Improving the management of blood pressure in acute stroke: the Efficacy of Nitric Oxide in Stroke (ENOS) trial

Lead Research Organisation: University of Nottingham
Department Name: Sch of Medical & Surgical Sciences

Abstract

The Efficacy of Nitric Oxide in Stroke (ENOS) Trial examines treating high blood pressure within 48 hours of stroke. Many patients have high blood pressure immediately after a stroke and we know that these people are more likely to die or be disabled than patients with normal blood pressure. At present, doctors do not usually treat high blood pressure immediately after a stroke so this trial investigates whether or not lowering blood pressure helps people to recover.
We are using a well-established medication called glyceryl trinitrate (GTN) which relaxes blood vessels to lower blood pressure. The trial will recruit 5,000 patients and compares patients treated with GTN for 7 days against patients who do not receive GTN. The trial also examines whether or not patients blood pressure treatment should stop or continue for 7 days. Patients are followed up by telephone call at 90 days. The main outcome is comparison of the number of patients who have died or are too disabled to care for themselves after their stroke.
ENOS is an international trial with 52 current centres recruiting patients across 13 countries. The trial is funded by the MRC until November 2011. The University of Nottingham is the sponsor.

Technical Summary

High blood pressure (BP 140+/90+ mmHg) affects 75+% of patients presenting with acute stroke and is independently associated with a poor outcome (increased death or dependency) and early recurrence. Lowering a high BP could improve outcome providing cerebral blood flow is not reduced. Additionally, about 50% of patients are taking antihypertensive treatment prior to their stroke but it remains unclear whether this should be continued or stopped temporarily. Our Cochrane ?Blood pressure in Acute Stroke Collaboration? review identified no completed large trials assessing these questions.

We have developed a way of lowering BP with transdermal glyceryl trinitrate (GTN, as used in patients with angina) in three small randomised controlled trials (total 145 patients) in acute/sub-acute stroke. GTN lowered BP in a controlled manner without altering cerebral blood flow or platelet function, allowed patients who were unable to swallow to be treated, was easy to administer, and appeared to be safe.

The start-up phase (395 patients recruited as at 26/09/05) of the ?Efficacy of Nitric Oxide in Stroke? (ENOS) trial is investigating the effects of GTN (5 mg daily for 7 days) versus control on safety (death, deterioration, recurrence), BP, and CT lesion size and swelling, in an international single-blind randomised controlled trial involving hypertensive patients with acute (within 48 hours) ischaemic or haemorrhagic stroke. The trial is also addressing whether prior antihypertensive therapy should be continued or stopped temporarily in relevant individuals. ENOS is the first acute stroke trial to use the internet for randomisation, data registration, and adjudication of CT scans/serious adverse events. Interim 6 monthly reviews by the Data Monitoring Committee have not identified hazard and have recommended that ENOS should continue. We now seek funding from the MRC to recruit 4600 patients (total 5000) into the main trial phase over 5 years starting April 2006. The trial will assess the effect of these interventions on functional outcome (modified Rankin Scale, primary outcome) as well as recurrence, cognition, mood and quality-of-life. Subgroup analyses will assess the interventions by stroke type, clinical syndrome, baseline BP, severity, time to randomisation, and presence of infarct swelling on CT.

Transdermal GTN is readily available, easy to administer and monitor, inexpensive (#5 per patient) and could be relevant to most patients with acute stroke. A positive large trial would benefit patients and society, reduce load on carers and health care, and contribute to the UK Government?s health strategy.

Publications

10 25 50
publication icon
Anderson CS (2019) Blood pressure reduction and intravenous thrombolysis - Authors' reply. in Lancet (London, England)

publication icon
Ankolekar S (2014) Relationship between poststroke cognition, baseline factors, and functional outcome: data from "efficacy of nitric oxide in stroke" trial. in Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

 
Description Project Grant
Amount £684,061 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2011 
End 10/2013
 
Title OAST - Tool for analysing ordinal data 
Description Database 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2007 
Provided To Others? Yes  
Impact The use of ordinal analyses is increasingly being used in acute stroke trials. 
 
Description Institute of Psychiatry and Neurology, Warsaw, Poland 
Organisation Medical University of Warsaw
Country Poland 
Sector Academic/University 
PI Contribution Recruitment of patients to ENOS trial, acting as National Coordinator for ENOS in Poland
Collaborator Contribution Publication
Impact 18512165
 
Description Romania 
Organisation Mures County Clinical Hospital
Country Romania 
Sector Hospitals 
PI Contribution Publication in print
Collaborator Contribution Publication
Impact Publication
Start Year 2008
 
Description Singapore General Hospital 
Organisation Singapore General Hospital
Department Stroke Division
Country Singapore 
Sector Hospitals 
PI Contribution Collaboration on ENOS trial and MRI publication is pending
Collaborator Contribution Collaboration on ENOS trial and MRI publication is pending
Impact Publication is pending
 
Description Prof Joanna Wardlaw feature in Health Matters magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact A feature in Health Matters magazine, Winter 2018-2019 issue, P 24-25. Wardlaw, JM. "MRI scans of the brain".
Year(s) Of Engagement Activity 2019
 
Description Prof Joanna Wardlaw lecture "Brain Health: a small matter of the blood vessels" in Edinburgh, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Edinburgh Neuroscience Public Christmas Lecture 2018
Year(s) Of Engagement Activity 2018
 
Description Prof Joanna Wardlaw lecture "Neuroimaging in acute ischaemic stroke: history, current and future" in Stockholm, Sweden. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Joanna Wardlaw gave a special lecture on "Neuroimaging in acute ischaemic stroke: history, current and future" at the ESO-Karolinska Stroke Update Conference in Stockholm, Sweden on November 12, 2018.
Year(s) Of Engagement Activity 2018
 
Description Prof Joanna Wardlaw talk "What makes a good paper and how to prepare it? Suggestions based on my person experience",Beijing, China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Joanna Wardlaw talk "What makes a good paper and how to prepare it? Suggestions based on my person experience", at the Tiantan International Stroke Conference 2019, 28 June 2019, Beijing, China
Year(s) Of Engagement Activity 2019
 
Description Prof Joanna Wardlaw talk "Where next for stroke research?" in Edinburgh, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Prof Joanna Wardlaw talk "Where next for stroke research?"at the 6th Edinburgh Stroke Winter School, 19th February 2019, Edinburgh, UK.
Year(s) Of Engagement Activity 2019
 
Description Royal College of Physicians 'Women in medicine: a celebration' project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Royal College of Physicians (RCP)'s 'Women in medicine: a celebration' project is a free exhibition of specially commissioned photographic portraits to honour contemporary and historical women in medicine. The project showcased a number of today's leading female clinicians and the women from the history of medicine who have inspired them. Prof Joanna Wardlaw is featured in the project alongside someone who inspired her, Marie Sklodowska Curie: https://www.rcplondon.ac.uk/projects/outputs/women-medicine-joanna-wardlaw-and-marie-curie
Year(s) Of Engagement Activity 2017
URL https://www.rcplondon.ac.uk/events/women-medicine-celebration
 
Description SVD Research LinkedIn 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact SVD Research LinkedIn social media channel promoting work of the University of Edinburgh SVD Research groups, including publications, awards, press releases, recent vacancies and other associated activities, aiming to build an international network of professionals specialising in the SVD Research and promote the research to funding bodies, policy makers and industry professionals.
Year(s) Of Engagement Activity 2021
URL https://uk.linkedin.com/in/svd-research-5aaa27199
 
Description The Row Fogo Centre for Research into Ageing and the Brain website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Being officially recognised as a Research Centre in 2018, The Row Fogo Centre for Research into Ageing and the Brain launched a new website. The website is directed in multiple audiences. Content includes a comprehensive description of the Centre research activity, updates on recent publications, news and organised events. The website contains information for PhD candidates and medical imaging researchers about related programmes and courses, and for visiting staff and students on how to join SVD Research Groups. The website gives a breadth of ways to fundraise and donate to support SVD research.
Year(s) Of Engagement Activity 2020
URL https://www.ed.ac.uk/clinical-brain-sciences/research/row-fogo-centre
 
Description UK Stroke Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact UKSF, SRN Events, ESC, WSC, ISC.
Talk led to questions and discussion.

Stroke conferences now regularly include patients, representatives and carers.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014
URL https://www.stroke.org.uk/events/training-conference/uk-stroke-forum-conference-2015
 
Description UK Stroke Forum 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Health professionals
Results and Impact Poster presentation of the ongoing "STEMS2" trial to an audience of health professionals and lay members. Members of the press also attend this conference.

Increased public awareness of our ongoing research.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013
 
Description UKSF 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Conference to present updates from current trials
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014,2015
 
Description Workshop at Clare College, Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Discussion of RIGHT-2 and ENOS studies at Clare College, Cambridge
Year(s) Of Engagement Activity 2018