Transient ischemic attack (TIA) represents a clinical emergency due to the increased risk of stroke and short-term cardiovascular events (1–4). Prior population-based studies showed that the risk of recurrent stroke after TIA may reach up to 17% at 3 months, with a higher incidence in the first 48 h (~50%) after the index TIA. Therefore, current guidelines recommend adopting organizational protocols based on timely diagnostic assessment and early secondary prevention, the so-called “fast-track care.” Benefits of the fast-track care were documented by several real-world studies which showed a consistent decrease in the 90-day risk of stroke recurrence after the index TIA (5, 6). However, recent evidence showed that patients with TIA may have an increased risk of recurrent cardiovascular events even beyond the first 3 months after the index event. Indeed, the 60-month incidence of recurrent stroke in patients presenting with first-ever TIA was shown to be of 9.5% (7.7% for ischemic stroke only) in the large multicentric TIA registry (2009–2011) (7), 16.1% in the Framingham cohort study (2000–2017) (8) and 6.1% in the Danish Stroke Registry (2014–2020) (9). The increased long-term stroke risk after TIA underscores the necessity of identifying predictors associated with a higher risk of long-term stroke recurrence, especially considering that factors influencing later recurrences may differ from those contributing to early ones. Hereafter, we aimed to investigate the risk of stroke and to characterize short- and long-term stroke predictors in a large population of TIA patients undergoing fast-track management.

Study definitions are reported elsewhere (5, 10, 11). We enrolled all consecutive patients aged ≥18 years and with symptoms consistent with TIA (12) that were referred to the emergency department (ED) of the S. Orsola-Malpighi University Hospital of Bologna between August 1, 2010 and December 31, 2017. The catchment area of our ED covers a population of about 250,000 inhabitants. We included only patients with probable or definite TIA according to the National Institute of Neurological Disorders and Stroke (NINDS) criteria (13), as diagnosed after a careful examination of the medical history and neurological features. All TIA diagnoses were adjudicated by a senior vascular neurologist (MG) who decided about the study inclusion in case of discrepancy with the neurologist who initially evaluated the case.

Our prospective study demonstrated an increasing incidence of stroke over time (from 2.2% at 90 days to 7.1% at 60 months) in a large population of TIA patients undergoing fast-track care. Predictors of post-TIA stroke recurrence were different between the short- and long-term follow-up. Specifically, we found that multiple TIA, speech disturbances at TIA onset and presence of ischemic lesion at neuroimaging performed on ED admission were independently associated with an increased risk of stroke at each timepoint. On the other hand, male sex and increasing age were independent predictors of stroke occurrence at 90-day and 60-month, respectively, while history of hypertension independently predicted both the 90-day and 60-month stroke risk. Lastly, the overall incidence of stroke at 90 days within our cohort was lower than expected based on the baseline ABCD₂ score. We estimated NNT for fast-track care in preventing stroke of 14.5 [95% CI 11.3–20.4] in the overall cohort and of 6.8 [95% CI 4.6–13.5] in patients with baseline ABCD₂ of 6 to 7.

Considering baseline characteristics, the mean age of TIA patients within our cohort (70.6 years) was higher compared to the prior large multicentric TIA registry (66.1 years) (6), but in line with a recent European nationwide study which found a mean age at TIA onset of 70.8 years (9). The relatively advanced mean age of our population, coupled with our comprehensive investigation of TIA causes through fast-track care, could explain the peculiar distribution of TIA etiologies observed within our cohort. Specifically, we noted a higher proportion of patients experiencing cardioembolic TIAs (21.9%) compared to prior population-based studies (17, 18). Conversely, while the prevalence of TIA cases with undetermined etiology (34.5%) was comparatively lower in respect to prior studies (19, 20), it still remained consistently high. This highlights the persistent challenge of identifying a well-defined cause in a significant percentage of TIA patients, despite implementing a thorough diagnostic work-up.

The short-term risk of stroke observed within our cohort (2.2%) was one of the lowest if compared to current literature, especially when considering studies predating the implementation of fast-track care for patients with TIA (21–25). A systematic review conducted by Valls et al. in 2016 analyzed several studies applying accelerated TIA management from 2007 to 2015 and reported a pooled 90-day stroke risk of 3.4% (26). Furthermore, studies conducted prior to the implementation of fast-track care (2000–2003) estimated a 90-day stroke risk ranging from 12 to 20% (27, 28). Although the cumulative risk of stroke increased over time, we found a lower incidence of stroke events at each timepoint in respect to prior cohort studies. Specifically, our 12-month stroke incidence (3.3%) was lower than those observed in the Aarhus study (25) and in the large multicentric TIA registry (6) (4.2, and 5.1%, respectively). Similarly, the observed 60-month stroke rate observed within our cohort (7.1%) was lower than those reported in the more recent update of the same TIA registry (9.5%) (7). Importantly, our sensitivity analysis revealed no significant differences in recurrent stroke incidence following TIA at each timepoint when excluding patients with ischemic lesion(s) on neuroimaging. This suggests a comparable stroke risk within our population whether employing a “time-based” or “tissue-based” definition of the index TIA. This finding aligns with recent observations from a prospective cohort study showing substantial stroke risk even after tissue-negative TIAs (29).

Our recorded stroke risk, along with the observation that 56.5% of all 90-day strokes occurred within the first 48 h after TIA, corroborate the need of immediate care to facilitate early diagnosis and initiate effective secondary prevention. This effort may have the potential not only to reduce early stroke risk but also to ameliorate long-term TIA prognosis. Accordingly, it is crucial to extend the follow-up monitoring for patients who have experienced a TIA even beyond the initial high-risk period.

Predictors of stroke incidence after TIA have been scarcely characterized especially in the long-term. In line with prior prospective studies (10, 11), our analysis confirmed that multiple TIA, speech disturbances and presence of ischemic lesion at neuroimaging show the strongest association with an increased risk of stroke independently of the follow-up duration. The association between multiple TIA presentation and increased stroke risk is well-established, especially for patients with recurrent lacunar syndrome (11). Similarly, TIA with lesion has emerged as a condition of very high risk (10). This recognition might carry significant implications for selecting the most suitable antiplatelet regimen to prevent early recurrent stroke, since dual antiplatelet therapy might offer enhanced efficacy in this specific TIA subtype (30). In terms of speech disturbances, the variable localization of this non-specific symptom might delay targeted secondary prevention, thus increasing the subsequent stroke risk, as noted elsewhere (31). Additionally, concerning demographic factors, male sex and increasing age independently predicted higher 90-day and 60-month stroke risk, respectively. This finding aligns with observations from prior studies, which found a significant interaction between sex and age in determining post-TIA stroke risk (32, 33). In particular, whilst male sex may be related with a higher burden or greater severity of cardiovascular risk factors which concur in enhancing the short-term risk of stroke, sex differences might attenuate in the long-term, when increasing age overcomes biological disparities in stroke pathophysiology. Remarkably, when considering the 12-month and 60-month follow-up, history of hypertension emerged as an independent risk factor for stroke recurrence. This association was also observed in another prospective study with long-term follow-up (31). It is likely that the chronic injury inflicted by hypertension on brain vessels may, to some extent, resist secondary preventive interventions, which may effectively mitigate the short-term risk of stroke but could prove insufficient in preventing late recurrences.

Of interest, no specific TIA etiology was found to independently predict a higher stroke risk within our population. Prior studies found that large artery atherosclerosis (LAA) TIA etiology was independently associated with a higher short-term risk of stroke recurrence, (34, 35) while no etiological TIA subtype has been identified as robust predictor of increased stroke risk in the long-term (36). We may speculate that implementing urgent measures to prevent ischemic recurrences within our cohort, as provided by our fast-track care, may have mitigated the unfavorable effect of LAA etiology on future stroke risk. Additionally, as a shift toward DAPT was documented within our cohort during the study period, we cannot exclude that the impact of TIA etiology on stroke risk may have been nuanced by the rising utilization of DAPT over time. Indeed, we observed a significantly lower risk of recurrent stroke events in patients treated with DAPT versus SAPT throughout the study follow-up. This finding underscores the critical importance of strict adherence to current international guidelines recommending early DAPT as the best option for preventing ischemic recurrences in patients with non-cardioembolic high-risk (ABCD₂ ≥ 4) TIA (37). Furthermore, within this evolving treatment paradigm, expedited diagnostic protocols can offer crucial insights for treatment planning. Swift identification of particular TIA etiologies (i.e., cardioembolism or symptomatic LAA) can significantly refine patient selection for prompt interventions like DAPT, anticoagulation, or other tailored approaches, regardless of their initial ABCD₂ score. In fact, within our cohort, a relevant proportion of patients with baseline ABCD₂ score < 4 was diagnosed with underlying high-risk conditions such as atrial fibrillation (2.3%), symptomatic inner carotid artery stenosis (15.0%), or intracranial stenosis (6.7%).

Lastly, we estimated that within our cohort the fast-track care was highly effective in reducing the expected risk of recurrent stroke based on the baseline ABCD₂ score. In particular, the NNT for fast-track care in preventing future stroke was 14.5 [95% CI 11.3–20.4] in the overall cohort and 6.8 [95% CI 4.6–13.5] in the high-risk TIA subgroup (ABCD₂ of 6 to 7). The sensitivity analysis excluding patients with ischemic lesion(s) at neuroimaging showed even lower NNT in the overall cohort 12.8 [95% CI 11.5–13.3] for “tissue-based” TIAs. Our estimated NNT for fast-track care indicates a potentially greater magnitude of benefit compared to hospitalization in an acute stroke unit, where the estimated NNT in preventing bad outcomes typically ranges between 10 to 25 (38). This result strengthens the value of fast neurovascular specialist-driven ED management in improving outcomes of TIA patients, as previously also observed in an outpatient clinic setting (39).

Strengths of our study lie in its prospective design, the large cohort dimension, and the comprehensive evaluation of enrolled patients, as ensured by the systematic application of the fast-track diagnostic work up, which was implemented at our site, well before it was recommended by the National Institute for Health and Care Excellence (NICE) guidelines (2019) (40). However, there are some limitations that need to be acknowledged. Firstly, due to the lack of systematic data collection on TIA patients before the implementation of fast-track care at our site (2010), we were unable to rely on a control group of TIA patients to directly compare figures on fast-track care effectiveness. As a consequence, we could not assess the extent of observed benefit on stroke risk following TIA in relation to the timeliness or thoroughness of the work-up. Secondly, on the one side, the small number of stroke recurrences in the short-term follow-up might reflect the effectiveness of fast-track care in reducing early stroke risk after TIA, but on the other it might limit the reliability of the identified 90-day stroke predictors. Additionally, we did not record information on patients’ adherence to prescribed medications. Therefore, identified predictors of stroke recurrence should be interpreted in light of this limitation. It is also important to note that advanced and more sensitive neuroimaging (i.e., Diffusion-Weighted MRI) was precluded to most patients of our cohort (>80%). Consequently, the number of patients with ischemic lesion(s) at neuroimaging may have been consistently underestimated limiting the reliability of our sensitivity analysis on “tissue-based” TIAs. However, the adoption of a “time-based” rather than a “tissue-based” definition for TIA diagnosis ensures comparability of our findings with prior prospective studies evaluating stroke predictors. Moreover, in our fast-track workup, the majority of patients underwent color Doppler ultrasound to assess both extra- and intracranial vessels, while CTA/MRA were predominantly reserved for those with significant brain vessel stenosis. This strategy leverages the rapid availability of Doppler exams within 24 h at our facility. However, it may not be suitable for different organizational settings where CTA, contextual with admission non-contrast CT, could offer a quicker and more accessible evaluation, as highlighted in a recent scientific statement by the American Heart Association (41). Lastly, we cannot exclude that the incidence of recurrent strokes recorded in our study has been underestimated because we did not search all regional hospitals but only our hospital records.

In conclusion, our findings provide compelling evidence for the efficacy of fast-track care in mitigating both the short- and long-term risk of stroke recurrence following a TIA. Particular effort should be made to identify and monitor patients with baseline predictors of higher stroke risk, which may vary according to the follow-up duration. This underscores the necessity for tailored risk assessment and intervention strategies to prevent the occurrence of future ischemic events after TIA, even beyond the initial high-risk period.

The raw data supporting the conclusions of this article are available at the URL: https://zenodo.org/records/11096699.

The studies involving humans were approved by S. Orsola-Malpighi University Hospital Research Ethics Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

VB: Data curation, Writing – original draft, Writing – review & editing. MF: Data curation, Formal analysis, Methodology, Visualization, Writing – original draft, Writing – review & editing. LP: Writing – original draft, Writing – review & editing. FR: Writing – original draft, Writing – review & editing. RR: Writing – original draft, Writing – review & editing. MN: Writing – original draft, Writing – review & editing. RD’A: Writing – original draft, Writing – review & editing. EF: Writing – review & editing, Writing – original draft. CBr: Writing – review & editing, Writing – original draft. BC: Writing – review & editing, Writing – original draft. DD: Writing – review & editing, Writing – original draft. SD’A: Writing – original draft, Writing – review & editing. SB: Writing – original draft, Writing – review & editing. FG: Writing – review & editing, Writing – original draft. DP: Writing – review & editing, Writing – original draft. LS: Writing – original draft, Writing – review & editing. LF: Writing – original draft, Writing – review & editing. GF: Writing – original draft, Writing – review & editing. AD: Writing – review & editing, Writing – original draft. CBo: Writing – review & editing, Writing – original draft. PC: Writing – original draft, Writing – review & editing. MG: Conceptualization, Supervision, Validation, Writing – original draft, Writing – review & editing.