The PRECIOUS trial enrolled 1,493 patients aged 66 or older with acute ischaemic stroke or intracerebral haemorrhage and a National Institutes of Health Stroke Scale score of at least 6, across 68 sites in nine European countries: Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom. Patients were randomised within 24 hours of symptom onset to receive preventive metoclopramide, ceftriaxone, paracetamol, or combinations thereof. After excluding patients lost to follow-up, those who withdrew consent, and those ultimately diagnosed with a stroke mimic, 1,451 patients remained for this analysis. The mean age was 79.7 years, 50.6 percent were male, and 86.1 percent had ischaemic stroke while 13.9 percent had intracerebral haemorrhage.

Researchers prospectively recorded whether any treatment restriction was installed in the first 24 hours after randomisation and during the first seven days, using a structured electronic case report form. Options included do-not-resuscitate orders, do-not-intubate directives, withholding other life-prolonging treatments, withholding food or fluids, and palliation with morphine or benzodiazepines. Overall, 276 patients (19.0 percent) had a restriction within the first 24 hours, and 360 (24.8 percent) within the first week. Do-not-resuscitate orders were the most common type. Restrictions were more frequent in patients with intracerebral haemorrhage (25.4 percent) than ischaemic stroke (18.0 percent), and affected patients were older, more often female, had greater stroke severity, and more pre-stroke dependency.

The variation across countries was striking. Early treatment restrictions ranged from zero percent in Estonia, Poland, and Hungary, to just 0.4 percent in Italy and 2.1 percent in Greece, up to 17.8 percent in Germany, 19.4 percent in the United Kingdom, and 48.1 percent in the Netherlands. This means nearly one in two Dutch patients in the trial had a restriction placed within the first day, while patients in Eastern and Southern European countries almost never did. Such wide practice variation, despite all countries following the same European Stroke Organisation guidelines for stroke management, points to deep cultural differences in end-of-life decision-making rather than differences in clinical standards.

To test whether early restrictions actually cause death, the researchers used two complementary approaches. First, they applied inverse probability of treatment weighting, a propensity score method that reweights patients to balance observed confounders such as age, sex, diabetes, atrial fibrillation, pre-stroke dependency, stroke severity, stroke type, time to randomisation, country, and trial treatment allocation. After adjustment, early restrictions remained strongly associated with death within 90 days (39.1 percent versus 15.5 percent; weighted odds ratio 3.39, 95% CI 2.71–4.25), death within seven days (16.7 percent versus 6.2 percent; weighted odds ratio 3.44), and worse functional outcome on the modified Rankin Scale at 90 days. E-value sensitivity analyses indicated that only very strong unmeasured confounders could fully explain these associations.

Second, the team exploited the natural experiment created by cross-country practice variation. They divided patients into those enrolled in countries where early restrictions were common (the Netherlands, Germany, Norway, and the United Kingdom; 914 patients) and those in countries where they were rare (Greece, Estonia, Hungary, Italy, and Poland; 537 patients). If restrictions truly shortened lives, death rates should be higher where they are used more. Yet 90-day mortality was comparable between the two groups: 21.3 percent in the restriction group versus 23.5 percent in the no-restriction group, with an adjusted odds ratio of 1.39 (95% CI 0.81–2.39). Similar null findings emerged for ischaemic stroke and intracerebral haemorrhage subgroups, and for functional outcome and independence in activities of daily living.

The authors argue that this pattern is most consistent with confounding by indication: restrictions are placed on patients already expected to do poorly, so the association with death reflects prognosis rather than harm. If restrictions primarily prevented prolonged survival with severe disability, one might expect fewer patients surviving in a minimally conscious or severely disabled state (modified Rankin Scale score of 5) in countries that restrict more often, but no such pattern was observed. Hospital-level funnel plots showed no consistent relationship between expected and observed restriction rates, further suggesting institutional variation rather than a systematic causal effect.

These findings challenge current guideline recommendations. European Stroke Organisation guidance on intracerebral haemorrhage advises against general policies of do-not-resuscitate orders within the first 24 hours, and American Heart Association guidelines suggest postponing new such orders until at least the second full day of hospitalisation. Care-bundle trial protocols, such as the ongoing I-CATCHER study, embed avoidance of early restrictions as a quality measure. The PRECIOUS analysis suggests such recommendations may be premature, as they are based on retrospective observational data with high risk of residual confounding, and the new evidence indicates restrictions are more a marker of poor prognosis than a cause of it.

Limitations remain. This was a post hoc, non-randomised analysis, so unmeasured confounding cannot be excluded despite the dual approach. Data on restrictions and care were only available for the first week and at 90 days, with no information on later decisions or causes of death. Trial eligibility criteria excluded patients under 66, those with severe pre-stroke disability, and those with imminent death at screening, so the cohort may underrepresent the most severely affected patients in whom restrictions are most common. Between-country comparisons also lack detailed data on healthcare system differences, and it remains unknown whether patients without restrictions received more aggressive care overall.

Nevertheless, the study offers a sobering message for clinicians, guideline developers, and families navigating the hardest decisions in acute stroke care. Rather than treating early treatment restrictions as inherently harmful interventions to be banned, the evidence suggests they should be understood as signals of severity and as expressions of culturally shaped attitudes toward end-of-life care. Whether restricting or continuing aggressive treatment changes outcomes in severely affected patients remains an open question, one that only carefully designed prospective research, sensitive to cultural context and patient values, can ultimately answer.

Subject of Research: Treatment restrictions after acute stroke and their association with 90-day mortality

Article Title: Treatment restrictions after acute stroke across nine European countries and their association with 90-day mortality: a post hoc analysis of the PRECIOUS randomised controlled trial

Article References: Sluis, W. M., van Amsterdam, W. A., de Jonge, J. C., Reinink, H., Ntaios, G., Kõrv, J., Aamodt, A. H., Thomalla, G., Csiba, L., Ciccone, A., Kurkowska-Jastrzebska, I., Macleod, M. R., Bath, P. M., van der Worp, H. B., Reinink, H., de Jonge, J. C., Bart van der Worp, H., Bath, P. M., van de Beek, D., … Thomalla, G. (2026). Treatment restrictions after acute stroke across nine European countries and their association with 90-day mortality: a post hoc analysis of the PRECIOUS randomised controlled trial. The Lancet Regional Health – Europe, 71, Article 101894. https://doi.org/10.1016/j.lanepe.2026.101894

Image Credits: AI Generated

DOI: 10.1016/j.lanepe.2026.101894

Keywords: stroke, treatment restrictions, do-not-resuscitate, PRECIOUS trial, intracerebral haemorrhage, ischaemic stroke, 90-day mortality, end-of-life care, propensity score, confounding, European practice variation, guidelines