Acta Neurol Scand 2015: 131: 111–119 DOI: 10.1111/ane.12291

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA

Prediction of myocardial infarction in patients with transient ischaemic attack Vilanova MB, Mauri-Capdevila G, Sanahuja J, Quilez A, Pi~ nol-Ripoll G, Begue R, Gil MI, Codina-Barios MC, Benabdelhak I, Purroy F. Prediction of myocardial infarction in patients with transient ischaemic attack. Acta Neurol Scand 2015: 131: 111–119. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – Determinants of risk of myocardial infarction (MI) after transient ischaemic attack (TIA) are not well defined. The aim of our study was to determine the risk and risk factors for MI after TIA. Methods – We prospectively recruited patients within 24 h of transient ischaemic cerebrovascular events between October 2006 and January 2013. A total of 628 TIA patients were followed for six months or more. MI and stroke recurrence (SR) were recorded. The duration and typology of clinical symptoms, vascular risk factors and aetiological work-ups were prospectively recorded and established prognostic scores (ABCD2, ABCD2I, ABCD3I, Essen Stroke Risk Score, California Risk Score and Stroke Prognosis Instrument) were calculated. Results – Twenty-eight (4.5%) MI and 68 (11.0%) recurrent strokes occurred during a median follow-up period of 31.2 months (16.1–44.9). In Cox proportional hazards multivariate analyses, we identify previous coronary heart disease (CHD) (hazard ratio [HR] 5.65, 95% confidence interval [CI] 2.45–13.04, P < 0.001) and sex male (HR 2.72, 95% CI 1.02–7.30, P = 0.046) as independent predictors of MI. Discrimination for the prognostic scores only ranged from 0.60 to 0.71. The incidence of MI did not vary among the different aetiological subtypes. Positive diffusion weighted imaging (DWI) (7.5% vs 2.5%, P = 0.007), and ECG abnormalities (Q wave or ST-T wave changes) (13.6% vs 3.6%, P = 0.001) were associated to MI. Conclusion – According to our results, discrimination was poor for all previous risk prediction models evaluated. Variables such as previous CHD, male sex, DWI and ECG abnormalities should be considered in new prediction models.

Background

Stroke and coronary heart disease (CHD) share common risk factors and pathological mechanisms (1, 2). Moreover, CHD is an important cause of death in patients with cerebrovascular disease (3). Autopsy studies have shown that patients with transient ischaemic attack (TIA) and stroke have a high prevalence of asymptomatic CHD (4–7), which ranges from 15% to 60%. The annual incidence of MI in these patients is between 1 and 2%, which approximately doubles the incidence of the general population (3, 8, 9).

M. B. Vilanova1, G. Mauri-Capdevila2, J. Sanahuja2, A. Quilez2, G. Pi~nol-Ripoll2, R. Begue3, M. I. Gil3, M. C. Codina-Barios2, I. Benabdelhak2, F. Purroy2 1 Centre d’atencio primaria Igualada Nord, Consorci Sanitari de l’Anoia, Igualada, Spain; 2Stroke Unit, Hospital Universitari Arnau de Vilanova, Grup Neurociencies Cl ıniques IRBLleida, Lleida, Spain; 3 Institut de diagnostic per la Imatge, Hospital Universitari Arnau de Vilanova, Grup Neurociencies Cl ıniques IRBLleida, Lleida, Spain

Key words: risk factors; transient ischaemic attack; myocardial infarction; coronary disease; prognosis; incidence F. Purroy, Stroke Unit, Department of Neurology, Professor Universitat de Lleida, IRBLleida, Hospital Universitari Arnau de Vilanova deLleida, Avda Rovira Roure, 80, Lleida 25198, Spain Tel.: +34 973248100 Fax: +34 973785367 e-mail: [email protected] Accepted for publication July 14, 2014

Whether patients with stroke and TIA should be investigated for CHD remains a matter of debate (10). The relevance of coronary investigations strongly depends on the prevalence of asymptomatic CHD, the spontaneous risk of coronary events and the feasibility of preventive therapies (3). It is therefore essential to determine highest-risk patients who will benefit mostly from specific additional therapeutic measures so as to prevent an episode of CHD. Lately, the American Heart Association has stated that validated prediction models for longterm cardiovascular risk in patients with ischaemic stroke or TIA are not available (1). 111

Vilanova et al. The purpose of our study was to determine the risk and predictors of myocardial infarction (MI) after a TIA and to investigate the capacity of some existing prognostic models to accurately select those patients who are most likely to develop episodes of CHD. Methods Patient selection and diagnostic protocol

Consecutive patients with incident TIA were prospectively enroled between October 2006 and January 2013 [REGITELL registry (11)]. TIA was defined as a reversible episode of focal neurological deficit of ischaemic origin that resolved itself completely within 24 h (12). The diagnosis of TIA was made by a single senior stroke neurologist who attended all patients within the first 48 h after the onset of symptoms. Neuroimaging was performed in all cases. Patients with previous stroke or TIA were also included. We excluded a total of 55 patients with transient clinical episodes attributable to causes other than brain ischaemia: rheumatoid pachymeningitis (one case), cervical myelopathy (two cases), cerebral tumours (eight cases), hyponatremia (one case), hypoglycaemia (five cases), migraine (15 cases), psychosomatic disorders (10 cases), cerebral amyloid angiopathy (three cases), subdural haematoma (three cases) and transient global amnesia (seven cases). The study was approved by the ethics committee of the Arnau de Vilanova University Hospital. Written informed consent was obtained from all study participants. The duration and typology of clinical symptoms, vascular risk factors and aetiological work-ups were prospectively recorded. The punctuation in six established prognostic scores was also registered: ABCD2 (13), ABCD2I (14), ABCD3I (15), Essen Stroke Risk Score (ESRS) (16), California Risk Score (17) and Stroke Prognosis Instrument-II (18). Baseline vascular risk factors

Hypertension was defined as a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or current use of antihypertensive medications (19). Cigarette smoking was defined as present if the patient reported smoking cigarettes during the past five years. Alcohol consumption was defined as present if the patient reported an alcohol intake >20 gr. per day during the past five years. Hypercholesterolaemia (HCL) was defined as a total cholesterol concentration 112

>220 mg/dl or the current use of lipid-lowering agents. Diabetes mellitus was defined as a history of fasting glucose ≥126 mg/dl (20) or the current use of hypoglycaemic medication. Age, gender, history of CHD, heart failure, atrial fibrillation, valvular heart disease and peripheral artery disease (PAD) were also recorded. Pathological Q wave on ECG was also recorded. It was defined as any Q wave in leads V2–V3 ≥ 0.02 s or Q wave≥0.03 s and ≥0.1 mV deep in other leads (21). Ultrasonography study

High-resolution B-mode and Doppler ultrasonography of the carotid arteries were performed on a Micromaxx device from 2008 to 2010 and on a Toshiba applio after 2010. Common and internal carotid arteries were examined in the anterolateral, posterolateral and mediolateral directions. A plaque was defined as a focal structure encroaching into the arterial lumen of at least 0.5 mm (22). Cervical atherosclerosis was categorized by Eco Doppler, according to Society of Radiologists in Ultrasound Consensus Conference criteria (23) as follows: absent; mild, if one or both internal carotids arteries (ICAs) had 70% stenoses. Neuroimaging

All TIA patients underwent cranial CT on a multislice MX8000 Philips spiral CT scanner (Philips Healthcare, Best, the Netherlands) with four rows of detectors. Patients who presented a non-ischaemic brain lesion that could explain their acute symptoms were excluded. The MRI protocol was described previously (11). A total of 531 (84.6%) patients were evaluated by MRI within seven days {4.1 [standard deviation (SD) 2.2] days} of symptom onset. Before the MRI examination, all cases had been studied with non-enhanced CT. Tissue abnormality was defined as areas of high signal intensity on isotropic DWI with corresponding acquired diffusion coefficient dark lesions reflecting an acute ischaemic lesion. Neuroradiologists, blinded to clinical features, established the presence of DWI abnormalities. Classification of stroke subtypes

TIA aetiology was classified as large-artery atherosclerosis (LAA), cardioembolism, small-artery

Risk and predictors of myocardial infarction after TIA or lacunar, undetermined, or uncommon according to the trial of ORG 10172 (TOAST) criteria (24). LAA was defined as >50% narrowing of the ipsilateral internal carotid artery lumen or intracranial vessels lumen on imaging, including Doppler or duplex ultrasound, magnetic resonance angiogram (MRA) or computerized tomographic angiography (CTA). Clinical endpoints

The primary outcome measure was the occurrence of MI. MI was defined as an episode of precordial chest pain accompanied by electrocardiography abnormalities including Q waves or marked ST-T changes and release of cardiac biomarkers (21). Stroke recurrence (SR) was also recorded and defined as ‘rapidly developing focal (or global) clinical signs of cerebral dysfunction that lasted more than 24 h with no apparent cause other than a vascular origin’ (25). Face-toface clinical interviews were performed during follow-up at seven days, three months, six months and every year. Minimum follow-up after TIA was six months. All MI events were confirmed by a cardiologist. We also established a secondary combined endpoint: MI, stroke recurrence and vascular death. Statistical analysis

Statistical analysis was performed with the SPSS statistical package (IBM, Armork, NYSE, USA), version 17.0. Cumulative event-free rates for the time to an ischaemic event were estimated by the Kaplan–Meier product-limit method. The incidence of CHD after TIA was determined using incidence rate: we plotted the proportion of patients who had an outcome against the average follow-up time. The statistical significance of intergroup differences was assessed using the v2 test for categorical variables and Student’s test and the Mann–Whitney U test for continuous variables. Univariate analysis was performed to detect variables associated with the occurrence of MI. We used proportional hazards regression analysis to examine the associations between clinical variables and the occurrence of MI and the combined endpoint after TIA. Those variables showing P < 0.1 on univariate testing were included into the multivariable predictive model. Discriminatory power of the established prognostic scores was calculated from the area under the receiver-operating characteristic curve (AUC) for a 95% confidence interval (CI) using standard methods. Ideal discrimination produces an AUC

of 1.0, whereas discrimination that is no better than chance produces an AUC of 0.5. A probability value 50% was associated with the appearance of a combined endpoint. The same as with MI; hypertension, previous CHD, previous PAD, positive DWI and ECG abnormalities were also associated with the combined endpoint. In the Cox proportional hazard multivariate analyses (Table 2), previous CHD [hazard ratio (HR) 5.65, 95% confidence interval (CI) 2.45– 13.04, P < 0.001] and sex male remained as an independent predictor of CHD (HR 2.72, 95% CI 1.02–7.30, P = 0.046). Furthermore, in a model in which positive DWI was included, this variable also remained as an independent predictor for the endpoint (HR 3.40, 95% CI 1.30– 8.92, P = 0.013). Previous coronary disease (HR 2.70, 95% CI 1.55–4.69, P < 0.001), positive diffusion (HR 2.21, 95% CI 1.30–3.75, P = 0.003) and the presence of carotid plaques (HR 3.34, 113

Vilanova et al. Table 1 Univariate analyses of variable associated with myocardial infarction and the combined endpoint after transient ischaemic attack Myocardial infarction Variable Risk factors

Clinical features

Aetiology

ECG MRI Discharge treatment

Age, years (SD) Male Hypertension Previous stroke Diabetes mellitus Coronary disease Smoking Alcoholism Hypercholesterolaemia Peripheral artery disease Previous Atrial fibrillation Cluster TIA Speech impairment Motor weakness Isolated sensory symptoms Vertebrobasilar symptoms Duration 50% Q wave or T negative Positive diffusionn=531 Antiaggregation Anticoagulation Statins Renin-angiotensin blockers Carotid endarterectomy or carotid angioplasty

No (n = 600)

Yes (n = 28)

70.6 (11.9) 338 (56.4) 393 (65.5) 118 (19.8) 179 (29.8) 74 (12.3) 83 (13.8) 17 (2.8) 194 (32.3) 18 (3.0) 70 (11.7) 132 (22.2) 373 (62.8) 301 (50.8) 48 (8.0) 62 (10.3)

71.0 (12.3) 23 (82.1) 24 (85.7) 6 (21.4) 9 (32.1) 16 (57.1) 7 (25.0) 2 (7.1) 16 (57.1) 4 (14.3) 3 (10.7 7 (25.0) 12 (44.4) 19 (67.9) 2 (7.1) 4 (14.3)

70 (11.7) 211 (35.2) 319 (53.2) 104 (17.3) 182 (30.3) 223 (37.2) 91 (15.2) 330 (55.0) 74 (12.3) 38(6.3) 198 (39.1) 480 (80.0) 122 (20.3) 245 (40.8) 303 (50.5) 20 (3.3)

5 (17.9) 8 (25.0) 15 (53.6) 7 (25.0) 8 (28.6) 9 (32.1) 4 (14.3) 19 (67.8) 7 (25.0) 6 (21.4) 16 (66.7) 24 (85.7) 5 (17.9) 17 (60.7) 15 (53.6) 0 (0)

Combined endpoint P

No (n = 535)

Yes (n = 93)

0.855 0.007 0.027 0.829 0.794

Prediction of myocardial infarction in patients with transient ischaemic attack.

Determinants of risk of myocardial infarction (MI) after transient ischaemic attack (TIA) are not well defined. The aim of our study was to determine ...
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