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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: gdonnan@unimelb.edu.au 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.
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