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High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK-based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants' systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting. British Heart Foundation.

Background and Objectives: Radial artery spasm (RAS) is a frequent complication during invasive angiography using the transradial approach, leading to patient discomfort and procedural challenges. While intra-arterial nitroglycerine (NTG) effectively reduces RAS after sheath insertion, preprocedural prevention strategies are limited. This study evaluates the efficacy of topical NTG in improving radial artery puncture success and reducing RAS incidence. Materials and Methods: In a randomized, double-blind single-center study 100 patients undergoing angiography were pretreated with either topical NTG or placebo. Outcomes assessed included RAS incidence, radial artery puncture success, number of attempts, procedural duration, patient discomfort, and complications. RAS was evaluated angiographically and clinically, with additional subgroup analyses for diabetic and smoking patients. Results: Topical NTG significantly reduced RAS incidence (53.2% vs. 73.6%; p = 0.0349) and increased radial puncture success on the first attempt (89.4% vs. 77.4%; p = 0.0488). Diabetic patients particularly benefited from NTG application, with lower RAS rates (36.4% vs. 76.2%; p = 0.0296). No significant differences were observed in procedural duration, patient discomfort, or complication rates between groups. The placebo group demonstrated a higher incidence of diffuse RAS (p = 0.0109). Conclusions: Preprocedural topical NTG application is a safe, non-invasive intervention that improves radial artery access success and reduces RAS, especially in high-risk subgroups such as diabetics. These findings support its potential as a procedural optimization tool in cardiovascular interventions, particularly in patients with heart failure, who often require repeated and reliable vascular access.

Central adjudication of serious adverse events (SAEs) can be undertaken in clinical trials, especially for open-label studies where outcome assessment may be at risk of bias. This study explored the effect of central adjudication of SAEs on the safety results of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. ENOS assigned patients with acute stroke at random to receive either transdermal glyceryl trinitrate (GTN) or no GTN and to Stop or Continue previous antihypertensive treatment. SAEs were reported by local investigators who were not blinded to treatment allocation. Central adjudicators, blinded to treatment allocation, reviewed the investigators reports and used evidence available to confirm or re-categorise the classification of event, likely causality, diagnosis and expectedness of event. Of 4011 patients enrolled in ENOS, 1473 SAEs were reported by local investigators; this was reduced to 1444 after the review by adjudicators, with 29 re-classified as not an SAE. There was fair agreement between investigators and adjudicators regarding likely causality, with 808 agreements and 644 disagreements (56% crude agreement, weighted kappa, κ = 0.31). Agreement increased upon dichotomisation of the causality categories, with 1432 agreements and 20 disagreements (99% crude agreement, kappa = 0.54). Repeating the main trial safety analysis with investigator reported events showed that adjudication had no effect on the main trial safety conclusions. In a large trial, with many SAEs reported, central adjudication of these events did not affect trial conclusions. This suggests that adjudication of SAEs in a clinical trial where the intervention already has a well-established safety profile may not be necessary. Potential efficiency savings (financial, logistical) can be made through not adjudicating SAEs.

Patients with hypertensive acute heart failure (H-AHF) can decompensate rapidly and require immediate medical attention; the use of high-dose nitroglycerin is a topic of growing interest in this patient population. The purpose of this review is to provide an evidence-based approach for the utilization of high-dose nitrates in the emergent management of H-AHF. Two randomized controlled trials, three prospective studies, two retrospective cohorts, two case series, and one case report were evaluated. Level of robust evidence and heterogeneity limit the ability to draw strong conclusions regarding the use of high-dose nitrates. Despite these limitations, high-dose nitrates appeared to have an overall beneficial effect across all studies reviewed, including lower rates of mechanical ventilation, improvement in blood pressure, shorter LOS, and lower rates of ICU admission. Adverse effects were mild and infrequently reported. High-dose nitrates are likely safe and may be effective, as demonstrated in the studies reviewed. High-dose NTG may be appropriate in H-AHF patients presenting with severe respiratory distress and SBP ≥160 mmHg or MAP ≥120 mmHg. Future well-designed randomized controlled trials are needed to elucidate optimal dosing strategies and confirm safety and efficacy of high-dose nitrates.

Objective MQX-503 is a novel nitroglycerine preparation designed to absorb quickly and allow local vasodilatation in the skin. We examined the efficacy and tolerability of this medication in Raynaud phenomenon (RP) in a laboratory-based study. Methods In this multi-centre, double-blind, randomised, placebo-controlled, cross-over study, subjects were treated with 0.5% or 1.25% nitroglycerine or placebo gel. Subjects received each dose twice in a randomised order. Each study session consisted of baseline laser Doppler measurements, study gel application and 5 min of cold chamber exposure (−20°C). Blood flow (BF) was measured at the end of exposure and for the next 120 min at set intervals. Other outcome measures included achievement of baseline BF; the time to achieve 50% and 70% baseline skin temperature (ST); and pain, tingling and numbness scores. Results 37 subjects completed 214 treatment periods. Time to achieve baseline BF was significantly shorter in the two treated groups (HR=1.77 and 2.02 for 0.5% and 1.25% vs placebo, respectively). The proportion of subjects achieving baseline BF was 45.8% for placebo, 66.2% for 0.5% and 69% for 1.25% (p=0.01 and p=0.002 for 0.5% and 1.25% vs placebo, respectively). No meaningful differences were seen in ST or pain/numbness/tingling scores. Treatment was well tolerated with no serious adverse events. Conclusions Treatment with MQX-503 caused a significant improvement in skin BF compared with placebo. Data from this proof of concept study suggest benefit of MQX-503 in subjects with RP.

Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset. MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308. On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1–4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65–1·47]). In the target population (n=291), the 90-day mRS score was 2 (2–4) in the glyceryl trinitrate group and 3 (1–4) in the control group (0·92 [0·59–1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53–2·14]) or serious adverse events (unadjusted OR 1·23 [0·76–1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78–44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18–4·17]). We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting. The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

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. 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. 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). 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. UK Medical Research Council.

Acute cardiogenic pulmonary edema (ACPE) is a life-threatening manifestation of acute heart failure characterized by abrupt pulmonary congestion and hypertension. Rapid blood pressure (BP) reduction with intravenous vasodilators is a cornerstone of emergency management. Nitroglycerin is widely used but may be limited by side effects, while urapidil, an α1-adrenergic antagonist with additional central serotonergic activity, has been proposed as an alternative. In this prospective cohort study at a tertiary university emergency department, adults with hypertensive ACPE received either intravenous nitroglycerin or urapidil as part of initial management. Hemodynamic parameters were recorded at baseline and every 30 min up to 330 min. The primary outcome was achievement of target systolic BP (<140 mmHg). Secondary outcomes included time-resolved changes in systolic/diastolic BP and heart rate, need for rescue therapy, mechanical ventilation, disposition, and adverse events. A total of 296 patients were analyzed (nitroglycerin n = 142, urapidil n = 154; median age 69 years, 51 % female). Urapidil achieved earlier and higher cumulative attainment of the BP target from 60 min onward (p < 0.001) and produced faster early declines in systolic/diastolic BP and heart rate. However, invasive mechanical ventilation (13.6 % vs. 6.3 %, p = 0.038) and intensive care admissions (55.2 % vs. 38.7 %, p = 0.010) were more frequent with urapidil. Rescue therapy was required more often with nitroglycerin (28.2 % vs. 16.9 %, p = 0.020). Headache occurred more frequently with nitroglycerin, while other adverse events were comparable. In hypertensive ACPE, urapidil reaches blood pressure targets in a more timely manner, but may be associated with higher rates of endotracheal intubation and ICU admission in this cohort. These observations may support consideration of nitroglycerin when early clinical stabilization is prioritized, while urapidil remains a reasonable alternative. Safety profiles were broadly similar, aside from more frequent headaches with nitroglycerin. •Urapidil achieved faster and higher rates of blood pressure control.•Nitroglycerin was associated with fewer intubations and ICU admissions.•Rescue therapy was used more frequently in the nitroglycerin group.•Headache was more common with nitroglycerin, other adverse events were similar.•Findings suggest pragmatic preference for nitroglycerin in hypertensive ACPE.

Background Chronic anal fissures (CAFs) are the second most common anorectal disease. Non-surgical treatment includes several options with controversial efficacy. The aim of this study was to evaluate the efficacy and safety of a new ointment based on methylene blue in addition to glyceryl trinitrate. Methods A phase II randomized single-centre triple-blinded study was carried out in a tertiary proctology unit on patients with CAF. The enrollment started after local ethics committee approval (study n. 6461, protocol approval n. 0045085). Eligible consecutive patients were randomized to one of three different groups, each receiving a different ointment. The efficacy of the treatment was evaluated with the REALISE score. Results Nine patients were treated with cream A (median age 47 years, IQR 40–56, 22% female), nine with cream B (median age 52 years, IQR 49–57, 33% female), and nine with cream C (median age 58 years, IQR 46–62, 55% female). In group A, REALISE scores decreased significantly from a median of 22 (IQR 12–25) to 6 (IQR 4–8) ( p  < 0.05) after 40 days. In group B, REALISE scores improved significantly from a median of 20 (IQR 17–22) to 5 (IQR 4–9) ( p  < 0.05). In group C, REALISE scores decreased significantly from a median of 19 (IQR 19–20) to 4 (4–5) ( p  < 0.05). No statistically differences were recorded. The healing rate was 77% with creams A and C, while it was 44% with cream B. Conclusion Methylene blue-based ointments could be a new and innovative treatment for the non-operative management and healing of CAFs.

Background: Currently, the main goal for the use of tocolytic therapy is to delay the birth so as to allow the use of corticosteroids for accelerating fetal lung maturity and maternal transfer to a tertiary care center and thereby reducing neonatal morbidity and mortality. Aims and Objectives: The aims amd objectives were to compare the safety and efficacy of transdermal nitroglycerine patch with oral nifedipine as a tocolytic agent to arrest preterm labor and prevent preterm birth. Materials and Methods: Based on the selection criteria, 50 patients were selected randomly in Group A and Group B. Group A women were given transdermal nitroglycerin patch, which delivered 10 mg Nitroglycerin (NTG) over 24 h and it was applied to the woman's abdomen followed by another patch of 10 mg after 1 h if contractions persisted. After 24 h, it was replaced by a fresh patch. Group B women were given an oral loading dose of nifedipine 20 mg followed by a similar dose if contractions persisted after 1 h. A maintenance dose of 10 mg thrice daily was given if contractions were suppressed. Patients were monitored from the time of admission to the time of discharge. Results: The mean duration of prolongation of pregnancy in Group B (3.68 ± 1.91 days) was significantly more than Group A (2.78 ± 1.39 days). Headache was seen significantly more in Group A (42%) than group B (6%). Tachycardia, hypotension, and palpitation showed no statistically significant difference between them. There was no statistically significant difference in the birth weight of the babies in both the groups. Conclusion: Nifedipine is a safe and effective drug in prolonging preterm labor and has minimal maternal and neonatal side effects.