Blood pressure in acute stroke: which questions remain?
Authors: Peter M Rothwell
Journal: The Lancet (2014)

In ENOS, one of the largest randomised trials of blood pressure-lowering in acute stroke now published in The Lancet, Philip Bath and colleagues1The ENOS Trial InvestigatorsEfficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial.Lancet. 2014; (published online Oct 22.)http://dx.doi.org/10.1016/S0140-6736(14)61121-1Google Scholar assessed whether blood pressure could be safely lowered with a daily glyceryl nitrate patch for 7 days after acute stroke, and whether antihypertensive drugs should be continued or withdrawn. Blood pressure is increased in about 70% of patients with acute stroke and often falls spontaneously over the next few days.2Qureshi AI Acute hypertensive response in patients with stroke: pathophysiology and management.Circulation. 2008; 118: 176-187Crossref PubMed Scopus (261) Google Scholar The potential causes of this transient rise include disturbed cerebral autoregulation, damage or compression of brain regions that regulate blood pressure, neuroendocrine disturbance, and non-specific mechanisms such as headache, urine retention, infection, and psychological stress.2Qureshi AI Acute hypertensive response in patients with stroke: pathophysiology and management.Circulation. 2008; 118: 176-187Crossref PubMed Scopus (261) Google Scholar, 3Carlberg B Asplund K Hägg E Factors influencing admission blood pressure levels in patients with acute stroke.Stroke. 1991; 22: 527-530Crossref PubMed Scopus (157) Google Scholar There is also evidence, particularly in patients with intracerebral haemorrhage, that high post-stroke blood pressure might be due to an increase in the hours or days before the event.4Fisher U Cooney MT Bull LM et al.Acute post-stroke blood pressure relative to premorbid levels in intracerebral haemorrhage versus major ischaemic stroke: a population-based study.Lancet Neurol. 2014; 13: 374-384Summary Full Text Full Text PDF PubMed Scopus (88) Google Scholar Observational data have consistently shown that high blood pressure after acute stroke is associated with poor outcomes.5Willmot M Leonardi-Bee J Bath PM High blood pressure in acute stroke and subsequent outcome: a systematic review.Hypertension. 2004; 43: 18-24Crossref PubMed Scopus (495) Google Scholar Raised blood pressure might increase cerebral oedema or haemorrhagic transformation in ischaemic stroke, or lead to haematoma expansion and rebleeding in intracerebral haemorrhage, but lowering of blood pressure might reduce cerebral blood flow and increase infarction or perihaematomal ischaemia.2Qureshi AI Acute hypertensive response in patients with stroke: pathophysiology and management.Circulation. 2008; 118: 176-187Crossref PubMed Scopus (261) Google Scholar Indeed, some small trials of acute blood pressure-lowering after ischaemic stroke did suggest increased early mortality and worse functional outcome.6Wang H Tang Y Rong X et al.Effects of early blood pressure lowering on early and long-term outcomes after acute stroke: an updated meta-analysis.PLoS One. 2014; 9: e97917Crossref PubMed Scopus (33) Google Scholar More recently, of the two previous largest trials of blood pressure-lowering in predominantly acute ischaemic stroke,7Sandset EC Bath PMW Boysen G et al.on behalf of the SCAST Study GroupThe angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.Lancet. 2011; 377: 741-750Summary Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 8He J Zhang Y Xu T et al.for the CATIS InvestigatorsEffects of immediate blood pressure reduction on death and major disability in patients with acute ischaemic stroke.JAMA. 2014; 311: 479-489Crossref PubMed Scopus (301) Google Scholar one reported an increase in stroke progression in patients treated with candesartan versus placebo and a worse functional outcome,7Sandset EC Bath PMW Boysen G et al.on behalf of the SCAST Study GroupThe angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.Lancet. 2011; 377: 741-750Summary Full Text Full Text PDF PubMed Scopus (411) Google Scholar and the other reported no reduction in rates of death or disability with lowering versus discontinuation of any antihypertensive treatment.8He J Zhang Y Xu T et al.for the CATIS InvestigatorsEffects of immediate blood pressure reduction on death and major disability in patients with acute ischaemic stroke.JAMA. 2014; 311: 479-489Crossref PubMed Scopus (301) Google Scholar A recent systematic review of these and 15 other randomised trials, including 13 236 participants, showed no effect of early blood pressure-lowering versus control on functional outcome, with some evidence of increased early mortality.6Wang H Tang Y Rong X et al.Effects of early blood pressure lowering on early and long-term outcomes after acute stroke: an updated meta-analysis.PLoS One. 2014; 9: e97917Crossref PubMed Scopus (33) Google Scholar Practice has therefore been to tolerate high blood pressure in most patients who are not candidates for thrombolysis, although recent evidence that early reduction of high blood pressure after intracranial haemorrhage might improve outcome is changing clinical management of patients with this disorder.9Anderson C Heeley E Huang Y et al.for the INTERACT2 InvestigatorsRapid blood-pressure lowering in patients with acute intracerebral hemorrhage.N Engl J Med. 2013; 368: 2355-2365Crossref PubMed Scopus (1027) Google Scholar ENOS1The ENOS Trial InvestigatorsEfficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial.Lancet. 2014; (published online Oct 22.)http://dx.doi.org/10.1016/S0140-6736(14)61121-1Google Scholar was a multicentre, randomised, partial-factorial trial that enrolled patients within 48 h of acute ischaemic (83%) or haemorrhagic (16%) stroke with systolic blood pressure between 140 mm Hg and 220 mm Hg. 4011 patients with mean blood pressure of 167/90 mm Hg were randomly assigned to receive either transdermal glyceryl trinitrate 5 mg every day versus a matching patch without glyceryl trinitrate (placebo) for 7 days. Mean blood pressure was 7·0/3·5 mm Hg lower in those given glyceryl trinitrate than in those given no glyceryl trinitrate on day 1. Although adherence to treatment was very high, this difference was no longer significant by day 3, and there was no difference between the treatment groups in neurological deterioration, recurrent stroke, or death at 7 days, and no difference in the primary outcome of functional status (change in modified Rankin scale score) at 90 days. Given previous concern about increased early progression of acute ischaemic stroke after treatment of hypertension, as reported in the SCAST trial (6% on candesartan vs 4% on placebo; risk ratio 1·47, 95% CI 1·01–2·13),7Sandset EC Bath PMW Boysen G et al.on behalf of the SCAST Study GroupThe angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.Lancet. 2011; 377: 741-750Summary Full Text Full Text PDF PubMed Scopus (411) Google Scholar the absence of adverse effects with glyceryl trinitrate in ENOS is reassuring. ENOS also showed no adverse effect of glyceryl trinitrate on functional outcome in patients with acute stroke with severe symptomatic extracranial carotid stenosis, analogous with previous evidence that low blood pressure is only associated with an increased risk of recurrent stroke in the small subset of patients with bilateral severe stenosis or occlusion.10Rothwell PM Howard SC Spence D Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease.Stroke. 2003; 34: 2583-2590Crossref PubMed Scopus (185) Google Scholar The median time from stroke onset to randomisation in ENOS was 26 h, which is similar to the delay in previous large trials of blood pressure-lowering in acute ischaemic stroke.7Sandset EC Bath PMW Boysen G et al.on behalf of the SCAST Study GroupThe angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.Lancet. 2011; 377: 741-750Summary Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 8He J Zhang Y Xu T et al.for the CATIS InvestigatorsEffects of immediate blood pressure reduction on death and major disability in patients with acute ischaemic stroke.JAMA. 2014; 311: 479-489Crossref PubMed Scopus (301) Google Scholar However, blood pressure is highest in the first few minutes after stroke onset,4Fisher U Cooney MT Bull LM et al.Acute post-stroke blood pressure relative to premorbid levels in intracerebral haemorrhage versus major ischaemic stroke: a population-based study.Lancet Neurol. 2014; 13: 374-384Summary Full Text Full Text PDF PubMed Scopus (88) Google Scholar at which point any adverse pathophysiological effects might also be greatest. In the 273 (7%) patients recruited to ENOS within 6 h of stroke onset, allocation to glyceryl trinitrate did improve the primary outcome (OR=0·55, 95% CI 0·36–0·84). However, although this apparent subgroup–treatment effect interaction was significant, there was no evidence of any continuing interaction with increasing time beyond 6 h, and a more conservative analysis of the four equal 12 h periods would be non-significant. In the two previous large trials in acute ischaemic stroke, there was also no evidence of benefit in functional outcome in the subgroups randomised earliest.7Sandset EC Bath PMW Boysen G et al.on behalf of the SCAST Study GroupThe angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.Lancet. 2011; 377: 741-750Summary Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 8He J Zhang Y Xu T et al.for the CATIS InvestigatorsEffects of immediate blood pressure reduction on death and major disability in patients with acute ischaemic stroke.JAMA. 2014; 311: 479-489Crossref PubMed Scopus (301) Google Scholar Nevertheless, it remains possible that ENOS has identified a specific acute effect of glyceryl trinitrate, rather than a generic effect of early blood pressure-lowering, and some supporting evidence has been provided by a small previous pilot trial of ambulance initiation of glyceryl trinitrate in hyperacute stroke.11Ankolekar S Fuller M Cross I et al.Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824).Stroke. 2013; 44: 3120-3128Crossref PubMed Scopus (104) Google Scholar A large trial of this intervention by Bath and colleagues (the RIGHT-2 trial) is now funded and will address this question. Investigators for ENOS also randomly assigned 2097 patients to continue versus stop their existing antihypertensive drugs. The only previous trial to have addressed this clinically important question did not show any harms from continuing drugs,12Robinson TG Potter JF Ford GA et al.on behalf of the COSSACS InvestigatorsEffects of antihypertensive treatment after acute stroke in the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial.Lancet Neurol. 2010; 9: 767-775Summary Full Text Full Text PDF PubMed Scopus (170) Google Scholar but was potentially underpowered. In ENOS, whether drugs were continued versus stopped had no significant effect on the primary outcome or on the risk of early deterioration at 7 days, but continuation did significantly worsen the Barthel index (<60) at 90 days and increased cognitive impairment in the subset of patients tested (1272 of 2095). Continuation also increased the risk of pneumonia, possibly related to aspiration. Risk of post-stroke cognitive impairment is strongly related to severity and complications of stroke,13Pendlebury ST Rothwell PM Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.Lancet Neurol. 2009; 8: 1006-1018Summary Full Text Full Text PDF PubMed Scopus (1098) Google Scholar and so this pattern of outcomes is plausible. Thus, although the primary outcome was not significantly adversely affected by continuation of drugs, the authors' conclusion that withholding blood pressure-lowering drugs after acute ischaemic stroke until patients are neurologically stable and treatment can be given safely is reasonable, and clinical guidelines will now need to make specific recommendations. ENOS was a very well designed and executed trial, and outstanding questions relate mainly to how far the results should be generalised. Firstly, ENOS and almost all previous similar trials of acute blood pressure-lowering either excluded or recruited very few patients with transient ischaemic attack and minor stroke, although patients with these events now represent more than 70% of all referrals with acute cerebrovascular events in routine practice. Blood pressure-lowering a few days or weeks after transient ischaemic attack or minor stroke is known to be safe and effective to reduce long-term risk of major stroke, and early initiation of blood pressure-lowering drugs is associated with a low risk of recurrent stroke.14Rothwell PM Giles MF Chandratheva A et al.on behalf of the Early use of Existing Preventive Strategies for Stroke (EXPRESS) StudyEffect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.Lancet. 2007; 370: 1432-1442Summary Full Text Full Text PDF PubMed Scopus (955) Google Scholar Therefore, any conclusions from the results of trials of acute blood pressure-lowering in major acute stroke should not be generalised to transient ischaemic attack and minor stroke. Secondly, although ENOS included 629 patients with intracerebral haemorrhage and showed no improvement in functional outcome, consistent with the similar subgroup analysis of 274 patients with intracerebral haemorrhage in the SCAST trial,7Sandset EC Bath PMW Boysen G et al.on behalf of the SCAST Study GroupThe angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial.Lancet. 2011; 377: 741-750Summary Full Text Full Text PDF PubMed Scopus (411) Google Scholar this finding does not conflict with the non-significant benefits reported in the INTERACT trials in more than 3000 patients with intracerebral haemorrhage.9Anderson C Heeley E Huang Y et al.for the INTERACT2 InvestigatorsRapid blood-pressure lowering in patients with acute intracerebral hemorrhage.N Engl J Med. 2013; 368: 2355-2365Crossref PubMed Scopus (1027) Google Scholar In these trials, blood pressure-lowering was started much earlier after the onset of stroke (mean time to randomisation was about 4 h) and treatment was more aggressive. It is hoped that future pooled analyses of data from all of these trials might cast further light on the interactions between these parameters and the effects of treatment in intracerebral haemorrhage. Thirdly, there remains uncertainty about the optimum early management of blood pressure in patients with acute ischaemic stroke who are candidates for thrombolysis. It is common practice to avoid thrombolysis when systolic blood pressure is higher than 185 mm Hg because of an increased risk of symptomatic intracranial haemorrhage. The continuing ENCHANTED trial (NCT01422616) aims to assess whether intensive blood pressure-lowering (130–140 mm Hg target) improves outcomes compared with the guideline-recommended level of 180 mm Hg in patients eligible for thrombolysis in acute ischaemic stroke. Finally, there is evidence that variability of blood pressure in acute stroke is associated with a poor outcome, independently of mean blood pressure.15Manning L Hirakawa Y Arima H et al.for the INTERACT2 investigatorsBlood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial.Lancet Neurol. 2014; 13: 364-373Summary Full Text Full Text PDF PubMed Scopus (166) Google Scholar Future analyses of data from ENOS should establish the effects of glyceryl trinitrate on variability. I declare no competing interests. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trialIn patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke. Full-Text PDF Open Access