Interventions for deliberately altering blood pressure in acute stroke

Background: It is unclear whether blood pressure should be altered actively during the acute phase of stroke. This is an update of a Cochrane review first published in 1997, and previously updated in 2001 and 2008. Objectives: To assess the clinical effectiveness of altering blood pressure in people with acute stroke, and the effect of different vasoactive drugs on blood pressure in acute stroke. Search methods: We searched the Cochrane Stroke Group Trials Register (last searched in February 2014), the Cochrane Database of Systematic reviews (CDSR) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 2), MEDLINE (Ovid) (1966 to May 2014), EMBASE (Ovid) (1974 to May 2014), Science Citation Index (ISI,Web of Science, 1981 to May 2014) and the Stroke Trials Registry (searched May 2014). Selection criteria: Randomised controlled trials of interventions that aimed to alter blood pressure compared with control in participants within one week of acute ischaemic or haemorrhagic stroke. Data collection and analysis: Two review authors independently applied the inclusion criteria, assessed trial quality and extracted data. The review authors crosschecked data and resolved discrepancies by discussion to reach consensus. We obtained published and unpublished data where available. Main results: We included 26 trials involving 17,011 participants (8497 participants were assigned active therapy and 8514 participants received placebo/control). Not all trials contributed to each outcome. Most data came from trials that had a wide time window for recruitment; four trials gave treatment within six hours and one trial within eight hours. The trials tested alpha-2 adrenergic agonists (A2AA), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARA), calcium channel blockers (CCBs), nitric oxide (NO) donors, thiazide-like diuretics, and target-driven blood pressure lowering. One trial tested phenylephrine. At 24 hours after randomisation oral ACEIs reduced systolic blood pressure (SBP, mean difference (MD) -8 mmHg, 95% confidence interval (CI) -17 to 1) and diastolic blood pressure (DBP, MD -3 mmHg, 95% CI -9 to 2), sublingual ACEIs reduced SBP (MD - 12.00 mm Hg, 95% CI -26 to 2) and DBP (MD -2, 95%CI -10 to 6), oral ARA reduced SBP (MD -1 mm Hg, 95% CI -3 to 2) and DBP (MD -1 mm Hg, 95% CI -3 to 1), oral beta blockers reduced SBP (MD -14 mm Hg; 95% CI -27 to -1) and DBP (MD -1 mm Hg, 95% CI -9 to 7), intravenous (iv) beta blockers reduced SBP (MD -5 mm Hg, 95% CI -18 to 8) and DBP (-5 mm Hg, 95% CI - 13 to 3), oral CCBs reduced SBP (MD -13 mmHg, 95% CI -43 to 17) and DBP (MD -6 mmHg, 95% CI -14 to 2), iv CCBs reduced SBP (MD -32 mmHg, 95% CI -65 to 1) and DBP (MD -13, 95% CI -31 to 6), NO donors reduced SBP (MD -12 mmHg, 95% CI -19 to -5) and DBP (MD -3, 95% CI -4 to -2) while phenylephrine, non-significantly increased SBP (MD 21 mmHg, 95% CI -13 to 55) and DBP (MD 1 mmHg, 95% CI -15 to 16). Blood pressure lowering did not reduce death or dependency either by drug class (OR 0.98, 95% CI 0.92 to 1.05), stroke type (OR 0.98, 95% CI 0.92 to 1.05) or time to treatment (OR 0.98, 95% CI 0.92 to 1.05). Treatment within six hours of stroke appeared effective in reducing death or dependency (OR 0.86, 95% CI 0.76 to 0.99) but not death (OR 0.70, 95% CI 0.38 to 1.26) at the end of the trial. Although death or dependency did not differ between people who continued pre-stroke antihypertensive treatment versus those who stopped it temporarily (worse outcome with continuing treatment, OR 1.06, 95% CI 0.91 to 1.24), disability scores at the end of the trial were worse in participants randomised to continue treatment (Barthel Index, MD -3.2, 95% CI -5.8, -0.6). Authors’ conclusions: There is insufficient evidence that lowering blood pressure during the acute phase of stroke improves functional outcome. It is reasonable to withhold blood pressure-lowering drugs until patients are medically and neurologically stable, and have suitable oral or enteral access, after which drugs can then be reintroduced. In people with acute stroke, CCBs, ACEI, ARA, beta blockers and NO donors each lower blood pressure while phenylephrine probably increases blood pressure. Further trials are needed to identify which people are most likely to benefit from early treatment, in particular whether treatment started very early is beneficial

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 trial

Background High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure. Methods In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140–220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122. Findings Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16–37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference −7·0 [95% CI −8·5 to −5·6] mm Hg/–3·5 [–4·4 to −2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference −9·5 [95% CI −11·8 to −7·2] mm Hg/–5·0 [–6·4 to −3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison—the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91–1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90–1·22; p=0·55). Interpretation In 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

Systematic reviews as a tool for planning and interpreting trials

Background Systematic reviews followed by ameta-analysis are carried out in medical research to combine the results of two or more related studies. Stroke trials have struggled to show beneficial effects and meta-analysis should be used more widely throughout the research process to either speed up the development of useful interventions, or halt more quickly research with hazardous or ineffective interventions. Summary of review. This review summarises the clinical research process and illustrates how and when systematic reviews may be used throughout the development programme. Meta-analyses should be performed after observational studies, preclinical studies in experimental stroke, and after phase I, II, and III clinical trials and phase IV clinical surveillance studies. Although meta-analyses most commonly work with summary data, they may be performed to assess relationships between variables (meta-regression) and, ideally, should utilise individual patient data. Meta-analysis techniques may alsoworkwith ordered categorical outcome data (ordinal meta-analysis) and be used to perform indirect comparisons where original trial data do not exist. Conclusion Systematic review/meta-analyses are powerful tools in medical research and should be used throughout the development of all stroke and other intervention

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 trial

BackgroundHigh blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure.MethodsIn our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140–220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122.FindingsBetween July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16–37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference −7·0 [95% CI −8·5 to −5·6] mm Hg/–3·5 [–4·4 to −2·6] mm Hg; both

Blood pressure management in acute stroke

Blood pressure (BP) is elevated in 75% or more of patients with acute stroke and is associated with poor outcomes. Whether to modulate BP in acute stroke has long been debated. With the loss of normal cerebral autoregulation, theoretical concerns are twofold: high BP can lead to cerebral oedema, haematoma expansion or haemorrhagic transformation; and low BP can lead to increased cerebral infarction or perihaematomal ischaemia. Published evidence from multiple large, high-quality, randomised trials is increasing our understanding of this challenging area, such that BP lowering is recommended in acute intracerebral haemorrhage and is safe in ischaemic stroke. Here we review the evidence for BP modulation in acute stroke, discuss the issues raised and look to on-going and future research to identify patient subgroups who are most likely to benefit

Stem cells for enhancing recovery after stroke: a review

The potential application for stem cell therapy is vast, and development for use in ischaemic stroke is still in its infancy. Access to stem cells for research is contentious; however, stem cells are obtainable from both animal and human. Despite a limited understanding of their mechanisms of action, clinical trials assessing stem cells in human stroke have been performed. Trials are also underway evaluating haematopoietic precursors mobilised with granulocyte-colony stimulating factor, an approach offering an autologous means of administrating stem cells for therapeutic purposes. This review summarises current knowledge in regard to stem cells and their potential for helping improve recovery after stroke