Trends in clinical features and early outcome in patients with acute cardioembolic stroke subtype over a 19-year period
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.98513
Source of Support: None, Conflict of Interest: None
Objectives: To assess changing trends in clinical characteristics and early outcome of patients with acute cardioembolic stroke (ACS) over a 19-year period. Materials and Methods: Data of 575 patients with first-ever ACS included in the Sagrat Cor Hospital of Barcelona Stroke Registry were analyzed. Changing trends for 1986-1992, 1993-1998, and 1999-2004 periods were compared. Results: A statistically significant increase (P < 0.001) in the age of patients (74.6 years in 1986-1992 vs. 81.4 years in 1999-2004) and the percentage of patients older than 85 years of age (16% vs. 38.2%) was observed. Patients with hypertension increased from 40.5 to 60.8% (P = 0.001) as were patients with diabetes, chronic bronchitis, and obesity (P = NS). The median length of hospital stay decreased from 18 to 12 days (P = 0.031) and prolonged hospital stay (>12 days) from 18.3 to 13.1 (P = 0.033). In-hospital death rate remained around 20%. Conclusions: ACS continues to be a severe ischemic stroke subtype with high risk of in-hospital death. The lack of improvement in the early prognosis over a 19-year period may be explained by an increase in the prevalence of major cardiovascular risk factors and progressive aging of the population.
Keywords: Cardioembolic infarction, epidemiology, risk factors, secular trends, stroke registry
Cardioembolic infarction is a frequent and severe type of ischemic stroke,  with a low chance of full neurological recovery at hospital discharge and a non-negligible risk of early embolic recurrence (1-10%). ,,, Early mortality in these patients may be as high as 27%. ,, However, despite the frequency of cardioembolic stroke, some clinical aspects of the natural course of the disease are still poorly defined. Analysis of data collected from stroke registries is useful to improve our knowledge of the natural history of acute cerebral events. Such analysis, however, will generally be limited to a particular period of time, usually between 1 and 6 years after the recruitment of patients.  Assessment of secular trends in vascular risk factors, clinical features, and outcome of patients with different stroke subtypes is important to improve the quality of care and the design of effective preventive strategies that may contribute to reduce stroke-related healthcare costs. Epidemiological trends for patients with first-ever stroke included in the Sagrat Cor Hospital of Barcelona Stroke Registry have been previously reported.  This prospective stroke registry is one of the largest and oldest hospital-based stroke registries in Spain. A previous analysis for patients with lacunar infarcts has been also published.  The present complementary study is focused on the analysis of the subset of patients with first-ever cardioembolic stroke.
The primary objective of this study was to assess changing trends in clinical characteristics at presentation and early outcome of patients with first-ever cardioembolic stroke seen from 1986 to 2004 using data of the same ongoing hospital-based stroke registry. Secular trends for the periods 1986-1992, 1993-1998, and 1999-2004 were analyzed. The secondary objective was to compare salient features of the cohort of patients with cardioembolic stroke with the cohort of patients with first-ever non-cardioembolic infarction.
Stroke registry and patient selection
Since January 1986, data from all consecutive patients with cerebral infarction or primary cerebral hemorrhage admitted to the Department of Neurology, Sagrat Cor Hospital, Barcelona, have been entered in a prospective database. Data from all the patients are entered following a standardized protocol with 186 items; demographic features, risk factors, clinical characteristics, laboratory and neuroimaging data, complications, and outcome. , The use of the same protocol for all patients ensures completeness of the information in the database. Our institution is an acute-care 350-bedded teaching hospital in the city of Barcelona and serves a population of ~250,000. Patients with symptoms of acute cerebrovascular diseases are attended initially in the emergency department and then admitted to the cerebrovascular division of the Department of Neurology. Patients are routinely admitted to the department when the reason for consultation was an acute stroke, independently of the presence or absence of severe concomitant medical conditions. Stroke subtypes were classified according to criteria of the Cerebrovascular Study Group of the Spanish Society of Neurology,  which is similar to the National Institute of Neurological Disorders and Stroke classification.  Patients with first-ever ischemic infarction were included in the study. Excluded were patients with transient ischemic attack and hemorrhagic stroke. Prior to conducting the study, approval was obtained from Ethical Committee on Clinical Research of the hospital.
Definition of cardioembolic infarction
To classify a patient as having cardioembolic infarction required the presence of a medium-sized (maximal diameter of the lesion 1.5-3 cm) or large (>3 cm) cerebral infarction, cerebral cortex involvement on the brain computer tomography (CT) and/or magnetic resonance imaging (MRI) scans, sudden (minutes) or acute (hours) onset, stroke onset during ordinary daily activities, peak of deficit at onset, duration of focal neurological deficit >24 h, absence of lacunar clinical syndrome, and identification of a commonly accepted cardiac source of embolus in the absence of confirmatory clinical (ipsilateral carotid bruit) or investigative results (Doppler ultrasonography, carotid angiography, or angio-MRI) of lesions (stenosis ≥ 50%) in the ipsilateral supra-aortic trunks. Patients with cerebral infarction documented by neuroimaging studies, who did not meet the criteria of cardioembolic infarction, were classified as non-cardioembolic stroke.
All patients were admitted to the hospital within 48 h of onset of symptoms. On admission, demographic characteristics; salient features of clinical and neurological examination and results of laboratory tests (blood cell count, biochemical profile, serum electrolytes, urine analysis); chest radiography; and 12-lead electrocardiography; and brain CT and/or MRI were recorded. Other investigations, such as angio-MRI, echo-Doppler of the extracranial carotid and vertebral arteries, arterial digital subtraction angiography, two-dimensional echocardiography, and lumbar puncture were performed at the discretion of the neurologist in charge.
Patients were treated in accordance with the recommendations of the Spanish Cerebrovascular Study Group of the Spanish Society of Neurology.  Main strategies included: control of blood pressure with the use of antihypertensive agents in the presence of systolic blood pressure ≥220 mm Hg or diastolic blood pressure ≥120 mm Hg; (b) early treatment of hyperglycemia without the use of glucose infusion; (c) administration of low-dose heparin for preventing pulmonary thromboembolism; (d) early anticoagulation therapy except when antiplatelet therapy was recommended; and (e) physical and respiratory therapy during the patient's stay in hospital. None of the patients received recombinant tissue plasminogen activator because thrombolytic therapy was introduced in our hospital in January 2006.
For each patient, demographic data, vascular risk factors, clinical features, neuroimaging findings, and outcome were recorded. Medical complications (respiratory, urinary, cardiac, vascular, and infectious) and mortality during the acute phase of the disease were recorded. Respiratory complications included aspiration pneumonia, respiratory superinfection, and pulmonary embolism. Cardiac complications were arrhythmia, heart failure, and acute myocardial infarction. Vascular complications were deep venous thrombosis and peripheral arterial embolism. Causes of death were analyzed according to criteria of Silver et al. 
Secular trends were analyzed for three time periods (from 1986 to 1992, from 1993 to 1998, and from 1999 to 2004). Data for the second two periods (1993-1998 and 1999-2004) were compared with the reference category 1986-1992 with the χ2 for trend (the Mantel-Haenszel test) and Bonferroni correction for multiple comparisons. For continuous variables, the analysis of variance (ANOVA) with the Scheffe's procedure for multiple comparisons was used in the case of age and the Mann-Whitney U test with Bonferroni correction for multiple comparisons in the case of length of hospital stay. Statistically significant variables in the cardioembolic cerebral infarct comparison were then compared with the non-cardioembolic cerebral infarct group. Significance for P-values was set at P < 0.05. Analyses were performed using the SPSS-PC + and BMDP computer programs.
The study population included 575 [65.4% females, mean (standard deviation, SD) age 78.6 (9.4) years] patients with first-ever cardioembolic stroke. The non-cardioembolic ischemic infarction consisted of 1507 [52.3% males, mean age 73.4 (12.8) years] patients. The frequency of different cardiac source of emboli included: atrial fibrillation (isolated atrial fibrillation or associated with structural cardiac disease) in 433 (75.3%) patients, ischemic heart disease (acute myocardial infarction, left ventricular aneurysm, left ventricular ejection fraction <40%, akinesia/dyskinesia > or =2 segments) in 119 (20.6%) patients, and rheumatic mitral valvular disease in 94 (16.3%) patients.
Secular trends of cardioembolic infarction
The distribution of patients with cardioembolic stroke during the time periods was: 131 for the 1986-1992 period, 245 for the 1993-1998 period, and 199 for the 1999-2004 period. The demographics, clinical data, neuroimaging findings, and early outcome for patients included in each group are shown in [Table 1].
A statistically significant (P < 0.001) increase in older patients throughout the study period was observed. The percentage of very old patients (≥85 years) increased from 16% in 1986-1992 to 38.2% in 1999-2004 (P<0.001). The distribution of patients by gender did not vary significantly during the study period. In relation to cardiovascular risk factors, the prevalence of hypertension increased significantly from 40.5% in 1986-1992 to 60.8% in 1999-2004 (P = 0.001). Moreover, the percentage of patients with diabetes mellitus, chronic obstructive pulmonary disease (COPD), and obesity also showed an increasing trend, but the differences were not statistically significant. In contrast, the percentage of patients who were heavy smokers (>20 cigarettes/day) decreased significantly from 9.2% in 1986-1992 to 2.0% in 1999-2004 (P = 0.021).
The use of echocardiography also increased significantly from 39.7% in 1986-1992 to 73.9% in 1999-2004 (P < 0.001), and in relation to topography of infarction, there was a significant decrease in the percentage of patients with infarction of the middle cerebral artery (77.9% vs. 59.3%, P = 0.002).
In-hospital mortality rate remained around 20%. The percentage of symptom-free patients with complete neurological recovery at hospital discharge increased from 11.5 to 19.1%, but the difference was not statistically significant. The median length of hospital stay and the percentage of patients with prolonged hospitalization (>12 days) also decreased significantly between the first and the third study periods.
Comparison with non-cardioembolic infarction
The comparison of variables in cardioembolic stroke patients with those in patients with non-cardioembolic infarction is shown in [Table 2]. In the cardioembolic stroke group, there were a lower percentage of males (34.6% vs. 52.3%) and patients were significantly older (mean 79.0 vs. 73.4 years, P < 0.001) than those in the non-cardioembolic stroke group. Atrial fibrillation, topography of infarction in the middle cerebral artery, and use of echocardiography were significantly more frequent in the cardioembolic stroke group. Moreover, cardioembolic infarction was associated with a worse prognosis, with a higher in-hospital mortality rate (21.9% vs. 8.2%, P < 0.001), lower percentage of symptom-free patients at hospital discharge (14.3% vs. 19.9%, P = 0.003), and significantly longer hospital stay and prolonged hospital stay (>12 days) than patients in the group of non-cardioembolic infarction [Table 2].
Little information exists on the comparison of demographic, clinical, and outcome data for different time periods in the characteristics of patients with cardioembolic cerebral infarction admitted to Department of Neurology over a time span. , In agreement with the data from other stroke registries, ,, our results based on the 575 patients with first-ever cardioembolic cerebral infarction and 1507 patients with first-ever non-cardioembolic ischemic stroke showed significant changes regarding age, frequency of risk factors, use of echocardiography studies, and outcome from 1986 to 2004. This evolution is more likely to reflect in part major changes in demographic patterns of patients with acute stroke in developed countries and improvement in acute stroke management and patient referral to the hospital due to the development of the cerebrovascular division.
There was a significant increase in age and percentage of very old patients (≥85 years) across the 19-year study period. This is in accordance with the growing relevance of acute cerebrovascular disease in old patients in Western countries. , As life expectancy continues to increase in industrialized countries, elderly patients will eventually constitute a vast majority of stroke victims.
In our study, there was a significant increase in the percentage of patients with hypertension and a decrease in heavy smokers and middle cerebral artery topography across the study period. The increase in the percentage of patients with hypertension, the main cerebrovascular risk factor in our stroke registry,  may be explained along with other reasons by a change in the criterion of hypertension, using a systolic/diastolic blood pressure level of >160/90 mm Hg before 1999 and >140/90 mm Hg after 1999.  The significant reduction in the percentage of heavy smokers from 9.2% in 1986-1992 to 2.0% in 1999-2004 may be related to the negative trend of this habit in the general population and as a result of public health campaigns, promotion of smoking cessation programs, and the overall public sensibilization to the harmful effects of smoking on health.
In our study, a significant increase in the use of echocardiography examination from 39.7% in 1986-1992 to 66.3% in 1993-1998 and 73.9% in 1999-2004 was observed. This finding is consistent with the general recommendations of diagnostic and therapeutic guidelines for the management of stroke patients. ,
The median length of hospital stay and prolonged hospital stay >12 days decreased significantly. These results tend to confirm in part the benefits of current acute stroke management and are in accordance with the results of other studies. , The most frequent cardiac source of emboli in cardioembolic stroke in a previous study of our group included hyperthrophic hypertensive cardiac disease complicated with atrial fibrillation, isolated atrial fibrillation, rheumatic mitral valve disease, and systolic left ventricular dysfunction of ischemic and non-ischemic cause. 
In comparison with non-cardioembolic stroke, the percentage of very old patients (≥85 years) (28.5% vs. 18.3%) was more frequent and the percentage of males (34.6% vs. 54.3%) was less frequent in cardioembolic stroke. This may be explained as due to the increase in the prevalence of atrial fibrillation with age. In the Framingham study on a growing population, attributable risk of stroke to atrial fibrillation with age was found, with a prevalence of atrial fibrillation of 1.8% in patients aged 60-69 years, 4.8% in those aged 70-79 years, and 8.8% in the 80-90 year group. 
The higher frequency of female patients with cardioembolic infarction as compared with non-cardioembolic infarcts, which were more frequent among males, may also be related to the progressive increase of age in the study sample as it is well known that life expectancy is higher in women than in men.  On the other hand, the higher frequency of atrial fibrillation in the cardioembolic stroke group and the lower frequency of elevated blood pressure, heavy smoking, and diabetes mellitus in comparison with the non-cardioembolic stroke group is also consistent with data reported in most series published in the literature. ,,,,, The lack of prognostic clinical improvement in patients with cardioembolic stroke over a 19-year span despite advances in the management of patients with this stroke subtype attended in the last time period may be explained by the impact of the progressive increase of the patients' ages, particularly of patients over 85 years of age, a situation that involves a higher severity with more neurological sequelae and a higher in-hospital mortality.  The vascular topography involving the territory of distribution of the middle cerebral artery was significantly more frequently found in patients with cardioembolic infarction than in those with non-cardioembolic stroke (68% vs. 46.6%); this coincides with the greater volume of cerebral infarctions mainly affecting the cerebral hemispheres. ,,,
In agreement with other studies, ,, our results show that the short-term prognosis of patients with cardioembolic cerebral infarction is poor in comparison with other subtypes of cerebral infarction, with higher in-hospital mortality (21.9% vs. 8.2%) and a lower percentage of symptom-free patients at discharge from the hospital (14.3% vs. 19.9%).
The present results show that the analysis of prospective stroke registries is a useful tool to characterize better the clinical profile and early outcome of patients with a particular stroke subtype. In patients with first-ever stroke of cardioembolic origin, significant changes between 1989 and 2004 included an increase in the patient's age, frequency of hypertension, and use of echocardiography, whereas the frequency of heavy smoking and the length of hospital stay decreased. Cardioembolic cerebral infarction is a severe subtype of ischemic stroke with a higher risk of early death and lower frequency of symptom-free at discharge as compared with non-cardioembolic ischemic infarctions. The lack of improvement in the early prognosis of cardioembolic stroke patients over a 19-year study period may be explained by an increase in the prevalence of major cardiovascular risk factors and progressive aging of the population.
We thank Miquel Balcells, MD, for the care of many of the patients included, Michael Lowak, MD, Arne Saßmannshausen, MD, Anna Cartanyà, MD, and Noemí Amorós, MD, for valuable collaboration in the collection of data, and Marta Pulido, MD, for editing the manuscript and editorial assistance.
[Table 1], [Table 2]