The management of elevated blood pressure in acute stroke

Acute stroke is often accompanied by a transient rise in blood pressure, both in individuals who are otherwise normotensive or hypertensive [1]. There is much debate regarding whether it is advisable to intervene with drugs against this transient hypertension. A regularly updated Cochrane survey of controlled trials suggests that clinical outcome in acute stroke is the same regardless of whether pressure is lowered acutely or left to settle spontaneously [2]. Most trials in the survey were small and, until recently, most have used a calcium antagonist as active treatment. In acute ischaemic stroke, the infarcted brain tissue may be surrounded by a so-called penumbra zone of underperfused but viable tissue [3]. Acute blood pressure lowering immediately at the onset of stroke carries the risk of jeopardizing the perfusion of the penumbra, leading to enlargement of the infarct. Spontaneous thrombolysis may occur, and the ischaemic area may become hyperaemic. At this stage, a very high blood pressure might cause propagation of infarct-related brain oedema or haemorrhagic transformation of the infarct. Unfortunately, there is no clinical correlate of spontaneous thrombolysis in acute ischaemic stroke and, in routine clinical care, it is not possible to judge when it is better to leave a very high blood pressure untreated or when it is necessary to intervene. Blockade of the renin–angiotensin system with angiotensin-converting enzyme (ACE)-inhibitors or angiotensin II receptor antagonists may shift the lower and upper limit of autoregulation of cerebral blood flow towards lower blood pressure [4,5]. Following bilateral nephrectomy and 48 h of peritoneal dialysis in the rat, when renin has disappeared from the circulating blood, captopril still shifts the lower limit towards lower pressure, suggesting an effect on components of the renin–angiotensin system in the vessel wall [6]. However, in acute stroke, there has been no evidence to suggest a beneficial effect of blockade of the renin–angiotensin system. Intuitively, it might be assumed that, in a somewhat dehydrated patient admitted to hospital with acute stroke, the renin–angiotensin system would be activated and that acute blockade would produce an untoward excessive fall in blood pressure. In major clinical trials of antihypertensive treatment, ACE inhibitors have failed to prevent primary stroke beyond the effect of pressure lowering itself [7]. By contrast, a slight tendency to more strokes was observed during ACE inhibitor treatment compared to treatment with other classes of antihypertensives [7]. In the PROGRESS study of secondary stroke prevention, lowering of blood pressure with indapamide + perindopril had a strong protective effect on the brain. On the other hand, monotherapy with the ACE-inhibitor had no such effect [8]. By contrast to the results of the ACE-inhibitor studies, in the LIFE-study, the angiotensin II receptor antagonist losartan markedly prevented primary stroke compared to the beta-blocker atenolol [9]. The VALUE study is soon due to be published and we will learn whether the angiotensin II receptor antagonist valsartan has a similar protective effect on the brain compared to the calcium antagonist amlodipine [10]. If this is the case, the beneficial effect on stroke prevention found in the LIFE study would be judged as a class effect of the angiotensin II receptor antagonists. Is the administration of an angiotensin receptor antagonist in the acute phase of ischaemic stroke safe, or could it even be beneficial? In the recently published ACCESS study, candesartan was given to patients with acute ischaemic stroke and high blood pressure from admission, and led to a decrease in 12-month mortality and the number of vascular events compared to placebo. Stroke outcome did not appear to be influenced [11]. In this issue of the journal, Nazar et al. [12] studied patients who were treated with losartan 2–7 days after admission with minor/lacunar stroke [12]. Regional cerebral blood flow was measured, and was unaffected by the treatment, as was clinical outcome. On the other hand, and as the authors correctly note, untoward effects on penumbral perfusion around minor infarcts might remain undetected with the technology used. Experimental studies in rats suggest that, during cerebral ischaemia, activation of angiotensin II subtype 2 receptors has a protective effect on brain tissue [13]. When these observations are considered in the context of the observations made by Nazar et al. [12], together with those of the LIFE study, it is plausible that the angiotensin II antagonists have an advantage over ACE inhibitors in the cerebral circulation, even though the two classes of drugs appear to have the same effect on autoregulation. Further controlled clinical studies of angiotensin II receptors in the acute phase of major ischaemic stroke are now warranted, with the main emphasis being on clinical stroke outcome. However, great care should be taken to ensure that patients entering such studies are not dehydrated with an activated renin–angiotensin system, and that precipitous falls in blood pressure are avoided.