Effects of four antiplatelet/statin combined strategies on immune and inflammatory responses in patients with acute myocardial infarction undergoing pharmacoinvasive strategy: Design and rationale of the B and T Types of Lymphocytes Evaluation in Acute Myocardial Infarction (BATTLE-AMI) study: study protocol for a randomized controlled trial

Abstract

Background: Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling.

Methods/design: BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow-cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months. The trial will also evaluate the improvement in the immune/inflammatory responses mediated by B and T lymphocytes. Omics field (metabolomics and proteomics) will help to understand these responses by molecular events.

Discussion: BATTLE-AMI is aimed to (1) evaluate the role of subsets of lymphocytes on microcirculation improvement and (2) show how the choice of statin/antiplatelet therapy may affect cardiac remodeling after acute myocardial infarction with ST elevation.

Trial registration: ClinicalTrials.gov, NCT02428374 . Registered on 28 September 2014.

Keywords: Acute myocardial infarction; B lymphocytes; cardiac magnetic resonance imaging; metabolomics; proteomics.

Conflict of interest statement

Author’s information

Department of Medicine, Cardiology Division, Federal University of São Paulo, Rua Loefgren 1350, 04040-001, São Paulo, SP, Brazil.

Ethics approval and consent to participate

The BATTLE-AMI study has been approved by the local Ethics Committee (Universidade Federal de São Paulo – Hospital São Paulo) ethical approval reference number IRB:0297/2014 and CAEE: 38692514.1.1001.5505. Any important protocol modifications will be submitted and/or communicated to relevant parties.

Consent for publication

Not applicable.

Competing interests

FAH was a member of the Steering Committee of the JUPITER trial sponsored by Astra Zeneca. All the remaining authors declare that they have no competing interests for this trial.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

The BATTLE-AMI hypothesis – lymphocytes. After successful coronary reperfusion by a pharmacoinvasive strategy, patients with STEMI might have greater or smaller infarcted mass depending on the balance of B and T lymphocytes. B CD11b– and B memory cells seem to be related to smaller infarcted mass and better left ventricular ejection fraction (LVEF). Conversely, B CD11b + and B-naive cells are possibly related to greater infarcted mass. The role of B and T derived microparticles, extracellular vesicles, or exosomes in the ischemic tissue after coronary reperfusion is not yet established. PCI percutaneous coronary intervention

Fig. 2

The BATTLE-AMI hypothesis – microcirculation. Microcirculation will be improved by adenosine and nitric oxide. Ticagrelor increases intra- and extracellular levels of adenosine by blocking the adenosine transporter ENT1. Rosuvastatin increases nitric oxide availability through the decrease in the intracellular signaling mediated by Rho GTPases. Decrease in Rho protein is followed by increased bioavailability of nitric oxide, promoting vasodilation. Thus, the synergism between rosuvastatin and ticagrelor will improve the microcirculation of the ischemic myocardium decreasing the final infarcted mass. The absence of effect in adenosine levels following clopidogrel use and the characteristics of simvastatin as a prodrug might have lower beneficial effect on the microcirculation

Fig. 3

The BATTLE-AMI study flowchart. After fibrinolytic therapy performed in the 6 h after onset of symptoms, subjects with STEMI will be referred to the hospital for coronary angiography and PCI, if necessary. Those patients admitted to the hospital within 24 h of STEMI will be randomized to one of the four assignments in a 1:1:1:1 ratio (ticagrelor/rosuvastatin, ticagrelor/simvastatin plus ezetimibe, clopidogrel/rosuvastatin, or clopidogrel/simvastatin plus ezetimibe). Blood, urine, and feces samples will be collected at baseline, 30 days, and 180 days for metabolomics, proteomics, microbiota, and flow-cytometry studies. cMRI studies will be performed during peri-hospitalization period and at 30 and 180 days

Fig. 4

Schedule of enrolment, interventions, and assessments. TICA ticagrelor, RSV rosuvastatin, Sinva simvastatin, CLO clopidogrel, EZE ezetimibe, cMRI cardiac magnetic resonance imaging