International Journal of Cardiovascular ResearchISSN: 2324-8602

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Research Article, Int J Cardiovas Res Vol: 5 Issue: 5

Clinical Characteristics of Atrial Fibrillation in First-ever Ischemic Stroke Patients; Results from Malaysia National Neurology Registry

Zariah A Aziz1*, Norsima Nazifah Sidek2, Bahari Awang Ngah3, Irene Looi4, Md Rafia Hanip5, Hamidon B Basri6 and Yvonne Lee YL7
1Department of Neurology, Hospital Sultanah Nur Zahirah, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Malaysia
2Department of Pharmacy, Hospital Sultanah Nur Zahirah, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Malaysia
3Hospital Sultan Haji Ahmad Shah, Jalan Maran, Temerloh, 28000 Pahang, Malaysia
4Department of Medicine, Hospital Seberang Jaya, Prai, 13700 Pulau Pinang, Malaysia
5Department of Neurology, Hospital Kuala Lumpur, Jalan Pahang, 50586 Kuala Lumpur, Malaysia
6Department of Medicine, Universiti Putra Malaysia, Level 3, Block B (Academic), Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
7Health and Value, Pfizer Malaysia, Level 10 & 11, Wisma Averis, Tower 2, Avenue 5, Bangsar South, No. 8 Jalan Kerinchi, 59200 Kuala Lumpur, Malaysia
Corresponding author : Zariah Abdul Aziz
Department of Neurology, Hospital Sultanah Nur Zahirah, Jalan Sultan Mahmud, 20400 Kuala Terengganu
E-mail: [email protected]
Received: July 18, 2016 Accepted: September 09, 2016 Published: September 14, 2016
Citation: Aziz ZA, Sidek NN, Ngah BA, Looi I, Hanip MR, et al. (2016) Clinical Characteristics of Atrial Fibrillation in First-ever Ischemic Stroke Patients; Results from Malaysia National Neurology Registry. Int J Cardiovasc Res 5:5. doi:10.4172/2324-8602.1000278

Abstract

Objective: Clinical implications of atrial fibrillation (AF) are stroke and cognitive dysfunction. AF led to substantial economic burden if not well managed and data is limited in developing countries. We aim to describe the characters of first-ever ischemic stroke patients with AF. Methods: All stroke patients diagnosed with first-ever ischemic stroke enrolled in the multiethnic National Neurology Registry were included in this study. Stroke diagnosis was performed in accordance to the World Health Organization recommendations with corresponding imaging, standard blood and urine tests. Baseline characteristics, risk factors, neurological findings, treatment during hospitalization, complications and outcome data were recorded using standardized electronic case report form. Descriptive and logistic regression analysis was performed. Results: 4762 first-ever ischemic stroke patients were available for analysis from July 29, 2009 to June 1, 2015. 311 (6.5%) had AF and they were 5.6 years older than patients without AF (p<0.001). Patients with AF had severe stroke, poorer functional outcome, increased stroke complications and mortality. Stroke recurrence was not an independent AF risk factor. Increasing age, (OR: 1.07, 95% CI: 1.04-1.10), smoking (OR: 2.60, 95%CI: 1.35-5.06) and stroke recurrence (OR: 4.76, 95% CI: 2.14-10.59) were associated with increased 30-day mortality risk after controlling for confounders. While female gender (OR: 2.31, 95% CI: 1.01-5.27), severe stroke (OR: 1.09, 95% CI: 1.02-1.17) and increased hospitalizations days (OR: 1.21, 95% CI: 1.07-1.38) were related to poorer functional outcome among AF patients. Conclusions: Our hospital-based registry indicates that firstever ischemic patients with AF have markedly reduced functional outcome, increased stroke severity and 30-day mortality compared to patients without AF.

Keywords: Atrial fibrillation; Clinical; Outcomes; Registry; Ischemic; Malaysia

Keywords

Atrial fibrillation; Clinical; Outcomes; Registry; Ischemic; Malaysia

Introduction

Atrial fibrillation (AF) has been widely studied in the Western countries [1-3]. However, there are few published studies about AF in developing countries particularly in South East Asia. AF posed a major public health issues in these developing countries as they transition from communicable to non-communicable diseases [4]. Economic burden of AF was substantial. Rizzo and colleagues estimated annual AF direct health care cost in selected developing countries range from USD 24 million in India to USD 84 million in Turkey, USD 178 million in Russia and USD 397 million in China [5].
Clinical implications of AF are stroke and cognitive dysfunction [6,7]. Framingham longitudinal cohort study suggested that age is a main contributor to development of AF. They observed incidence of AF increases significantly with increasing age. Besides increasing age, several large epidemiological studies reported male gender, hypertension, ischemic heart disease, diabetes, obesity, alcohol use and smoking may increase rate of AF [8,9]. Patients with AF had poorer outcomes with longer hospital stays and in-hospital mortality as described in the Austrian cohort [10].
Stroke is the third leading cause of mortality in Malaysia after ischemic heart disease and pneumonia [11]. The impact of AF on first-ever ischemic stroke patients at the local settings is unknown. Understanding primary determinants of mortality and morbidity may shed lights in identifying new approaches to improve stroke outcome in AF patients. In this study, we aim to examine the characteristics of first-ever ischemic stroke patients with AF and distinguish the factors that were associated with increased mortality and poorer functional outcome in AF patients.

Materials and Methods

Study population
All patients with primary diagnosis of stroke who were admitted at public hospital were prospectively enrolled in the National Neurology Registry from year 2009. The multiethnic NNEUR is a multicenter hospital based registry with 13 participating neurology departments across the country documenting acute stroke patients’ data. All acute stroke patient information was validated by neurologist at each participating sites prior to data entry using the standardized electronic case report form (http://app.acrm.org.my/nneur). Data were retrieved from medical case notes if electronic medical records were not available. Patients who had acute stroke diagnosis greater than 2 weeks of onset will be excluded from registry enlistment. NNEUR study protocol was approved by Ministry of Health medical research and ethics committee
Stroke classification and data definition
Stroke diagnosis was performed in accordance to the World Health Organization recommendations with corresponding imaging, standard blood and urine tests. Stroke etiology subtype was categorized using Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria [12] and Oxford Community Stroke Project classification (OCSP) [13]. AF was diagnosed based on electrocardiogram by treating clinician at hospital admission. Stroke etiology subtypes were reexamined to ensure data consistency for this study.
Documentation of data was performed at admission, during hospitalization and at discharge by neurologist. We recorded baseline characteristics, risk factors, neurological findings, treatment during hospitalization, complications and outcome. Stroke severity was evaluated according to National Institutes of Health Stroke Scale (NIHSS) while functional status (disability) obtained at discharged was appraised by modified Rankin Scale (mRS). NIHSS score quantifies stroke related neurologic deficit based on levels of consciousness, language, neglect, visual field loss, extra-ocular movement, motor strength, ataxia and sensory loss. Mortality outcome is defined as 30 days from stroke diagnosis to death at hospital.
Statistical analysis
Descriptive analysis was computed. Categorical variables were presented in frequency and proportions while continuous variables were shown as mean ± standard deviation. χ2 tests was used to evaluate independence between two categorical variables meanwhile t-test was applied to determine significance between continuous and categorical variables. Logistic regression analyses were performed to identify variables that were significantly associated with increased mortality and functional outcome in AF patients. All statistical analyses were performed with STATA 13 software (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP.). Significance level was established at p<0.05.

Results

A total of 8050 stroke patients were admitted to 13 public hospitals from July 29, 2009 to June 1, 2015. Stroke patients with and without AF diagnosed with first-ever ischemic stroke during this period were extracted for study analysis. Overall, we have 4762 first-ever ischemic stroke of which 5.7% AF were recorded ECG at admission and 2.9% self-reported AF. First-ever ischemic AF patients were 5.6 years older than patients without AF (p<0.001). AF patients had significantly lower BMI values and proportions of smoker compare to patients without AF. Table 1 showed the baseline demographics of the study population. Proportion of AF patients increased with increasing age as illustrated in Figure 1.
Table 1: Baseline demographic characteristics of 4762 first-ever ischemic stroke patients by presence of atrial fibrillation status.
Figure 1: Distribution of atrial fibrillation by age groups and gender among first-ever ischemic stroke.
Clinical characteristics of first-ever ischemic stroke were presented in Table 2. At hospital admission, AF patients found to have increased proportion of moderate and severe stroke as quantified by NIHSS (p<0.001). There was no significant difference in the clinical presentation of symptoms between patients with AF and without AF. Patients with AF had poorer functional outcome (greater disability) and they had increased proportion of stroke complications (Table 3). Stroke associated pneumonia was the most frequent complications recorded. 50.2% of those with AF patients died within 30 days compared to 30.8% patients without AF (excess mortality 19.4%, p<0.001). Furthermore AF patients had increased hospitalization days (excess 2.3 days, p<0.001).
Table 2: Clinical characteristics of 4762 first-ever ischemic stroke patients by presence of atrial fibrillation status.
Table 3: Clinical outcome of first-ever ischemic stroke among patients with and without atrial fibrillation.
We found increasing age, NIHSS score, number of stroke complications, mRS scores and stroke recurrence were associated with increased 30-day mortality risk among patients with AF in univariate logistic regression analysis (Table 4). After adjustment for gender, race, NIHSS scores, mRS scores, risk factors and complications in the multivariate model; increasing age (OR: 1.07, 95% CI: 1.04-1.10), smoking (OR: 2.60, 95%CI: 1.35-5.06) and stroke recurrence (OR: 4.76, 95% CI: 2.14-10.59) remained significantly associated with increased 30-day mortality risk.
Table 4: Factors that influenced 30-day mortality outcome and poor functional outcome among AF patients with first-ever ischemic stroke.
Further analysis was performed to investigate factors related to poorer functional outcome in AF patients. In this cohort, female gender (OR: 2.31, 95% CI: 1.01-5.27), severe stroke (OR: 1.09, 95% CI: 1.02-1.17) and increased hospitalizations days (OR: 1.21, 95% CI: 1.07-1.38) were factors associated with poorer functional outcome among AF patients after controlling for covariates such as age, race, smoking, risk factors and complications in the multivariate model.

Discussion

In this study period (2009 to 2015), 4762 first-ever ischemic stroke patients were admitted, of whom 311 (6.5%) had AF. Our hospitalbased registry indicates that first-ever ischemic patients with AF have markedly reduced neurology deficit, greater disability and 30-day in hospital mortality.
In a systematic review of the profile and burden of AF, Ball and colleagues noted in the general population prevalence of AF ranges from 0.5% (aged 40 years and below) to 12% (aged 85 years and above) [14]. From the Framingham Study [2] of 5070 individuals with 34 years follow up, AF is reported as an independent risk factor for stroke with 3- to 5- fold increased risk. Three large stroke databases from Copenhagen [6], Sweden [15] and Austrian [10] found the prevalence of AF range from 15% to 30% at the time of clinical presentation. The relatively low prevalence of AF in Malaysia cohort may be attributed to the genetic variations of genes that were associated with development of AF [16]. Individuals of non-European ancestry have lower prevalence of AF as shown in large US studies [17,18]. Early stroke onset (younger mean age) is another possible explanation for the small proportion of AF patients observed in this study population.
Accurate assessment of stroke etiology is critical because of the marked difference in the management of stroke subtypes including neurological and medical complications. AF patients with CT brain showing lacunes require extensive investigations apart from the CT, ECG and transthoracic echocardiogram. The proportions of AF patients with lacunar (10.5%) in this cohort is similar to the reported Barcelona Stroke Registry (11.1%) [19]. 6.6% of our AF patients were classified as undetermined and we observed lacunar clinical presentation. Their neuroimaging showed evidence for lacunar infarcts but there was no indication of cardiac source embolism using echocardiogram. Gan and colleagues showed that about 1 in 4 patients presenting with lacunar syndromes that were confirmed radiologically may prove to have non-lacunar infarct mechanism in the Northern Manhattan Stroke Study [20]. A complete diagnostic assessment of large vessels and cardiogenic sources of embolism is warranted in this group of patients as AF may not equate to CE.
Evidence has been well established that age was highly related to AF, results from large epidemiological studies in the United States [2,3], Canada [21] and Scotland [22]. Proportion of AF in our cohort dramatically increased with age, from 6.1% for those 55 to 64 years to 17.7% for those ≥ 75 years. Furberg and colleague showed in their Cardiovascular Health Study that proportion of AF was higher in male patients compared to female patients with increasing age categories [3]. However, in the oldest age groups, absolute number of AF in female essentially outdoes prevalence of AF in male. Our clinical cohort data replicate the same findings in relation to increasing age contribute to increasing proportion of AF in the overall first-ever ischemic stroke. There is gender variation in the AF proportion. AF is generally higher in male than female but in the oldest age categories ( ≥ 75 years), female proportion exceed male. This may simply due to women predominantly live longer.
Clinical risk factors such as diabetes, hypertension [8], heart disease [23], and hyperlipidemia imposed greater burden to predisposition of AF. Interestingly, these comorbidities were not profound in our AF patients and contrast with Western countries except for ischemic heart disease. In this respect, we may rule out the role of these comorbidities as the potential etiologic among AF patients in this cohort. Other risk factor such as obesity has been associated with increased susceptibility to AF. However, the independent role of obesity in the pathogenesis of AF remained to be classified. There were controversial findings in which some studies demonstrated stroke independent association between AF [22,24] and obesity while others showed no relationship [8,23]. Our data showed no relationship between increasing BMI and AF.
As expected, AF patients had poorer neurology deficit, greater disability, increased number of stroke complications and mortality. The present outcomes findings are in accordance to results from other studies which demonstrated stroke patient with AF have poorer outcomes [25-27]. Steger et al. [10] rationalized that increased complications was a results of increased neurology deficit that led to impaired consciousness, immobilization and incontinence. Subsequently, AF patients developed pneumonia [10]. In our cohort, stroke associated pneumonia was the common complications (AF: 23% and without AF: 12.4%). We found increasing age, neurology deficit and recurrent stroke to be major determinant of mortality after controlling for other confounders.
Besides poorer outcome, we observed increased length of hospital stays in AF patients. Many other studies also revealed the similar results that patients with AF had increased number of hospitalizations [28-30]. In the United States, over 14 year period (1985 to 1999), AF hospitalization increased 2 to 3-fold [31]. The increased stroke complications in AF patients may contribute to the prolonged hospital stay. This translates to expanded healthcare costs with longer inpatient stays.
The role of AF as predictor of mortality in stroke is unclear as some investigators reported AF as an independent mortality factor [6,27] while others found contradicting results [32,33]. The effect of AF on mortality was clearly evident in the present study. We observed 2 fold increased mortality risk in stroke patients with AF compared to patients without AF, statistically significant. This finding supports the results from Framingham study which reported 2-fold increased mortality risk [2,27] as well.
Our findings have implication for clinical practice and future research. The strengths of this study include large prospective sample size of patients, clinically meaningful outcome measures and completeness of follow-up at hospital discharge. However, we are limited in classification of AF whether there were paroxysmal, persistent, permanent of recurrent arrhythmia [34]. Also, we may underdiagnose AF in this cohort as some patients may have brief or mild episodes [8].
AF can be asymptomatic and this accounts for significant proportion of the total AF burden. Detection of AF is crucial as delay in AF diagnoses may impede initiation of stroke prevention strategies and lead to debilitating disease, severely impaired quality of life.Primarily, AF is a progressive condition which ranged from primary electrical disturbance to an arrhythmia in response to electrical, structural and functional transformation result from diverse cardiovascular stressors. Hence, development of tools and strategies to detect AF early should be made a priority among clinicians and healthcare policy makers. Last but not least, initiatives are mandated in primary prevention of AF.

Conclusion

Based on the existing evidence, magnitude of AF in this region is unknown. Our first-ever ischemic patients with AF experienced poor neurology deficit, greater disability and mortality outcome. These data are the earliest in Southeast Asia that enable comparison between populations in Asia Pacific and Western countries.

Acknowledgments

The authors thank the Ministry of Health Malaysia for financial support; National Network of Clinical Research Center, MOH, for web-based application support; all affiliated institutes for participating in data collection for this registry; and Dr Rose Izura for reexamining stroke etiology for this study.

Disclosure

Yvonne Y.L. Lee is an employee of Pfizer Malaysia Sdn Bhd. All other authors declared no conflicts of interest.

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