Introduction High blood pressure is present in 70% or more of patients with acute ischaemic stroke1 or haemorrhagic stroke. Affected patients have a worse outcome, whether judged as early recurrence, death within a few weeks, or combined death and dependency after several months.14 Lowering of blood pressure acutely after stroke might therefore reduce these events and improve functional outcome, providing that cerebral perfusion is not reduced in the presence of dysfunctional cerebral autoregulation. Several large trials have tested the safety and efficacy of individual drugs or management strategies that lower blood pressure, with investigators reporting results for functional outcomes ranging from near-negative (SCAST)5 to neutral (IMAGES,6 CATIS),7 to near-positive (INTERACT-2).8 With use of meta-regression, a U-shaped relation was shown between outcome and difference in blood pressure between treatment groups in previous trials, with both large reductions or any increase in blood pressure associated with a worse functional outcome.9 Nitric oxide donors are candidate treatments for acute stroke because of several effectsnitric oxide is a cerebral and systemic vasodilator that lowers blood pressure, modulates vascular and neuronal function, is neuroprotective, and inhibits apoptosis.10 In preclinical studies of cerebral ischaemia, nitric oxide donors reduced infarct lesion size and improved regional cerebral blood flow and functional outcome.11 Five small clinical studies of nitric oxide donors have been done:1216 intravenous sodium nitroprusside reduced blood pressure without changing cerebral blood flow and had antiplatelet effects,12 thereby precluding its use in haemorrhagic stroke. In four pilot trials,1316 transdermal glyceryl trinitrate lowered blood pressure, had no negative effects on platelet function, did not change middle cerebral artery blood flow velocity or regional cerebral blood flow, improved aortic compliance, and could be given to patients with dysphagia. No safety concerns were present in these studies, and in one small single-centre trial, functional outcome was improved with glyceryl trinitrate when given within 4 h of stroke onset.16 Treatment of hypertension effectively prevents first and recurrent stroke.17, 18 As a result, many patients are taking blood pressure-lowering drugs at the time of any subsequent stroke. A common clinical problem is whether these drugs should be continued or stopped temporarily during the acute phase after stroke; the answer remains unclear,19 guidelines mostly ignore the question, and clinical practice varies.20 The multicentre Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS)21 examined this question and reported, in 763 patients, that continuing antihypertensive drugs, as compared with stopping them, did not change death or dependency at either 2 weeks or 6 months. Continuing antihypertensive drugs might help to reduce early recurrence and haematoma expansion, and improve functional outcome after stroke, much as long-term blood pressure reduction reduces recurrence;18 by preventing rebound increases in blood pressure and heart rate (when blockers are stopped), which might induce stroke recurrence and myocardial infarction, respectively; and by ensuring that antihypertensive drugs are continued beyond hospital discharge. Alternatively, stopping treatment temporarily might be advantageous for several reasons. First, some antihypertensive drugs might be hazardous when started in acute stroke, as reported in trials of angiotensin-receptor antagonists, blockers, and calcium-channel blockers.2224 Second, many patients do not take their blood pressure drugs regularly, and so correct administration of these drugs in hospital can lead to large and potentially harmful falls in blood pressure.25 Third, antihypertensive drugs can cause substantial hypotension in the presence of hypovolaemia and dehydration, which are commonly present in patients with acute stroke who might not be taking fluids appropriately. Fourth, stopping of treatment might increase perfusion through collateral vessels and optimise salvage of penumbral tissue. Fifth, blood pressure-lowering drugs might worsen cerebral perfusion in the presence of severe ipsilateral carotid artery stenosis. Sixth, drugs taken orally could lead to aspiration and pneumonia in the presence of dysphagia. Finally, oral administration of drugs might not be possible if the patient has dysphagia and enteral access has not yet been done; furthermore, those antihypertensive drugs that are embedded in a slow-release or modified-release mechanism are not suitable to be taken via nasogastric tubes. As a result, continuation of treatment immediately after admission might not be possible in many patients after stroke.
We report the findings of the Efficacy of Nitric Oxide in Stroke (ENOS) partial-factorial randomised controlled trial. We aimed to assess the safety and efficacy of glyceryl trinitrate given within 48 h to patients with acute ischaemic or haemorrhagic stroke and high blood pressure. We also aimed to assess outcomes for a subset of patients who continued or stopped taking antihypertensive drugs for 1 week after their stroke.
The study was approved by national and local ethics committees and competent authorities in each participating country and site, and was adopted by the Australian, Canadian, and UK National Institute for Health Research Stroke Research Networks. The trial was overseen by a trial steering committee (which included three independent members) and an international advisory committee (which comprised each national coordinator). The day-to-day conduct of the trial was run by a trial management committee that was based at the coordinating centre in Nottingham, UK. An independent data monitoring committee reviewed unmasked data every 6 months. We obtained written informed consent from each patient, or from a relative or independent physician when the patient did not have capacity, before enrolment and in accordance with national regulations.
Treatment was started immediately after randomisation, was given daily for 7 days, and consisted of a glyceryl trinitrate dermal patch (5 mg) or no patch. Glyceryl trinitrate patches were sourced locally from any licensed manufacturer, and included the following brands: Deponit-5 (UCB Pharma, Brussels, Belgium; 38% of sites), Transiderm-Nitro (Novartis, Basel, Switzerland; 28%), NitroDur (MSD/Schering-Plough, Kenilworth, NJ, USA; 25%), and Minitran (Meda/3M Healthcare, St Paul, MN, USA; 10%). Chinese sites obtained patches from a local manufacturer (Wuhan Jianmin Pharmaceutical Group, Wuhan, China). Patients were masked to glyceryl trinitrate by placing a gauze dressing over the patch or over a similar area of skin if they were assigned to no glyceryl trinitrate. The gauze dressing, with or without glyceryl trinitrate patch, was changed every day (07000900 h) with rotation of the site of placement on the shoulders or back. The dose of glyceryl trinitrate was not adjusted during treatment, and patches were left on for 24 h, such that there was no overnight glyceryl-trinitrate-free period. In patients randomly assigned to continue antihypertensive drugs, the same drugs and doses were started at the next normal time when due, and were given for 7 days. When appropriate, drugs were given via a nasogastric tube.
Study drugs were stopped when the patient withdrew consent, for safety reasons, or when unacceptable adverse events developed. Non-trial nitrates and other antihypertensive drugs were not given during the 7-day treatment period unless the local investigator deemed them necessary. Treatments under investigation were given in addition to standard care; thrombolysis was permitted in patients with ischaemic stroke according to local practice guidelines at the recruiting site. Systematic use of antihypertensive drugs (all patients, after 7 days), and oral antithrombotic and lipid-lowering drugs (in patients with ischaemic stroke) were recommended for secondary prevention.
Study profile
Data are n (%). ENOS=efficacy of nitric oxide in stroke. BP=blood pressure. GTN=glyceryl trinitrate.
Distribution of modified Rankin Scale scores at 90 days
OR=odds ratio.
Subgroup analysis of effects on functional outcome at 90 days for glyceryl trinitrate versus no glyceryl trinitrate
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philip.bath@nottingham.ac.uk