Clinical trial NCT04347434: Assessment of the Effects of Long-term Lipid-lowering Therapy in Patients With Primary STEMI or NSTEMI
Official title: Assessment of the Effects of Long-term Lipid-lowering Therapy on Parameters of Electrical Myocardial Heterogeneity, Myocardial Deformation Characteristics, Vascular Rigidity, and Quality of Life in Patients With Primary STEMI or NSTEMI
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Myocardial Infarction, Acute
Myocardial Strain
Arterial Stiffness
Quality of Life
Keywords: STEMI
NSTEMI
myocardial strain,
arterial stiffness,
lipid-lowering therapy,
electrical myocardial heterogeneity
Lead sponsor: Penza State University
Sponsor class: OTHER
First posted: 2020-04-15
Enrollment: 300
Sex: ALL
Minimum age (years): 30
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Initially, hypolipidemic treatment with atorvastatin at a dose of 80 mg / day is prescribed from the first 24-96 hours of AMI in addition to standard therapy for the disease.
Primary purpose: TREATMENT

Brief summary: In a single-center, open-label, prospective, controlled, clinical study, it is planned to include 300 patients hospitalized in the cardiology department of SBHI Penza regional clinical hospital n.a. N.N. Burdenko. Recruitment of patients will be carried out at the Department of Therapy of the Medical Institute of the Penza State University. Patients meeting the inclusion criteria and not meeting the exclusion criteria will be included in the study.

Initially, lipid-lowering treatment with atorvastatin is prescribed at a dose of 80 mg / day from the first 24-96 hours of AMI in addition to the standard therapy.

If there is no achievement of the target level of LDL-C, ≤1.5 mmol / L after 5-6 weeks from the AMI onset, patients additionally receive ezetimibe at a dose of 10 mg 1 time / day.

Standard AMI treatment includes dual antiplatelet therapy, ACE inhibitors, beta-blockers (if indicated). Prescription of proton pump inhibitors and nitrates is possible (if indicated).

The total follow-up is 96 weeks. Prescreening - 600 people; screening and randomization - 300 people. Parameters of electrical myocardial heterogeneity, myocardial deformation characteristics, vascular rigidity, and quality of life will be assessed according to the study plan.

Detailed description: Methods

1. Blood chemistry test. Total cholesterol, LDL, HDL, triglycerides, AST, ALT, CPK, glucose, CRP, creatinine, glycosylated hemoglobin
2. 2D and 3D transthoracic echocardiography (Vivid GE 95 Healthcare (USA). 3D speckle echocardiography (3DSTE) for a detailed study of the phase-by-phase movement and spatial interaction of all muscle layers of the left ventricle in different phases of the cardiac cycle to obtain quantitative values of the deformation of the left ventricle individual segments in the longitudinal, circumferential and radial directions.

   The analysis of standard indicators of echocardiography: biplane ejection fraction according to the Simpson method, 3D ejection fraction, EDV (end-diastolic volume), ESV (end-systolic volume) and their indices. The left ventricular myocardial mass index (LVMI).

   Using a tissue doppler, the parameters characterizing the diastolic function are recorded: the LA volume, the early diastolic velocity of the mitral valve fibrous ring, the ratio of the early diastolic transmitral flow E to the average early diastolic speed of the fibrous ring e´, and the maximum tricuspid regurgitation rate.

   Myocardial strain is analyzed using specialized software - EchoPac Software Only (General Electric Co., 2018). For three-dimensional strain analysis, the left ventricle is automatically divided into 17 segments using standard segmentation schemes. The software allows obtaining strain values in the endocardial, middle and epicardial layers of the myocardium. Over a period of time, indicators for each segment are automatically calculated:

   longitudinal strain/strain rate (LS,%/LSR, cm / s-1), circumferential strain/strain rate (CS,%/CSR, cm / s-1), radial strain/strain rate(RS,%/RSR, cm / s-1), area strain), rotation, rotation along the axis of the left ventricle (Torsion).
3. Long-term ECG monitoring over 3 leads with an assessment of the parameters of myocardial electrical instability A long-term ECG recording (120 hours) in patients with myocardial infarction will be performed using the Astrocard ECG system (CJSC Meditek, Russia) with 3-channel recorders. Long-term recordings will be analyzed separately for 3 time intervals: 24, 72 and 120 hours.

   Pauses of rhythm, rhythm disturbances - extrasystole, unstable tachycardia, AF paroxysm and atrial flutter, ventricular fibrillation, conduction disturbance will be recorded.

   Assessment of the ST segment dynamics will be carried out with detection of ischemia episodes, which will be detected when the ST segment is displaced ≥10 mV from the baseline 80 ms after the J point for at least 1 min - episodes of elevation and depression of the ST segment.

   According to the long-term ECG monitoring recordings, the following parameters will be analyzed (separately for 3 intervals - 24, 72 and 120 hours):

   circadian dynamics of heart rate; late ventricular potentials (LVP); variance and duration of the QT interval; heart rate variability (HRV); heart rate turbulence (TCP); chronotropic load (CL). Circadian dynamics of heart rate. The circadian dynamics of heart rate will be analyzed with an estimate of the minimum, average and maximum heart rate per day, during waking hours and night sleep. The circadian index (CI) will be defined as the ratio of the average heart rate in the daytime and the average heart rate in the night.

   LVP. The LVP will be evaluated in the standard averaging mode in the range of 40-100 Hz by the noise level not exceeding 0.9 μV. Records of the 24-h ECG in patients who have a decrease in intraventricular conduction, bundle branches blockade, will not be subjected to LVP analysis. An automatic analysis of late post-depolarization begins with a search for the QRS reference complex, which will be used later as a reference for averaging. Subsequently, the ECG signal will be processed programmatically by the time analysis method, at the end of which the following parameters will be evaluated: the width of the filtered QRS complex (QRSf), the duration of the low-amplitude potentials at the end of the QRS complex of the final part of the complex (HFLA), the rms value of the last 40 ms QRS (RMS ) Dispersion and QT interval duration. For a detailed study of the repolarization process in the analysis of records, close attention will be paid to the analysis of the duration, variability and variance of the QT interval.

   HRV. The following HRV time indicators will be considered:
   * Mean NN (ms) - average value of all RR-intervals;
   * SDNN (ms) - standard deviation of the average values of RR-intervals;
   * SDNNi (ms) - average value of standard deviations RR for 5-minute recording periods;
   * SDANN (ms) is the standard deviation of the mean values of the sinus intervals RR for 5 min;
   * rMSSD (ms) is the square root of the sum of the differences of subsequent RR intervals;
   * pNN50 (%) is the percentage of successive RR intervals differing by more than 50 ms;
   * HRVti - triangular index;
   * TINN is the index of triangular interpolation of the histogram of RR-intervals.

   HRV frequency parameters:
   * TotP (ms2) is the power of the total spectrum;
   * ULfP (ms2) - spectrum power in the ultralow frequency range;
   * VLfP (ms2) is the power of the spectrum within very low frequencies;
   * LfP (ms2) - low-frequency range of frequencies; HfP (ms2) - high-frequency component of HRV; L / H - an indicator of the balance of the vagosympathetic balance. Evaluation of the above HRV parameters will be carried out per day, night and day hours.

   TCP is characterized by two independent parameters - the beginning of turbulence (TO) and the slope of turbulence (TS).

   Heart CL is assessed by the level and duration of exceeding the actual (observed in the patient during monitoring) heart rate values of the threshold heart rate calculated individually according to the proposed formulas with differentiation for periods of wakefulness and night sleep:

   THR-W (bpm) = HRmax (bpm) × 0.45, where THR-W is the threshold value of the heart rate during wakeful hours in beats per minute, heart rate max is the age-appropriate value of the maximum possible heart rate in beats per minute, 0.45 is the coefficient of the threshold level of heart rate; THR-S (bpm) = THR-W (bpm): 1.24, where THR-S (bpm) is the threshold value of the heart rate during the night's sleep.
4. Ultrasound of the common carotid arteries with RF high frequency signal technology The study of local vascular stiffness by high-frequency RF signal technology using ultrasound of the common carotid arteries (CCA) will be carried out in B mode using MyLab 90 (Esaote, Italy).

   The RF signal technology includes two programs: RF-QIMT and RF-QAS. The following CCA indicators are analyzed: IMT - intima-media thickness, loc Psys - local systolic pressure in the carotid artery, loc Pdia - local diastolic pressure, P (T1) - pressure at the local point, stiffness indices β and α, DC is the coefficient of lateral distensibility, CC - coefficient of lateral compliance, Aix is the augmentation index, AP is the amplification pressure, PWV is the local pulse wave velocity in the carotid artery.
5. Ultrasound of the brachiocephalic and femoral arteries The brachiocephalic and femoral arteries will be scanned using a Vivid GE 95 ultrasound scanner (Healthcare, USA) using a linear sensor in B-mode, spectral Doppler imaging and color Doppler imaging.

   Quantitative analysis of atherosclerotic plaque includes determining the extent and degree of narrowing of the lumen of the vessel (percentage of stenosis) by the cross-sectional area (Sa) of the vessel:

   Sa = (A1 - A2) × 100% / A1, where A1 is the true cross-sectional area of the vessel, A2 is the passable cross-sectional area of the vessel.
6. Applanation tonometry. SphygmoCor apparatus (AtCor Medical, Australia) uses pulsed wave to calculate the characteristics of central pressure in aorta.

   The applanation tonometry technique includes two programs: PWA and PWV. The first allows to record central aortic pressure indicators: systolic aortic pressure - SBPao, diastolic - DBPao, pulse - PPao, mean hemodynamic - MBPao based on registration of the radial artery PWV. Using the PWV program, sequential recording of PWV from the common carotid and femoral arteries simultaneously with the ECG channel analyzes the PWV in the aorta (cfPWV).
7. Volume sphygmography. The measurements will be carried out with the VS-1000 device (Fukuda Denshi, Japan) while simultaneously recording plethysmograms on four limbs (using cuffs), ECG, phonocardiogram, and PWV on the carotid and femoral arteries.

   PWV is evaluated in different parts of the circulatory system (i.e., aorta (PWV), predominantly elastic arteries (R/L-PWV) and predominantly muscular arteries (B-PWV)).

   Cardio-Ankle Vascular Index (CAVI) is determined - an indicator that reflects the true stiffness of the vascular wall. CAVI is calculated by registering PWV at two points and measuring SBP and DBP. Additionally augmentation index and biological age will be calculated automatically.
8. Flow-mediated dilation. Endothelial function is evaluated by ultrasonic determination of flow-mediated dilation (FMD) during the postocclusive reactive hyperemia test using the method described by D. Celenmajer et. al.
9. Six-minute walk (6MW) test. The patient should not take cardiological drugs and should not smoke within at least 2 hours before the test. Before the 6MW test, the patient should have a 10-minute quiet rest in a sitting position. During this rest period, the following text should be read to the patient: "You will have to walk for 6 minutes, without using continuous running or alternate running and walking, with the aim to cover a maximum distance. You will walk back and forth along the corridor. You can slow down the pace, stop and have a rest in case of dyspnea or weakness. You can lean against the wall during rest. Then, you will have to resume the walk. Remember that your aim is to cover maximum distance in 6 minutes." At the 6-minute time point, the patient should be asked to stop and stand still until the covered distance has been measured.
10. Computer Pulse Oximetry. During the 6-minute walk test, computer pulse oximetry is planned on a PulseOx 7500 instrument (SPO medical, Israel) to study saturation dynamics in comparison groups.
11. Treatment compliance will be evaluated by standard methods (counting the remaining tablets). Morisky-Green Questionnaire
12. Quality of Life Assessment. The following questionnaires are planned to be completed: Seattle Angina Questionnaire (SAQ), Minnesota Questionnaire, Clinical Assessment Scale for CHF (MQCAS) (modified by Mareev VY, 2000), analog-visual scale.
13. Assessment of physical activity. It is planned to fill out a questionnaire for assessing the level of physical activity and a short international questionnaire for determining the physical activity of the International Questionnaire On Physical Activity - IPAQ
14. Assessment of Anxiety Depression. An analysis of anxiety and depressive disorders in patients using the hospital scale of anxiety and depression (HADS) is planned

Eligibility criteria: Inclusion Criteria:

1. Signed Informed Consent Form 2 Primary STEMI or NSTEMI confirmed by ECG, troponin I and CPK-MB levels, coronary angiography.

3. Presence of an infarct-related artery according to coronary angiography.

Exclusion Criteria:

1. Presence of hemodynamically relevant stenosis exceeding 30% in several coronary arteries confirmed by CAG;
2. Recurrent or repeated myocardial infarction.
3. Exogenous hypertriglyceridemia (type 1 hyperchilomicronemia).
4. The development of acute heart failure III-IV prior to randomization
5. Individual intolerance to statins, ezetimibe.
6. Congenital and acquired heart diseases.
7. Severe concomitant diseases in the stage of decompensation.
8. Non-sinus rhythm, established artificial pacemaker.
9. Sinoatrial and atrioventricular blockade of 2-3 degrees.
10. QRS complex exceeding 100 ms.
11. The presence of severe LV hypertrophy according to echocardiography.
12. Uncontrolled hypertension with SBP\> 180 mm Hg and DBP\> 110 mmHg
13. Diabetes mellitus (DM) type 1 and 2.
14. Current existence of severe anemia (Hb \< 100 g/L)
15. Chronic kidney disease (creatinine clearance less than 30 ml / min / 1.73 m2 according to the CKD-EPI).
16. Non-corrected thyroid dysfunction with hyper / hypothyroidism.
17. Body mass index (BMI) ≥35 kg / m2.
18. Pregnancy, lactation.
19. Alcohol abuse, drug addiction.
20. Other serious concomitant diseases that exclude the possibility of study participation.
21. Participation in other clinical trials within the last two months.

Primary outcomes:
measure: Ventricular arrhythmias
timeFrame: up to 48 months
measure: Systolic function
timeFrame: up to 48 months
measure: Myocardial deformation of the LA and LV
timeFrame: up to 48 months
measure: PCI / CABG for a new case of coronary atherosclerosis, hospitalization for unstable angina
timeFrame: up to 48 months
measure: Myocardial electrical instability
timeFrame: up to 120 hours for 2 years period
measure: Heart rate turbulence
timeFrame: up to 120 hours for 2 years period
Secondary outcomes:
measure: Cardiovascular mortality
timeFrame: up to 48 months
measure: Frequency of repeated fatal / non-fatal MI
timeFrame: up to 48 months
measure: Hospitalization due to acute decompensation of heart failure
timeFrame: up to 48 months
measure: Structural state of arteries different types
timeFrame: up to 48 months
measure: Structural state of carotid artery
timeFrame: up to 48 months
measure: Functional state of arteries
timeFrame: up to 48 months
measure: Progression of CHF, exercise tolerance
timeFrame: up to 48 months
measure: Progression of CHF, laboratory data
timeFrame: up to 48 months
measure: Left ventricular remodeling
timeFrame: up to 48 months
measure: Lipid profile
timeFrame: up to 48 months
measure: Laboratory parameters
timeFrame: up to 48 months
measure: Angina episodes
timeFrame: up to 48 months
measure: Quality of life questionnaire
timeFrame: up to 48 months
measure: Quality of life questionnaire in СHF
timeFrame: up to 48 months
measure: Patients wellbeing
timeFrame: up to 48 months
Other outcomes:
Locations:
city: Penza
country: Russian Federation
facility: Valentin Oleynikov
Study officials:
affiliation: Penza State University
name: Valentin E Oleynikov, DM
role: PRINCIPAL_INVESTIGATOR
References: