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Meta-Analysis
. 2017 Apr 21;4(4):CD000398.
doi: 10.1002/14651858.CD000398.pub2.

Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke

Philip Mw Bath  1 , Kailash Krishnan  1 , Jason P Appleton  1
Affiliations
Meta-Analysis

Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke

Philip Mw Bath et al. Cochrane Database Syst Rev. .

Abstract

Background: Nitric oxide (NO) has multiple effects that may be beneficial in acute stroke, including lowering blood pressure, and promoting reperfusion and cytoprotection. Some forms of nitric oxide synthase inhibition (NOS-I) may also be beneficial. However, high concentrations of NO are likely to be toxic to brain tissue. This is an update of a Cochrane review first published in 1998, and last updated in 2002.

Objectives: To assess the safety and efficacy of NO donors, L-arginine, and NOS-I in people with acute stroke.

Search methods: We searched the Cochrane Stroke Group Trials Register (last searched 6 February 2017), MEDLINE (1966 to June 2016), Embase (1980 to June 2016), ISI Science Citation Indexes (1981 to June 2016), Stroke Trials Registry (searched June 2016), International Standard Randomised Controlled Trial Number (ISRCTN) (searched June 2016), Clinical Trials registry (searched June 2016), and International Clinical Trials Registry Platform (ICTRP) (searched June 2016). Previously, we had contacted drug companies and researchers in the field.

Selection criteria: Randomised controlled trials comparing nitric oxide donors, L-arginine, or NOS-I versus placebo or open control in people within one week of onset of confirmed stroke.

Data collection and analysis: Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. The review authors cross-checked data and resolved issues through discussion. We obtained published and unpublished data, as available. Data were reported as mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CI).

Main results: We included five completed trials, involving 4197 participants; all tested transdermal glyceryl trinitrate (GTN), an NO donor. The assessed risk of bias was low across the included studies; one study was double-blind, one open-label and three were single-blind. All included studies had blinded outcome assessment. Overall, GTN did not improve the primary outcome of death or dependency at the end of trial (modified Rankin Scale (mRS) > 2, OR 0.97, 95% CI 0.86 to 1.10, 4195 participants, high-quality evidence). GTN did not improve secondary outcomes, including death (OR 0.78, 95% CI 0.40 to 1.50) and quality of life (MD -0.01, 95% CI -0.17 to 0.15) at the end of trial overall (high-quality evidence). Systolic/diastolic blood pressure (BP) was lower in people treated with GTN (MD -7.2 mmHg (95% CI -8.6 to -5.9) and MD -3.3 (95% CI -4.2 to -2.5) respectively) and heart rate was higher (MD 2.0 beats per minute (95% CI 1.1 to 2.9)). Headache was more common in those randomised to GTN (OR 2.37, 95% CI 1.55 to 3.62). We did not find any trials assessing other nitrates, L-arginine, or NOS-I.

Authors' conclusions: There is currently insufficient evidence to recommend the use of NO donors, L-arginine or NOS-I in acute stroke, and only one drug (GTN) has been assessed. In people with acute stroke, GTN reduces blood pressure, increases heart rate and headache, but does not alter clinical outcome (all based on high-quality evidence).

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Conflict of interest statement

  1. PM Bath was chief investigator for the five included trials (Ankolekar 2013; Bath 2001; ENOS 2015; Rashid 2002; Willmot 2006) and is chief investigator of the ongoing RIGHT‐2 2015 trial; he was Wolfson Foundation Senior Lecturer in Stroke Medicine, and is Stroke Association Professor of Stroke Medicine, and a NIHR Senior Investigator.

  2. JA was funded by the British Heart Foundation (RIGHT‐2 2015 trial).

  3. KK was funded by the Medical Research Council (ENOS 2015 trial).

Figures

1
1
Results of Database Search
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome: 1.1 Death or dependency (mRS>2), end of trial.
5
5
Funnel plot of comparison: Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, outcome: 1.81 Systolic BP, first treatment measurement.
1.1
1.1. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 1 Death or dependency (mRS>2), end of trial.
1.2
1.2. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 2 Death or dependency (mRS>2), end of trial, by stroke type.
1.3
1.3. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 3 Death or dependency (mRS>2), end of trial, by time to randomisation.
1.4
1.4. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 4 Death or dependency (mRS>2), end of trial, by baseline SBP.
1.5
1.5. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 5 Death or dependency (mean mRS), end of trial.
1.6
1.6. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 6 Death or dependency (mean mRS), end of trial, by stroke type.
1.7
1.7. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 7 Death or dependency (mean mRS), end of trial, by time to randomisation.
1.8
1.8. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 8 Death or dependency (mean mRS), end of trial, by baseline SBP.
1.9
1.9. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 9 Death, end of treatment.
1.10
1.10. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 10 Death, end of treatment, by stroke type.
1.11
1.11. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 11 Death, end of treatment, by time to randomisation.
1.12
1.12. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 12 Death, end of treatment, by baseline SBP.
1.13
1.13. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 13 Death, end of trial.
1.14
1.14. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 14 Death, end of trial, by stroke type.
1.15
1.15. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 15 Death, end of trial, by time to randomisation.
1.16
1.16. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 16 Death, end of trial, by baseline SBP.
1.17
1.17. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 17 Neurological deterioration, end of treatment.
1.18
1.18. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 18 Neurological deterioration, end of treatment, by stroke type.
1.19
1.19. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 19 Neurological deterioration, end of treatment, by time to randomisation.
1.20
1.20. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 20 Neurological deterioration, end of treatment, by baseline SBP.
1.21
1.21. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 21 NIH Stroke Scale, end of treatment.
1.22
1.22. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 22 NIH Stroke Scale, end of treatment, by stroke type.
1.23
1.23. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 23 NIH Stroke Scale, end of treatment, by time to randomisation.
1.24
1.24. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 24 NIH Stroke Scale, end of treatment, by baseline SBP.
1.25
1.25. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 25 Barthel Index, end of trial.
1.26
1.26. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 26 Barthel Index, end of trial, by stroke type.
1.27
1.27. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 27 Barthel Index, end of trial, by time to randomisation.
1.28
1.28. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 28 Barthel Index, end of trial, by baseline SBP.
1.29
1.29. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 29 Mood (Zung), end of trial.
1.30
1.30. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 30 Mood (Zung), end of trial, by stroke type.
1.31
1.31. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 31 Mood (Zung), end of trial, by time to randomisation.
1.32
1.32. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 32 Mood (Zung), end of trial, by baseline SBP.
1.33
1.33. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 33 EQ5D‐3L, end of trial.
1.34
1.34. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 34 EQ5D‐3L, end of trial, by stroke type.
1.35
1.35. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 35 EQ5D‐3L, end of trial, by time to randomisation.
1.36
1.36. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 36 EQ5D‐3L, end of trial, by baseline SBP.
1.37
1.37. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 37 EQ VAS, end of trial.
1.38
1.38. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 38 EQ VAS, end of trial, by stroke type.
1.39
1.39. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 39 EQ VAS, end of trial, by time to randomisation.
1.40
1.40. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 40 EQ VAS, end of trial, by baseline SBP.
1.41
1.41. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 41 t‐MMSE, end of trial.
1.42
1.42. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 42 t‐MMSE, end of trial, by stroke type.
1.43
1.43. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 43 t‐MMSE, end of trial, by time to randomisation.
1.44
1.44. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 44 t‐MMSE, end of trial, by baseline SBP.
1.45
1.45. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 45 TICS, end of trial.
1.46
1.46. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 46 TICS, end of trial, by stroke type.
1.47
1.47. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 47 TICS, end of trial, by time to randomisation.
1.48
1.48. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 48 TICS, end of trial, by baseline SBP.
1.49
1.49. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 49 Animal naming, end of trial.
1.50
1.50. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 50 Animal naming, end of trial, by stroke type.
1.51
1.51. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 51 Animal naming, end of trial, by time to randomisation.
1.52
1.52. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 52 Animal naming, end of trial, by baseline SBP.
1.53
1.53. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 53 Physiotherapy.
1.54
1.54. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 54 Physiotherapy, by stroke type.
1.55
1.55. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 55 Physiotherapy, by time to randomisation.
1.56
1.56. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 56 Physiotherapy, by baseline SBP.
1.57
1.57. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 57 Occupational therapy.
1.58
1.58. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 58 Occupational therapy, by stroke type.
1.59
1.59. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 59 Occupational therapy, by time to randomisation.
1.60
1.60. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 60 Occupational therapy, by baseline SBP.
1.61
1.61. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 61 Speech and language therapy.
1.62
1.62. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 62 Speech and language therapy, by stroke type.
1.63
1.63. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 63 Speech and language therapy, by time to randomisation.
1.64
1.64. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 64 Speech and language therapy, by baseline SBP.
1.65
1.65. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 65 Feeding route (non‐oral feeding at day 7).
1.66
1.66. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 66 Feeding route (non‐oral feeding at day 7), by stroke type.
1.67
1.67. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 67 Feeding route (non‐oral feeding at day 7), by time to randomisation.
1.68
1.68. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 68 Feeding route (non‐oral feeding at day 7), by baseline SBP.
1.69
1.69. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 69 Length of stay.
1.70
1.70. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 70 Length of stay, by stroke type.
1.71
1.71. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 71 Length of stay by time, to randomisation.
1.72
1.72. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 72 Length of stay, by baseline SBP.
1.73
1.73. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 73 Headache, on treatment.
1.74
1.74. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 74 Headache, on treatment, by stroke type.
1.75
1.75. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 75 Headache, on treatment, by time to randomisation.
1.76
1.76. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 76 Headache, on treatment, by baseline SBP.
1.77
1.77. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 77 Treatment stopped early.
1.78
1.78. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 78 Treatment stopped early, by stroke type.
1.79
1.79. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 79 Treatment stopped early, by time to randomisation.
1.80
1.80. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 80 Treatment stopped early, by baseline SBP.
1.81
1.81. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 81 Systolic BP, first treatment measurement.
1.82
1.82. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 82 Systolic BP, first treatment measurement, by stroke type.
1.83
1.83. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 83 Systolic BP, first treatment measurement, by time to randomisation.
1.84
1.84. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 84 Diastolic BP, first treatment measurement.
1.85
1.85. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 85 Diastolic BP, first treatment measurement, by stroke type.
1.86
1.86. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 86 Diastolic BP, first treatment measurement, by time to randomisation.
1.87
1.87. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 87 Heart rate, first treatment measurement.
1.88
1.88. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 88 Heart rate, first treatment measurement, by stroke type.
1.89
1.89. Analysis
Comparison 1 Glyceryl trinitrate (GTN) compared with no GTN for acute stroke, Outcome 89 Heart rate, first treatment measurement, by time to randomisation.
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Update of

References

References to studies included in this review

Ankolekar 2013 {published and unpublished data}
    1. Ankolekar S, Fuller M, Cross I, Renton C, Cox P, Sprigg N, et al. Feasibility of an ambulance‐based stroke trial, and safety of glyceryl trinitrate in ultra‐acute stroke: the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial (RIGHT). Stroke 2013;44:3120‐8. [ISRCTN66434824] - PubMed
    1. Ankolekar S, Parry R, Sprigg N, Siriwardena AN, Bath PMW. Views of paramedics on their role in an out‐of‐hospital ambulance‐based trial in ultra‐acute stroke: qualitative data from the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT). Annals of Emergency Medicine 2014;64(6):640‐8. - PubMed
    1. Ankolekar S, Sare G, Geeganage C, Fuller M, Stokes L, Sprigg N, et al. Determining the feasibility of ambulance‐based randomised controlled trials in patients with ultra‐acute stroke: study protocol for the "Rapid Intervention with GTN in Hypertensive Stroke Trial" (RIGHT). Stroke Research and Treatment 2012;2012:385753. [ISRCTN66434824] - PMC - PubMed
Bath 2001 {published and unpublished data}
    1. Bath PMW, Pathansali R, Iddenden R, Bath FJ. The effect of nitric oxide, given as transdermal glyceryl trinitrate, on blood pressure in acute stroke. Cerebrovascular Diseases 1999;9 Suppl 1:101. - PubMed
    1. Bath PMW, Pathansali R, Iddenden R, Bath FJ. The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. Cerebrovascular Diseases 2001;11:265‐72. - PubMed
ENOS 2015 {published and unpublished data}
    1. Bath PMW, Houlton A, Woodhouse L, Sprigg N, Wardlaw J, Pocock S, the ENOS Trialists. Statistical analysis plan for the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial. International Journal of Stroke 2014;9:372‐4. - PMC - PubMed
    1. ENOS Investigators. Baseline characteristics of the 4011 patients recruited into the 'Efficacy of Nitric Oxide in Stroke' (ENOS) trial. International Journal of Stroke 2014;9:711‐20. - PubMed
    1. The ENOS Trial Investigators. 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. Lancet 2015;385:617‐28. - PMC - PubMed
    1. The ENOS Trial Investigators. 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. International Journal of Stroke 2006;1:245‐9. [ISRCTN99414122] - PubMed
Rashid 2002 {published and unpublished data}
    1. Rashid PA, Leonardi‐Bee JA, Weaver CS, Bath FJ, Bath PM. The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and middle cerebral artery blood velocity in acute stroke. Stroke 2002;33:383.
    1. Rashid PA, Weaver C, Leonardi‐Bee JA, Bath FJ, Fletcher S, Bath PMW. The effects of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure, cerebral and cardiac hemodynamics, and plasma nitric oxide levels in acute stroke. Journal of Stroke and Cerebrovascular Diseases 2003;12(3):143‐51. - PubMed
Willmot 2006 {published and unpublished data}
    1. Willmot M, Ghadami A, Whysall B, Clarke W, Wardlaw J, Bath PMW. Transdermal glyceryl trinitrate lowers blood pressure and maintains cerebral blood flow in recent stroke. Hypertension 2006;47:1209‐15. - PubMed

References to studies excluded from this review

Butterworth 1998 {published data only}
    1. Butterworth RJ, Cluckie A, Jackson SHD, Buxton‐Thomas M, Bath PMW. Sodium nitroprusside, a spontaneous nitric oxide donor in acute ischaemic stroke. Cerebrovascular Diseases 1998;8:158‐65. - PubMed
El Mously 2014 {published data only}
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El‐Zammer 2012 {published data only}
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FAST‐BP 2013 {published data only}
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Flinders 2014 {published data only}
    1. Flinders A, Sanossian N, Kim MA, Liebeskind D, Eckstein M, Stratton S, et al. Antihypertensive utilization in hyperacute intracerebral haemorrhage presenting to the emergency room. Stroke 2014;45 Suppl 1:A199.
Kate 2015 {published data only}
    1. Kate M, Asdaghi N, Gioia L, Buck B, Jeerakathil T, Shuaib A, et al. Blood pressure reduction in acute ischaemic stroke does not affect ischemic core tissue perfusion.. International Journal of Stroke 2015;10 Suppl S2:226.
Kerr 2000 {published data only}
    1. Kerr S. The effect of nitric oxide donation on regional cerebral blood flow and metabolism in acute ischaemic stroke. National Research Register: sites.google.com/a/york.ac.uk/yhectrialsregisters/home/researchregisters... (accessed prior to 6 April 2017).
MAPAS 2009 {published data only}
    1. NCT00848770. Manipulation of Arterial Pressure in Acute ischemic Stroke (MAPAS). clinicaltrials.gov/ct2/show/NCT00848770?term=NCT00848770&rank=1 (accessed prior to 6 April 2017). [NCT00848770]
Nakamura 2010 {published data only}
    1. Nakamura T, Tsutsumi Y, Shimizu Y, Uchiyama S. Renin‐angiotension system blockade safely reduces blood pressure in patients with minor ischemic stroke during the acute phase. Journal of Stroke and Cerebrovascular Diseases 2010;19(6):435‐40. - PubMed
PATICH 2014 {published data only}
    1. Zheng J, Lin S, Li H, Ma J, Fang Y, Ma L, et al. Perioperative Antihypertensive Treatment in patients of spontaneous IntraCerebral Haemorrhage (PATICH): a clinical trial protocol. Contemporary Clinical Trials 2014;39(1):9‐13. - PubMed
PATIS 2009 {published data only}
    1. NCT02327793. Perfusion and Antihypertensive Therapy in Acute Ischemic Stroke (PATIS). clinicaltrials.gov/ct2/show/NCT02327793?term=NCT02327793&rank=1 (accessed prior to 6 Apri 2017). [NCT02327793]
Roitberg 2008 {published data only}
    1. Roitberg BZ, Hardman J, Urbaniak K, Merchant A, Mangubat EZ, Alaraj A, et al. Prospective randomised comparison of safety and efficacy of nicardipine and nitroprusside drip for control of hypertension in the neurosurgical intensive care unit. Neurosurgery 2008;63(1):115‐20. - PubMed
Sakamoto 2015 {published data only}
    1. Sakamoto Y, Koga M, Todo K, Okuda S, Okada Y, Kimura K, et al. Relative systolic blood pressure reduction and clinical outcomes in hyperacute intracerebral haemorrhage: the SAMURAI‐ICH observational study. Journal of Hypertension 2015;33(5):1069‐73. - PubMed
Sanossian 2012 {published data only}
    1. Sanossian N, Flinders A, Olivas E, Starkman S, Liebeskind D, Eckstein M, et al. Door to blood pressure goal achievement in community management of hyperacute intracerebral haemorrhage. Annals of Emergency Medicine 2012;60:S56.
Suri 2009 {published data only}
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Xu 2007 {published data only}
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References to ongoing studies

RIGHT‐2 2015 {published data only}
    1. ISRCTN26986053. Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial‐2. www.isrctn.com/ISRCTN26986053 (accessed prior to 6 April 2017). [ISRCTN26986053]

Additional references

Anderson 2013
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References to other published versions of this review

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