whichhave provided additional evidence for the effects of
From the combined results of seven prospective observational studies of
blood pressure lowering on primary prevention of stroke.
843 events. Solid squares represent stroke risk in each category relativeto risk in the whole study population; sizes of squares are proportional to
Further, intriguing evidence has emerged that blockade
the number of events in each diastolic blood pressure (DBP) category
of the angiotensin system at various levels may have an
and 95% confidence intervals for estimates of relative risk are denoted
additionally beneficial protection against stroke. Recent
by vertical lines. SBP, systolic blood pressure. Reproduced withpermission [2].
studies which should be considered include HeartOutcomes Prevention Evaluation (HOPE) [17], LosartanIntervention for Endpoint Reduction to Hypertension(LIFE) [18.], Study on Cognition and Prognosis in the
[11,12]. There are few data available about blood
Elderly (SCOPE) [19] and Australian National Blood
pressure lowering in the acute stroke setting [13]. The
Pressure Study (ANBP2), details of which are shown in
purpose of this article is to briefly review existing
Table 1. At the time of writing, HOPE and LIFE have
information about blood pressure lowering before and
been published but SCOPE and ANBP2 have only been
after stroke with an emphasis on more recent data. We
will also discuss current uncertainties and future researchdirections.
In the HOPE study, 9297 high risk patients withvascular disease, the majority of which were not
hypertensive, were randomized to the ACE inhibitor
Up to about 10 years ago, trials of blood pressure
ramipril or placebo [17]. In the ramipril group the blood
lowering mainly involved comparisons between beta
pressure was reduced by 3.8 mmHg systolic/2.8 mmHg
blockers or diuretics versus placebo and were well
diastolic, while in the placebo group by 0.7 mmHg/
summarized in an initial overview analysis [5]. The
1.1 mmHg. Non-fatal stroke was reduced by 24% and
populations studied were mainly middle aged and white
fatal stroke by 61%. There was a consistent effect
with essential hypertension, although later trials in-
regardless of baseline blood pressure, thus confirming
cluded older people so that updated meta-anlayses were
the log-linear relationship between blood pressure and
necessary [2,3]. It was well established that either of
stroke risk. There was no evidence of an increase in risk
these regimes would protect against vascular events,
at the lower range of blood pressures as had been feared
particularly all forms of stroke and myocardial infarction.
because of the possible impact of high grade major
Perhaps surprisingly, protection against stroke was
vessel stenoses (J curve effect). Given that the level of
greater than that for heart disease [11]. The reasons for
blood pressure lowering was modest, the effect on stroke
this are unclear but the heterogeneity of stroke may be
risk appeared to be greater than could be explained by
important: cerebral haemorrhage and lacunar infarction
blood pressure lowering alone although there were some
may be particularly sensitive to the effects of hyperten-
concerns about the timing of blood pressure measure-
ment (late in the day). In other words, one interpretationof the HOPE study is that there might be benefits for
Newer drugs such as the calcium channel blockers
ACE-inhibitors in the blockade of the renin–angiotensin
and Angiotensin Converting Enzyme (ACE) inhibitors
system, independent of any blood pressure lowering
were then introduced and a further meta-analysis was
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Blood pressure lowering and stroke Donnan et al.
Table 1. New evidence for blood pressure lowering and primary stroke prevention
RRR, relative risk reduction; ARR, absolute risk reduction; HOPE, Heart Outcomes Prevention Evaluation; LIFE, Losartan Intervention for EndpointReduction to Hypertension; SCOPE, Study on Cognition and Prognosis in the Elderly; ANBP2, Australian National Blood Pressure Study; NA, datacurrently not available.
Investigators who conducted the LIFE study rando-
may involve increased bradykinin levels as well as
mized 9193 patients with essential hypertension to
downstream effects of angiotensin escape, as shown in
either the angiotensin II type 1 (AT1) receptor blocker
Fig. 2. Angiotensin II has central effects on autoregula-
losartan or the beta blocker atenolol [18.]. This was the
tion of cerebral blood flow, sodium intake, natriuresis
first major head to head study of differing antihyperten-
and vasopressin release many of which may be reversed
sive therapies. Blood pressure reduction was similar in
by AT1 receptor blockade. In general, the angiotensin II
both groups but, interestingly, fatal and non-fatal stroke
type 2 receptor tends to have opposite effects to the AT1
was reduced by 25% in the losartan group (P = 0.001)
receptor. Both ACE inhibition and AT1 receptor
while there was no benefit seen for fatal or non-fatal
blockade may be neuroprotective in reducing infarct
myocardial infarction. This further raises the possibility
volumes in models of focal cerebral ischaemia which may
that blockade of the angiotensin system may have quite
be independent of blood pressure lowering effects [23–
specific effects on stroke prevention.
25]. The data are supported by the initial findings fromSCOPE and from ANBP2 as verbally reported. Our view
In the SCOPE study [19,20], 4937 high risk patients
is that the concept of a non-blood pressure lowering
were randomized to the AT1 receptor blocker cande-
effect of angiotensin system blockade should still be
sartan or placebo (both groups included people using
categorized as hypothesis generating: more data are
other antihypertensive medications). Although the re-
required. Secondly, reductions in blood pressure even in
sults are, as yet, unpublished, it is reported that non-fatal
so-called normotensive individuals results in definite
stroke was reduced by 28% (P50.05) associated with an
protection from first stroke events. This supports the
overall trial blood pressure reduction of 3.2 mmHg/
epidemiological data where a log-linear relationship
1.6 mmHg. There was no difference in the primary
between blood pressure and stroke risk is seen and
endpoints of major cardiovascular events. When the
refutes the idea that there may be a threshold where
subgroup of candesartan versus placebo alone was
benefit is lost and, indeed, even risk is increased.
considered, there was a blood pressure reduction of4.7/2.6 and a primary endpoint reduction of 32.1%
(P = 0.02). The ANBP2 study has also just been
Whether to lower blood pressure soon after the onset of
completed. In this, 6083 patients with mild hypertension
acute stroke is one of the longest running conundrums in
were randomized to an ACE inhibitor or diuretic. Blood
stroke management [26]. It is well known that blood
pressure reduction was marked in both groups. Overall
pressure is elevated in about 70% (depending upon
there was a borderline reduction in all cardiovascular
definition) of patients with acute stroke [27,28]. Whether
events and no difference in total stroke events between
this is cause or effect is debated. High initial systolic
blood pressure may be a predictor of poor strokeoutcome (death or dependency), although this relation-
The additional information provided by these more
ship may be J or U shaped because of higher mortality
recent trials is two-fold. First, both HOPE and LIFE
among patients with low blood pressures and massive
provide evidence that blockade of the angiotensin
ischaemic stroke or myocardial infarction [29–33]. How-
system by either ACE inhibition or AT1 receptor
ever, it should be noted that blood pressure settles
blockade may provide stroke protection by a mechanism
spontaneously in most cases with bedrest [27,28]. While
beyond that of blood pressure lowering alone. It is
it may seem tempting to lower blood pressure, restraint
known that ACE inhibitors have stabilizing effects on
is often exercised by clinicians because of concerns
atherosclerotic plaque, perhaps by reducing oxidative
about its effects on the ischaemic penumbra and on
stress as well as inflammatory and proliferative responses
occult critical arterial stenoses. Within the ischaemic
[21,22]. The effects of ACE inhibition are complex and
penumbra there is loss of autoregulation and a direct
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
relationship develops between blood pressure levels and
[38] showed in a small randomized controlled trial that
cerebral blood flow [34,35] (Fig. 3). Hence, reductions in
three patients receiving captopril did not have reduction
blood pressure may deprive an area of brain dependent
in cerebral blood flow imaged by single photon emission
upon adequate perfusion. There are well documented
tomography whereas four patients receiving nicardipine
reports of border-zone infarction resulting from hypoten-
may have had cerebral blood flow reductions [38].
sion in the presence of critical arterial stenoses [36], but
Further, in the National Institute of Neurological
Disorders and Stroke trial of intravenous tissue plasmi-nogen activator for acute ischaemic stroke, patients with
There is some evidence that blood pressure reduction
systolic blood pressures above 180 or diastolic above 110
after ischaemic stroke may be safe. Dyker et al. [37] used
had blood pressure lowered with intravenous labetalol
transcranial Doppler as an index of intracranial blood
within 3 h of onset of acute ischaemic stroke [39]. No
flow to show that a reduction in blood pressure of 19/
11 mmHg using perindopril did not significantly changeipsilateral middle cerebral artery velocities. Lisk et al.
At the time of writing, there are no fully published,large, randomized controlled trial data of blood pressurelowering in acute ischaemic stroke. However, there aresome interesting developments. The first of these is the
Figure 2. Sites and potential effects of angiotensin convertingenzyme and angiotensin II type 1 receptor inhibition
conduction of a pilot study for a large, multicentre trial ofblood pressure lowering in this setting using glycerol-trinitrate [40–42]. Pilot data from a number of sites have
already been accrued without serious adverse eventsbeing reported.
More recently, the results of the Acute Candesartan
Cilexetil Evaluation in Stroke Survivors (ACCESS) trial
were verbally reported [43,44]. In this study, 342
patients within 72 h (mean about 30 h) of acuteischaemic stroke were randomized to receive candesar-
tan (4–16 mg once daily) or placebo for 7 days. After thistime, if patients were still hypertensive, candesartan was
continued for 1 year. After a mean treatment time of
about 280 days the safety committee terminated the
study because of a significantly more favourable outcome
in the candesartan group. There were 31 primaryoutcome events in the placebo group (18.7%) and 17in the treated group (9.8%), a relative risk reduction of47.5%. It is of interest, that the majority of excess
Figure 3. The relationship between cerebral blood flow andsystemic blood pressure changes
outcome events were cardiac (10 placebo, two treated)rather than stroke (19 placebo, 13 treated) related. It ispremature to interpret these data prior to full publica-
tion, but it does suggest that lowering of blood pressure
early after ischaemic stroke may be safe and that there is
a need for further studies. Indeed, there are a number
planned investigating therapeutic time windows, degreeof blood pressure reduction, duration and type of therapy
Some of the importance of defining secondary preven-
tion for cerebral vascular disease (see earlier) relates to
the identification of a high risk group prone to further
stroke events. There were no proven useful secondaryprevention strategies for stroke until the introduction of
Under normal circumstances an autoregulatory response is mounted,
antiplatelet agents (first aspirin) in the late 1970s [45–
but within the ischaemic penumbra this is lost and a direct relationshipbetween systemic blood pressure and cerebral blood flow exists.
47], then carotid endarterectomy [48,49] and warfarin forpatients in atrial fibrillation [50]. With the recent
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Blood pressure lowering and stroke Donnan et al.
publication of the Perindopril Protection against Recur-
is more effective in reducing vascular events in 23 400
rent Stroke Study (PROGRESS), blood pressure low-
high risk subjects. In TRANSCEND, which is a
ering becomes the fourth major secondary prevention
substudy of ONTARGET, 4200 ACE inhibitor intoler-
strategy [51,52.]. While there was some evidence from a
ant patients will be randomized to telmisartan or
number of smaller randomized controlled trials that
placebo. For secondary stroke prevention, it is clear that
blood pressure lowering may be effective, definitive
the ACE inhibitor perindopril with indapamide has a
powerful protective effect on both fatal and non-fatalstroke and should be regarded as standard secondary
In the PROGRESS trial, 6103 patients with transient
stroke prevention management. For blood pressure
ischaemic or minor stroke (ischaemic or haemorrhagic)
lowering in acute stroke the evidence is less clear and
were randomized to receive perindopril based therapy
there is a need for new trials using a variety of
(perindopril alone or perindopril plus indapamide) or
placebo. Patients were recruited from both western(Europe, Australasia) and eastern (China, Japan) coun-tries and, of importance, normotensive as well as
hypertensive individuals were included. This allowed
Papers of particular interest, published within the annual period of review, havebeen highlighted as:
testing of the hypothesis that reduction of blood pressure
in normotensive people would reduce stroke risk. After
an average of 3.5 years, there was a 28% relative
Bonita R. Epidemiology of stroke. Lancet 1992; 339:342–344.
reduction in non-fatal or fatal stroke as the primary
endpoint. As hypothesized, this occurred regardless of
Collins R, MacMahon S. Blood pressure, antihypertensive drug treatmentand the risks of stroke and of coronary heart disease. Br Med Bull 1994;
baseline blood pressure. Further, protection was main-
tained across eastern and western racial groups and
MacMahon S, Rodgers A. Blood pressure, antihypertensive treatment and
stroke risk. J Hypertens Suppl 1994; 12:S5–S14.
Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calciumantagonists, and other blood-pressure-lowering drugs: results of prospec-
In the PROGRESS trial, unlike the primary prevention
tively designed overviews of randomised trials. Blood Pressure Lowering
study HOPE, the degree of protection against stroke was
Treatment Trialists’ Collaboration. Lancet 2000; 356:1955–1964.
consistent with the degree of blood pressure lowering
Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronaryheart disease. Part 2, Short-term reductions in blood pressure: overview of
determined from epidemiological studies. While not
randomised drug trials in their epidemiological context. Lancet 1990;
precluding a specific ACE effect, the data were
consistent with blood pressure lowering as a major
Bonita R, Beaglehole R. Does treatment of hypertension explain the decline inmortality from stroke? Br Med J (Clin Res Ed) 1986; 292:191–192.
component to the protection observed.
MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronaryheart disease. Part 1, Prolonged differences in blood pressure: prospective
observational studies corrected for the regression dilution bias. Lancet 1990;
Significant advances in primary and secondary preven-
tion of stroke using various blood pressure lowering
Rodgers A, MacMahon S, Gamble G, et al. Blood pressure and risk of strokein patients with cerebrovascular disease. The United Kingdom Transient
agents have been made recently. This has been less so
Ischaemic Attack Collaborative Group. Br Med J 1996; 313:147.
for blood pressure lowering in management of acute
Eastern Stroke and Coronary Heart Disease Collaborative Research Group.
ischaemic stroke. There is now clear evidence that blood
Blood pressure, cholesterol, and stroke in eastern Asia. Lancet 1998;352:1801–1807.
pressure lowering using a variety of therapeutic agents
10 MacMahon S, Rodgers A. Primary and secondary prevention of stroke. Clin
reduces the risk of first-ever stroke. Also, evidence from
the recent HOPE and LIFE studies would suggest that
11 Chalmers J, MacMahon S, Anderson C, et al. Clinician’s manual on blood
blockade of the angiotensin system using either ACE
pressure and stroke prevention. 2nd ed. London: Science Press; 2000.
inhibitors or AT1 receptor blockers may have a beneficial
12 Chalmers J, Chapman N. Challenges for the prevention of primary and
effect above that of blood pressure lowering. We await
secondary stroke: the importance of lowering blood pressure and totalcardiovascular risk. Blood Press 2001; 10:344–351.
full publication of SCOPE and ANBP2 studies to
13 Blood pressure in Acute Stroke Collaboration. Interventions for deliberately
determine if these trials add further information. Current
altering blood pressure in acute stroke. Blood pressure in Acute Stroke
studies such as the Ongoing Telmisartan Alone and in
Collaboration (BASC). Cochrane Database Syst Rev 2000; (2):CD000039.
Combination with Ramipril Global Endpoint Trial
14 Thrift AG, Donnan GA, McNeil JJ. Epidemiology of intracerebral hemorrhage.
(ONTARGET) and the Telmisartan Randomized As-
15 You R, McNeil JJ, O’Malley HM, et al. Risk factors for lacunar infarction
sessment Study in ACE Intolerant Subjects with
syndromes [see comments]. Neurology 1995; 45:1483–1487.
Cardiovascular Disease (TRANSCEND) will also be of
16 Donnan G, You R, Thrift A, et al. Hypertension as a risk factor for stroke
interest [54.]. In ONTARGET, a head to head
subtypes. Hypertens Res1994; 17:S51–S54.
comparison of the angiotensin II antagonist telmisartan
17 Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-
with the ACE inhibitor ramipril and the combination of
enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. TheHeart Outcomes Prevention Evaluation Study Investigators. N Engl J Med
both was designed to determine which of these regimes
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
18 Lindholm L, Ibsen H, Dahlor B, et al. The LIFE Study Group. Cardiovascular
38 Lisk DR, Grotta JC, Lamki LM, et al. Should hypertension be treated after
morbidity and mortality in patients with diabetes in the Losartan Intervention
acute stroke? A randomized controlled trial using single photon emission
For Endpoint reduction to hypertension study (LIFE): a randomised trial
computed tomography. Arch Neurol 1993; 50:855–862.
against atenolol. Lancet 2002; 359:1004–1010.
39 The National Institute of Neurological Disorders and Stroke rt-PA Stroke
This describes the LIFE study, the first head to head study between an A2
Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl
antagonist and a beta blocker. Significant protection against fatal and non-fatal
stroke was shown for losartan in spite of similar blood pressure reductions seen inthe atenelol group.
40 Bath PM, Weaver C, Iddenden R, Bath FJ. A trial of blood pressure reduction
in acute stroke. Age Ageing 2000; 29:554–555.
19 Hansson L, Lithell H, Skoog I, et al. Study on COgnition and Prognosis in the
Elderly (SCOPE): baseline characteristics. Blood Press 2000; 9:146–151.
41 Bath P, Bath F, Rashid P, Weaver C. Acute ischaemic stroke. Large trial of
effect of reducing blood pressure in acute stroke is being set up [letter]. Br
20 Hansson L, Lithell H, Skoog I, et al. Study on COgnition and Prognosis in the
Elderly (SCOPE). Blood Press 1999; 8:177–183.
42 Bath PM. Efficacy of nitric oxide in stroke (ENOS) Trial [abstract]. Stroke
21 Lonn EM, Yusuf S, Jha P, et al. Emerging role of angiotensin-converting
enzyme inhibitors in cardiac and vascular protection. Circulation 1994;90:2056–2069.
43 Schrader J, Rothemeyer M, Luders S, Kollmann K. Hypertension and stroke
rationale behind the ACCESS trial. Acute Candesartan Cilexetil Evaluation in
22 Pepine CJ. Improved endothelial function with angiotensin-converting enzyme
Stroke Survivors. Basic Res Cardiol 1998; 93 (suppl 2):69–78.
inhibitors. Am J Cardiol 1997; 79:29–32.
44 Schrader J, Luders S, Kulschewski A, et al. ACCESS-Study: Acute
23 Inada Y, Wada T, Ojima M, et al. Protective effects of candesartan cilexetil
candesartan dilexetil evaluation in stroke survivors [abstract]. Am J Hypertens
(TCV-116) against stroke, kidney dysfunction and cardiac hypertrophy in
stroke-prone spontaneously hypertensive rats. Clin Exp Hypertens 1997;19:1079–1099.
45 Canadian Cooperative Study Group. A randomized trial of aspirin and
sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299:53–59.
24 Ravati A, Junker V, Kouklei M, et al. Enalapril and moexipril protect from free
radical-induced neuronal damage in vitro and reduce ischemic brain injury in
46 Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2.
mice and rats. Eur J Pharmacol 1999; 373:21–33.
Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. JNeurol Sci 1996; 143:1–13.
25 Culman J, Blume A, Gohlke P, Unger T. The renin-angiotensin system in the
brain: possible therapeutic implications for AT(1)-receptor blockers. J Hum
47 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel
Hypertens 2002; 16 (suppl 3):S64–S70.
versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339.
26 Bath P, Boysen G, Donnan G, et al. Hypertension in acute stroke: what to
48 North American Symptomatic Carotid Endarterectomy Trial Collaborators.
Beneficial effect of carotid endarterectomy in symptomatic patients with high-
27 Broderick J, Brott T, Barsan W, et al. Blood pressure during the first minutes
grade carotid stenosis. N Engl J Med 1991; 325:445–453.
of focal cerebral ischemia. Ann Emerg Med 1993; 22:1438–1443.
49 European Carotid Surgery Trialists’ Collaborative Group. MRC European
28 Britton M, Carlsson A, de Faire U. Blood pressure course in patients with
Carotid Surgery Trial: interim results for symptomatic patients with severe
acute stroke and matched controls. Stroke 1986; 17:861–864.
(70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991; 337:1235–
29 Irie K, Yamaguchi T, Minematsu K, Omae T. The J-curve phenomenon in
stroke recurrence. Stroke 1993; 24:1844–1849.
50 EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention
30 Dandapani BK, Suzuki S, Kelley RE, et al. Relation between blood pressure
in non-rheumatic atrial fibrillation after transient ischaemic attack or minor
and outcome in intracerebral hemorrhage. Stroke 1995; 26:21–24.
stroke. Lancet 1993; 342:1255–1262.
31 Ahmed N, Wahlgren G. High initial blood pressure after acute stroke is
51 Neal B, MacMahon S. PROGRESS (perindopril protection against recurrent
associated with poor functional outcome. J Intern Med 2001; 249:467–473.
stroke study): rationale and design. PROGRESS Management Committee. JHypertens 1995; 13(12 Pt 2):1869–1873.
32 Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA. Blood pressure and
clinical outcomes in the International Stroke Trial. Stroke 2002; 33:1315–
52 PROGRESS Collaborative Group. Randomised trial of a perindopril-based. .
blood-pressure-lowering regimen among 6,105 individuals with previousstroke or transient ischaemic attack. Lancet 2001; 358:1033–1041.
33 Ahmed N, Nasman P, Wahlgren NG. Effect of intravenous nimodipine on
This describes the PROGRESS study, the first study to show that reduction of
blood pressure and outcome after acute stroke. Stroke 2000; 31:1250–
blood pressure in both hypertensive and normotensive people using perindopril
based therapy reduces the probability of recurrent stroke, independent of baseline
34 Olsen TS, Bruhn P, Oberg RG. Cortical hypoperfusion as a possible cause
of ‘subcortical aphasia’. Brain 1986; 109 (Pt 3):393–410.
53 Gueyffier F, Boissel JP, Boutitie F, et al. Effect of antihypertensive treatment
35 Touzani O, Roussel S, MacKenzie ET. The ischaemic penumbra. Curr Opin
in patients having already suffered from stroke. Gathering the evidence. The
INDANA (INdividual Data ANalysis of Antihypertensive intervention trials)Project Collaborators. Stroke 1997; 28:2557–2562.
36 Bladin CF, Chambers BR. Frequency and pathogenesis of hemodynamic
54 Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND studies:
stroke. Stroke 1994; 25:2179–2182.
challenges in improving prognosis. Am J Cardiol 2002; 89:18A–25A;
37 Dyker AG, Grosset DG, Lees K. Perindopril reduces blood pressure but not
cerebral blood flow in patients with recent cerebral ischemic stroke. Stroke
This presents background details on recent and continuing studies of blood
pressure lowering using ACE inhibitors and T1 antagonists.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Looking after young squirrels and preparing them for release Contents 1 - What do you do first? 1 - What do you do first? If you have found a young squirrel, you will need to ensure that its immediate well-being is taken care of. See our website and/or other document (Feeding Baby/Young Squirrels). You may decide that you are unable to look after it for very long. Please contact us a
Modern passenger trains don’t use steam engines. They travel on powered cable lines from station to station. It’s cheaper and more reliable than burning coal to heat a boiler in the end for a variety of reasons. Each wire’s current is ninety degrees to the frequency of its neighbor, so the train gets a steady push of electricity all the way down. They’re called phases. They run over