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

Summary Background High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure. Methods In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140–220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122. Findings Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16–37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference −7·0 [95% CI −8·5 to −5·6] mm Hg/–3·5 [–4·4 to −2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference −9·5 [95% CI −11·8 to −7·2] mm Hg/–5·0 [–6·4 to −3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison—the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91–1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90–1·22; p=0·55). Interpretation In patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke. Funding UK Medical Research Council.


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All authors contributed to the interpretation of the results and writing of this report. As

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Chief Investigator, PMB prepared the protocol, supervised and reviewed the progress of 443 the trial, recruited patients, and wrote the first draft of this report. Members of the 444 writing committee participated in the steering committee, supervised and reviewed the 445 progress of the trial, and commented on the draft of this report. LW and PS analysed 446 trial data and commented on a draft of this report. All members of the writing committee 447 listed here have seen and approved the final version of this report. The Data Monitoring

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Committee reviewed the manuscript.

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The trial was designed, run and funded independently of any manufacturer of glyceryl

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The trial was originally designed to recruit 5,000 patients so as to detect an absolute risk 482 reduction in the binary outcome of death or dependence (modified Rankin Scale, 483 mRS>2) of 5% from 50% in the control group to 45% in the GTN group (equivalent to 484 odds ratio 0.82), with power 90%, significance 5%, and allowance for losses to follow-485 up. The original planned method of analysis, as published in the protocol paper, 2 was to 486 compare the proportion of patients who were dead or dependent at 90 days between the 487 treatment groups.

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The method for the primary analysis of the mRS was changed when it became clear that 490 binary analysis of the 7-level mRS is sub-optimal and that statistical power is increased 491 by using all the data at each level by comparing differences in distribution across the 492 whole scale between the treatment groups. 3 This approach is now recommended by the CONFIDENTIAL: ENOS V0.99 safety and efficacy of the intervention during the trial, assessing data integrity, and for 512 monitoring the overall conduct of the trial. The DMC reviewed the recruitment of 513 patients, and assessed safety and efficacy measures by treatment group. Data were 514 reviewed twice yearly throughout the recruitment period of the trial. The DMC was 515 charged with informing the Trial Steering Committee if, at any time, the data showed 516 evidence beyond reasonable doubt of a difference between the randomised groups in the 517 primary outcome. They also considered these data in the light of external information 518 such as results from completed trials. No formal interim analyses were performed.

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However, the DMC could perform statistical comparisons as they deemed necessary, 520 with stopping criteria based on the Haybittle-Peto stopping rule (i.e. a difference of 3 521 standard errors is considered as clear evidence of a treatment effect). The study was not 522 terminated early and the committee did not request any additional analyses of the data.

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When reviewed, some images were in non-DICOM format (e.g. .PNG, .JPG) and these 628 were converted to DICOM. The anonymised image files, collected as above, were 629 presented to a panel of adjudicators using a browser-based system driven from the trial 630 database. Adjudicators were trained and assessed using the ACCESS system 631 (www.neuroimage.co.uk/sirs), 6,7 and reviewed scans blinded to treatment assignment.

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Adjudication parameters were derived from the IST-3 image adjudication system (J

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Wardlaw, submitted for publication), and included information on:  Data are mean. Comparison assessed using multiple regression adjusted for baseline.
CONFIDENTIAL: ENOS V0.99 Web Table 5. Interaction between treatment with GTN versus no GTN, and continue versus stop pre-stroke antihypertensive drugs, for baseline-adjusted systolic and diastolic blood pressure, and heart rate, and absolute mean and median modified Rankin Scale score, across the 6 treatment groups.  The primary outcome of the study was independence, dependence or death, assessed 30 using the modified Rankin scale (scores of 0, 5 and 6 indicate no symptoms, severe 31 dependency, and death respectively) at 90 days. The black squares represent point 32 estimates for the odds ratio (with the area of the square proportional to the number of 33 events), and the horizontal lines represent 95% confidence intervals. The rectangle 34

GTN
incorporates the point estimate and the 95% confidence intervals of the overall effects 35 within categories. P values are for the interaction between subgroup and allocated 36 treatment. Stroke type covers ischaemic stroke, haemorrhagic stroke, stroke of 37 unknown type and non-stroke. Stroke severity is measured using the Scandinavian 38 Stroke Scale (SSS) which ranges from 0 (deep coma) to 58 (normal neurological status).