Ticagrelor has many protective cardiovascular properties beyond potent antiplatelet action. This study aimed to compare the effects of ticagrelor versus clopidogrel on infarcted mass, quantified by cardiac magnetic resonance (CMR), in patients with ST-segment elevation acute myocardial infarction (STEMI). Adult patients of both sexes with STEMI under a pharmaco-invasive strategy were included (n=225). Patients were treated by thrombolysis within six hours of symptom onset and underwent angiography with percutaneous coronary interventions, when needed, within the first 24 hours. Prior to the invasive procedures, patients were randomly assigned to receive either ticagrelor or clopidogrel using a centralized computerized system. Patients were followed on a weekly basis to optimize their medical therapy. After 30 days, CMR was performed and a smaller percentage of left ventricular infarcted mass was found with ticagrelor (p=0.012), despite similar angiographic findings at baseline (Syntax score, Gensini score, culprit artery, TIMI flow, and myocardial blush). At 30 days, left ventricular ejection fraction (LVEF) was comparable between groups. Still, the K-means algorithm displayed more homogeneous responses for smaller infarcted mass and better LVEF among those patients treated with ticagrelor. Standard lipid panel and most inflammatory parameters were similar at baseline and after 30 days. However, lower high-sensitivity troponin T and high-sensitivity C-reactive protein levels were found in samples collected from patients treated with ticagrelor on the first day of STEMI. In patients with STEMI under a pharmaco-invasive strategy, therapy with ticagrelor was associated with a smaller infarct size than clopidogrel.

The CONSORT checklist is available as a supplementary file.

Ethics approval

The study protocol was approved by the local ethics committee (IRB 0297/2014; CAAE: 71652417.3.0000.5505), which follows the last version of the Helsinki Declaration. All patients signed the informed consent prior to any study procedure.

Study design

The comparison between ticagrelor and clopidogrel in patients with STEMI is part of a thematic study with pre-specified analyses that also included two lipid-lowering strategies. The study design, including objectives and inclusion/exclusion criteria, was previously published. Briefly, the BATTLE-AMI study (NCT02428374) is a prospective, randomized, open-label clinical trial with blinded CMR and angiographic analyses. Adult STEMI patients who underwent thrombolytic therapy were included. After providing written informed consent, eligible patients were randomized in a 1:1 ratio to receive either ticagrelor or clopidogrel using a centralized computerized system before coronary angiography.

Patient Recruitment and Treatment

Consecutive STEMI patients of both sexes, aged 18-75 years, were treated by tenecteplase (Metalyse^Ò, Boehringer Ingelheim) in the first 6 hours of symptom onset, according to patients' weight, and received 300 mg of clopidogrel and 300 mg of aspirin in public hospitals of the city of São Paulo, Brazil, as part of the SP STEMI treatment network. In the network routine, patients were subsequently transferred to a tertiary teaching hospital and underwent systematic early invasive coronary angiography. Thus, the patients of the study were referred to our university hospital in the first 24 hours, and randomly assigned 1:1 to either ticagrelor (Brilinta^Ò, Astrazeneca) 90 mg b.i.d. after a loading dose of 180 mg or clopidogrel (Plavix^Ò, Sanofi) 75 mg q.d. with an additional loading dose of 300 mg of clopidogrel at the discretion of the attending physician. Coronary angiography was performed in all patients in the first 24 hours, and PCI, when needed, in the culprit lesion. Additional coronary interventions in non-culprit lesions were performed at the same time or electively according to the hemodynamic team's decision. All these interventions conform to the recommended guidelines. As part of the BATTLE-AMI study, patients were randomized to receive rosuvastatin 20 mg (Crestor^Ò, Astrazeneca) or simvastatin 40 mg combined with ezetimibe 10 mg (Vytorin^Ò, MSD). Patients with clinical instability, previous myocardial infarction or coronary revascularization, severe renal insufficiency, active liver disease, immune diseases, or known intolerance to the study drugs were excluded. Thirty days after STEMI, a CMR was performed. Patients were included from May 2015 to March 2020. All laboratory, angiographic, or CMR analyses were performed blindly.

Laboratory analysis

Blood samples were collected on the first day, or in the morning of the next day, in case of overnight hospital admission, and also after 30 days.

Routine laboratory parameters were performed in the central laboratory of the university hospital. B and T Lymphocyte subtypes were examined by flow cytometry as previously reported. Circulating cytokines were determined by enzyme-linked immunosorbent assay (ELISA).

Quantitative Coronary Angiography

An independent angiographic core laboratory assessed quantitative coronary angiography blinded to randomization assignment and clinical outcomes for baseline and post-PCI lesions with the use of validated quantitative methods (CMS; Medis Medical Imaging Systems, Leiden, The Netherlands). The path line, vessel contour, lumen, reference diameters, and lesion length were determined automatically by the contrast density, occasionally requiring editing by analysts. The following parameters were obtained through quantitative coronary angiography: (i) minimal lumen diameter; (ii) reference vessel diameter; (iii) obstruction length; (iv) percent diameter stenosis. Rentrop score, TIMI flow, myocardial blush, and the corrected TIMI frame count grades in the infarcted vessel were defined as previously reported. Each lesion with ≥50% diameter stenosis in vessels ≥1.5 mm was scored using the syntax score algorithm (https://syntaxscore.org/), fully described elsewhere.

Cardiac Magnetic Resonance

In 3.0 T clinical scanners (Siemens, Erlangen, Germany, Philips), patients remained in the supine position, and a phased-array receiver cardiac coil was placed on the chest. Cine images were ECG-gated and were acquired with approximately 8 sec breath holds for each slice. Cine images were acquired in the short-axis view (from the mitral valve insertion plane through the left ventricle until the apex) and three long-axis views. Slice thickness was 8 mm, and slice spacing was 2 mm. All indexes studies were done with the injection of a commercially available gadolinium-based contrast agent (gadopentetate dimeglumine or gadoteridol) administered intravenously at a dose of 0.2 mmol per kilogram of body weight, and a dynamic, breath-hold MR first-pass perfusion examination were obtained and resulted in three short-axis slices of 8–10 mm thickness were acquired every heart beat along the long axis, with spatial resolution of 2–3 × 2–3 mm. Stress data were acquired following 6 min of dipyridamole (0.56 mg/min/kg intravenous), followed by an aminophylline injection to reverse hyperemia. A rest injection of the same contrast agent (0.2 mmol per kilogram of body weight) was done to obtain images that would be compared with those of the stress phase. After a 5-minute delay to allow for washout of the contrast agent from healthy myocardium, magnitude and phase-sensitive inversion recovery images following an inversion recovery pulse were recorded to allow the detection of late gadolinium enhancement. These were registered in the same views used for cine MRI and used to assess for myocardial viability. The inversion time suggested by the protocol could be adjusted by the technologist to optimize image quality. Typical voxel size was 1.9 by 1.4 by 8 mm. Scanning protocol for the follow-up study included segmented cine CMR (short and long axis views) for cardiac function, followed by segmented late gadolinium enhancement imaging for viability. Myocardial infarction size was quantified by manual contouring of the late gadolinium enhancement areas in each of the short-axis slices, using dedicated software, as described elsewhere.

Study endpoints and predictor definitions

The primary objective of the study was to compare the amount of infarcted myocardial mass measured by CMR after 30 days of treatment with ticagrelor or clopidogrel, among STEMI patients under the pharmaco-invasive strategy. A secondary objective was the left ventricular ejection fraction (LVEF). Circulating inflammatory cells and biochemical variables were also examined.

Statistical analysis

All analyses were made using software R Core Team (2024), and the level of significance was stated at 5%. Data was reported as median and interquartile range or mean and standard deviation. Qualitative variables were reported as numbers and percentages. The Shapiro-Wilk test was used to examine normality. The Mann-Whitney test was used to compare nonparametric variables for independent groups, including myocardial fibrosis (% and g), and LVEF. Categorical variables were compared by the Pearson's Chi-square test or Fisher's exact test. Correlations between variables were examined by the Spearman's Rho test. The K-means algorithm was used for cluster analysis involving LVEF and myocardial fibrosis. Sensitivity analysis was conducted for infarcted mass and LVEF using Multivariate Imputation by Chained Equations in the R software.