Editorial

This issue of the Journal includes two articles that consider influences on outcome among patients treated with thrombolysis, and that should raise our awareness of the distinction between outcome modifiers and treatment effect modifiers.

Using data from the Thrombolysis in Ischemic Stroke Patients (TRISP) registry, Nybondas et al. ¹ report the outcomes of intravenous (IV) thrombolysis in 1346 young adults (aged 18–49) with ischaemic stroke, compared to over 15,000 older patients. The young adults fared better. More achieved functional independence at 3 months (82% vs 56%), with lower rates of symptomatic intracranial haemorrhage (1.6% vs 4.6%) and mortality (2.3% vs 14.2%). ¹ However, the younger group showed lower severity at presentation, less functional impairment and fewer comorbidities prior to symptoms onset. With an observational design, we cannot distinguish the relative contribution to their better recovery of their more favourable patient profile versus benefits from thrombolysis. The authors’ data certainly underline the safety and efficacy of IV thrombolysis in young-onset stroke and reinforce the need for prompt symptom identification, hospital transfer and treatment delivery in younger individuals. However, acknowledging the inverse relationship between age and the probability for favourable outcomes following a stroke should never constitute a reason to withhold the administration of IV thrombolysis for any eligible individual.

An ancillary observation in the study by Nybondas et al. ¹ is the predominance of males, particularly in the younger cohort (59.6% vs 54% in the older group). This is not surprising. Women tend to experience strokes at older ages and are less likely to receive IV thrombolysis for acute ischaemic stroke, compared to men. Lower IV thrombolysis rates in younger women have been attributed to perceived cardiovascular risk being less and to concerns about functional overlay. Among older women, the lower rates of IV thrombolysis have been attributed to delays in symptoms identification and hospital transfer through insufficient family support and social isolation. Does sex influence outcome? A second paper in this issue examines that. In Fukuda-Doi et al.’s ² individual patient-level data meta-analysis of five clinical trials evaluating imaging-based IV thrombolysis for stroke of unknown time onset, the women were older and presented with more severe deficits than men. Rather than sex itself, age and stroke severity accounted for the worse functional outcomes among the women treated. ²

In reaching therapeutic decisions for any individual, it is important to differentiate between outcome modifiers and treatment effect modifiers. Outcome modifiers influence prognosis regardless of intervention whereas treatment effect modifiers determine whether and how effectiveness of the intervention varies across patient subgroups. Clinical trials and meta-analyses have established the benefit of IV thrombolysis across all age groups, and in both sexes. The studies by Nybondas et al. ¹ and Fukuda-Doi et al. ² published in this issue assess the impact of age and sex as outcome modifiers for individuals with acute ischaemic stroke eligible for IV thrombolysis. They underscore the sustained benefit of IV thrombolysis in both younger adults and women but suggest no modification of the treatment effect by age or sex.

Tailoring the decision to administer IV thrombolysis based on perceived outcomes solely tied to demographic factors – such as age, sex, gender or ethnicity – is not personalising treatment: it suggests inappropriate practice. It may lead to prejudiced care and unjustly withholding effective therapy from individuals who may derive important benefit.