Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. METHODS: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. FINDINGS: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13-3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14-3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69-1·21]) and unfractionated heparin (0·81 [0·61-1·08]) led to a non-significant shift towards worse modified Rankin Scale scores. INTERPRETATION: Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. FUNDING: 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.

[Endarterectomy more favourable than stenting in symptomatic significant carotid stenosis: higher risk of ischaemic stroke or death following stenting]. / Endarteriëctomie gunstiger dan stent bij symptomatische carotisstenose: hoger risico op CVA of overlijden na stentplaatsing.

Carotid endarterectomy (CEA) has proven its value in the treatment of patients with recent significant carotid artery stenosis. Percutaneous transluminal angioplasty with carotid artery stenting ('stenting' in short) is an alternative to CEA. The results of stenting and CEA in patients with symptomatic significant carotid artery stenosis were evaluated in 9 prospective randomized controlled trials and 11 meta-analyses. Almost all of these trials failed to show superiority of stenting to CEA. According to the 4 largest and most recent studies in this field the risk of a stroke or death within 30 days after the intervention is considerably higher following stenting than following CEA. In the long run the results of stenting and CEA seem to be comparable. CEA remains the gold standard in treatment of significant carotid artery stenosis, in particular in patients older than 70.

A detailed profile of cognitive dysfunction and its relation to psychological distress in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM2) is a common metabolic disorder. DM2 is associated with cognitive impairments, and with depressive symptoms, which occur in about one third of patients. In the current study we compared the cognitive profile and psychological well-being of 119 patients with DM2 (mean age: 66 +/- 6; mean duration: 9 +/- 6 years) with 55 age and education matched-control participants. Groups were compared on cognitive performance in five major cognitive domains, psychological wellbeing [assessed by Symptom Checklist (SCL)-90-R and the Beck Depression Inventory (BDI-II)] and abnormalities on brain MRI. We hypothesized an interrelationship between cognition, MRI abnormalities, and psychological well-being. DM2 patients performed significantly worse than controls on cognitive tasks, especially on tasks that required more mental efficiency, although the differences were modest (effect sizes Cohen d < .6). We speculate that DM2 patients have a diminished ability to efficiently process unstructured information. Patients with DM2 had significantly higher scores on the SCL-90-R (p < .001) and on the BDI-II (p < .001) and worse MRI ratings than controls, but psychological distress did not correlate with cognition, MRI ratings or biomedical characteristics. Contrary to our hypothesis, cognitive disturbances and psychological distress thus seem independent symptoms of the same disease.

Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes.

The structural correlates of impaired cognition in type 2 diabetes are unclear. The present study compared cognition and brain magnetic resonance imaging (MRI) between type 2 diabetic patients and nondiabetic control subjects and assessed the relationship between cognition and MRI findings and blood pressure and metabolic control. The study included 113 patients and 51 control subjects. Brain MRI scans were rated for white matter lesions (WMLs), cortical and subcortical atrophy, and infarcts. Neuropsychological test scores were divided into five cognitive domains and expressed as standardized Z values. Type 2 diabetes was associated with deep WMLs (P = 0.02), cortical (P < 0.001) and subcortical (P < 0.05) atrophy, (silent) infarcts (P = 0.06), and impaired cognitive performance (attention and executive function, information-processing speed, and memory, all P < 0.05). Adjustment for hypertension did not affect the results. Within the type 2 diabetic group, cognitive function was inversely related with WMLs, atrophy, and the presence of infarcts (adjusted for age, sex, and estimated IQ), and there was a modest association with HbA1c and diabetes duration. This association was strongest for age, even more so than in control subjects. We conclude that cognitive impairments in patients with type 2 diabetes are not only associated with subcortical ischemic changes in the brain, but also with increased brain atrophy.

Nerve conduction velocity and evoked potential latencies in streptozotocin-diabetic rats: effects of treatment with an angiotensin converting enzyme inhibitor.

BACKGROUND: Diabetes mellitus is associated with deficits in cerebral function. Vascular disorders may play a role in the pathogenesis and provide a potential target for treatment. The present study examined if prevention and intervention treatment with the angiotensin converting enzyme inhibitor enalapril could improve peripheral and central neurophysiological deficits in streptozotocin-diabetic rats. METHODS: Sciatic nerve conduction velocities were measured prior to diabetes induction and again every three weeks. In the prevention study, the final nerve conduction measurements were performed at 15 weeks and in the intervention study at 24 weeks. Brain stem auditory and visual evoked potential latencies were measured every 3 weeks from 10 weeks after diabetes induction. In the prevention study, the final evoked potential measurements were performed at 16 weeks and in the intervention study at 25 weeks. Treatment with the angiotensin converting enzyme inhibitor enalapril was started directly after diabetes induction (prevention treatment) and after 15 weeks of diabetes (intervention treatment). RESULTS: Nerve conduction velocity, brain stem auditory and visual evoked potential latencies were impaired in diabetic rats. Enalapril prevented deficits in nerve conduction velocity (p < 0.001), brain stem auditory evoked potential latencies (p < 0.01) and visual evoked potential latencies (p < 0.005). Enalapril intervention treatment had no effect on nerve conduction velocity and on visual evoked potential latencies, but improved brain stem auditory evoked potential latencies (p < 0.05) after 10 weeks of treatment. CONCLUSION: Enalapril partially prevents the development of neurophysiological alterations in the peripheral and central nervous system and partially reverses deficits in brain stem auditory evoked potential latencies in STZ-diabetic rats.

Angiotensin converting enzyme inhibition partially prevents deficits in water maze performance, hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-diabetic rats.

Vascular dysfunction is important in the pathogenesis of peripheral complications of diabetes. However, the effects of diabetes on cerebral blood flow and the role of vascular deficits in the pathogenesis of diabetic encephalopathy are still unknown. The present study examined whether experimental diabetes is associated with reduced cerebral blood flow and whether treatment with enalapril can improve cerebral perfusion and function (blood flow and functional cerebral deficits). Streptozotocin-diabetic rats were treated with the ACE inhibitor enalapril (24 mg/kg) from onset of diabetes. After 14 weeks of diabetes, 12 enalapril treated and 12 untreated diabetic rats, and 12 nondiabetic age-matched control rats were tested in a spatial version of the Morris water maze. After 16 weeks of diabetes, in the same groups, blood flow in the hippocampus and thalamus was measured by hydrogen clearance microelectrode polarography. In a separate study, hippocampal long-term potentiation was measured after 26 weeks of diabetes. Water maze performance and hippocampal long-term potentiation were impaired in diabetic rats. Furthermore, blood flow in diabetic rats was reduced by 30% (P<0.001) in the hippocampus and by 37% (P<0.005) in the thalamus compared to nondiabetic controls. Enalapril treatment significantly improved water maze performance (P<0.05), hippocampal long term potentiation (P<0.05) and hippocampal blood flow (P<0.05). Cerebral perfusion is reduced in diabetic rats compared to controls. Treatment aimed at the vasculature can improve cerebral blood flow, deficits in Morris maze performance and long term potentiation. These findings suggest that vasculopathy plays a role in the development of cerebral dysfunction in diabetic rats.