Efficacy of Nitric Oxide in Stroke (ENOS) trial

Summary of protocol (version 1.7)

Background to study: Three-quarters of patients have high blood pressure at the time of acute stroke, and this 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. Varying results have been obtained from a number of small studies. For example, outcome was worse in some trials of calcium channel blockers and beta receptor antagonists, possibly through negative effects on cerebral perfusion and cardiac output. In contrast, recurrent vascular events (a secondary outcome) were reduced in a trial of an angiotensin receptor antagonist. Additionally, small studies involving drugs from several antihypertensive classes, including nitric oxide donors, suggest that they can reduce blood pressure without altering cerebral blood flow. In a related question, no studies have assessed whether anti-hypertensive medications taken before a stroke should be continued or stopped temporarily. A definitive trial is now required to:

• Assess the balance of risk and benefit of lowering blood pressure immediately after ischaemic and haemorrhagic stroke.
• Assess whether pre-stroke antihypertensive therapy should be continued or stopped temporarily after stroke.

Trial design: ENOS is a collaborative, prospective, international, multicentre, randomised, parallel-group, single-blind, outcome-blinded trial designed to test the safety and efficacy of transdermal glyceryl trinitrate (a nitric oxide donor) in up to 5,000 patients with acute ischaemic or haemorrhagic stroke. Those patients taking antihypertensive agents immediately prior to their stroke will also be randomised to continue or stop this temporarily.

Previously independent adult patients who are conscious and have residual limb weakness are eligible for enrolment. Central randomisation will be performed over a secure internet link. Treatment must be initiated within 48 hours of stroke onset and is given as daily glyceryl trinitrate patches for 7 days. A CT scan is required within 7 days of randomisation. Early follow-up is performed locally over the 7 days of treatment, including blood pressure, early stroke events, and adverse events. Telephone central follow-up by the national co-ordinating centre will be performed at 90 days. The primary outcome is combined death and dependency using the modified Rankin Scale with comparison of the groups assessed with a 'shift' analysis.

Inclusion criteria:

1. Adult (age > 18 years).
2. Clinical stroke syndrome.
3. Motor weakness lasting at least 1 hour AND present at the time of randomisation.
4. Treatment can be started within 48 hours of stroke onset (and ideally much earlier).
5. Systolic blood pressure 140 - 220 mmHg
6. Pre-morbid Rankin score 0-2.
7. Consent, or proxy consent from a relative/carer if the patient is unable to give meaningful consent (e.g. in cases of dysphasia or reduced conscious level), or proxy consent from an independent physician if no relative or carer is available.

Exclusion criteria:

1. Unconscious (Glasgow Coma Scale <8)
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. Patients expected to require surgical intervention (e.g. clot evacuation, carotid endarterectomy) during the treatment or follow-up period.
6. Refusal to consent.
7. Patient dependent on others prior to stroke (e.g. Rankin score >2).
8. Known intracerebral pathology other than ischaemic stroke, e.g. subarachnoid haemorrhage, brain tumour, cerebral abscess.
9. Other serious condition which is likely to prevent outcome assessment, e.g. advanced cancer.
10. Involvement in a trial of another experimental intervention (drug or surgery) for acute stroke.
11. Not available for follow-up, e.g. no fixed address, overseas visitor.
12. Females of childbearing potential, pregnancy or breastfeeding.

Follow-up: End-of-treatment, hospital discharge, and adverse event forms will be completed by the recruiting centre. A questionnaire assessing dependency ADL, quality-of-life, and cognitive function will be administered by telephone at 90 days by the trial coordinating office.

Primary outcome: Death and dependency (shift in modified Rankin Scale).

Secondary outcomes:

1. Events by 7 days - recurrent stroke, deterioration, 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 (0-55, including death), Barthel Index (0-90, including death), Quality of Life (EuroQol), cognition (abbreviated mental test score), mood (Zung).
4. Safety measures - death at 7 days and 90 days; symptomatic intracranial haemorrhage at 7 days, major extracranial haemorrhage at 7 days.

Further information: please contact: ENOS, Division of Stroke Medicine, University of Nottingham, Clinical Sciences Building, City Hospital campus, Hucknall Road, Nottingham NG5 1PB, UK.

Telephone: +44 115 823 1770

Fax: +44 115 823 1771

e-mail: enos@nottingham.ac.uk