Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment

BackgroundInfections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. MethodsWe conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR 1 harm). This trial is registered (ISRCTN82217627). FindingsFrom April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81–1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77–1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96–1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. InterpretationWe observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. FundingThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No: 634809

Anticoagulation for cerebral venous sinus thrombosis

Treatment of cerebral venous sinus thrombosis with anticoagulants has been controversial. Anticoagulants may prevent new venous infarcts, neurologic deterioration and pulmonary embolism but may also promote haemorrhages. To assess the effectiveness and safety of anticoagulant therapy in patients with confirmed cerebral venous sinus thrombosis. We searched the Cochrane Stroke Group Trials Register (last searched August 2010), MEDLINE (1950 to August 2010), EMBASE (1980 to August 2010) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011 Issue 1). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers and reference lists of relevant articles, and contacted authors. Unconfounded randomised controlled trials in which anticoagulant therapy was compared with placebo or open control in patients with cerebral venous sinus thrombosis (confirmed by intra-arterial contrast, or venography with magnetic resonance, or venography with computed tomography imaging). Two review authors independently extracted outcomes for each of the two treatment groups (anticoagulant treatment and control). The outcome data for each patient were analysed in the treatment group to which the patient was originally allocated (intention-to-treat analysis). We calculated a weighted estimate of the treatment effects across trials (relative risk, absolute risk reduction). We included two small trials involving 79 patients. One trial (20 patients) examined the efficacy of intravenous, adjusted dose unfractionated heparin. The other trial (59 patients) examined high dose, body weight adjusted, subcutaneous, low-molecular weight heparin (nadroparin). Anticoagulant therapy was associated with a pooled relative risk of death of 0.33 (95% confidence interval (CI) 0.08 to 1.21) and of death or dependency of 0.46 (95% CI 0.16 to 1.31). The absolute reduction in the risk of death or dependency was 13% (95% CI 30% to -3%). No new symptomatic intracerebral haemorrhages were observed. One major gastro-intestinal haemorrhage occurred after anticoagulant treatment. Two control patients (placebo) had a diagnosis of probable pulmonary embolism (one fatal). Based upon the limited evidence available, anticoagulant treatment for cerebral venous sinus thrombosis appeared to be safe and was associated with a potentially important reduction in the risk of death or dependency which did not reach statistical significanc