Wpływ wybranych czynników sercowo-naczyniowych na bezpieczeństwo i skuteczność dożylnego leczenia trombolitycznego u chorych z niedokrwiennym udarem mózgu w codziennej praktyce w szpitalu w rejonie wiejskim

Introduction

The co-occurrence of heart and cerebrovascular diseases is very common. This is related to common risk factors and in many cases similar etiopathogenesis and therapeutic decisions that are mutually dependent on each other. According to previous studies, cardiogenic etiology occurs in 22–39% of ischemic strokes [1]. Studies using prolonged cardiac monitoring indicate higher incidence of serious arrhythmias, which leads to the conclusion that cardiogenic stroke occurs in a greater proportion.
Cardiac and electrocardiogram (ECG) abnormalities are common in acute stroke patients, especially if the insular cortex is involved [2, 3]. Cardiac dysfunction in stroke patients may be particularly damaging. Within the territory of tissue affected by an acute ischemic stroke (AIS) intrinsic autoregulation of the vasculature is lost, rendering cerebral blood flow directly dependent only on cardiac function [4]. An admission ECG, cardiac biomarkers and cardiovascular monitoring should be conducted routinely after an acute cerebrovascular event to screen for serious cardiac arrhythmias [5]. Holter monitoring is superior to routine ECG for the detection of atrial fibrillation (AF) in patients anticipated to have thromboembolic stroke [6]. Transthoracic echocardiography (TTE) and especially transesophageal echocardiography (TEE) can detect a potential cardiac source of embolism [7, 8].
Systemic thrombolysis (i.v. thrombolysis) with recombinant tissue plasminogen activator (rt-PA), initiated within 4.5 h of the onset of symptoms, is an effective medical therapy for acute ischemic stroke, but is associated with a number of hemorrhagic complications and is contraindicated in patients with severe hemostatic disorders [5, 9].

Aim of the research

Our study aimed to evaluate the relationship between selected cardiovascular factors, TTE and TEE findings and the long-term functional outcome, the presence of hemorrhagic complications and mortality in Caucasian patients with AIS treated with i.v. thrombolysis in routine practice.

Material and methods

Study design and patients

We prospectively evaluated the clinical and epidemiological data of 286 Caucasian patients with AIS who were consecutively treated with i.v. thrombolysis from January 2008 to December 2012 in the Department of Neurology and Stroke Unit of the Holy Spirit Specialist Hospital in Sandomierz. Our study center was recognized as a stroke unit according to the Polish national criteria and was equipped with the proper monitoring and diagnostic facilities [10]. Our unit provided a 24-h stroke service 7 days a week. All patients were examined at the time of admission by a stroke physician, and the severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) [11]. Stroke was diagnosed on the basis of the ICD 10 criteria and was confirmed on discharge by clinical evaluation and using neuroimaging findings. All biochemical samples were routinely taken at the time of admission and the results of biochemical analyses were obtained before starting i.v. thrombolysis. Computed tomography (CT) scans were performed in all patients upon admission to hospital and between 22 and 36 h after i.v. thrombolysis. In selected cases, especially in case of hemorrhagic complications, additional CT scans were performed according to the patient’s status and clinical indications. Magnetic resonance imaging (MRI) was not routinely performed.
Clinical cardiovascular evaluation was performed through a general physical examination, ECG on admission, 3-day monitoring of heart rate and blood pressure, the Holter-ECG test, chest X-ray and TTE and in selected cases TEE performed according to the current echocardiography guidelines and standards [12]. Assessment of cardiovascular risk factors was also performed. In the evaluation of congestive heart failure (CHF) the following variables were registered: history of heart failure, New York Heart Association functional classification (NYHA) dichotomized as < stage II and ≥ stage II, left ventricular ejection fraction (dichotomized as ≤ 44% and > 44%, left atrium diameter (dichotomized as ≤ 38 mm and > 38 mm for women and ≤ 46 mm and > 46 mm for men) and end-diastolic left ventricular diameter (dichotomized as ≤ 57 mm and > 57 mm for women and ≤ 63 mm and > 63 mm for men). The adopted values of TTE corresponded to moderately and severely abnormal (in accordance with the American Society of Echocardiography Guidelines and Standards) [12]. Cases related to AF, valvular disease, congestive heart failure, patent foramen ovale and aortic embolism were defined as cardiogenic stroke.
Cerebral thrombolysis with the intravenous infusion of rt-PA was administered according to the current guidelines [5, 12]. Patients treated > 4.5 h from the stroke onset and patients treated with combination therapy (intravenous and intraarterial thrombolysis) were excluded from the study.
The 90-day stroke outcomes were measured with the modified Rankin scale (mRS) [13]. A favorable outcome was defined as an mRS score ≤ 2 points, while an unfavorable outcome was defined as an mRS of 3–6 points. Hemorrhagic transformation (HT) and symptomatic intracerebral hemorrhage (SICH) rates were assessed according to the European Cooperative Acute Stroke Study (ECASS) II criteria [14].
The ethics committee approved all data analyses.

Statistical analysis

This study was based on a prospective data analysis. A statistical analysis was performed with Statistica v. 9.1 All continuous variables were tested for normal distribution and equality of variance. Because of the non-normality of the variables, the non-parametric Mann-Whitney U test was used to perform the univariate analysis of the continuous variables. Categorical data were compared using the 2 test. The multivariate analysis was performed using multiple logistic regression. For logistic regression those variables which showed discrimination power p < 0.1 in univariate analysis were selected. The results of the logistic regression models were presented as odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). P-values < 0.05 were considered statistically significant.

Results

In the analyzed group a favorable outcome was found in 56.6% of patients and an unfavorable outcome was identified in 43.4% of patients; 17.8% of patients died within 90 days of the stroke onset. The HT was found in 15.7% of patients, and SICH was found in 4.2% of patients. We found AF in 35.3% and congestive heart failure in 8.4% of patients, but we recognized cardiogenic stroke in 31.5% of patients.
The first abnormal ECG and the presence of AF were more frequent in patients with an unfavorable outcome than in patients with a favorable outcome. There were no differences between groups according to vascular risk factors or TTE and TEE parameters (Table 1). There were also no differences between groups of patients with and without HT according to vascular risk factors or TTE parameters. The presence of an enlarged left ventricle was more frequent in patients with a HT than in those without a HT, but the difference was not significant (Table 2).
The first abnormal ECG and the presence of AF were more frequent in patients who died within 3 months’ follow-up than in those who survived (Table 3). Only median NIHSS score at the time of admission, beyond the presence of AF, and pre-stroke coagulant use, was associated with cardiogenic stroke when compared to patients with other types of strokes. Significant differences in the long-term outcome, HT and SICH rates and mortality between the subgroups of patients with cardiogenic and other types of strokes were not observed (Table 4).
Multivariate analysis showed the impact of AF on the long-term unfavorable outcome and mortality rate. Only the presence of AF was associated with cardiogenic stroke (Table 5).

Discussion

The etiology of stroke is undoubtedly multifactorial. It determines the future management of the patients. If cerebral ischemia is associated with cardiac thrombi, oral anticoagulation is the treatment of choice. Therefore, for the detection of both serious cardiac arrhythmias and subclinical disorders, changes in TTE and TEE are essential.
About 15% of strokes are attributable to documented AF [15]. Epidemiologic studies indicate that many patients with AF on screening ECGs had not previously received a diagnosis of AF. One quarter of AIS are of unknown cause. Subclinical AF is often suspected to be the cause in patients with AIS and without an etiologic factor identified [16, 17]. On the other hand, in 50% to 60% of patients with AF cerebral ischemic incidents were documented [15].
Approximately 1% to 2% of all adults in developed countries have CHF; its prevalence increases steeply with age [18]. Major risk factors for CHF are arterial hypertension, myocardial infarction (MI), valvular heart disease, diabetes and AF [19]. The 1-year survival rate is 55% in CHF patients associated with limitation of moderate activity (NYHA class III) and the 1-year survival rate as low as 5% to 15% in patients with symptoms occurring at rest (NYHA class IV) was found [20]. The prevalence of accompanying AF in CHF patients is 10% to 17%. This is relevant, because AF is associated with increased stroke risk and mortality in patients with CHF [21]. The CHF is a common cause of ischemic stroke [19, 22]. The most frequently recognized reasons for cardioembolic stroke in patients with CHF are thrombus formation due to AF and left ventricular hypokinesia [22]. Patients with CHF are at risk for stroke of large-artery atherosclerosis and small-vessel occlusion [23]. In addition, hypotension in CHF patients is also a risk factor for stroke [24].
In the previous trials evaluating the safety and effectiveness of i.v. thrombolysis with use of alteplase, AF was found with different rates. In the NINDS study, there were 18–20% with AF [25]; in ECASS 1 – 17.5% [26], ECASS 2 – 21.8% [27], ECASS 3 – 12.7% [28] and IST-3 – 31% [29]. In these trials, the incidence and the impact of the CHF on the long-term outcome were not studied.
In the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) AF occurred in 23.2% of patients and was a predictor of symptomatic intracerebral hemorrhage (SICH) (independently from the definition), unfavorable outcome and death, and CHF occurred in 7.3% of patients and was a predictor of unfavorable outcome and death [30]. The previously published paper by Palumbo et al. revealed that clinical diagnosis of CHF, with estimation of the left ventricular ejection fraction, predicts mortality, but not disability, in AIS patients undergoing i.v. thrombolysis [31]. In our sample, we found AF in 35.5% and CHF in 8.4% of patients. Only AF was associated with unfavorable long-term outcome and mortality rate.
In our sample we found 2 cases of patients with AIS after percutaneous coronary intervention (PCI) [32]. Although the overall rate of stroke after PCI is low, ranging from 0.2% to 0.4% [33, 34], it is a complication associated with a high rate of morbidity and mortality [35, 36]. Dukkipati et al. found that the occurrence of stroke was more frequently associated with diabetes mellitus, hypertension, prior stroke, and renal failure and was associated with in-hospital death [33]. De Marco et al. reported 6 cases of periprocedural ischemic stroke complicating cardiac interventions in which immediate cerebral angiography followed by local thrombolysis was the key factor in their successful management [37]. Other authors indicate the possibility of treating such patients using alteplase [38].
Four patients with AIS and concomitant MI on admission were also treated. In half of these cases good long-term outcome was found. The MI is a frequent complication in the acute phase of stroke. On the one hand, brain and myocardial damage may be related to endogenous catecholamine release [39]. On the other hand, in MI left ventricular thrombi occur, appearing mainly in anterior MI. The factors associated with the formation of post-infarction left ventricular thrombus are: apical akinesia, aneurysm, and poor myocardial contractility, especially with an ejection fraction below 35% [40].
A limitation of our study was the lack of echocardiography and ECG-Holter tests in all patients (81.5%). We did not perform these examination in patients who died within the first days of hospitalization or in disturbed patients in whom Holter-ECG monitoring was difficult to perform. Echocardiography at the time of admission was impossible, because of the extension of onset to treatment times, which would be adverse to the outcome of treatment. In the group of patients without echocardiography, there were 72% of all patients who died within 90 days’ follow-up.

Conclusions

It was found that AF is a strong predictor of unfavorable long-term outcome and death in patients with AIS treated with IV thrombolysis in routine practice. Echocardiographic findings which determined long-term outcome, HT and mortality rate were not found. All patients with AIS should undergo complete cardiologic diagnostic tests, including prolonged cardiac monitoring and TTE and TEE.

Conflict of interest

The authors declare no conflict of interest.

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