Introduction
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is associated with increased morbidity and mortality in the globally aging population (1). The prevalence of AF is increasing, primarily due to better diagnostic methods and longer life expectancy (2).
AF is usually classified as clinical or subclinical. The diagnosis of clinical AF, which may be symptomatic or asymptomatic, is established by either a standard 12-lead ECG or a single-lead ECG detecting an episode of AF longer than 30 seconds (3). Subclinical AF refers to asymptomatic individuals with observed episodes of fast atrial rhythm with a frequency greater than >175 beats per minute in an intracardiac electrograms, which have been confirmed as episodes of AF, atrial undulation, or atrial tachycardia (4-6).
AF is one of the preventable risk factors for embolic ischemic stroke (7). The growing prevalence, the high proportion of asymptomatic fibrillation, and the possibility of stroke prevention suggest the need to introduce effective screening for this arrhythmia (8,9). The current recommendation of the European Society of Cardiology (ESC) is to employ opportunistic screening of the population over the age of 65 by palpating the pulse or recording a 12-lead ECG (4).
The most significant issue related to screening, apart from the need for continuous monitoring, is the difficulty of diagnosing AF due to its often paroxysmal nature, which is why we may miss some AF episodes when monitoring in-hospital patients immediately after a stroke (10,11).
Frequently used 24-hour Holter monitoring, in a series of studies on the detection of AF after stroke or transient ischemic attack, showed an AF detection rate between 1.2% and 45%. Despite the high detection rates in some studies, most studies showed a detection rate between 2% and 9%. For comparison, 6.3% of serial 12-lead ECGs recordings in patients with stroke in the first 72 hours after admission detected AF, in a study by Douen et al. Similarly, in a study by Kamel et al., 6.9% of serial 12-lead ECGs in the first 90 days after ischemic stroke detected AF (12-14).
This study aimed to examine the clinical aspects of patients hospitalized for ischemic stroke, especially those with AF, and to determine the frequency and method of detection of AF in these patients. We examined the demographic characteristics of patients, the frequency and adequacy of oral anticoagulant therapy in patients with AF, the comorbidities, and their impact on the frequency of AF.
Patients and Methods
This was a retrospective observational study conducted at the University Hospital Center Split, Department of Neurology. Data on all patients with the leading diagnosis of ischemic stroke (MKB-10 diagnosis I63.0-I63.9) in 2019 were collected from the protocol and medical history. Data for each subject included: age, sex, AF history, history of anticoagulant and antiplatelet therapy, MSCT brain scan and history on pre-existing ischemic stroke, 12-lead ECG, 24-hour Holter monitoring results, and comorbidities (hypertension, diabetes, heart failure (HF), and cardiovascular disease). AF was diagnosed from previous medical records, a 12-lead ECG or Holter monitoring record, and records from implantable cardiac devices. HF was defined according to the current ESC Guidelines, while cardiovascular diseases were defined using the CHA2DS2-VASc score definition (4,15). Age groups of patients were also determined by the CHA2DS2-VASc score groups (≤65, 65-74, ≥75) (4). The CHA2DS2-VASc score was calculated for all patients. The study was approved by the Ethics Committee of the University Hospital Center Split.
All data were analyzed in SPSS 20. Continuous variables were presented as a median and interquartile range, while categorical variables were presented as absolute numbers and percentages. Assessment of the normality of the distribution was performed using the Kolmogorov-Smirnov test. For data processing, we used the χ2 test, the Mann-Whitney test, and logistic regression. The results were interpreted at a significance level of p <0.05. The obtained data are presented in tables and graphs.
Results
In 2019, 887 subjects were hospitalized with a diagnosis of ischemic stroke. Eight were excluded from the statistical analysis; four because of incomplete documentation, and four because the discharge diagnosis was an epileptic seizure, not an ischemic stroke.
The median age of participants was 78 years (Q1-Q3: 69-84 years; min-max: 20-99 years). Of the total number of patients, 424 (48%) were women, with a median age of 81 years (Q1-Q3: 72-86 years; min-max 42-99 years) while 455 (52%) were men, with a median age of 73 years (Q1-Q3; 65-81 years; min-max 20-94). The median age of women was significantly higher than that of men (z = 8.2; p <0.001).
Of all participants, 346 (39%) had AF. Of these, 172 (49.7%) had previously documented AF, while 174 (50.3%) had newly diagnosed AF.
Table 1 shows the relationship between risk factors for the development of AF (and also the components of the CHA2DS2-VASc score) as well as the relationship between the incidence of recurrent ischemic stroke and the incidence of AF.
The probability of developing AF in the group of subjects with HF was higher than in the group of subjects without HF. In this study, the probability of having AF was twice as high in women than in men. There was also a statistically significant association between age groups and AF (Table 1).
The median CHA2DS2-VASc score in the AF group was higher than in the group without AF (z = 9.1) (Table 2).
| CHA2DS2-VASc score MED (Q1-Q3; min-max) | Pa | ||
|---|---|---|---|
| Atrial fibrillation | No | 5 (4-6; 2-9) | <0.001 |
| Yes | 6 (5-7; 2-8) | ||
| Total | 5 (4-6;2-9) | ||
| aMann-Whitney test | |||
The probability of a fatal outcome was higher in the group of subjects with AF than in the group of subjects without it. The probability of a fatal outcome increased with each increase in the CHA2DS2-VASc score by 1 (Table 3).
Furthermore, we conducted multivariate logistic regression for mortality in which mortality was the dependent variable, while the CHA2DS2-VASc score and AF were independent variables. We confirmed the association of both AF and CHA2DS2-VASc score with fatal outcome (Table 3). After conducting logistic regression, the probability of a fatal outcome was 3.1 times higher in the group of subjects with AF (95% CI = 2-4.7; p <0.001), while the probability of fatal outcomes increased 1.5 times with each increase in score by 1 (95% CI = 1.3-1.8).
ANTICOAGULATION THERAPY STATUS OF PATIENTS WITH PREVIOUSLY DIAGNOSED ATRIAL FIBRILLATION
In the group of patients with previously diagnosed AF (49.7% of subjects with AF), we also analyzed the regularity of anticoagulant therapy. Out of the 172 patients who were aware they had AF, 170 were analyzed. According to the data, 125 subjects (73%) did not take anticoagulation therapy at all or did not take it regularly (inadequate INR and medical history on discontinuation of therapy).
Of the total of 172 patients with known AF, 25% (43 patients) were taking vitamin K antagonists. INR values were analyzed in 42 patients, and 83% had INR outside the therapeutic range. 45 patients (26.2%) were receiving NOAC in their therapy, however, 10 of them (22.0%) did not take therapy regularly. As many as 19.8% of respondents were on antiplatelet therapy. Finally, 46 patients (26.7%) were not receiving anticoagulant nor antiplatelet therapy. Therapeutic status was unknown in one patient (0.6%), and 3 patients were on enoxaparin (1.7%).
DIAGNOSIS OF ATRIAL FIBRILLATION IN ALL PATIENTS WITH ISCHEMIC STROKE
In the group of patients with newly diagnosed AF (174 subjects), arrhythmia was mostly detected by a 12-lead ECG, while 24-h Holter monitoring detected AF in 22 patients (12.5%), and a cardiac electronic device (ICD-DR) detected AF in one patient.
24-h Holter monitoring was performed in 400 patients. Among all the patient records examined in the study, 15 (4%) were lacking results from a 12-lead ECG. Of these 15 patients, 13 were in sinus rhythm (87%), while 2 (13%) patients had been previously diagnosed with AF according to medical records.
24-h Holter monitoring was performed in 96 patients (24%) in whom AF had already been diagnosed by 12-lead ECG. The recorded rhythm was AF in 78 (81%) of these patients, while 18 (19%) patients were in sinus rhythm.
Finally, 24-h Holter monitoring was performed in 289 patients with sinus rhythm according to the initial 12-lead ECG. Previously unknown AF was detected in 22 patients (8%), accounting for 5.5% of the total number of subjects (n = 400) in whom 24-hour Holter monitoring was performed (Figure 1).
DIAGNOSIS OF ATRIAL FIBRILLATION IN THE SUB-GROUP OF PATIENTS WITH FIRST ISCHEMIC STROKE
In the group of patients with first stroke (424 subjects), 163 patients (38.4%) had AF, of whom 93 (57.0%) were newly diagnosed. Newly diagnosed AF was mostly detected by a 12-lead ECG (82.7%), while 24-h Holter monitoring detected AF in 15 patients (16%), and a cardiac electronic device (ICD-DR) detected AF in one patient (1.3%).
24-h Holter monitoring was performed in 217 patients with first stroke (n=424). 5 (2.3%) patient records were lacking a 12-lead ECG examination. Of these 5 patients, all five were in sinus rhythm (100%).
24-h Holter monitoring was performed in 51 patients (23.5%), in whom AF was already diagnosed by a 12-lead ECG. In 40 (78.0%) of these patients, the recorded rhythm was AF, while 11 (22%) patients were in sinus rhythm.
Finally, 24-h Holter monitoring was performed in 161 patients (74.2%) with sinus rhythm according to the initial 12-lead ECG. Previously unknown AF was found in 17 patients (10.5%), accounting for 7.8% of the total number of subjects (n = 217) in whom 24-hour Holter monitoring was performed (Figure 2).
Discussion
AF was diagnosed in 39% of the patients with ischemic stroke, and only 50% the total number of patients diagnosed with AF already knew about their condition. The very concerning data obtained from this study, almost 20 years after the AFFIRM study, is that 73% of patients with previously diagnosed AF were not adequately treated to prevent thromboembolic events (16). There is a growing trend in prescribing NOAC in Europe, and in the GLORIA-AF study, 52.3% of patients with newly-diagnosed AF received NOAC (17). Only 23.8% of patients were on NOAC in this study, but one should consider the difference in the price due to which many patients in this community still opt for warfarin.
The incidence of AF was increased threefold in the older age groups in this study. This finding is consistent with the Rotterdam study in which the prevalence of AF also increased with each subsequent age group (18). The incidence of AF was twice as high in women as in men. We must consider that women with stroke in this study were older, which is an important confounding factor. In Friberg’s study, AF was also more common in women with ischemic stroke whose mean age was 5.1 years higher than the mean age of men (19).
The lack of a statistically significant difference in the prevalence of previous ischemic strokes may be explained by a large proportion of lacunar incidents. These are mainly attributed to small blood vessel disease, not cardio embolism, and in this study they were classified as a previous stroke (20). Subjects in this study had high age median, so an increase in the prevalence of lacunar strokes is expected. In a study by Bejot et al., history of AF was significantly more common in patients with non-lacunar infarction than those with lacunar infarction. The same study showed a significant increase in the prevalence of lacunar infarction after the age of seventy (21). Additionally, in a study by Grau et al., the incidence of hypertension and diabetes in patients with ischemic stroke was higher in the group of patients with micro and macroangiopathy than in those with cardio embolism, which may explain the absence of statistically significant differences between the groups (22).
AF is common in patients with HF (23). In this study, HF statistically significantly increased the chance of developing AF, which is consistent with the pathophysiological mechanism of the diseases themselves. AF is known to increase the risk of cardiovascular and overall fatal outcomes (24). In this study, fatal outcomes were three times more likely in patients with AF compared with patients without AF, which is consistent with the research of Keller et al. (25).
We found CHA2DS2-VASc to be a cumulative factor of thromboembolic risk in all patients, including those in sinus rhythm. In a study by Rende et al., the cumulative incidence of ischemic stroke in patients without AF with a CHA2DS2-VASc score ≥4 was similar to the incidence of ischemic stroke in patients with AF and a CHA2DS2-VASc score of 2. A CHA2DS2-VASc score ≥2 was also shown to be a predictor of fatal outcome and AF incidence (26). In this study, patients with AF, as well as with a fatal outcome, had a higher median CHA2DS2-VASc score than the group without AF. These results are important because the literature mentions the possibility of introducing anticoagulant therapy after ischemic stroke in patients who have a high CHA2DS2-VASc score even though they have not been diagnosed with AF.
Components of thromboembolic risk are also risk factors for AF itself, and these results suggest the need for more frequent screening of AF in patients with a higher CHA2DS2-VASc score (27).
Of the 400 24-hour Holter monitoring examinations performed in patients with stroke at this center, 5.5% of them detected unknown AF that was not observed on 12-lead ECG at admission. It should be noted that 4.75% of 24-hour Holter monitoring examinations showed sinus rhythm, and AF was detected only by a 12-lead ECG. A quarter of 24-hour Holter monitoring examinations were performed in patients who already had AF in a 12-lead ECG, which is sufficient for diagnosis according to ESC guidelines (4).
A recent study by Huang et al. focused on this issue, comparing the effectiveness of detecting AF in patients admitted for ischemic stroke with a 24-hour Holter monitoring and serial recording of a 12-lead ECG for five consecutive days. No statistically significant difference was found between these two methods. This approach is more pragmatic and could be considered the first-choice method for the diagnosis of paroxysmal AF among elderly patients with ischemic stroke (28).
This study has several limitations. Firstly, data were collected retrospectively. Data and clinically documented previous ischemic strokes do not detail their characteristics, so analysis of stroke subtypes was not possible. Silent lacunar ischemic strokes, which are very common in the elderly population, have also been reported as a previous ischemic incident, although more commonly associated with microangiopathy (20). History on the regular use of anticoagulant therapy was not completely reliable, so there is a possibility that the compliance of subjects in this study was even lower.
This study has shown that CHA2DS2-VASc score and AF are independent risk factors for death. A high CHA2DS2-VASc score is not predictive of poor outcomes only in patients with AF, but also in patients in sinus rhythm. Therefore, future research should focus on the potential benefits of anticoagulant therapy in this group of patients. The CHA2DS2-VASc score was higher in patients with AF, suggesting the need for more careful monitoring of patients with ischemic stroke and high CHA2DS2-VASc scores, who are more likely to have occult AF (29).