Condition category
Circulatory System
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting

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 will be 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 will also be 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

Trial website

Contact information



Primary contact

Prof Philip Bath


Contact details

Division of Clinical Neuroscience
School of Medicine
University of Nottingham
City Hospital Campus
United Kingdom
+44 (0)115 823 1768

Additional identifiers

EudraCT number

2004-003870-27 number


Protocol/serial number


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



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:

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
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
3. Management of blood pressure in acute stroke.
Phillips at al. Canadian J Neurological Sciences 2002;29;404
4. ENOS Efficacy of Nitric Oxide in Stroke Trial.
Stroke Center Stroke Trials Registry (2002)

On 28/01/2010 the following countries of recruitment were added: Egypt, India, Malaysia, Romania, Saudi Arabia, Spain, and Sri Lanka.

On 01/02/2010 the anticipated end date was changed from 31/10/2011 to 31/10/2013.

On 19/06/2014 the following changes were made to the trial record:
1. The scientific title was added
2. Denmark, Republic of Ireland, Georgia, Greece, Norway, Sweden and Turkey were added to the countries of recruitment and Belgium and Saudi Arabia were removed
3. The target number of participants was changed from 5000 to 3500+

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


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Patient information can be found at:


Acute stroke


1. Glyceryl trinitrate (transdermal)
2. Continue/temporarily stop prior anti-hypertensive therapy

Intervention type



Not Applicable

Drug names

Glyceryl trinitrate

Primary outcome measures

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


Overall trial end date


Reason abandoned


Participant inclusion criteria

1. Patients with acute ischaemic or haemorrhagic stroke within 48 hours
2. Systolic blood pressure 140-220 mmHg

Participant type


Age group




Target number of participants


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


Recruitment end date



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
United Kingdom

Sponsor information


University of Nottingham (UK)

Sponsor details

University Park
United Kingdom

Sponsor type




Funder type


Funder name

UK Medical Research Council: from 01/112006

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

Singapore A*STAR (MRI sub-study)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

UK BUPA Foundation: 01/042004 - 31/10/2006

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

UK Medical Research Council (as part of NeuroGRID)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

UK Hypertension Trust: 01/09/2002 - 31/08/2004

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

UK Reichstadt bequest

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

UK Stroke Association

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

UK University of Nottingham (through Information Services)

Alternative name(s)

Funding Body Type

Funding Body Subtype


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

Results - basic reporting

Publication summary

1. 2006 protocol in:
2. 2009 interim results in:
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:
5. 2013 results in:
6. 2014 statistical analysis plan in:
7. 2014 patient baseline characteristics in:
8. 2015 results in:
9. 2015 results in:
10. 2015 results in:

Publication citations

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

Additional files

Editorial Notes