Granulocyte-colony stimulating factor for large

anterior ST-elevation myocardial infarction: Rationale

and design of the prospective randomized phase III
STEM-AMI OUTCOME trial
Felice Achilli, MD, a Cristina Malafronte, MD, a Francesca Cesana, MD, PhD, a Stefano Maggiolini, MD, b Ciro Mauro, MD, c
Gaetano M. De Ferrari, MD, d Laura Lenatti, MD, e Maurizio Tespili, MD, f Paola Pasqualini, MD, g Francesco Gentile, MD, h
Maurizio C. Capogrossi, MD, i Aldo Maggioni, MD, j Attilio Maseri, MD, k Gianluca Pontone, MD, l Gualtiero I. Colombo, MD, PhD, m,1
and Giulio Pompilio, MD, PhD n,1, for the STEM-AMI OUTCOME Trial Investigators Monza, Merate, Napoli, Pavia,
Lecco, Seriate, Grosseto, Cinisello Balsamo, Rome, Florence, and Milan, Italy

Background Granulocyte-colony stimulating factor (G-CSF) has been clinically tested in ST-elevation myocardial
infarction (STEMI) with mixed results. Our 3-year follow-up data from STEM-AMI trial documented a sustained benefit of G-CSF
on adverse ventricular remodeling after large anterior STEMI, when administered early and at a high-dose in patients with left
ventricular (LV) dysfunction. The Aim of the present trial is to establish whether G-CSF improves hard clinical long-term
outcomes.
Methods The STEM-AMI OUTCOME is a prospective, multicenter, randomized, open-label, phase III trial. It will include
1,530 patients with anterior STEMI undergoing primary percutaneous coronary intervention 2 to 24 hours after symptoms
onset and with LV ejection fraction ≤45% after successful reperfusion. Patients will be randomized 1:1 to G-CSF and/or
standard treatment. The primary end point is a reduced occurrence of all-cause death, recurrence of myocardial infarction, or
hospitalization due to heart failure in G-CSF–treated patients. Left ventricular remodeling will be assessed via cardiac
ultrasound and a substudy with cardiac magnetic resonance will be carried out in 120 subjects. Accrual and follow-up periods
will last 3 and 2 years, respectively.
Conclusions The STEM-AMI OUTCOME study is designed to be a rigorous controlled phase III trial with adequate
statistical power to conclusively assess efficacy of G-CSF treatment in STEMI. (Am Heart J 2015;170:652-658.e7.)

Early development of left ventricular (LV) dysfunction

From the aCardiology Unit and Intensive and Coronary Care Unit, San Gerardo Hospital, is a powerful marker of increased mortality after a large
Monza, Italy, bDepartment of Cardiology, San Leopoldo Mandic Hospital, Merate, Italy, myocardial infarction with ST-elevation (STEMI). 1–4
c
Department of Cardiology, Cardarelli Hospital, Napoli, Italy, dCardiology Unit and
Intensive and Coronary Care Unit, Fondazione Policlinico San Matteo IRCCS, Pavia, Italy,
Despite fundamental advances in reperfusion strategies,
e
Department of Cardiology, Alessandro Manzoni Hospital, Lecco, Italy, fCardiology to date, no specific therapies address the substantial
Department, Bolognini Hospital, Seriate, Italy, gCardiology Unit, Misericordia Hospital, loss of cardiomyocytes leading to postinfarction adverse
Grosseto, Italy, hDepartment of Cardiology, Bassini Hospital, Cinisello Balsamo, Italy,
i
LV remodeling.
Laboratory of Vascular Pathology, Istituto Dermopatico dell'Immacolata IRCCS, Rome,
Italy, jResearch Center of the Italian Association of Hospital Cardiologists (ANMCO), Bone marrow (BM) cell–based therapies have attracted
Florence, Italy, kPer il Tuo Cuore Onlus Foundation, Florence, Italy, lDepartment of interest as potentially capable of fine tuning postischemic
Cardiovascular Imaging, Cardiac Magnetic Resonance Unit, Centro Cardiologico inflammation and apoptosis after acute myocardial
Monzino IRCCS, Milan, Italy, mImmunology and Functional Genomics Unit, Centro
Cardiologico Monzino IRCCS, Milan, Italy, and nVascular Biology and Regenerative
infarction (AMI), thus preventing excessive cellular
Medicine Unit, Centro Cardiologico Monzino IRCCS, and Cardiovascular Section, damage. 5 Notably, in the early post-STEMI period, BM
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. cells, including circulating CD34 + progenitors, are
1
These authors contributed equally to this work.
naturally mobilized in the systemic circulation and
Submitted November 20, 2014; accepted July 2, 2015.
Reprint requests: Felice Achilli, MD, Cardiology Unit and Intensive and Coronary Care
attracted to the site of the ischemic insult to modulate
Unit, Cardiothoracovascular Department, San Gerardo Hospital, Via Pergolesi 33, 20052 the repair process. 6–8 Clinical trials of intracoronary
Monza, Italy. delivery or cytokine mobilization of BM-derived cells have
E-mail: felice.achilli@gmail.com
0002-8703
been conducted in the last decade in order to reduce scar
© 2015 Elsevier Inc. All rights reserved. size and, consequently, attenuate adverse LV remodeling.
http://dx.doi.org/10.1016/j.ahj.2015.07.005 In particular, granulocyte-colony stimulating factor