Dataset Information

Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis.

ABSTRACT: Background: Thrombolysis, with or without thrombectomy, for acute ischaemic stroke is associated with an increased risk of intracranial bleeding. We assessed whether treatment with glyceryl trinitrate (GTN), a nitric oxide donor, may influence the associated bleeding risk. Methods: We searched for completed randomized controlled trials of GTN vs. no GTN in acute ischaemic stroke with data on reperfusion treatments (thrombolysis and/or thrombectomy). The primary efficacy outcome was functional status as assessed by the modified Rankin Scale (mRS) at day 90; the primary safety outcome was intracranial bleeding. Secondary safety outcomes included symptomatic intracranial hemorrhage and haemorrhagic transformation of infarction. Individual patient data were pooled and meta-analysis performed using ordinal or binary logistic regression with adjustment for trial and prognostic variables both overall and in those randomized within 6 h of symptom onset. Results: Three trials met the eligibility criteria. Of 715 patients with ischaemic stroke who underwent thrombolysis (709, >99%) or thrombectomy (24, 3.4%), 357 (49.9%) received GTN and 358 (50.1%) received no GTN. Overall, there was no difference in the distribution of the mRS at day 90 between GTN vs. no GTN (OR 0.94, 95% CI 0.72-1.23; p = 0.65); similarly, there was no difference in intracranial hemorrhage rates between treatment groups (OR 0.90, 95% CI 0.43-1.89; p = 0.77). In those randomized to GTN vs. no GTN within 6 h of symptom onset, there were numerically fewer bleeding events, but these analyses did not reach statistical significance. Conclusions: In ischaemic stroke patients treated predominantly with thrombolysis, transdermal GTN was safe, but did not influence functional outcome at 90 days.

SUBMITTER: Appleton JP

PROVIDER: S-EPMC7606455 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis.

Appleton Jason P JP Woodhouse Lisa J LJ Sprigg Nikola N Wardlaw Joanna M JM Bath Philip M PM

Frontiers in neurology 20201020

<b>Background:</b> Thrombolysis, with or without thrombectomy, for acute ischaemic stroke is associated with an increased risk of intracranial bleeding. We assessed whether treatment with glyceryl trinitrate (GTN), a nitric oxide donor, may influence the associated bleeding risk. <b>Methods:</b> We searched for completed randomized controlled trials of GTN vs. no GTN in acute ischaemic stroke with data on reperfusion treatments (thrombolysis and/or thrombectomy). The primary efficacy outcome was ...[more]

PMID: 33193044

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Project description:A Phase I, double-blind, randomized, crossover study in healthy males (N=106) was conducted between March 21, 2004, and May 17, 2004, to determine the magnitude and duration of the hemodynamic interaction of avanafil (a phosphodiesterase type-5 inhibitor for treating males with erectile dysfunction) when coadministered with glyceryl trinitrate (NTG) compared with sildenafil and placebo. Subjects received avanafil (200 mg), sildenafil (100 mg), and placebo (on separate days) via the oral route followed by NTG (0.4 mg) 12, 8, 4, 1, or 0.5 hours post-dose via the sublingual route. Blood pressure (BP) and heart rate (HR) were assessed at defined intervals. Throughout the study (after administration of the study drug, and including the period after NTG administration), the effects of avanafil and sildenafil on BP and HR were significantly greatest overall, at the shortest (0.5-hour) time interval compared with placebo. By the 8- and 12-hour time intervals, no significant difference in BP or HR was observed for avanafil (8 and 12 hours) or sildenafil (12 hours) (p>0.05, compared with placebo). Compared with avanafil, sildenafil had a significantly greater effect when dosed 0.5 hours before NTG on standing HR (p=0.05); 1 hour before NTG on standing systolic blood pressure (SBP) (p<0.05), sitting SBP (p=0.01) and standing HR (p<0.01); and 12 hours before NTG on standing SBP (p=0.05). Throughout the study, symptomatic hypotension adverse events occurred in 27%, 29%, and 12%, and clinically significant reductions in standing SBP (?30 mmHg) occurred in 15%, 29%, and 12% of subjects dosed with avanafil, sildenafil, and placebo, respectively (overall treatment differences: p<0.01 and p<0.05, respectively). These data show that avanafil and sildenafil have no significant effect on BP and HR if administered to healthy males ?8 hours (avanafil) or ?12 hours (sildenafil) before a sublingual dose of NTG. However, results may differ in populations with known vascular disease, especially those using other concurrent pharmacotherapy. These findings may be of interest to clinicians who treat patients with erectile dysfunction and who also have a cardiovascular condition. Of note, the applicability of these results in such patients may be limited because the enrollment comprised healthy, normal subjects.

Project description:BackgroundCerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke.MethodsWe did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602.FindingsBetween Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82-3·29) for intracranial haemorrhage and 1·23 (1·08-1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08-6·72] for intracranial haemorrhage vs 1·47 [1·19-1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36-9·05] vs 1·43 [1·07-1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69-15·81] vs 1·86 [1·23-1·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years).InterpretationIn patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden.FundingBritish Heart Foundation and UK Stroke Association.

Project description:BackgroundPrehospital stroke trials will inevitably recruit patients with non-stroke conditions, so called stroke mimics. We undertook a pre-specified analysis to determine outcomes in patients with mimics in the second Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial (RIGHT-2).MethodsRIGHT-2 was a prospective, multicentre, paramedic-delivered, ambulance-based, sham-controlled, participant-and outcome-blinded, randomised-controlled trial of transdermal glyceryl trinitrate (GTN) in adults with ultra-acute presumed stroke in the UK. Final diagnosis (intracerebral haemorrhage, ischaemic stroke, transient ischaemic attack, mimic) was determined by the hospital investigator. This pre-specified subgroup analysis assessed the safety and efficacy of transdermal GTN (5 mg daily for 4 days) versus sham patch among stroke mimic patients. The primary outcome was the 7-level modified Rankin Scale (mRS) at 90 days.ResultsAmong 1149 participants in RIGHT-2, 297 (26%) had a final diagnosis of mimic (GTN 134, sham 163). The mimic group were younger, mean age 67 (SD: 18) vs 75 (SD: 13) years, had a longer interval from symptom onset to randomisation, median 75 [95% CI: 47,126] vs 70 [95% CI:45,108] minutes, less atrial fibrillation and a lower systolic blood pressure and Face-Arm-Speech-Time tool score than the stroke group. The three most common mimic diagnoses were seizure (17%), migraine or primary headache disorder (17%) and functional disorders (14%). At 90 days, the GTN group had a better mRS score as compared to the sham group (adjusted common odds ratio 0.54; 95% confidence intervals 0.34, 0.85; p = 0.008), a difference that persisted at 365 days. There was no difference in the proportion of patients who died in hospital, were discharged to a residential care facility, or suffered a serious adverse event.ConclusionsOne-quarter of patients suspected by paramedics to have an ultra-acute stroke were subsequently diagnosed with a non-stroke condition. GTN was associated with unexplained improved functional outcome observed at 90 days and one year, a finding that may represent an undetected baseline imbalance, chance, or real efficacy. GTN was not associated with harm.Trial registrationThis trial is registered with International Standard Randomised Controlled Trials Number ISRCTN 26986053 .

Project description:IntroductionHigh blood pressure (BP) in acute stroke has adverse outcomes. Transdermal glyceryl trinitrate (GTN) has beneficial properties in controlling BP. The 2016 meta-analysis and 2017 Cochrane review showed that transdermal GTN was beneficial in a small patient subgroup with stroke onset ≤6 hours. Larger studies focusing on this patient subgroup have since been conducted. We report the protocol for an updated systematic review and meta-analysis on the safety and benefits of transdermal GTN in acute stroke.Methods and analysisWe will search Medline, Pubmed, Embase, CINAHL and Cochrane Library from inception until June 2020 for randomised trials that report the efficacy and safety of transdermal GTN versus placebo/control therapy among adult patients with acute stroke. Primary outcomes include in-hospital mortality, BP lowering and late functional status. Secondary outcomes include early, late, resource utilisation and surrogate outcomes. Safety outcomes include reported adverse events. Reviewers will first screen titles and abstracts, and then full texts, to identify eligible studies. Independently and in duplicate, they will extract data, assess risk of bias (RoB) using a modified Cochrane RoB tool and quality of evidence using Grading of Recommendations, Assessment, Development and Evaluation. Disagreement will be resolved by discussion and consultation with an external reviewer if necessary. Using a random-effects model, we will report effect sizes using relative risks and 95% CIs. We will perform predefined subgroup analyses: intracerebral haemorrhage versus ischaemic stroke; minor (NIHSS (National Institutes of Health Stroke Scale) ≤five) versus major (NIHSS >five) ischaemic stroke; ischaemic stroke with versus without thrombolysis; prehospital versus non-prehospital settings; time from stroke to randomisation ≤6 versus >6 hours and high versus low overall RoB studies. We will also perform trial sequential analysis for the primary outcomes.Ethics and disseminationEthics board approval is unnecessary. PROSPERO registration has been obtained. The results will be disseminated through publication in a peer-reviewed journal.Prospero registration numberCRD42020173093.

Dataset Information

Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis.

Publications

Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis.

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