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

de Jonge, Jeroen C.; Sluis, Wouter M.; Reinink, Hendrik; Bath, Philip M.; Woodhouse, Lisa J.; Zweedijk, Berber; van de Beek, Diederik; Aamodt, Anne Hege; Alpers, Iris; Ciccone, Alfonso; Csiba, Laszlo; Demotes, Jacques; Kõrv, Janika; Kurkowska-Jastrzebska, Iwona; Dawson, Jesse; Macleod, Malcolm R.; Ntaios, George; Poli, Sven; Milionis, Haralampos; Ricci, Stefano; Cenciarelli, Silvia; Candelaresi, Paolo; de Bruijn, Sebastiaan FTM.; Pathansali, Rohan; Krishnan, Kailash; Clarke, Brian; Thomalla, Götz; van der Worp, H Bart

Abstract

Background

Infections 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.

Methods

We 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 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627).

Findings

From 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.

Interpretation

We 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.

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No: 634809.

Citation

de Jonge, J. C., Sluis, W. M., Reinink, H., Bath, P. M., Woodhouse, L. J., Zweedijk, B., …van der Worp, H. B. (2024). 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. Lancet Regional Health – Europe, 36, Article 100782. https://doi.org/10.1016/j.lanepe.2023.100782

• Journal Article Type: Article
• Acceptance Date: Oct 30, 2023
• Online Publication Date: Dec 1, 2023
• Publication Date: 2024-01
• Deposit Date: Jan 17, 2024
• Publicly Available Date: Jan 17, 2024
• Journal: Lancet Regional Health - Europe
• Electronic ISSN: 2666-7762
• Peer Reviewed: Peer Reviewed
• Volume: 36
• Article Number: 100782
• DOI: https://doi.org/10.1016/j.lanepe.2023.100782
• Keywords: Stroke; Ischaemic stroke; Intracerebral haemorrhage; Fever; Infection; Pneumonia
• Public URL: https://nottingham-repository.worktribe.com/output/28416425
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2666776223002016?via%3Dihub
• PMID: 38074444
• Additional Information: This article is maintained by: Elsevier; Article Title: 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; Journal Title: The Lancet Regional Health - Europe; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.lanepe.2023.100782; Content Type: article; Copyright: © 2023 The Author(s). Published by Elsevier Ltd.