Plain English Summary
Background and study aims
Lowering blood pressure reduces the risk of further strokes in patients who have already had one or more strokes. High blood pressure is common in the first hours and days following a stroke and increases the risk of the patient not recovering fully and being left with some disability. Lowering blood pressure in the first hours and days after stroke with medications might help patients to recover. Although at present we routinely treat high blood pressure long term after a stroke, we do not do so immediately after the stroke. We aim to find out what effect glyceryl trinitrate (or GTN) has on how well people recover from strokes. GTN is a tried and tested drug used in other medical conditions that acts quickly to relax blood vessels and lower blood pressure. The data will help doctors decide whether blood pressure lowering treatments like GTN can be used in patients with acute stroke to improve recovery. We also aim to assess whether or not usual blood pressure medicines should be stopped or continued for 7 days after a stroke.
Who can participate?
Adult (age > 18 years) patients presenting with an acute stroke syndrome with residual motor weakness within 48 hours of onset
What does the study involve?
Patients are randomly allocated to receive either transdermal glyceryl trinitrate patches (GTN) or no GTN for 7 days. Patients who are already receiving blood pressure lowering treatments are also randomly allocated to either continue or stop this treatment for 7 days.
What are the possible benefits and risks of participating?
Participation in the study may reduce the symptoms of the stroke or improve long-term recovery. The information received from patients involvement may benefit other people who may have a stroke in the future. All drugs have the possibility of side effects. The side effects from GTN are generally mild. They can include headache, low blood pressure and dizziness.
Where is the study run from?
The University of Nottingham (UK)
When is the study starting and how long is it expected to run for?
January 2004 to October 2013
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Prof. Philip Bath
enos@nottingham.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Prof Philip Bath
ORCID ID
Contact details
Stroke
Division of Clinical Neuroscience
School of Medicine
University of Nottingham
City Hospital Campus
Nottingham
NG5 1PB
United Kingdom
+44 (0)115 823 1768
enos@nottingham.ac.uk
Additional identifiers
EudraCT number
2004-003870-27
ClinicalTrials.gov number
NCT00989716
Protocol/serial number
N/A
Study information
Scientific title
A prospective, collaborative, international, multicentre, randomised, parallel-group, single and outcome blinded, controlled, factorial trial to investigate the safety and efficacy of treatment with transdermal glyceryl trinitrate, a nitric oxide donor, and of continuing or stopping temporarily pre-stroke antihypertensive therapy, in patients with acute stroke
Acronym
ENOS
Study hypothesis
Three-quarters of patients are hypertensive at the presentation of acute stroke while a high blood pressure is independently associated with a poor outcome. No large trials have specifically assessed whether blood pressure should be actively altered during the acute phase of stroke although outcome was worse in some trials of calcium channel blockers and beta receptor antagonists, probably through negative effects on cerebral blood perfusion and cardiac output. However, small studies involving drugs from other antihypertensive classes, including nitric oxide donors, suggest they may reduce blood pressure without reducing cerebral blood flow. Similarly, no studies have assessed whether prior anti-hypertensive medication should be stopped or continued. A definitive trial is now required to:
1. Assess the balance of risk and benefit of lowering blood pressure immediately after ischaemic and haemorrhagic stroke.
2. Assess whether prior antihypertensive therapy should be continued or stopped temporarily after stroke.
Protocol can be found at: http://www.enos.ac.uk/enosprotocolv15.pdf
Further reading (added 28/01/2010):
1. The NeuroGrid stroke exemplar clinical trial protocol.
Wardlaw JM et al. International Journal of Stroke 2007;2:63-69
http://www.ncbi.nlm.nih.gov/pubmed/18705995
2. Effect of nitric oxide donors on blood pressure and pulse pressure in acute and subacute stroke.
Gray LJ et al. International Journal of Stroke 2007;2:63-69
http://www.ncbi.nlm.nih.gov/pubmed/17904083
3. Management of blood pressure in acute stroke.
Phillips at al. Canadian J Neurological Sciences 2002;29;404
http://www.ncbi.nlm.nih.gov/pubmed/12463498
4. ENOS Efficacy of Nitric Oxide in Stroke Trial.
Stroke Center Stroke Trials Registry (2002)
http://www.strokecenter.org/trials/TrialDetail.aspx?tid=103
Ethics approval
Trent Regional Ethics Committee (REC) and the National Research Ethics Service (NRES), 03/09/2001, ref: MREC/01/4/046
Study design
Prospective international multicentre randomised parallel-group double-blind placebo-controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Patient information can be found at: http://www.enos.ac.uk/enospisv211.pdf
Condition
Acute stroke
Intervention
1. Glyceryl trinitrate (transdermal)
2. Continue/temporarily stop prior anti-hypertensive therapy
Intervention type
Drug
Phase
Not Applicable
Drug names
Glyceryl trinitrate
Primary outcome measure
Death and dependency (Rankin score more than two).
Secondary outcome measures
1. Events by 7 days - recurrent stroke, symptomatic deep vein thrombosis, symptomatic pulmonary embolism, blood pressure daily between 1 and 7 days
2. Hospital events - length of stay in hospital, discharge disposition (death, institution or home)
3. Outcome at 90 days - Barthel Index (less than 60, including death), Barthel Index more than 95/100 at three months (good outcome), quality of life (EuroQol), abbreviated mental test score
4. Safety measures - death at 7 and 90 days, symptomatic intracranial haemorrhage at 7 days, major extracranial haemorrhage at 10 days
Overall trial start date
01/01/2004
Overall trial end date
31/10/2013
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patients with acute ischaemic or haemorrhagic stroke within 48 hours
2. Systolic blood pressure 140-220 mmHg
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
3500+
Participant exclusion criteria
1. Unconscious (Glasgow Coma Scale less than eight)
2. Definite need for nitrate therapy: concurrent myocardial infarction, unstable angina, left ventricular failure
3. Dehydration
4. Contraindication to nitrate therapy: hypersensitivity to nitrates, hypovolaemia, hypertrophic obstructive cardiomyopathy, aortic stenosis, cardiac tamponade, constrictive pericarditis, mitral stenosis, marked anaemia, closed-angle glaucoma, sildenafil (Viagra) within previous 24 hours
5. Systolic blood pressure less than 140 mmHg or more than 220 mmHg
6. Patients expected to require surgical intervention (e.g. clot evacuation, carotid endarterectomy) during the treatment or follow-up period
7. Refusal to consent
8. Patient dependent on others prior to stroke (e.g. Rankin score more than three)
9. Known intracerebral pathology other than ischaemic stroke, e.g. subarachnoid haemorrhage, brain tumour, cerebral abscess
10. Other serious condition which is likely to prevent outcome assessment, e.g. advanced cancer
11. Involvement in a trial of another experimental intervention (drug or surgery) for acute stroke
12. Not available for follow-up, e.g. no fixed address, overseas visitor
13. Females of childbearing potential, pregnancy or breastfeeding
Recruitment start date
01/01/2004
Recruitment end date
31/10/2013
Locations
Countries of recruitment
Australia, Canada, China, Denmark, Egypt, Georgia, Greece, Hong Kong, India, Ireland, Italy, Malaysia, New Zealand, Norway, Philippines, Poland, Romania, Singapore, Spain, Sri Lanka, Sweden, Turkey, United Kingdom
Trial participating centre
University of Nottingham
Nottingham
NG5 1PB
United Kingdom
Sponsor information
Organisation
University of Nottingham (UK)
Sponsor details
University Park
Nottingham
NG7 2RD
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Charity
Funder name
Medical Research Council: from 01/112006
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
Singapore A*STAR (MRI sub-study)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Bupa Foundation: 01/042004 - 31/10/2006
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
Trusts, charities, foundations (both public and private)
Location
United Kingdom
Funder name
Medical Research Council (as part of NeuroGRID)
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
Hypertension Trust: 01/09/2002 - 31/08/2004
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
Other non-profit organizations
Location
United Kingdom
Funder name
UK Reichstadt bequest
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Stroke Association
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
Associations and societies (private and public)
Location
United Kingdom
Funder name
University of Nottingham
Alternative name(s)
Funding Body Type
private sector organisation
Funding Body Subtype
Universities (academic only)
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
1. 2006 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/18706028
2. 2009 interim results in: http://www.ncbi.nlm.nih.gov/pubmed/19106795
3. Conference proceedings:
Continuing prior antihypertensive medication in acute stroke lowers blood pressure: Data from the continue vs stop arm of the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial. World Congress of Neurology, Sydney, November 2005
4. 2012 results in: http://www.ncbi.nlm.nih.gov/pubmed/23117488
5. 2013 results in: http://www.ncbi.nlm.nih.gov/pubmed/24149005
6. 2014 statistical analysis plan in: http://www.ncbi.nlm.nih.gov/pubmed/24588789
7. 2014 patient baseline characteristics in: http://www.ncbi.nlm.nih.gov/pubmed/25043647
8. 2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/25575847
9. 2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/25465108
10. 2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/26645254
11. 2017 results in: http://www.ncbi.nlm.nih.gov/pubmed/28752410
Publication citations
-
Protocol
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)., Int J Stroke, 2006, 1, 4, 245-249, doi: 10.1111/j.1747-4949.2006.00059.x.
-
Interim results
Sare GM, Gray LJ, Wardlaw J, Chen C, Bath PM, , Is lowering blood pressure hazardous in patients with significant ipsilateral carotid stenosis and acute ischaemic stroke? Interim assessment in the 'Efficacy of Nitric Oxide in Stroke' trial., Blood Press Monit, 2009, 14, 1, 20-25, doi: 10.1097/MBP.0b013e32831e30bd.
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Results
Ankolekar S, Renton C, Bereczki D, Sprigg N, Payne T, Gommans J, Berge E, Wardlaw J, Dennis MS, Bath PM, , Effect of the neutral CLOTS 1 trial on the use of graduated compression stockings in the Efficacy of Nitric Oxide Stroke (ENOS) trial., J. Neurol. Neurosurg. Psychiatr., 2013, 84, 3, 342-347, doi: 10.1136/jnnp-2012-303396.
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Results
Sprigg N, Selby J, Fox L, Berge E, Whynes D, Bath PM, , Very low quality of life after acute stroke: data from the Efficacy of Nitric Oxide in Stroke trial., Stroke, 2013, 44, 12, 3458-3462, doi: 10.1161/STROKEAHA.113.002201.
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Statistical analysis plan
Bath PM, Houlton A, Woodhouse L, Sprigg N, Wardlaw J, Pocock S, , Statistical analysis plan for the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial., Int J Stroke, 2014, 9, 3, 372-374, doi: 10.1111/ijs.12235.
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Patient baseline characteristics
Baseline characteristics of the 4011 patients recruited into the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial., Int J Stroke, 2014, 9, 6, 711-720, doi: 10.1111/ijs.12308.
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Results
Krishnan K, Mukhtar SF, Lingard J, Houlton A, Walker E, Jones T, Sprigg N, Dineen RA, Koumellis P, Adami A, Casado AM, Bath PM, Wardlaw JM, Performance characteristics of methods for quantifying spontaneous intracerebral haemorrhage: data from the Efficacy of Nitric Oxide in Stroke (ENOS) trial, J Neurol Neurosurg Psychiatry, 2015, doi: 10.1136/jnnp-2014-309845.
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Results
ENOS Trial Investigators, Bath PM, Woodhouse L, Scutt P, Krishnan K, Wardlaw JM, Bereczki D, Sprigg N, Berge E, Beridze M, Caso V, Chen C, Christensen H, Collins R, El Etribi A, Laska AC, Lees KR, Ozturk S, Phillips S, Pocock S, de Silva HA, Szatmari S, Utton S, 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, 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, 2015 , 385, 9968, 617-628, doi: 10.1016/S0140-6736(14)61121-1.
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Results
Krishnan K, Scutt P, Woodhouse L, Adami A, Becker JL, Berge E, Cala LA, Casado AM, Caso V, Chen C, Christensen H, Collins R, Czlonkowska A, Dineen RA, Gommans J, Koumellis P, Lees KR, Ntaios G, Ozturk S, Phillips SJ, Pocock SJ, de Silva A, Sprigg N, Szatmari S, Wardlaw JM, Bath PM, Glyceryl Trinitrate for Acute Intracerebral Hemorrhage: Results From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial, a Subgroup Analysis, Stroke, 2015.