Baseline characteristics of the 4011 patients recruited into the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial.

BACKGROUND High blood pressure is common in acute stroke and associated with a worse functional outcome. Many patients who present with acute stroke are taking prescribed antihypertensive therapy before their stroke. AIMS ENOS tested whether lowering blood pressure and continuing pre-stroke antihypertensive therapy are each safe and effective. METHODS This study is an international multi-centre prospective randomized single-blind blinded-endpoint parallel-group partial-factorial controlled trial of transdermal glyceryl trinitrate(a nitric oxide donor, given for seven-days) vs. no glyceryl trinitrate, and of continuing vs. stopping (temporarily for seven-days) pre-stroke antihypertensive drugs if relevant, inpatients with acute ischaemic stroke or intracerebral haemorrhage and high systolic blood pressure (140–220 mmHg). RESULTS Recruitment ran from July 2001 to October 2013. Four thousand eleven patients [2097 (52·3%) in the continue/stop arm] were recruited from 173 sites across 23 countries in 5 continents (Asia 14%, Continental Europe 16%, UK 64%). Baseline characteristics include: mean age 70 (standard deviation 12) years; male 57%; mean time from stroke to recruitment 26 (13) h; mean severity (Scandinavian Stroke Scale) 34(13) of 58; mean blood pressure 167 (19)/90 (13) mmHg; ischaemic stroke 83%; and intracerebral haemorrhage 16%. The main trial results will be presented in May 2014. The results will also be presented in updated Cochrane systematic reviews and included in individual patient data meta-analyses of all relevant randomized controlled trials. CONCLUSION ENOS is a large completed international trial of blood pressure management in acute stroke and includes patients representative of many stroke services worldwide.

[1]  K. Welch,et al.  Platelet Function in Acute Ischemic Stroke: Relevance of Granule Secretion , 1994 .

[2]  K. Lees,et al.  Blood pressure control after acute stroke , 1996, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[3]  M. Buxton-Thomas,et al.  Pathophysiological Assessment of Nitric Oxide (Given as Sodium Nitroprusside) in Acute Ischaemic Stroke , 1998, Cerebrovascular Diseases.

[4]  P. Bath,et al.  Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute ischaemic stroke. , 2000, The Cochrane database of systematic reviews.

[5]  P. Bath,et al.  The Effect of Transdermal Glyceryl Trinitrate, a Nitric Oxide Donor, on Blood Pressure and Platelet Function in Acute Stroke , 2001, Cerebrovascular Diseases.

[6]  P. Sandercock,et al.  Blood Pressure and Clinical Outcomes in the International Stroke Trial , 2002, Stroke.

[7]  Christopher J Weir,et al.  Comparison of stratification and adaptive methods for treatment allocation in an acute stroke clinical trial. , 2004, Statistics in medicine.

[8]  J. Leonardi-Bee,et al.  The effects of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure, cerebral and cardiac hemodynamics, and plasma nitric oxide levels in acute stroke. , 2003, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[9]  P. Bath,et al.  The potential of nitric oxide therapeutics in stroke , 2003, Expert opinion on investigational drugs.

[10]  I. Ford,et al.  Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial , 2004, The Lancet.

[11]  Jo Leonardi-Bee,et al.  High Blood Pressure in Acute Stroke and Subsequent Outcome: A Systematic Review , 2004 .

[12]  M. Edwards,et al.  Trial , 2004, The Lancet.

[13]  P. Bath,et al.  A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. , 2005, Nitric oxide : biology and chemistry.

[14]  S. Paul,et al.  COSSACS (Continue or Stop post-Stroke Antihypertensives Collaborative Study): rationale and design , 2005, Journal of hypertension.

[15]  Effect of nitric oxide donors on blood pressure and pulse pressure in acute and subacute stroke. , 2006, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[16]  D. Leys,et al.  Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial , 2006, Journal of hypertension.

[17]  J. Wardlaw,et al.  Transdermal Glyceryl Trinitrate Lowers Blood Pressure and Maintains Cerebral Blood Flow in Recent Stroke , 2006, Hypertension.

[18]  E. T. Investigators,et al.  Glyceryl Trinitrate vs. Control, and Continuing vs. Stopping Temporarily Prior Antihypertensive Therapy, in Acute Stroke: Rationale and Design of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial (ISRCTN99414122) , 2006, International journal of stroke : official journal of the International Stroke Society.

[19]  V. Serebruany NXY-059 for acute ischemic stroke. , 2006, The New England journal of medicine.

[20]  J. Saver Novel End Point Analytic Techniques and Interpreting Shifts Across the Entire Range of Outcome Scales in Acute Stroke Trials , 2007, Stroke.

[21]  Can We Improve the Statistical Analysis of Stroke Trials ? , 2007 .

[22]  W. Hacke,et al.  Shift Analysis Versus Dichotomization of the Modified Rankin Scale Outcome Scores in the NINDS and ECASS-II Trials , 2007, Stroke.

[23]  Eso Writing,et al.  Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack 2008 , 2008 .

[24]  P. Bath,et al.  Efficacy of Nitric Oxide in Stroke - a randomized trial. Characteristics of patients recruited in Poland. , 2008, Neurologia i neurochirurgia polska.

[25]  R. Conwit,et al.  Simultaneous Ring Voice-over-Internet Phone System Enables Rapid Physician Elicitation of Explicit Informed Consent in Prehospital Stroke Treatment Trials , 2009, Cerebrovascular Diseases.

[26]  Myzoon Ali,et al.  Interconversion of the National Institutes of Health Stroke Scale and Scandinavian Stroke Scale in acute stroke. , 2009, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[27]  P. Bath,et al.  Should Stroke Trials Adjust Functional Outcome for Baseline Prognostic Factors? , 2009, Stroke.

[28]  P. Bath,et al.  Vasoactive drugs for acute stroke. , 2010, The Cochrane database of systematic reviews.

[29]  C. Bulpitt,et al.  Effects of antihypertensive treatment after acute stroke in the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial , 2010, The Lancet Neurology.

[30]  P. Bath,et al.  The Effect of Transdermal Glyceryl Trinitrate on 24 h Ambulatory Blood Pressure in Acute/Subacute Stroke , 2011, International journal of stroke : official journal of the International Stroke Society.

[31]  D. Leys,et al.  Relationship Between Baseline Blood Pressure Parameters (Including Mean Pressure, Pulse Pressure, and Variability) and Early Outcome After Stroke: Data From the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST) , 2011, Stroke.

[32]  J. Saver,et al.  Statistical Analysis of the Primary Outcome in Acute Stroke Trials , 2012, Stroke.

[33]  W. Elliott The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial , 2012 .

[34]  P. Bath,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) , 2013, Stroke.

[35]  S. Christensen,et al.  Comparison of Small Volume Infarcts of Lacunar and Non-Lacunar Etiologies , 2013, International journal of stroke : official journal of the International Stroke Society.

[36]  Stephane Heritier,et al.  Rapid Blood-Pressure Lowering in Patients With Acute Intracerebral Hemorrhage , 2013 .

[37]  J. Chen,et al.  Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. , 2014, JAMA.

[38]  S. Pocock,et al.  Statistical analysis plan for the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial , 2014, International journal of stroke : official journal of the International Stroke Society.

[39]  P. Bath,et al.  Interventions for deliberately altering blood pressure in acute stroke. , 2014, The Cochrane database of systematic reviews.