Original Paper Received: December 19, 2014 Accepted: April 19, 2015 Published online: June 5, 2015
Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
Short- and Long-Term Stroke Risk after Urgent Management of Transient Ischaemic Attack: The Bologna TIA Clinical Pathway Maria Guarino a Francesca Rondelli a Elisabetta Favaretto b Andrea Stracciari a Massimo Filippini b Rita Rinaldi a Ivana Zele c Michelangelo Sartori b Gianluca Faggioli d Susanna Mondini a Andrea Donti e Enrico Strocchi e Daniela Degli Esposti e Antonio Muscari f Maddalena Veronesi e Sergio D’Addato e Luca Spinardi g Luca Faccioli g Marco Pastore Trossello g Fabio Cirignotta a
Neurology Unit, b Angiology and Blood Coagulation Unit, c Emergency Department, d Vascular Surgery Unit, Cardiothoracic and Vascular Department, f Hospital Care and Disability Assistance, and g Neuroradiology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
e
Key Words Transient ischaemic attack · Stroke · Cerebrovascular disease · TIA care models · Long-term vascular outcomes
Abstract Background: Rapid management can reduce the short stroke risk after transient ischaemic attack (TIA), but the long-term effect is still little known. We evaluated 3-year vascular outcomes in patients with TIA after urgent care. Methods: We prospectively enrolled all consecutive patients with TIA diagnosed by a vascular neurologist and referred to our emergency department (ED). Expedited assessment and best secondary prevention was within 24 h. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death at 12, 24 and 36 months. Results: Between August 2010 and July 2013, we evaluated 686 patients with suspected TIA; 433 (63%) patients had confirmed TIA. Stroke at 90 days was 2.07% (95% confidence interval (CI), 1.1–3.9) compared with the ABCD2-predicted risk of 9.1%. The longterm stroke risk was 2.6% (95% CI, 1.1–4.2), 3.7% (95% CI, 1.6–5.9) and 4.4% (95% CI, 1.9–6.8) at 12, 24 and 36 months,
© 2015 S. Karger AG, Basel 0014–3022/15/0742–0001$39.50/0 E-Mail [email protected] www.karger.com/ene
respectively. The composite outcome of stroke, myocardial infarction, and vascular death was 3.5% (95% CI, 1.7–5.1), 4.9% (95% CI, 2.5–7.4), and 5.6% (95% CI, 2.8–8.3) at 12, 24, and 36 months, respectively. Conclusions: TIA expedited management driven by vascular neurologists was associated with a marked reduction in the expected early stroke risk and low long-term risk of stroke and other vascular events. © 2015 S. Karger AG, Basel
Introduction
The high risk of stroke following a transient ischaemic attack (TIA) is now well recognised, with an untreated risk of recurrence by 90 days up to 17% [1]. Pioneering studies in 2007 [2, 3] showed that urgent TIA management was associated with an 80% reduction in the early risk of stroke recurrence. It was subsequently confirmed that low early stroke rates ranging from 1.7 to 3.2% [4–9] were attainable with timely efficient interventions. However an open question is whether fast track TIA management can maintain its benefit in the long term. The few Maria Guarino Neurology Unit, S. Orsola-Malpighi University Hospital Via Albertoni 15 IT–40138 Bologna (Italy) E-Mail maria.guarino @ aosp.bo.it
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a
studies available on this topic report a 1-year estimated stroke risk of 2.2% [2] (definite TIA with no lesion), 4.4% [10], and 6.2% over 18 months mean follow-up [11]. Another question is how the best urgent TIA service should be organised. National and local healthcare systems have different approaches, also based on available resources: outpatients clinic, admission, stroke risk stratification, emergency physician or stroke neurologist management. No randomised control trials (RCT) are available and most studies present methodological limitations: they are not population-based (a part of EXPRESS study [3]), have a very small sample size [5, 6, 8, 12], with mostly low-risk stroke patients [2, 3], and a retrospective design and outcome detection with questionnaire or telephone call [2, 4, 5, 7, 9]. Several aspects must be considered in organising a TIA service, including the difficulty of TIA diagnosis, and whether a risk score should be adopted for investigational prioritisation. Only about 40% of patients referred by non-neurologist specialists with a suspected TIA had the diagnosis confirmed [13]. It is already known that a low ABCD2 score could be associated with some high-risk subgroups as atrial fibrillation or carotid stenosis requiring immediate interventions [14]. Instead, use of the ABCD2 score after a full initial evaluation to decide on patient admission may reduce the early stroke risk in high-risk patients [15]. Lastly, a TIA care model should ensure the evaluation for thrombolysis therapy within minutes of any subsequent stroke. In August 2010, we implemented an urgent TIA management strategy in the emergency department (ED) of our hospital, adopting a predefined clinical pathway driven by stroke neurologists, and evaluated the shortand long-term stroke outcomes in the first 3 years. This is the first report on a large Italian unselected TIA population.
patients signed an informed consent form and the study was approved by the S. Orsola-Malpighi University Hospital Research Ethics Board of Bologna. Procedures Expedited management was carried out in the ED observation unit within 24 h, implementing a predefined clinical pathway driven by a vascular neurologist (fig. 1). The first-line work-up included immediate neurological evaluation, electrocardiography (ECG), brain CT scan, blood samples (complete blood count, coagulation tests, blood sugar, electrolytes, liver and kidneys test, lipid profile), blood pressure (BP) measurement, supra-aortic echo-Doppler, transcranial Doppler (TCD) and standard echocardiogram in the presence of cardioembolic high risk (known valvular disease, prosthetic valvular, dilated cardiomyopathy, new atrial fibrillation and recent myocardial infartcion) within 24 h. ABCD2 score was also recorded. Then the neurologist evaluated the vascular global risk profile and immediately decided on discharge or admission for at least 24 h. Admission was reserved for higher stroke risk patients such as those with TIA >1 h, recurrent TIA within the previous 72 h, new cardioembolic origin, carotid surgery need, intracranial symptomatic stenosis, ABCD2 score ≥4, and monitoring need also for severe active co-morbidity. A second-level assessment including standard and transesophageal echocardiogram, prolonged ECG and BP monitoring, CT or MR-angiography, MRI and diffusion-weighted (DW) MRI, bubble TCD study, thrombophilia testing, and infrequent causes search, was directed on the basis of neurological discernment and when a cryptogenetic origin persisted. Computerised platform management warranted the second-level investigations as outpatients within 2 weeks for the patients discharged immediately. Therapeutic interventions were based on Italian stroke guidelines [17]. Antiplatelet therapy (aspirin 100 mg/die), was initiated immediately except in patients with a cardioembolic origin where anticoagulants were the first choice. Hypertension was defined as medical history or BP ≥140/90 mm Hg and hypercholesterolemia was identified by medical history or blood cholesterol of 240 mg/ dl and above. Antihypertensive therapy was started or modified to obtain a target level of less 140/80 and 130/85 mm Hg in non-diabetic and diabetic patients, respectively. Statins were prescribed to achieve a low-density lipoprotein (LDL) target ≤100 or ≤70 mg/dl on the basis of a moderate or higher vascular risk profile, respectively. Each patient was given a leaflet on stroke prevention. Information on diagnosis, therapy, and follow-up was reported on a discharge card for the general practitioner.
Methods
2
Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
Follow-Up and Outcome All patients included were followed in a neurovascular clinic at 1, 3, and 12 months and subsequently once a year. The followup ended on December 31, 2013. Endpoints were all stroke at 90 days, all stroke and the combination of stroke, myocardial infarction, and vascular death at 12, 24, and 36 months. The risk of ischaemic stroke at 3 months was also compared with that expected by ABCD2 score. Stroke was defined following the WHO definition [16]. The outcome events were recorded by a vascular neurologist during face-to-face interview and medical records were reviewed when outcomes were reported. For patients lacking the predefined follow-up and not contactable, close relatives were interviewed and any hospital linkages after TIA were recruited and
Guarino et al.
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Study Design and Population We performed a prospective observational cohort study at the S. Orsola-Malpighi University Hospital (Bologna, Northern Italy). This is a teaching hospital with a Neurology Unit, Thrombolysis Center and Stroke Unit, covering a population of about 250,000 inhabitants. We evaluated all consecutive patients (over 14 years) presenting at the ED from August 1, 2010 to July 31, 2013 with signs and symptoms consistent with TIA and confirmed by a vascular neurologist. TIA definition was a sudden, focal neurological deficit lasting less than 24 h, presumed to be of vascular origin, and confined to an area of the brain or eye perfused by a specific artery [16]. All
ED admission Suspected TIA No TIA
First-line diagnostic work-up in ED - Neurological evaluation - ECG, blood pressure - CT brain - Blood tests - Supra-aortic echo-Doppler and transcranial Doppler - Echocardiogram Secondary prophylaxis - Antiplatelet/anticoagulation, statin, antihypertensive drugs
Specific clinical pathway
ZLWKLQK
TIA confirmed and taken on by a vascular neurologist
Presence of: 7,$KRXU - Recurrent TIA - Symptomatic extra and intracranial stenosis - New cardioembolic aetiology - ABCD2VFRUH - Monitoring need
Yes
No
Admission
Discharge home with second level assessment reservation (when indicated)
Neurovascular follow-up at PRQWKVRQFHD\HDU
Fig. 1. Flow diagram of the TIA care model.
Statistical Analysis Analysis was carried out using the SPSS software package (version 15; SPSS Inc., Chicago, Ill., USA). Fisher’s exact tests were used to compare stroke risk at 3 months and expected risk by ABCD2 score and stroke risk in discharged and non-discharged patients. The expected stroke risk by ABCD2 score was calculated as the product of the risk for each ABCD2 score category (0–3, 4–5, 6–7) measured according to Johnston et al. [19] in the enrolled patients in each ABCD2 score category and then the sum of expected events was divided by the total number of patients. The cumulative incidence rate of stroke and of combination of stroke, myocardial infarction, and vascular death during follow-up were measured according to the Kaplan-Meier method. The significance level was set at α = 0.05. Results are given as means ± SD, interquartile range (IQR), and 95% confidence interval (CI).
Bologna TIA Clinical Pathway
Results
From August 1, 2010, to July 31, 2013, 686 consecutive patients presenting with suspected TIA in ED were evaluated by a vascular neurologist. Of these, 433 (63%) had a definite TIA, whereas 253 (37%) were excluded because of TIA mimics. Baseline patient characteristics are reported in table 1. The delay from the onset of symptoms to the first evaluation ranged from 3 h to 6 days, but 95% were assessed within 24 h. Symptoms duration was ≤10’ in 29, 11–59’ in 30 and ≥60’ in 41% of patients. All patients underwent first-line investigations within 24 h, including extra and intracranial echo Doppler ultrasound. On the basis of clinical judgment (generally prolonged TIA duration), 51% of patients had a second brain CT scan at 24 h, which resulted negative for acute ischaemia. Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
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analysed. All TIA and outcome events were validated by a senior vascular neurologist (M.G.) using the TOAST classification [18] for stroke.
TIA patients (n = 433) Demographics Mean age, years, range Male sex, % Vascular risk factors, n (%) Hypertension Hypercholesterolaemia History of TIA or stroke Diabetes mellitus Atrial fibrillation Cardiovascular ischaemic disease Recurrent TIA ≤72 h from index TIA Smoking Symptoms of TIA, n (%) Speech impairment Weakness Findings ABCD2 score ≥4, n (%) Carotid atherosclerotic plaques, n (%) Systolic blood pressure, mm Hg, mean, range Diastolic blood pressure, mm Hg, mean, range
69 (22–98) 51 381 (88) 223 (51) 130 (30) 81 (19) 78 (18) 78 (18) 74 (17) 69 (16) 213 (49) 187 (43) 299 (69) 199 (46) 150 (85–230) 84 (50–140)
Table 2. Observed and expected 90-day risk of stroke
Stroke, % stroke n observed (95% CI) ABCD2 0–3 (n = 134) ABCD2 4–5 (n = 230) ABCD2 6–7 (n = 69) Combined (n = 433)
2 5 2 9
% p expected value risk
1.50 (0.41–5.28) 3.1 2.20 (0.93–4.99) 10 2.90 (0.8–9.87) 17.4 2.07 (1.10–3.90) 9.01
0.68 0.001 0.009 0.0001
Concerning second-level investigations, standard and/or transesophageal echocardiogram were performed in 88% of patients, CT-angiography in 10%, MRI/MR-angiography in 20%, DW MRI in 19%, bubble TCD study in 38%, prolonged ECG and BP monitoring in 52%, thrombophilia testing in 31%, and search for rare causes including genetic disease in 3%. Aetiology based on the TOAST classification [18] was defined in 76% of patients. Largeartery atherosclerosis (defined according the TOAST classification as cortical, brain-stem or cerebellar dysfunction plus significant (>50%) stenosis or occlusion of the extra or intracranial artery and confirmed by CT- or MR-angiography) was the most common cause (26%), 4
Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
followed by small vessel disease in 25%, cardioembolic origin in 22%, and other causes in 3% of patients. In the 23% of patients with a low ABCD2 score (0–3), conditions requiring urgent management were detected (i.e. symptomatic carotid stenosis undergoing surgery, symptomatic intracranial stenosis and cardiac source of embolism as atrial fibrillation requiring immediate anticoagulant therapy). On discharge, antiplatelet therapy was given to 86% of patients, anticoagulants to 20%, both to 6%, with a percentage increase of 110, and 62% respectively versus previous home treatment. Eighty-eight percent of patients received antihypertensive agents and 70% had lipid-lowering treatment, started or modified in more than half of patients. Revascularisation therapy was performed in 45 patients (10.4%), 43 underwent carotid, and 2 vertebral artery revascularisation, with a median time from initial examination of 6 days (IQR 4–10). Thirty-eight percent of patients were discharged after the first-line work-up, while 62% were admitted with a median stay of 4 days (IQR 2–8). All patients were followed up for a median of 19.9 months (IQR 12–30). Ninety-day follow-up was available in all patients, while 334, 225 and 121 patients had a follow-up of 1, 2 and, 3 years, respectively. Information was collected directly for 404 patients (93%), from relatives and clinical records for 29 (7%) patients. Stroke occurred at 90 days in 9 cases, within 24 h after TIA evaluation in 7 (78%), at 1 month and 2 months in the remaining 2 patients. The 7 patients with very early stroke were all admitted at TIA onset, and 5 (71%) underwent intravenous thrombolysis, with a complete recovery. The 90-day stroke rate was 2.07% (95% CI, 1.1–3.9). In the high-risk TIA subgroup (ABCD2 score ≥4), the stroke rate was 2.3% (95% CI, 1.14–4.75). With respect to 90 days stroke expected by ABCD2 score (table 2), the relative risk reduction (RRR) was 77% (95% CI, 51–89) and the absolute risk reduction 7% (95% CI, 4–9) with a number need to treat (NNT) of 14 (95% CI, 11–26). The long-term stroke risk was 2.6% (95% CI, 1.1–4.2), 3.7% (95% CI, 1.6–5.9) and 4.4% (95% CI, 1.9–6.8) at 12, 24, and 36 months, respectively. The composite outcome of stroke, myocardial infarction, or vascular death was 3.5% (95% CI, 1.7–5.1), 4.9% (95% CI, 2.5–7.4) and 5.6% (95% CI, 2.8–8.3) at 12, 24, and 36 months (table 3). All strokes were ischaemic, no intracranial haemorrhage or other bleeding occurred during the follow-up period. Using data linkage no further events were detected. The risk of stroke recurrence did not differ significantly between discharged and non-discharged patients. The clinical features of TIA patients with recurrent disease included mean age of 71 years (range 46–92), male sex in 54%, Guarino et al.
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Table 1. Baseline characteristics of TIA patients
12 months 24 months 36 months
% stroke (95% CI)
% stroke, myocardial infarction, and vascular death (95% CI)
2.6 (1.1–4.2) 3.7 (1.6–5.9) 4.4 (1.9–6.8)
3.5 (1.7–5.1) 4.9 (2.5–7.4) 5.6 (2.8–8.3)
cortical or cerebellar symptoms in 60%, and recurrent TIA within the previous 72 h in 33% of patients. Concerning the aetiology, small vessel disease was detected in 35% of patients, cardioembolic origin in 26% (3 paroxysmal atrial fibrillation, 1 patent foramen ovale), large artery disease in 26% (1 carotid dissection, 2 carotid stenosis, 1 vertebrobasilar stenosis) and cryptogenetic origin in 13%.
Discussion
We performed a prospective study, including unselected TIA patients confirmed by a vascular neurologist, with no loss to follow-up. We considered only definite TIA, whereas other studies included possible TIA [2, 5] or did not require a neurologist at first assessment [5, 7, 9], possibly undermining their results, since TIA misdiagnosis among non-neurologists was reported to be as high as 60% [13]. The outcome events were mostly recorded through a face-to-face neurologist interview, so that minor events were not missed, as they could have been in other studies using mostly questionnaires [4, 5, 7, 9]. We are confident that our sample size represents a near-complete ascertainment of all TIAs, because considering the Italian TIA incidence of 52–58/100,000 person-years [20, 21] and the 250,000 inhabitants referring to our ED, we expected to evaluate 130–145 TIA patients a year and we observed an average 144 definite TIA a year. One limitation of our study was the lack of a control group to compare the expected risk of stroke and other vascular events. However, like the SOS study [2], we used the ABCD2 score, which has also been validated in an Italian population [20] to estimate the early expected stroke risk, and we compared our overall results with the previous findings. In addition to ABCD2 score ≥4 predicting the 2-day high stroke risk up to 8.1% [19], higher stroke risk TIA patients were also defined considering other risk factors such as the longer TIA duration, recurBologna TIA Clinical Pathway
rent TIA, extra and intracranial symptomatic stenosis and new atrial fibrillation, implicated in high early stroke recurrence by several prognostic studies [22–26]. Our stroke rate of 2.07% at 90 days was among the lowest of other rapid-care TIA models. A lower early stroke rate of 2.3% was also found in our high-risk TIA subgroup compared to previous studies reporting a stroke rate of 4.7% [27]. We observed a significantly greater reduction of early stroke risk than expected on the basis of ABCD2 score with an RRR of 77% and an NNT to prevent one early stroke event of 14. Similar results were reported only by the SOS [2] and EXPRESS [3] studies. However, both these excluded patients with a higher risk of recurrent stroke such as those with symptoms at the time of the observation [2] or those requiring immediate hospital admission [3]. Concerning the long-term effects of urgent TIA management, although our cohort included 70% high-risk patients, we found a low stroke rate at 1, 2, and 3 years. Our results at 1 year were marginally higher than those of the SOS study [2], while they were lower than those in the Aarhus study (2.2 and 4.2, respectively vs. 2.6%) [10]. A long-term stroke risk after TIA (34 months) was evaluated only in a small sample [11], but it reported a higher rate (6.2 vs. 4.4%). Our 1-year combined vascular events were 3.5% closer the SOS value [2] (2.8%) and lower than that obtained from the Aarhus study (5.2%) [10]. Our 2- and 3-year risk of composite vascular outcome was also low (4.9 and 5.6%, respectively) compared with observational cohort studies, reporting a cumulative risk of a first vascular event after TIA as high as 6.8 at 1 year and 24.4% at 5 years [28]. Our long-term data after urgent TIA management are the first ever reported, but since a 3-year follow-up was achieved by only about 30% of patients our findings must be confirmed. To date, the best TIA care model is debated both in terms of setting and use of clinical tools to assess risk stratification and prioritise investigations. No RCTs are available to support the superiority of ED evaluation or admission versus outpatients care strategy. A poorer short-term outcome was observed in TIA patients discharged compared with those admitted [29], but the M3T study [7] found no statistically significant difference in TIA patients managed as outpatients versus those admitted. In addition, no definite cost-effective suggestions are available to prefer admission versus outpatient care for TIA patients requiring thrombolysis access [30]. Concerning the role of ABCD2 score in guiding triage Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
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Table 3. Long-term risk of stroke and composite outcome
decision-making, it is known that a low score (0–3) can also be associated with a modifiable high-risk mechanism of developing early stroke if not immediately treated [14]. In addition, by not taking into account vascular imaging or prior TIA, scores like ABCD2 failed to predict stroke risk especially when applied by neurologists [25]. Thus, we think that the ABCD2 score is not reliable to prioritise investigations and cannot replace extensive urgent diagnostic evaluations. Instead, we used an ABCD2 score ≥4 in addition to above-mentioned conditions, for hospital monitoring ≥24 h, because this cut-off per se identifies patients with multiple risk factors for early stroke [19]. Although there is still some uncertainty, hospital admission in these patients, could be safer than immediate discharge even after a complete initial work-up [15]. Thus, we performed a rapid TIA first-line diagnostic work-up in all TIA patients including cervical and intracranial vessel study, irrespective of the ABCD2 score, and we found that 23% of patients with an ABCD2 score
Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
Short- and Long-Term Stroke Risk after Urgent Management of Transient Ischaemic Attack: The Bologna TIA Clinical Pathway Maria Guarino a Francesca Rondelli a Elisabetta Favaretto b Andrea Stracciari a Massimo Filippini b Rita Rinaldi a Ivana Zele c Michelangelo Sartori b Gianluca Faggioli d Susanna Mondini a Andrea Donti e Enrico Strocchi e Daniela Degli Esposti e Antonio Muscari f Maddalena Veronesi e Sergio D’Addato e Luca Spinardi g Luca Faccioli g Marco Pastore Trossello g Fabio Cirignotta a
Neurology Unit, b Angiology and Blood Coagulation Unit, c Emergency Department, d Vascular Surgery Unit, Cardiothoracic and Vascular Department, f Hospital Care and Disability Assistance, and g Neuroradiology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
e
Key Words Transient ischaemic attack · Stroke · Cerebrovascular disease · TIA care models · Long-term vascular outcomes
Abstract Background: Rapid management can reduce the short stroke risk after transient ischaemic attack (TIA), but the long-term effect is still little known. We evaluated 3-year vascular outcomes in patients with TIA after urgent care. Methods: We prospectively enrolled all consecutive patients with TIA diagnosed by a vascular neurologist and referred to our emergency department (ED). Expedited assessment and best secondary prevention was within 24 h. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death at 12, 24 and 36 months. Results: Between August 2010 and July 2013, we evaluated 686 patients with suspected TIA; 433 (63%) patients had confirmed TIA. Stroke at 90 days was 2.07% (95% confidence interval (CI), 1.1–3.9) compared with the ABCD2-predicted risk of 9.1%. The longterm stroke risk was 2.6% (95% CI, 1.1–4.2), 3.7% (95% CI, 1.6–5.9) and 4.4% (95% CI, 1.9–6.8) at 12, 24 and 36 months,
© 2015 S. Karger AG, Basel 0014–3022/15/0742–0001$39.50/0 E-Mail [email protected] www.karger.com/ene
respectively. The composite outcome of stroke, myocardial infarction, and vascular death was 3.5% (95% CI, 1.7–5.1), 4.9% (95% CI, 2.5–7.4), and 5.6% (95% CI, 2.8–8.3) at 12, 24, and 36 months, respectively. Conclusions: TIA expedited management driven by vascular neurologists was associated with a marked reduction in the expected early stroke risk and low long-term risk of stroke and other vascular events. © 2015 S. Karger AG, Basel
Introduction
The high risk of stroke following a transient ischaemic attack (TIA) is now well recognised, with an untreated risk of recurrence by 90 days up to 17% [1]. Pioneering studies in 2007 [2, 3] showed that urgent TIA management was associated with an 80% reduction in the early risk of stroke recurrence. It was subsequently confirmed that low early stroke rates ranging from 1.7 to 3.2% [4–9] were attainable with timely efficient interventions. However an open question is whether fast track TIA management can maintain its benefit in the long term. The few Maria Guarino Neurology Unit, S. Orsola-Malpighi University Hospital Via Albertoni 15 IT–40138 Bologna (Italy) E-Mail maria.guarino @ aosp.bo.it
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a
studies available on this topic report a 1-year estimated stroke risk of 2.2% [2] (definite TIA with no lesion), 4.4% [10], and 6.2% over 18 months mean follow-up [11]. Another question is how the best urgent TIA service should be organised. National and local healthcare systems have different approaches, also based on available resources: outpatients clinic, admission, stroke risk stratification, emergency physician or stroke neurologist management. No randomised control trials (RCT) are available and most studies present methodological limitations: they are not population-based (a part of EXPRESS study [3]), have a very small sample size [5, 6, 8, 12], with mostly low-risk stroke patients [2, 3], and a retrospective design and outcome detection with questionnaire or telephone call [2, 4, 5, 7, 9]. Several aspects must be considered in organising a TIA service, including the difficulty of TIA diagnosis, and whether a risk score should be adopted for investigational prioritisation. Only about 40% of patients referred by non-neurologist specialists with a suspected TIA had the diagnosis confirmed [13]. It is already known that a low ABCD2 score could be associated with some high-risk subgroups as atrial fibrillation or carotid stenosis requiring immediate interventions [14]. Instead, use of the ABCD2 score after a full initial evaluation to decide on patient admission may reduce the early stroke risk in high-risk patients [15]. Lastly, a TIA care model should ensure the evaluation for thrombolysis therapy within minutes of any subsequent stroke. In August 2010, we implemented an urgent TIA management strategy in the emergency department (ED) of our hospital, adopting a predefined clinical pathway driven by stroke neurologists, and evaluated the shortand long-term stroke outcomes in the first 3 years. This is the first report on a large Italian unselected TIA population.
patients signed an informed consent form and the study was approved by the S. Orsola-Malpighi University Hospital Research Ethics Board of Bologna. Procedures Expedited management was carried out in the ED observation unit within 24 h, implementing a predefined clinical pathway driven by a vascular neurologist (fig. 1). The first-line work-up included immediate neurological evaluation, electrocardiography (ECG), brain CT scan, blood samples (complete blood count, coagulation tests, blood sugar, electrolytes, liver and kidneys test, lipid profile), blood pressure (BP) measurement, supra-aortic echo-Doppler, transcranial Doppler (TCD) and standard echocardiogram in the presence of cardioembolic high risk (known valvular disease, prosthetic valvular, dilated cardiomyopathy, new atrial fibrillation and recent myocardial infartcion) within 24 h. ABCD2 score was also recorded. Then the neurologist evaluated the vascular global risk profile and immediately decided on discharge or admission for at least 24 h. Admission was reserved for higher stroke risk patients such as those with TIA >1 h, recurrent TIA within the previous 72 h, new cardioembolic origin, carotid surgery need, intracranial symptomatic stenosis, ABCD2 score ≥4, and monitoring need also for severe active co-morbidity. A second-level assessment including standard and transesophageal echocardiogram, prolonged ECG and BP monitoring, CT or MR-angiography, MRI and diffusion-weighted (DW) MRI, bubble TCD study, thrombophilia testing, and infrequent causes search, was directed on the basis of neurological discernment and when a cryptogenetic origin persisted. Computerised platform management warranted the second-level investigations as outpatients within 2 weeks for the patients discharged immediately. Therapeutic interventions were based on Italian stroke guidelines [17]. Antiplatelet therapy (aspirin 100 mg/die), was initiated immediately except in patients with a cardioembolic origin where anticoagulants were the first choice. Hypertension was defined as medical history or BP ≥140/90 mm Hg and hypercholesterolemia was identified by medical history or blood cholesterol of 240 mg/ dl and above. Antihypertensive therapy was started or modified to obtain a target level of less 140/80 and 130/85 mm Hg in non-diabetic and diabetic patients, respectively. Statins were prescribed to achieve a low-density lipoprotein (LDL) target ≤100 or ≤70 mg/dl on the basis of a moderate or higher vascular risk profile, respectively. Each patient was given a leaflet on stroke prevention. Information on diagnosis, therapy, and follow-up was reported on a discharge card for the general practitioner.
Methods
2
Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
Follow-Up and Outcome All patients included were followed in a neurovascular clinic at 1, 3, and 12 months and subsequently once a year. The followup ended on December 31, 2013. Endpoints were all stroke at 90 days, all stroke and the combination of stroke, myocardial infarction, and vascular death at 12, 24, and 36 months. The risk of ischaemic stroke at 3 months was also compared with that expected by ABCD2 score. Stroke was defined following the WHO definition [16]. The outcome events were recorded by a vascular neurologist during face-to-face interview and medical records were reviewed when outcomes were reported. For patients lacking the predefined follow-up and not contactable, close relatives were interviewed and any hospital linkages after TIA were recruited and
Guarino et al.
Downloaded by: Univ. of California Santa Barbara 198.143.33.33 - 7/16/2015 6:52:01 AM
Study Design and Population We performed a prospective observational cohort study at the S. Orsola-Malpighi University Hospital (Bologna, Northern Italy). This is a teaching hospital with a Neurology Unit, Thrombolysis Center and Stroke Unit, covering a population of about 250,000 inhabitants. We evaluated all consecutive patients (over 14 years) presenting at the ED from August 1, 2010 to July 31, 2013 with signs and symptoms consistent with TIA and confirmed by a vascular neurologist. TIA definition was a sudden, focal neurological deficit lasting less than 24 h, presumed to be of vascular origin, and confined to an area of the brain or eye perfused by a specific artery [16]. All
ED admission Suspected TIA No TIA
First-line diagnostic work-up in ED - Neurological evaluation - ECG, blood pressure - CT brain - Blood tests - Supra-aortic echo-Doppler and transcranial Doppler - Echocardiogram Secondary prophylaxis - Antiplatelet/anticoagulation, statin, antihypertensive drugs
Specific clinical pathway
ZLWKLQK
TIA confirmed and taken on by a vascular neurologist
Presence of: 7,$KRXU - Recurrent TIA - Symptomatic extra and intracranial stenosis - New cardioembolic aetiology - ABCD2VFRUH - Monitoring need
Yes
No
Admission
Discharge home with second level assessment reservation (when indicated)
Neurovascular follow-up at PRQWKVRQFHD\HDU
Fig. 1. Flow diagram of the TIA care model.
Statistical Analysis Analysis was carried out using the SPSS software package (version 15; SPSS Inc., Chicago, Ill., USA). Fisher’s exact tests were used to compare stroke risk at 3 months and expected risk by ABCD2 score and stroke risk in discharged and non-discharged patients. The expected stroke risk by ABCD2 score was calculated as the product of the risk for each ABCD2 score category (0–3, 4–5, 6–7) measured according to Johnston et al. [19] in the enrolled patients in each ABCD2 score category and then the sum of expected events was divided by the total number of patients. The cumulative incidence rate of stroke and of combination of stroke, myocardial infarction, and vascular death during follow-up were measured according to the Kaplan-Meier method. The significance level was set at α = 0.05. Results are given as means ± SD, interquartile range (IQR), and 95% confidence interval (CI).
Bologna TIA Clinical Pathway
Results
From August 1, 2010, to July 31, 2013, 686 consecutive patients presenting with suspected TIA in ED were evaluated by a vascular neurologist. Of these, 433 (63%) had a definite TIA, whereas 253 (37%) were excluded because of TIA mimics. Baseline patient characteristics are reported in table 1. The delay from the onset of symptoms to the first evaluation ranged from 3 h to 6 days, but 95% were assessed within 24 h. Symptoms duration was ≤10’ in 29, 11–59’ in 30 and ≥60’ in 41% of patients. All patients underwent first-line investigations within 24 h, including extra and intracranial echo Doppler ultrasound. On the basis of clinical judgment (generally prolonged TIA duration), 51% of patients had a second brain CT scan at 24 h, which resulted negative for acute ischaemia. Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
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analysed. All TIA and outcome events were validated by a senior vascular neurologist (M.G.) using the TOAST classification [18] for stroke.
TIA patients (n = 433) Demographics Mean age, years, range Male sex, % Vascular risk factors, n (%) Hypertension Hypercholesterolaemia History of TIA or stroke Diabetes mellitus Atrial fibrillation Cardiovascular ischaemic disease Recurrent TIA ≤72 h from index TIA Smoking Symptoms of TIA, n (%) Speech impairment Weakness Findings ABCD2 score ≥4, n (%) Carotid atherosclerotic plaques, n (%) Systolic blood pressure, mm Hg, mean, range Diastolic blood pressure, mm Hg, mean, range
69 (22–98) 51 381 (88) 223 (51) 130 (30) 81 (19) 78 (18) 78 (18) 74 (17) 69 (16) 213 (49) 187 (43) 299 (69) 199 (46) 150 (85–230) 84 (50–140)
Table 2. Observed and expected 90-day risk of stroke
Stroke, % stroke n observed (95% CI) ABCD2 0–3 (n = 134) ABCD2 4–5 (n = 230) ABCD2 6–7 (n = 69) Combined (n = 433)
2 5 2 9
% p expected value risk
1.50 (0.41–5.28) 3.1 2.20 (0.93–4.99) 10 2.90 (0.8–9.87) 17.4 2.07 (1.10–3.90) 9.01
0.68 0.001 0.009 0.0001
Concerning second-level investigations, standard and/or transesophageal echocardiogram were performed in 88% of patients, CT-angiography in 10%, MRI/MR-angiography in 20%, DW MRI in 19%, bubble TCD study in 38%, prolonged ECG and BP monitoring in 52%, thrombophilia testing in 31%, and search for rare causes including genetic disease in 3%. Aetiology based on the TOAST classification [18] was defined in 76% of patients. Largeartery atherosclerosis (defined according the TOAST classification as cortical, brain-stem or cerebellar dysfunction plus significant (>50%) stenosis or occlusion of the extra or intracranial artery and confirmed by CT- or MR-angiography) was the most common cause (26%), 4
Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
followed by small vessel disease in 25%, cardioembolic origin in 22%, and other causes in 3% of patients. In the 23% of patients with a low ABCD2 score (0–3), conditions requiring urgent management were detected (i.e. symptomatic carotid stenosis undergoing surgery, symptomatic intracranial stenosis and cardiac source of embolism as atrial fibrillation requiring immediate anticoagulant therapy). On discharge, antiplatelet therapy was given to 86% of patients, anticoagulants to 20%, both to 6%, with a percentage increase of 110, and 62% respectively versus previous home treatment. Eighty-eight percent of patients received antihypertensive agents and 70% had lipid-lowering treatment, started or modified in more than half of patients. Revascularisation therapy was performed in 45 patients (10.4%), 43 underwent carotid, and 2 vertebral artery revascularisation, with a median time from initial examination of 6 days (IQR 4–10). Thirty-eight percent of patients were discharged after the first-line work-up, while 62% were admitted with a median stay of 4 days (IQR 2–8). All patients were followed up for a median of 19.9 months (IQR 12–30). Ninety-day follow-up was available in all patients, while 334, 225 and 121 patients had a follow-up of 1, 2 and, 3 years, respectively. Information was collected directly for 404 patients (93%), from relatives and clinical records for 29 (7%) patients. Stroke occurred at 90 days in 9 cases, within 24 h after TIA evaluation in 7 (78%), at 1 month and 2 months in the remaining 2 patients. The 7 patients with very early stroke were all admitted at TIA onset, and 5 (71%) underwent intravenous thrombolysis, with a complete recovery. The 90-day stroke rate was 2.07% (95% CI, 1.1–3.9). In the high-risk TIA subgroup (ABCD2 score ≥4), the stroke rate was 2.3% (95% CI, 1.14–4.75). With respect to 90 days stroke expected by ABCD2 score (table 2), the relative risk reduction (RRR) was 77% (95% CI, 51–89) and the absolute risk reduction 7% (95% CI, 4–9) with a number need to treat (NNT) of 14 (95% CI, 11–26). The long-term stroke risk was 2.6% (95% CI, 1.1–4.2), 3.7% (95% CI, 1.6–5.9) and 4.4% (95% CI, 1.9–6.8) at 12, 24, and 36 months, respectively. The composite outcome of stroke, myocardial infarction, or vascular death was 3.5% (95% CI, 1.7–5.1), 4.9% (95% CI, 2.5–7.4) and 5.6% (95% CI, 2.8–8.3) at 12, 24, and 36 months (table 3). All strokes were ischaemic, no intracranial haemorrhage or other bleeding occurred during the follow-up period. Using data linkage no further events were detected. The risk of stroke recurrence did not differ significantly between discharged and non-discharged patients. The clinical features of TIA patients with recurrent disease included mean age of 71 years (range 46–92), male sex in 54%, Guarino et al.
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Table 1. Baseline characteristics of TIA patients
12 months 24 months 36 months
% stroke (95% CI)
% stroke, myocardial infarction, and vascular death (95% CI)
2.6 (1.1–4.2) 3.7 (1.6–5.9) 4.4 (1.9–6.8)
3.5 (1.7–5.1) 4.9 (2.5–7.4) 5.6 (2.8–8.3)
cortical or cerebellar symptoms in 60%, and recurrent TIA within the previous 72 h in 33% of patients. Concerning the aetiology, small vessel disease was detected in 35% of patients, cardioembolic origin in 26% (3 paroxysmal atrial fibrillation, 1 patent foramen ovale), large artery disease in 26% (1 carotid dissection, 2 carotid stenosis, 1 vertebrobasilar stenosis) and cryptogenetic origin in 13%.
Discussion
We performed a prospective study, including unselected TIA patients confirmed by a vascular neurologist, with no loss to follow-up. We considered only definite TIA, whereas other studies included possible TIA [2, 5] or did not require a neurologist at first assessment [5, 7, 9], possibly undermining their results, since TIA misdiagnosis among non-neurologists was reported to be as high as 60% [13]. The outcome events were mostly recorded through a face-to-face neurologist interview, so that minor events were not missed, as they could have been in other studies using mostly questionnaires [4, 5, 7, 9]. We are confident that our sample size represents a near-complete ascertainment of all TIAs, because considering the Italian TIA incidence of 52–58/100,000 person-years [20, 21] and the 250,000 inhabitants referring to our ED, we expected to evaluate 130–145 TIA patients a year and we observed an average 144 definite TIA a year. One limitation of our study was the lack of a control group to compare the expected risk of stroke and other vascular events. However, like the SOS study [2], we used the ABCD2 score, which has also been validated in an Italian population [20] to estimate the early expected stroke risk, and we compared our overall results with the previous findings. In addition to ABCD2 score ≥4 predicting the 2-day high stroke risk up to 8.1% [19], higher stroke risk TIA patients were also defined considering other risk factors such as the longer TIA duration, recurBologna TIA Clinical Pathway
rent TIA, extra and intracranial symptomatic stenosis and new atrial fibrillation, implicated in high early stroke recurrence by several prognostic studies [22–26]. Our stroke rate of 2.07% at 90 days was among the lowest of other rapid-care TIA models. A lower early stroke rate of 2.3% was also found in our high-risk TIA subgroup compared to previous studies reporting a stroke rate of 4.7% [27]. We observed a significantly greater reduction of early stroke risk than expected on the basis of ABCD2 score with an RRR of 77% and an NNT to prevent one early stroke event of 14. Similar results were reported only by the SOS [2] and EXPRESS [3] studies. However, both these excluded patients with a higher risk of recurrent stroke such as those with symptoms at the time of the observation [2] or those requiring immediate hospital admission [3]. Concerning the long-term effects of urgent TIA management, although our cohort included 70% high-risk patients, we found a low stroke rate at 1, 2, and 3 years. Our results at 1 year were marginally higher than those of the SOS study [2], while they were lower than those in the Aarhus study (2.2 and 4.2, respectively vs. 2.6%) [10]. A long-term stroke risk after TIA (34 months) was evaluated only in a small sample [11], but it reported a higher rate (6.2 vs. 4.4%). Our 1-year combined vascular events were 3.5% closer the SOS value [2] (2.8%) and lower than that obtained from the Aarhus study (5.2%) [10]. Our 2- and 3-year risk of composite vascular outcome was also low (4.9 and 5.6%, respectively) compared with observational cohort studies, reporting a cumulative risk of a first vascular event after TIA as high as 6.8 at 1 year and 24.4% at 5 years [28]. Our long-term data after urgent TIA management are the first ever reported, but since a 3-year follow-up was achieved by only about 30% of patients our findings must be confirmed. To date, the best TIA care model is debated both in terms of setting and use of clinical tools to assess risk stratification and prioritise investigations. No RCTs are available to support the superiority of ED evaluation or admission versus outpatients care strategy. A poorer short-term outcome was observed in TIA patients discharged compared with those admitted [29], but the M3T study [7] found no statistically significant difference in TIA patients managed as outpatients versus those admitted. In addition, no definite cost-effective suggestions are available to prefer admission versus outpatient care for TIA patients requiring thrombolysis access [30]. Concerning the role of ABCD2 score in guiding triage Eur Neurol 2015;74:1–7 DOI: 10.1159/000430810
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Table 3. Long-term risk of stroke and composite outcome
decision-making, it is known that a low score (0–3) can also be associated with a modifiable high-risk mechanism of developing early stroke if not immediately treated [14]. In addition, by not taking into account vascular imaging or prior TIA, scores like ABCD2 failed to predict stroke risk especially when applied by neurologists [25]. Thus, we think that the ABCD2 score is not reliable to prioritise investigations and cannot replace extensive urgent diagnostic evaluations. Instead, we used an ABCD2 score ≥4 in addition to above-mentioned conditions, for hospital monitoring ≥24 h, because this cut-off per se identifies patients with multiple risk factors for early stroke [19]. Although there is still some uncertainty, hospital admission in these patients, could be safer than immediate discharge even after a complete initial work-up [15]. Thus, we performed a rapid TIA first-line diagnostic work-up in all TIA patients including cervical and intracranial vessel study, irrespective of the ABCD2 score, and we found that 23% of patients with an ABCD2 score
