ST-Elevation Myocardial Infarction Clinical Trial
Official title:
Brasilia Heart Study of Outcome Markers in ST-elevation Myocardial Infarction
BHS is a cohort study of consecutive myocardial infarction (MI) patients admitted within the first 24 hours of symptoms and has been ongoing since May of 2006. The purpose of this study is to assess for possible markers for increased risk after MI.
In-hospital assessment Patients admitted into the study are being submitted to in-hospital
evaluation and blood samples collection upon admission (D1) and at the fifth day (D5) of MI.
Patients are treated according to current US guidelines for STEMI and assistant physicians
are responsible for all medical decisions without any influence of the investigators. Plasma
and DNA samples are aliquoted for storage at -80 °C. DNA is extracted using QIAamp DNA Blood
Mini Kit (Quiagen, GmBH Hilden).
Follow-up After hospital discharge, patients are referred for a guideline-driven medical
therapy at the study outpatient clinic and were reevaluated during visits every three months.
Lifestyle counseling for diet, smoking cessation, regular physical activity and weight loss
was oriented for all patients. Follow-up prescriptions include simvastatin with the addition
of ezetimibe when necessary (LDL-C goal of 70 mg/dL), captopril or losartan for hypertension
or reduced ejection fraction (<40%); hypoglycemic treatment to achieve a HbA1c goal ≤7% or 8%
for individuals aged of 60 years or older; aspirin 100 mg/day and clopidogrel 75 mg/day; and
anti-ischemic therapy as required (propranolol and isosorbide dinitrate, alone or in
combination).The physicians involved in the clinical follow-up were blind to all the analysis
performed in the study.
Biochemical analysis Blood plasma samples are assessed for the following: blood glucose
(Glucose GOD-PAP, Roche Diagnostics, Mannheim, Germany), total cholesterol (CHOD-PAP, Roche
Diagnostics, Mannheim, Germany), triglycerides (TG) (GPO-PAP, Roche Diagnostics, Mannheim,
Germany), high-density lipoprotein cholesterol (HDL-C) (HDL cholesterol without sample
pre-treatment, Roche Diagnostics, Mannheim, Germany), C-reactive protein (CRP)
(high-sensitivity CRP, Cardiophase, Dade Behring, Marburg, Germany), 8-isoprostane (EIA kit,
Cayman Chemical Company, Ann Arbor, MI, USA), interleukin-2 (IL-2) (Fluorokine® MAP Human
IL-2 Kit, R&D Systems, Minneapolis, MN, USA), tumor necrosis factor type α (TNF-α)
(Fluorokine MAP Human TNF-α Kit, R&D Systems), and HbA1c (Variant II, Bio-Rad Laboratories,
Hercules, CA, USA). Low-density lipoprotein cholesterol (LDL-C) is calculated by the
Friedewald formula. Plasma insulin and C-peptide concentrations were determined by
electrochemiluminescence (Roche Diagnostics, Mannheim, USA) and by imunoquimioluminescence
(Immulite 2000, Diagnostic Products Corporation, Los Angeles, CA, USA), respectively. The
Homeostasis Model Assessment version 2 (HOMA2) is used to estimate β-cell function (HOMA2%β)
and insulin sensitivity (HOMA2%S). We use fasting plasma insulin levels to compute HOMA2%S,
and plasma C-peptide to compute HOMA2%β. To evaluate nitric oxide (NO) production, the plasma
levels of nitrite and nitrate (NOx) are measured by an NO chemiluminescence analyzer (model
NOA, Sievers Instruments, Boulder, CO) after reduction with acidic vanadium (III) chloride.
Brachial Artery Reactivity Brachial artery reactivity is assessed systematically 30 days
(D30) after STEMI to estimate the decline in endothelial function that persists after the
acute phase stress. At the time of the measurement, all patients are on the abovementioned
secondary prevention protocol for at least 3 weeks, including simvastatin at the starting
dose of 20 mg/day. Brachial artery measurements are performed after over-night fasting and
any vasoactive medications were withdrawn 24 hours before assessment. After 10 minutes of
rest in a quiet room with the temperature controlled around 22°C, the brachial artery is
located above the elbow, and a longitudinal image of 6 to 8 cm was taken as the resting scan.
A blood pressure cuff is placed on the forearm and inflated to 50 mm Hg above the systolic
blood pressure for 5 min. The cuff is deflated, and the flow-mediated dilation (FMD) scan is
obtained for two minutes. Ten minutes later, baseline measurements were repeated before and
after five mg of isosorbide dinitrate. The percentage change in diameter for FMD and
nitrate-mediated dilation was calculated in relation to the respective baseline scans.
Brachial artery reactivity is analyzed by the same experienced physician who is blinded to
the patients' data. The intra-observer reproducibility has been 95%.
Echocardiography All echocardiographic measurements are performed according to American
Society of Echocardiography and European Association of Echocardiography recommendations. All
subjects undergo complete 2D ECHO using standard ultrasound equipment (iE 33 system, 2-5MHz
sector transducer; Philips Medical Systems, Andover, MA), at D30. Images are acquired with
simultaneous electrocardiographic (ECG) monitoring. Images are stored in DICOM (Digital
Imaging and Communication in Medicine) for further measurements "offline". Quantifications
are performed by averaging of three measurements. For ventricular remodeling evaluation the
following measures are performed: LV end-diastolic diameter (LVEDD), LV end-systolic diameter
(LVESD), LV septum diastolic thickness (SD) and posterior wall diastolic thickness (PD). Left
ventricular mass (LVM) is calculated formula Devereux formula and indexed to body surface
area (LVMI). LV wall relative thickness (ER) is calculated using the formula (2 x PPD) /
LVEDD). Left ventricle end diastolic volume (LVEDV) and systolic volume (LVESV) and LE
ejection fraction (LVEF) are calculated using Simpson's method.
Carotid ultrasound The intima-media thickness (IMT) and the presence of carotid plaques are
assessed using high-resolution ultrasound (Philips, Model IE 33, 3-9 MHz linear transducer,
Philips Medical Systems, Andover, Massachusetts, USA) according to the protocols of the
American Society of Echocardiography. The measurements are performed bilaterally in the
posterior wall of the common carotid bulb and the internal carotid artery through an
automatic edge detection program (QLAB version 6.0 software). The carotid plaque is defined
as the presence of focal thickening of at least 50% higher than the adjacent areas or as a
focal region with IMT ≥ 1.5 mm.
Coronary angiography Coronary angiography is systematically performed in all enrolled
patients according to standard techniques. Lumen narrowing >70% is considered as a
significant stenosis. All coronary angiographies are classified by the Gensini score method.
Efficacy of reperfusion is estimated by TIMI flow grade and myocardial blush grade (MBG) in
the first angiogram after thrombolysis or percutaneous coronary intervention. All
angiographic data are obtained by consensus of two experienced interventional cardiologists
who are blinded to the investigation data.
Cardiac Magnetic Resonance Imaging (CMRI) CMRI are performed at D30 and all patients are
studied in supine position in a 1.5T scanner (Signa CV/i, General Electric Healthcare,
Milwaukee, Wisconsin) with an 8-element cardiac phased-array surface receiver coil. All CMRI
are acquired during breath-holds with ECG gating. LV size and function imaged by cine
steady-state free-precession (typical TR 3.4 ms; TE 1.2 ms; temporal resolution 40-50 ms;
in-plane spatial resolution 1.5-1.8 mm and 1.8-2.1 mm, depending on the field of view) are
performed in multiple parallel short-axis planes (8 mm thick without spacing) and three
radial long-axis planes. Using a previously described sequence[9] (repetition time, 4.8 ms;
echo time, 1.3ms; in-plane spatial resolution between 1.5 X 2.0 mm and 1.9 X 2.0 mm), late
gadolinium enhancement images (LGE) at matching cine-image slice locations are acquired 10 to
15 minutes after intravenous gadolinium-DTPA administration (0.15 to 0.20 mmol/kg; Magnevist,
Berlex Pharmaceuticals, Wayne, NJ).
Statistical methods Categorical variables are compared by use of the chi-square test.
Analysis of covariance (ANCOVA) is used to assess the association between the potential
markers. Adjustments for baseline levels, age and gender are performed in all comparisons.
Assumptions of the ANCOVA models (linearity, normality of distribution and equal variance)
are checked using histograms, normal probability plots and residual scatter plots. Estimates
of the cumulative event rate are calculated by the Kaplan-Meier method and the comparison
between curves is made by Log rank test. For Cox multivariable regression models, the
proportional hazard assumption is tested by adding time-dependent interaction variables that
are confirmed to be valid in each of the models. A two-sided p-value of 0.05 was considered
statistically significant.
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