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Effects of Ticagrelor and Clopidogrel on Coronary Microcirculation in Patients with Acute Myocardial Infarction

Introduction Clopidogrel has been demonstrated to be effective in improving coronary microcirculation (CM) among patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytics. Ticagrelor is a more potent adenosine diphosphate (ADP) receptor blocker proven to be superior to clopidogrel among patients with acute coronary syndromes. The present study aimed to compare the effects of ticagrelor and clopidogrel on CM in patients with STEMI treated with fibrinolytics. Methods The present study prospectively included 48 patients participating in the TREAT trial, which randomly assigned patients with STEMI undergoing fibrinolysis to ticagrelor versus clopidogrel. The primary endpoint of this study was the evaluation of the CM using the global myocardial perfusion score index (global MPSI) obtained by myocardial contrast echocardiography (MCE). Platelet aggregation to ADP was evaluated by Multiplate® and expressed as area under the curve (AUC). Results The global MPSI demonstrated no differences between the groups [mean 1.4 (1.2–1.5) in the ticagrelor group and 1.2 (1.2–1.5) in the clopidogrel group (p = 0.41)]. Platelet aggregability was lower in the ticagrelor group (18.1 ± 9.7 AUC), compared to the clopidogrel group (26.1 ± 12.5 AUC, p = 0.01). Conclusion We found no improvement in coronary microcirculation with ticagrelor compared to clopidogrel among patients with STEMI treated with fibrinolytics, despite the fact that platelet aggregation to ADP was lower with ticagrelor. Clinical Trials Registration NCT03104062. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-022-02061-0.

i) Any other condition that could put the patient at risk or influence the results of the study in the investigator's opinion (eg, cardiogenic shock, severe hemodynamic instability, active cancer). j) Pregnancy or lactation. k) Any condition that increases the risk of non-adherence or loss of follow-up. l) Contraindications to fibrinolytic therapy including: any previous intracranial hemorrhage or known structural cerebral vascular injury (eg, arterial venous malformation) or known malignant intracranial neoplasia (primary or metastatic) or ischemic stroke within 3 months or suspected aortic dissection or active bleeding or bleeding diathesis (excluding menstruation) or head trauma or significant facial trauma within 3 months. m) Participation in another study.

Study design
Following is the temporal summary of the study design:

Myocardial Contrasted Echocardiography (MCE)
The Myocardial Perfusion Score Index (MPSI) and Parametric Image (PI) are MCE methods for analyzing myocardial perfusion and evaluating the microcirculation. The MPSI analysis is performed using the Gray Scale (GS), and the PI from which the Infarction Area Analysis (IAA) is obtained, is performed by color coding, and both are displayed as a set of images of according to the relative degree of myocardial perfusion.(1) PI provides the area and transmural extension of the perfusion defect, that is, the infarcted area. Both echocardiographic analysis of quantitative myocardial perfusion using PI and GS were validated as a method for measuring the infarcted area in humans. (2) To obtain the MCE images, the ultrasonic contrast agent SonoVue® (Bracco Imaging -Florence, Italy) was used, which was administered in bolus of 1mL in 1mL in order to maintain an optimal infusion rate for each patient, to

Parametric image (PI) and the Infarction Area Analysis (IAA)
After obtaining the images, as previously described to generate the PI, an assisted edge detection algorithm was used to segment the myocardium from the rest of the image. A color map was applied to generate PI blood volume (), blood flow rate () and myocardial blood flow ( x ) for each pixel in the myocardium.
The values of each pixel were color-coded in relation to the average value. Color gradations were applied linearly based on the fractions of the mean value, with break points fixed in the mean (green), two-thirds of the mean (yellow) and onethird of the mean (red), corresponding to normal myocardial perfusion, moderate reduction and severe, respectively. Myocardial infarction was defined by PI as the red area in regions with abnormalities of wall movement using blood flow velocity (), while by PS it was defined as the area without opacification in regions with abnormalities in wall movement. PI was used to calculate the infarction area and the blood flow velocity () was chosen to calculate the infarcted area because it showed a better correlation with the magnetic resonance data.(2) The final systolic picture of each segment and its area of infarction were measured by planimetry using software PI (Image J [cm2], National Institutes of Health, Bethesda, MD). The total area of the myocardium was derived by the total count of each of the 17 measured myocardial segments and the area of infarction was derived from the count of each infarcted area of the segment. All images were analyzed by an experienced observer blinded to the clinical data of the intervention. The size of the infarction was classified as small when less than 19% of the entire area of the myocardium, medium when it was between 19% and 30% and large when greater than 30% of the entire area of the myocardium.

Evaluation of the Wall Motion Score Index (WMSI)
As in the perfusion assessment, to assess contractility, each segment was graded with a Montion Score (MS), where MS = 1 represents normal contractility, MS = 2 represents reduced contractility and MS = 3 represents absence of contractility. In case of visual limitations of a particular segment, it will receive MS = 0. The Global Wall Motion Score Index (Global WMSI) was then obtained by adding the MS of each segment divided by the number of total segments (17 segments). The Regional Wall Motion Score Index (Regional WMSI) was obtained by adding the MS of each segment related to the artery responsible for the infarction (Anterior and Non-Anterior Segments) (3,4) In the sequence ( Figure S3

Platelet aggregability
The method used for platelet aggregability assessment was Multiplate®.
No other tests regarding ADP activation nor ASPI activation were performed.
Multiplate® (Multiple Electrode Aggregometry -Roche): test that analyzes the platelet function in whole blood at 37 ° C by connecting the platelets to metal electrodes, leading to changes in electrical conductance (or impedance), after activation of the same via ADP receivers by the ADP-Test. The results are obtained in aggregation speed or area under the curve (AUC) and, the higher, the greater the platelet aggregability.(5) Since it's an Acute Myocardial Infarction trial, the patients were not fasting.