Đặc điểm lâm sàng, cận lâm sàng, các yếu tố nguy cơ đột quỵ của nhồi máu não cấp ở bệnh nhân rung nhĩ không do bệnh van tim tt tiếng anh

- Patients diagnosed with acute stroke ≤ 24 hours caused by cerebral infraction from valvular AF in the study group or without AF in control group, including newly discovered intermitten

INTRODUCTION

Atrial fibrillation is a common arrhythmia of which prevalance increases with ages; at 1% in adults and up to 9% in patients over 80 years old The hardship of atrial fibrillation related diseases includes hospitalizations due to hemodynamic disorders, occlusions, heart failure, stroke and death These conditions usually occur when there are structural or electrophysiological abnormalities of the atria that cause abnormal impulses and/or conduction They are characterized by rapid and irregular depolarization of the atria, and together with the lack of P waves on the electrocardiogram, promote the formation of blood clots and consequently increase the risk of stroke Rates of stroke recorded in patients with atrial fibrillation are 7.04% in China; 4.9% in Taiwan, and 13.3/1,000 in Japan The risk of annual stroke in atrial fibrillation patients reported in community-based studies worldwide is 1.09% The Framingham study has showed a five-fold increase in the incidence of overall stroke in patients with atrial fibrillation In Vietnam, regardless of the lack of national and systematic statistics, from a number of studies, frequency of atrial fibrillation in celebral stroke patients is estimated from about 5%/year (Pham Quoc Khanh- 2010) up to 17.3% (Nguyen Duc Long-2014)

The urgency of the thesis

Atrial fibrillation causes the formation of thrombosis in atrial chambers, usually originating from the left atrium, and therefore requires preventive treatment For valvular atrial fibrillation (artificial heart valve, valve repair surgery, moderate to severe mitral stenosis), anti-vitamin K with INR (International Normalized Ratio) are prescribed to reach a level of 2.0 to 3.0 For non-valvular atrial fibrillation, the thromboprophylaxis strategy is based on stroke risk stratification system using the Cha2DS2-VASc scale, and oral anticoagulants (NOACs-New oral anticoagulants) are additionalled prescribed While cerebral infarction from valvular atrial fibrillation has been well studied, there are still many questions about those from non-valvular atrial fibrillation In some prognosis stroke models, predicting factors often include atrial fibrillation as an important risk factor besides the NIHSS (National Institutes of Health Stroke Scale)

Bayesian Model Averaging (BMA - Bayes inference model) is one of the most popular modelling methods currently utilized worldwide instead of the stepwise regression method The basis of this method is to choose the optimal model based on not only the interaction between important groups of variables but also actual clinical conditions, instead of just calculating one final model final Building regression models concurrently with the development of a nomogram to predict the mortality risk in patients with stroke with nonvalvular AF has attacted many interests because of its usability and flexibility

Thesis content:

This 99-pages thesis includes: Introduction (3 pages), Literature review (36 pages), Study method and population (12 pages), Results (23 pages), Discussion (21 pages), Conclusion (3 pages), and Recommendation (1 page)

Chapter 1

LITERATURE REVIEW 1.1 Overview of nonvalvlar atrial fibrillation

1.1.1 Definition of atrial fibrillation

Atrial fibrillation is classified as a supraventricular arrhythmia characterized by an electrial asymmetry and atrial muscle contraction with following ECG features: varying R-R intervals (while with good atrioventricular conduction), no signs of P waves, irregularities of atrial waves Atrial fibrillation causes hemodynamic consequences associated with abnormal ventricular responses (too fast or too slow) and ataxia between atrial and ventricular Atrial fibrillation’s symptoms are varried: from asymptomatic to fatigue, nervousness, shortness of breath, or severe symptoms such as hypotension, fainting, or heart failure Atrial fibrillation increases the risk of stroke and/or peripheral embolism due to the formation of thrombus in atrial chambers Onset is usually in the left atrium

1.1.2 Classification of atrial fibrillation

In 2016, the Vietnamese Cardiologists Association classified AF based on the time course:

- Paroxysmal: ends spontanously, usually within 7 days of onset The attacks may

reappear with varying frequencies

- Persistent: continuous appearance lasting over 7 days

- Permanent: appears continuously for more than 12 months

- Chronic: atrial fibrillation cannot restore and/or revert sinus rhythm

- Nonvalvular AF: atrial fibrillation occurs when there is no mitral stenosis due to rheumatic heart, no mechanical or biological valve or repair mitral stenosis

1.2 Ischemic stroke in patients with Nonvalvula

1.2.1 Concept

Stroke: loss of functions of localized nerves from any cause Commonly used

interexchangeable with acute stroke due to insufficient blood flow

Acute ischemic stroke: Acute focal neurological defects appear acutely due to

insufficient blood flow

Cerebral infarction: A region of tissues that dies as a result of anemia

1.2.2 Pathophysiology of cerebral infarction stroke

1.2.2.2 Mechanism of recovery

When a stroke occurs, on average every minute, millions of brain cells die in the damaged brain areas due to blocked arteries The most serious damage is the necrotic area

because this is an non-recoverable area The cells surrounding the affected area in the stroke are called “light murals”/“Grey zones” (or “treatment areas”) - although not dead, they have reduced metabolism to a minimum and almost lost all functions The goal of treatment is to restore those areas and restore their activities

1.3 Prognostic models of risk factors of nonvalvular AF

1.3.1 Prognosis studies related to stroke with valvular and/or nonvalvular AF in several hospitals national wide

In 2016, Dang Viet Duc et al conducted a study to investigate the relation and prediction coronary artery disease and Cha2DS2-VASc and Cha2DS2-VASc-HS scores on 94 patients with coronary artery lesions images, and found that Cha2DS2-VASc average score was 3.55 ± 1.29 and that of Cha2DS2-VASc-HS was 5.13 ± 1.46 On coronary angiography image results: average Gensini lesions score was 22.7 ± 20.5 73 patients (77.7%) showed a significant coronary artery stenosis (≥ 50% of vascular diameter) The area under the ROC evaluates prediction of coronary artery diseases of Cha2DS2-VASc and Cha2DS2-VASc-HS scores with areas under the curve (AUC) of 0.77 and 0.81 respectively; The corresponding cut-off points

of the two scales are 3.5 and 4.5 with a sensitivity of 57.5% -72.6% and specificity 81% -71.4% The Cha2DS2-VASc and Cha2DS2-VASc-HS scales have a strong correlation with coronary artery damage on the Gensini scale with r = 0.64 and 0.69 with p <0.05

In 2018, Nguyen Huy Ngoc conducted a study of 308 60+ years-old patients with acute ischemic stroke at Phu Tho General Hospital to determine disease’ independent predictive factors and found that: factors statistically predicting more serious progression during the first

3 days of hospitalization are: having to need supporting oxygen (69.2%); Glasgow coma (below

13 points 31.2%; less than 8 points 5.2%; 8 to 12 points 26.0%) and number of risk factors (two factors 28.3%; three factors 17 , 9%) The study also showed more severe consequences in patients over 75 years of age Other factors include NIHSS score and clinical severity In patients older than 75yo, factors prior to ischemic stroke, including age, gender, and functional status, were identified as independent predictors

1.3.2 Prognosis model by Bayesian Model Averaging (Bayesian Model Averaging) and some initial studies in Vietnam

Linear regression model is one of the most popular statistical models It is the foundation for many other regression models such as logistic regression, binomial regression, and Poisson regression In research, there are two common types of data: quantitative and qualitative data Any type can be an important determinant of research results The most common method to solve problems related to directly impact edfactors is “stepwise regression” However, this approach often proposes non-optimal results because the provided final model often includes some unimportant (false positive) variables Therefore, BMA has recently become one of the most widely used and error-minimizing methods nowaday This is a method based on the Bayesian statistical principle, in which each model has a predetermined probability When in conjunction with actual data, the model can determine variables most related to research outcomes Unlike stepwise regression which proposes only one final model, BMA offers the best 5 models, consequently providing a variety of options depending on implementabilities and actual circumstances /feasibility/flexibility of the model For each model, BMA reports regression coefficients for each prognostic variable, coefficient R2 (coefficient that explains the percentage of variance of model); BIC values (Bayesian Information Criterion - coefficient

“penalty” for the model) and post-probability (post prob - probability of the model appearing

in 100 replicates) A nomogram will be developed to specify the prognostic scale to facilitate the evaluation process

Ha Tan Duc (2015) used BMA on 2,180 general emergency medical patients at Can Tho Central General Hospital who were admitted to the Emergency Department between March

13, 2013 and June 1, 2013 Main outcome was 30-days mortality, evaluated based on clinical characteristics and medical history Cox regression was used to analyze the association between mortality and risk factors to develop a prognosis model of mortality from non-invasive clinical parameters (gender, breathing rate, SpO2, Glasgow coma and treatments in the Department of Emergency Medicine) His study shows that these indices are well-delineated, helping to identify the high mortality risk for internal medicine conditions The selected BMA model has

an AUC of 0.842 (95% confidence interval from 0.809 to 0.875) The author also developed two graphs of mortality prognosis based on nomogram - the procedure used instead of other complex tools to predict prognosis and mortality at admission beds, circumstance of ER

- Patients diagnosed with acute stroke (≤ 24 hours) caused by cerebral infraction from valvular AF (in the study group) or without AF (in control group), including newly discovered intermittent atrial fibrillation at the time of the study or in history (see research criteria in section 2.3.6)

non-2.1.2 Exclusion criteria

- (Cerebral) hemorrhagic strokes

- Stroke from cerebral infraction which already passed the acute stage or brain infarction due

to tumors or injuries

- With valvular heart disease with or without atrial fibrillation according the Vietnam National Heart Association’s 2015 diagnosis guideline, including: rheumatic mitral valve stenosis, rheumatic aortic valve stenosis, using mechanical or biological valves, or after heart valve repair surgery

2.2 Place and time of the study

The study was conducted on 289 patients admitted to the Emergency Department of Bach Mai Hospital and the Vietnam National Heart Institute from March 1, 2013 through December 31, 2017, splitting into two groups:

- Study group includes 138 patients diagnosed with acute cerebral infarction with valvular AF

non Control group consists of 151 patients with acute cerebral infarction with neither atrial fibrillation nor heart valve diseases

2.3 Methods

2.3.1 Study design

This is a case-control study, in combination with descriptive, analytical, and longitudinal follow-up on the targeted groups who have acute stroke with AF (study group) or

without AF or (sinus rhythm - control group) not due to valvular heart diseases who were admitted at Bach Mai hospital’s ER

2.3.2 Study sample

The sample was targeted The sample size was calculated in accordance with control" study’s guideline The goal of the study was to investigate the characteristics of cerebral infarction stroke in patients without valvular heart disease and its associated risk factors

"case-Selected subjects were patients with acute cerebral ischemic stroke without valvular heart disease Patients were classified into 2 groups of (1) the atrial fibrillation group and the non-atrial fibrillation group The risk factors are then explored, described and analyzed to identify those directly related to stroke The hypothetical risk ratio for AF stroke is 2, with type

I error alpha = 0.05 and power = 0.8 Case-control sample size formula is:

n= (1+𝑟)

2 ×𝐶

𝑟 ×(ln 𝑂𝑅) 2 ×𝑝 ×(1−𝑝)

Whereas:

n: Number of patients needed for the study

OR: Odd ratio of cerebral infarction stroke in patients with non-valvular AF, assume OR = 2 p: Population prevalence of risk factors Since there is no previous studies, p of 0.5 is assumed

to maximize sample size

r: Sample size ratio between two groups, choose r = 1

Thus, this study requires 289 patients with non-valvular cerebral infraction, divided into two groups of with and without AF

2.3.3 Variables and indicators in the study

- Variable groups related to general characteristics: age (age group, average age), gender

(male and female), occupation (general labor, intellectual labor, other labor), medical history (hypertension, diabetes (type 1, type 2), dyslipidemia, previous strokes (cerebral infarction, cerebral hemorrhage), heart failure, vascular disease, combination pathology)

- Variables group related to clinical and subclinical characteristics:

+ Clinical symptoms: functional symptoms (paralysis, speechless/lisp/difficulty speaking, headache, dizziness/dizziness, fatigue, urination), physical symptoms (Glasgow coma , stroke assessment score (NIHSS)

+ Subclinical characteristics: echocardiography, CT-scanner (Computerized Tomography scanner), MRI (Magnetic resonance imaging), blood tests (red blood cells, leukocytes, hemoglobin, platelets, hemostasis), blood biochemistry (urea, creatinine, AST, ALT, glucose, HbA1c, blood lipids (total cholesterol, triglycerides, HDL-C, LDL-C))

- Variables group related to risk factors for ischemic stroke:

+ Factors related to the disease: onset time of cerebral infarction stroke (day and night); location (at home, work, on the road, unknown); comorbidities (none, in combination with other (2+) diseases

+ Patient-related factors: age/age group, gender, history of comorbidities (newly

diagnosed/acquired for many years); level of compliance to treatment (medication compliance, follow-up/periodic exams)

+ Treatment-related factors: the time from the onset of symptoms to the time of admission; time from admission to treatment intervention; treatment methods (mere internal medical treatment, combined treatment with venous/thromboembolism, instrumental therapy, combination therapy); treatment outcome (life/death), and average number of hospitalized days in hospital

- Variable group related to 30-day mortality prognosis in patients with acute MI due to atrial fibrillation: Prognostic variables included in Bayesian regression model (BMA): study

group (atrial fibrillation / non-atrial fibrillation), gender, age, Glasgow score, 24-hour NIHSS score, time from onset to intervention, intervention method (thrombosis, thromboembolism + vascular intervention, vascular intervention, internal medical treatment), medical history (hypertension, prior strokes, coronary artery disease, dyslipidemia, heart failure, diabetes), Cha2DS2 score -VASc scores Modelling will produce the most meaningful and predictive variables to build the nomogram

2.3.4 Utilized Medical equipment

- Computer tomography scan SOMATOM sensation 64, with Simen transducer, Germany made

- Magnetic resonance imaging machine 1.5 Tesla, Avanto of Simen, Germany

- 12-lead ECG recorder Nihon Kohden, Japan manufacturer

- Hematological analyzer at the Department of Hematology at Bach Mai Hospital

- Blood biochemical analyzer at Department of Biochemistry of Bach Mai Hospital

- AL-PK2 blood pressure monitor, manufactured by Tanaka Sangyo, has a tolerance of 3mmHg, made in Japan

- Littmann Classic II Infant Stethoscope 2114, made in USA

- Aurora temperature clamp, manufacturer Zhmie GMBH, originated from Berlin, Germany, measuring range from 35 to 42 degrees C, imported by Hanoi Medical Materials Company

2.3.5 Standards used in research

2.3.5.1 Diagnostic Criteria for acute stroke

Patients diagnosed with acute cerebral infarction when they meet the stroke diagnosis criteria of the World Health Organization (WHO) including:

- Sudden onset with clinical manifestations of localized or generalized neurological dysfunction lasting more than 24 hours or leading to death with no apparent cause other than brain vascular injury

- Time from onset to admission is no more than 24 hours

- Assessing the severity of stroke using NIHSS brain health assessment scale (Appendix 4) and/or images of cerebral infarction lesions on CT scan or MRI

2.3.5.2 Diagnostic criteria for atrial fibrillation

Atrial fibrillation is defined based on American Heart Association and European Heart Association ACC/AHA/ESC 2016 standards using the ECG:

+ RR intervals are varying

+ No clear sign of P waves on the electrocardiogram Some clear and regular atrial electrical activities can be observed in some ECG leads, commonly in V1

+ The length of the atrial cycle varies and is often less than 200 milliseconds over 350 cycles/minute))

2.3.5.3 Criteria for diagnosis of sinus rhythm

- P waves in front of the QRS complex; Positive P waves in DI, V5 and negative in aVL

- That P wave is at a constant distance from QRS, and usually lasts 0.1 to 0.2 seconds

2.3.5.4 Standards for non-valvular diseases

Not suffering from valvular heart diseases includes: no rheumatic mitral stenosis, no mechanical nor biological heart valve, no mitral stenosis repair

2.3.5.5 CHA 2 DS 2 -VASc Scale for assessing the risk of thrombotic stroke in patients with non-valvular atrial fibrillation

Table score

Table 2.1 CHA 2 DS 2 -VASc Scale scoring for assessing the risk of thrombotic stroke in

patients with non-valvular atrial fibrillation

(Congestive Heart Failure) (Hypertension)

2.3.5.6 Diagnostic Criteria for comorbidities

Heart failure: As recommended by the Vietnam National Heart Association 2015

(based on Framingham criteria), patient has a confirmed diagnosis when possessing all major criteria or a combination of one major criteria and 2 minor criteria Specifically: (1) Major criteria: Paroxysmal nocturnal dyspnea or orthopnea; neck vein distension; pulmonary rales; cardiomegaly; acute pulmonary edema; third heart sound gallop; systematic venous pressure above 16 cm H2O; circulation time over 25 seconds; positive hepatojugular reflex (2) Minor criteria: ankle edema; nocturnal cough; dyspnea on exertion; hepatomegaly; pleural effusion; Living capacity decrease by 1/3 compared to the maximum; tachycardia (120+ beats/min) (3) Other criteria: weight loss of 4.5kg/5 days of treatment of heart failure

Hypertension: According to the Vietnam National Heart Association 2015

recommendations, hypertension is defined as systolic blood pressure (maximum blood pressure) above 140mmHg and/or diastolic blood pressure (minimum blood pressure) Over 90mmHg

Diabetes: Diagnosed based on meeting one of the following three criteria as

recommended by the Association of Diabetes and Endocrinology in 2018 Specifically: (1) History of diabetes (type 1 or type 2 diagnosed) ); (2) Fasting blood glucose above 7.1 mmol /

l or 2 hours after eating / (hyperglycemia testing above) / (oral glucose tolerance test ??) of 11.1 mmol / l (twice on two consecutive days - excluding hyperglycemia due to psychological stress); (3) HbA1c above 6.5% in international standard labs

Vascular disease: Per recommendations of the European Heart Association 2011,

includes: Myocardial infarction (history of scarring/infarction scarring observed in

echocardiography); Peripheral vascular disease (history/angiographic ultrasound or computerized tomography); aortic atheroma (ultrasound of the chest wall/esophagus or computerized tomography)

2.3.5.7 Classifying Criteria of different assessment scales

Glasgow coma: classified into three levels based on the total score: (1) Mild level

(Glasgow coma from 13 to 15 points); (2) moderate level (Glassgow coma score from 9 to 12 points) and (3) severity (Glasgow coma score from 3 to 8 points)

NIHSS stroke assessment score: Classed into four levels based on total scores:: (1)

Mild level (NIHSS score ranges from 1 to 4 points); (2) moderate level (NIHSS score from 5

to 15 points); (3) Moderate to severe (NIHSS scores from 16 to 20 points); (4) Very severe level (NIHSS score from 21 to 42 points)

Score scale for assessing risk of thrombotic stroke in patients with non-valvular AF Cha2DS2-VASc: divided into 3 risk groups: (1) No risk (total Cha2DS2-VASc score is 0 points); (2) One risk factor (total score of Cha2DS2-VASc is 1 point) and over 2 risk factors (total score

of Cha2DS2-VASc over 2 points

2.3.6 Study procedure

Step 1: Patient is admitted to hospital with one or more manifestations: coma/conscious,

hemiplegia, speechlessness/speech disorder, headache, dizziness, urinary or bowel disorders, which lead to stroke would be clinically examined and paraclinical would be indicated for confirmed diagnosis

Step 2: Confirming diagnosis of cerebral infarction stroke

Step 3: Determine the cause of stroke (1) Atrial fibrillation or non-atrial fibrillation and

(2) No heart valve disease Invite the patient to participate in the study, sign a informed consent (Appendix 2) and provide a research fact sheet

Step 4: Collect administrative information, clinical and paraclinical characteristics and

information related to risk factors based on the criteria 2.3.4

Step 5: Collect information to build a prognosis model of mortality post 30 days

- If the patient is still hospitalized: collect on daily clinical examination at the treatment department

- If the patient has been discharged: Call the family member to inquire about the patient's progression and condition

Step 6: Data analysis

- For the groups of variables related to risk factors for stroke: calculating OR (odds - ratio ratio) ORs are considered statistically significant when the 95% confidence interval ranges (95% CI) does not contain value 1

- With prognostic model of mortality in stroke patients with non-valvular AF: utilizing Bayesian multivariate regression The best model selected was the one with the least number of variables, which best explained the risk of mortality in stroke patients with non-valvular AF and had the lowest BIC

2.5 Research ethics

The research was carried out after it was approved by the Science Council of Hanoi Medical University and Board of Directors of Bach Mai Hospital The patient has the right to leave the study at any time and for any reason without explanation

Chapter 3

RESULTS 3.1 General characteristics of study populations

Table 3.1 Demographics characteristics of study subjects (n=289)

Characteristics Study group

(n=138)

Control group (n=151) p (𝟀𝟐)

Max=90; Min=28

66,50±13,75 Max=95; Min=25 p=0,067

- Occupation classification distributions are similar in AR and non-AF groups

Table 3.2 Characteristics medical history (n=289) Characteristics Study group

(n=138)

Control group (n=151) p (𝟀𝟐)

* A patient can have multiple medical conditions

Results: Most common medical histoty conditions are hypertension and lipid disorder

3.2 Clinical and paraclinical Characteristics of study populations

3.2.1 Clinical Characteristics of subjects

3.2.1.1 Functional symptoms

Table 3.3 Functional symptoms * (n=289) Characteristics

Study group (n=138)

Control group (n=151) p (𝟀𝟐)

Speechless 68 49,3 71 47,0 p=0,056 Speech disorders (difficulty/lisp) 75 54,3 59 39,1 p=0,051

* A patient can have concurrent multiple symptoms

Results: Most common symptoms are paralysis and speech disorders, and least common

are nausea/vomiting, headaches, or diziness

3.2.1.2 Physical symptoms

Table 3.4 Glasgow coma score (n=289) Characteristics

Study group (n=138)

Control group (n=151) p (𝟀𝟐)

Classification

Moderate (9 – 12 points) 56 40,6 77 51,0 p=0,041 Severe (3 – 8 points) 71 51,4 54 35,8 p=0,029 Average Glasgow score (𝑋̅ ± SD) 8,73 ± 2,58

Max=15; Min=4

9,51 ± 2,61 Max=14; Min=4 p=0,032

Results: Study group has a statistically significantly higher mean Glasgow score than

control group

Table 3.5 NIHSS for assessing stroke at admission (n=289) Assessing Stroke NIHSS score (points)

Study group (n=138)

Control group (n=151) p (𝟀𝟐)

Results: Study group has higher score and worse condition compared to control group

of non-AF Mean NIHSS score in AF and non-AF groups are 15 vs 12 points, respectively (p<0,001)

3.2.1.3 Time from onset to intervention

Table 3.6 Time from onset to intervention (n=289) Time from onset to intervention

Study group (n=138)

Control group (n=151) p (𝟀𝟐)

Results: Time to intervention has highest frequency in 3- 4.5h group (45,7% in Study

group and 31,8% in Control group), and lowest frequency in <3h intervention group (11,6% in

AF) and >6h intervention group (16,6% in non-AF) The difference is statistically significant

Control group (n=151) p (𝟀𝟐)

invasive interventional thromboembolism 16 11,6 22 14,6 p=0,657

Results: Highest proportions are observed in patients treated with intravenous

thrombosis in both AF and non-AF groups (43,5% in Study group and 43% in Control group), and lowest in the combination treatment of intravenous thrombosis and invasive interventional thromboembolism (11,6% in Study group and 14,6% in Control group) There is no statistically significantly difference in all treatment methods in both groups (p>0,05)

Results: Mean number of days of hospitalization in Study group is statistically

significantly higher than that in Control group

Control group (n=151) p (𝟀𝟐)

Results: There is no statistically significantly differences between case and control

Control group (n=151) p (𝟀𝟐)

Middle cerebral artery occlusion at M1 46 41,4 38 32,5 p=0,021 Middle cerebral artery occlusion at M2 32 28,8 24 20,5 p=0,045