Exacerbation of Coronary Heart Disease: the Logic and Probabilistic Processes of Flow Prediction for Optimization of Treatment
Conditions: Acute Coronary Syndrome
Sponsor: Central State Medical Academy

ORACLE (ObseRvation after Acute Coronary syndrome for deveLopment of trEatment options) study 
 
Version 1 oct 2016 
 
The Russian multicenter observational study of ACS patients with at 
least one-year follow-up -the ORACLE (ObseRvation after Acute 
Coronary syndrome for deveLopment of trEatment options) study 
 
Protocol 
Version 1 oct 2016 
 
TABLE OF CONTENT 
1. Introduction 
2. The aim of the study 
3. Study design and patient selection 
4. Carried out during the study treatment 
5. Study procedures 
6. End-points 
7. Collection and analysis of statistical data.  
8. Ethical and legal aspects.  
9. Data ownership and use of research results. 
SUPPLEMENT 
1. Informed consent to participate in Clinical Research Participation 
2. Terms of patients numbering and labeling of genetically tubes 
3. Right to seize, storage and transportation of blood 
ABBREVIATIONS 
 
 
 
ACS Acute Coronary Syndrome 
AS acute stroke 
CABG Coronary artery bypass grafting 
CRF Case report form 
CAG coronary angiography 
CHD – coronary heart disease 
СРК Creatinе phosphokinase 
CPK-MB Creatine phosphokinase-MB 
ECG electrocardiogram 
MI Myocardial Infarction 
PCI Percutaneous Coronary Intervention  
TIA transitory ischemic attack 
Tn troponin 
UA unstable angina 
 
 
 
 
 

   
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Introduction 
The role of genetic factors in the development of CHD exacerbations studied 
not enough. Most research in this area planned and carried out on a "case-
control". Using a similar protocol entails significant errors are associated with 
a high incidence of subclinical atherosclerotic vascular lesions. Moreover, 
much of atheroma is extravasal, making it impossible to identify them by 
angiography. Therefore, necessary to conduct prospective studies to estimate 
the frequency of so-called hard endpoints. Previously, similar trials were 
conducted, mainly in connect with drug approving procedures. The spread data 
from them to other patients directly is not entirely justified. At the same time, 
the influence of genetic factors in this group of patients can be substantial. 
In the previous part of the study, the sample of patients of Moscow, St. 
Petersburg, Kazan, Chelyabinsk, Stavropol, Perm, and Rostov-on-the-Don was 
formed, of 1,200 people admitted due to acute coronary syndrome (ACS) 
including unstable angina and acute myocardial infarction, at coronary care 
units with follow-up for three years.  We found several factors, including 
genetic, that significantly affect the outcomes of the disease. Coronary 
atherosclerosis and its complications now considered as a multifactorial 
disease associated with inherent factors. Therefore, the project provides, 
besides accounting a significant amount of clinical and instrumental data, the 
determination of a wide range of genotypes and alleles of polymorphic markers 
candidate genes encoding the protein factors of the hemostatic system, 
enzymes of lipid metabolism system, and anti-inflammatory cytokines. It is 
assumed that the prediction outcomes of coronary heart disease should be 
carried out taking into account the fact that several factors (gender, diabetes, 
age, aortic stenosis, atrial fibrillation, etc.) can not only significantly change 
the forecast itself but also affecting the significance of other risk factors. Since 
the last study, the standards significantly of ACS management changed. 
Invasive treatment not only creates opportunities to reduce coronary mortality 
but also increased demands on the patient's adherence to the assigned 
medication and creates additional risks associated with its activity (especially 
with an antithrombotic treatment activity). In these circumstances, the 
development of personalized approaches to prescribing drugs is particularly 
important. Thus, the prediction of coronary heart disease outcomes after an 
ACS on a set of clinical, instrumental, biochemical and genetic indicators is of 
great importance, as it allows to plan the most optimal treatment for the 
individual patient. 
1. THE AIM OF THE STUDY 
To develop a model of individualized risk of coronary heart disease outcomes 
and side effects of therapy based on clinical and instrumental, biochemical, and 
genetic parameters in patients with ACS. 
2. STUDY DESIGN AND PATIENT’S SELECTION 

   
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2.1. STUDY DESIGN 
This is the Russian multicenter observational study of ACS patients with at 
least one-year follow-up. We planned to include 1700 ACS patients 
admitted to invasive hospitals. The follow-up will continue until at least 200 
deaths for any reason. 
2.2. INCLUSION CRITERIA 
• ACS patients with indications for PCI hospitalization, regardless of whether or 
not carried out PCI.  
• Signed informed consent to participate in the study. 
 
2.2.1. INCLUSION CRITERIA FOR ACS PATIENTS WITHOUT SEGMENT 
ST ELEVATION  
• All patients meet the criteria of very high, high, or intermediate risk and 
selected low-risk patients according to current guidelines. 
 
1.1.1. THE INCLUSION CRITERIA FOR PATIENTS WITH ACUTE 
CORONARY SYNDROME WITH ST ELEVATION OR ALREADY 
FORMED LARGE MYOCARDIAL INFARCTION 
Patients who have been hospitalized with symptoms caused by acute 
myocardial (heart attack prescription no more than 10 days, hospitalization 
time) and at least one of the following additional criteria identified at 
admission: 
• elevation ST: ST persistent increase 1 mm in two contiguous leads 
limb or ST rise to 2 mm in two adjacent precordial leads 
• the emergence of a new blockade of left bunch branch block 
• dynamics of acute myocardial infarction (appearance of pathological 
Q, reduction of R, change the final portion of the ventricular 
complex) 
1.2. EXCLUSIONARY CRITERIA 
• The lack of patient consent for participation in the study 
• Inability to contact with the patient after discharge 
2. TREATMENT 
All patients should receive the standard treatment for acute coronary syndrome 
and related diseases according to the current guidelines.  
 
3. STUDY PROCEDURES 
3.1. THE SEQUENCE OF STUDY 
Stationary Phase 
1st day: 
Symptoms of acute coronary syndrome, leading the patient to the hospital 
Conformity assessment criteria for inclusion in the study 

   
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Written informed consent 
blood samples for genetic analysis 
Filling Case Report Form (CRF) 
2nd - 5th day 
Filling in the missing information in the CRF 
During the CAG or PCI is an extensive video research and filled with a 
separate PCI card 
Upon cancellation of the CAG and PCI card is filled with the count of " 
rejection reason " 
Register endpoint - filling in the relevant sections of the CRF 
discharge planning 
6th day - discharge from the hospital 
Echocardiography - attached full movie, and is filled with a special card 
echocardiogram 
Final inspection and afterfilling CRF 
Talk with the patient follow-up plan 
The introduction of information into an electronic database 
Sending information to the Coordination Center for Research 
Outpatient treatment stage 
25 ± 5 days from the date of inclusion (but no earlier than 5 days after 
discharge) 
Telephone contact with the patient or his relatives 
Register endpoint and adherence to treatment - filling in the relevant sections 
of the CRF 
90 ± 15 days from the date of inclusion 
Telephone contact with the patient or his relatives 
Register endpoint and adherence to treatment - filling in the relevant sections 
of the CRF 
180 ± 15 days from the date of inclusion 
control monitoring visit 
ECG 
Register endpoint and adherence to treatment - filling in the relevant sections 
of the CRF. 
365 ± 15 days from the date of inclusion 
Telephone contact with the patient or his relatives. 
Register endpoint and adherence to treatment - filling in the relevant sections 
of the CRF 
Next phone contacts 1 time in 6 months to achieve thereof, the observation of 
the last patient included in the study (or up to 200 deaths, if for the planned 
observation period their number was less). 
The final filling of card and electronic form, sending the information to the 
coordination center. 
Appropriate CRFs and forms for the events should be completed in accordance 
with the instructions in the manual of the researcher. 

   
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In the case report of the patient information is recorded on the adverse clinical 
outcomes that have developed since the last contact with the patient (see. the 
relevant section of the CRF). Also recorded group of drugs, which the patient 
took over this time period. 
4. ENDPOINTS 
4.1. The primary endpoint 
• Dearth from any causes 
5.2. Secondary end-points 
1. cardiovascular (atherothrombotic) events    
(cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) 
2. non-fatal myocardial infarction    
3. recurrent acute coronary syndrome (all cases of recurrent myocardial 
infarction or unstable angina after the index events) 
4. recurrent PCI    
(all cases of recurrent PCI after the index hospitalization) 
5. complicated atherosclerosis  
6. non-fatal stroke 
5.3 Other Pre-specified Outcome Measures: 
1. Bleeding    
all cases of bleeding during and after the index hospitalization 
 
6.3. 
Defining endpoints 
6.3.1. 
Acute myocardial infarction 
any two of the following criteria meets the diagnosis of acute, evolving or 
recent myocardial infarction: 
typical dynamics of biochemical markers of myocardial necrosis to a value 
above the upper limit of normal two (or if the markers have increased by 
more than 50% of the minimum level of detection of the enzyme) and at 
least one of the following: 
a) symptoms of ischemia 
b) The appearance of pathological Q wave on ECG 
c) ECG changes indicating ischemia (increase or decrease of ST 
segment) 
d) Coronary intervention or pathological evidence for acute myocardial 
infarction 
4.1.1. Previous myocardial infarction 
The emergence of new wave Q on an electrocardiogram (ECG compared to 
the previous visit), the appearance of new zones in the a- or dyskinesia 
echocardiogram. 
Documented in another hospital myocardial infarction. 
4.1.2. Unstable angina 
It is defined as a recurrent chest pain / symptoms of ischemia, continuing 
for more than 5 minutes, with documented typical ECG changes indicative 

   
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of ischemia and / or improving cardiac enzymes and markers of myocardial 
damage and require hospitalization. 
4.1.3. Fatal case 
All cases of death will be merged the concept of "total mortality" and 
will be divided according to the genesis of "due to cardiovascular 
disease" and "not associated with cardiovascular disease," according 
to information provided to the physician-researcher. Fatal, "due to 
cardiovascular disease," it will be divided according to the genesis of 
"cardiovascular mortality" and mortality from "other cardiovascular 
disease." Death as a result of acute myocardial infarction, CABG, 
sudden cardiac death will be classified as "cardiovascular mortality." 
The category of death from other cardiovascular diseases will be 
charged any additional cases related to the cardiovascular system (ie, 
death from stroke, major bleeding, pulmonary embolism, as a result 
of the operation). For the category "non-cardiovascular disease 
deaths' are referred all cases of clearly non-cardiac origin (eg, death 
from cancer, injuries, infections, etc.). 
 
4.1.4. Stroke, TIA 
is defined as the presence of a new focal neurologic disorder 
considered vascular in origin, with signs or symptoms continued 
more than 24 hours. Stroke is classified as ischemic, haemorrhagic or 
indeterminate type. 
4.1.5. Complicated peripheral arterial disease 
Cases atherosclerosis peripheral arteries leading to the need for 
surgery (reconstructive vascular surgery, amputation, carotid 
endarterectomy, aorto-femoral bypass, etc.) 
4.1.6. Coronary revascularization 
Taking into account all the cases of revascularization procedures 
5. COLLECTION AND ANALYSIS OF STATISTICAL DATA.  
Statistical analysis was performed using a standard statistical package IBM SPSS 
Statistics Version 22 for Windows and MedCalc software version 18.3. It involves 
analysis of clinical predictors 
- all cause mortality 
- cardiovascular mortality 
- all cardiovascular events  
- stroke  
- any, significant and major hemorrhage 
For continuous variables will be analyzed and the distribution criteria for its 
compliance with the normal using the Kolmogorov-Smirnov test. To describe the 
features of the normal distribution using the mean with standard deviation 

   
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indication (M ± SD). For signs with non-normal distribution when reporting the 
results indicate the median and interquartile range - the 25th and 75th percentiles 
(Me (Q1-Q3)). Discrete values are calculated as a percentage, the significance of 
differences were compared by Pearson criterion χ2. Comparison of quantitative 
traits obeying the normal distribution, is carried out using t-criterion Student, 
unormal distribution - by using the non-parametric test, the Mann - Whitney and 
Kruskal - Wallis test for unrelated groups. For quantitative evaluation of the 
values calculated correlation coefficient is obtained and the accuracy depending 
on the Pearson's criteria (normal distribution) or Spearman (with a deviation from 
the normal distribution) for bilateral hypothesis testing criterion. The rating values 
of the predictor is conducted by plotting ROC curve and calculating the area under 
the curve (AUC). Treatment Evaluation of Frequency Allocations alleys and 
genotypes studied these genes will be performed using "Gene Expert" unified 
program. Genotype frequency distribution was calculated (the Hardy-Weinberg 
equilibrium test), genetic risk of NO using multiplicative general, dominant and 
recessive inheritance models. To assess the effect of clinical factors on the 
independence of the risk of adverse outcomes is performed using the Kaplan-
Meier method using the log-rank test (Log Rank) and using Cox regression.  
The regression analysis Univariate Cox included parameters are different when 
the comparative analysis between the groups of patients with a favorable and 
unfavorable outcome. The development of prognostic functions performed by 
using multivariate logistic regression. For all types of analysis were considered 
statistically significant value of p <0,05. 
It is supposed to analyze the prognostic data for specific groups of patients: 
- patients 75 years and older 
- patients with "early" debut atherosclerosis (men younger than 55 years, women 
younger than 60 years)  
- patients with diabetes  
- patients with CKD 
7. ETHICAL AND LEGAL ASPECTS.  
7.1 Informed consent of the patient. 
Patients who meet all eligibility criteria, are considered suitable. Before 
inclusion in the clinical study of the patient must provide written consent to 
participate in the study, after the nature of the study will be explained 
verbally and in writing. Patients should be informed that in the course of 
study they will have taken blood for research purposes, including for 
genetic analysis. 
7.2 The principle of confidentiality. 

   
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The data obtained from the study, and stored in the computer must be 
protected, as required by the law on personal data protection. The 
researchers will treat all personal information about the patient obtained 
during the investigation, in full respect of medical confidentiality and 
personal data protection law. 
8. DATA OWNERSHIP AND USE OF RESEARCH RESULTS. 
Each research group has the right to publish their own data, obtained as a result 
of the study. 
Publication and other use of materials produced in other centers, with the 
consent of researchers, guiding the work of the centers.