ESC CONGRESS 2010 Stockholm 28 August-1 September G-CSF ATTENUATES VENTRICULAR REMODELLING AFTER ACUTE STEMI. RESULTS OF STem cells Mobilization in Acute Myocardial Infarction C. Malafronte MD Alessandro Manzoni Hospital Lecco, Italy for the STEM-AMI Investigators C. Malafronte MD, L. Lenatti MD, G. Pompilio, F. Gentile MD, L. Squadroni MD, A. Di Lelio MD, M. Pesce PhD, P. Camisasca MD, L. Mircoli MD F. Achilli MD.
STEM-AMI TRIAL: rationale G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes Harada et al., Nature Medicine 2005;11:305-11
STEM-AMI TRIAL: rationale H.Ince, Preservation From Left Ventricular Remodeling by Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Use of Granulocyte-Colony Stimulating Factor (FIRSTLINE-AMI). Circ.2005 M.Valgimigli, Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. Eur Heart J 2005 S.G. Ellis, Granulocyte colony stimulating factor in patients with large acute myocardial infarction : results of a pilot dose-escalation randomized trial. AHJ 2006 Engelmann MG, Autologous bone marrow stem cell mobilization induced by granulocyte colony stimulating factor after subacute ST segment elevation myocardial infarction undergoing late revascularization. JACC 2006 Rasmus Sejersten Ripa, Stem Cell Mobilization Induced by Subcutaneous Granulocyte-Colony Stimulating Factor to Improve Cardiac Regeneration After Acute ST-Elevation Myocardial Infarction Result of the Double-Blind, Randomized, Placebo- Controlled Stem Cells in Myocardial Infarction (STEMMI) Trial. Circ 2006
STEM-AMI TRIAL: rationale 385 patients/8 randomized studies Am Heart J 2008;156:216-26.e9
STEM-AMI TRIAL: rationale
STem cells Mobilization in Acute Myocardial Infarction: STEM-AMI Trial F. Achilli MD a, C. Malafronte MD a, L. Lenatti MD a, F. Gentile MD b, V. Dadone MD b, G. Gibelli MD c, S. Maggiolini MD d, L. Squadroni MD e, C. Di Leo MD f, Burba PhD g, M. Pesce PhD g, L. Mircoli MD a, M.C. Capogrossi MD h, A. Di Lelio MD i, P. Camisasca MD j, Morabito k, G Colombo MD PhD l, and G. Pompilio MD PhD m. a Cardiology Department, A. Manzoni Hospital, Lecco, Italy; b Cardiology Department, Bassini Hospital, Cinisello Balsamo, Milan, Italy; c Cardiology Unit, Clinica San Carlo, Paderno D Adda, Italy; d Cardiology Department, San L.Mandic Hospital, Merate, Lecco, Italy; e Cardiology Department, San Carlo Hospital, Milan, Italy; f Nuclear Medicine Department, A. Manzoni Hospital, Lecco, Italy; g Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Milan, Italy; h Laboratory of Vascular Pathology, Istituto Dermopatico dell Immacolata IRCCS, Rome, Italy; I Radiology Department, San Gerardo Hospital, Monza, Italy; j Cardiology Department, San Gerardo Hospital, Monza, Italy; Medical Statistics, k University of Milano; l Laboratory of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS, Milan, Italy; m Cardiovascular Surgery Department, Centro Cardiologico Monzino - IRCCS, Milan, Italy European Heart Failure Journal 2010 (in press) San Carlo Hospital Bassini Hospital San Gerardo Hospital Centro Cardiologico Monzino
STEM-AMI TRIAL Multicenter, randomised, single blind, placebo controlled 60 Patients randomization ratio 1:1 G-CSF vs. PLACEBO G-CSF s.c. 10 mcg/die for 5 days (1-5 day) vs placebo TIMING Approved by the local Ethics Committee of A. Manzoni Hospital in Lecco (November 9th, 2005) Patients were enrolled in 4 Italian centres between July 2006 and May 2009 Follow-up was completed in November 2009
STEM-AMI TRIAL: end points Primary end point was a change of 5% of LVEF, from baseline to 6-months evaluated by MRI. Co-primary end point was a difference of 20 ml of LVEDV by MRI. Secondary end-points were infarct size reduction evaluated by MRI and improvement of myocardial perfusion by SPECT at 6- months. Major cardiac adverse events (MACE) and rate of restenosis were analysed during in-hospital and 6 months follow up. MACE were defined as death, reinfarction, acute heart failure, urgent revascularization and stroke.
STEM-AMI TRIAL: Inclusion and exclusion criteria INCLUSION CRITERIA Signed Informed consent Acute anterior STEMI undergoing PCI Time symptom-to-ballon > 2 h and < 12 h Ejection fraction post PCI 45% TIMI flow post PCI 2-3 EXCLUSION CRITERIA Previous myocardial infarction Leukemia, myeloproliferative or myelodysplastic disorders Immune system disease Malignant disease Age > 75 years Life expectancy < 6 months Previous cardiac surgery or stenting within 12 months Coronary lesions needing CAB Platelet count < 50.000 mm 3 STEMI=ST-elevation myocardial infarction; PCI= percutaneous coronary intervention; CAB=coronary artery bypass; TIMI= thrombolysis in myocardial infarction
STEM-AMI TRIAL: FLOW CHART 60 Patients with anterior AMI and FE 45% plus successful PCI/stent Randomization 30 Patients Standard post-ami care Plus PLACEBO 30 Patients Standard post-ami care plus 5 µg/kg bid of G-CSF within 12 h after PCI Echo (day 5) SPECT (day 5) ECG-Holter (day 1-7) Cardiac MRI (day 6) In-hospital f.u. ECG Blood sample Day 30 Echo ECG-Holter Day 90 Echo ECG Holter SPECT Cardiac MRI Coronary angiography Day 180
STEM-AMI TRIAL: Demographic and clinical characteristics of study population VARIABLE G-CSF (n 29) Placebo (n 27) p Age, y 61 ± 8 61 ± 10 0.97 Male sex, n (%) 29 (100) 24 (89) 0.21 Hypertension, n (%) 14 (48) 18 (67) 0.26 Diabetes, n (%) 6 (21) 3 (11) 0.47 Dyslipidemia, n (%) 17 (59) 16 (59) 0.82 Smoking, n (%) 17 (59) 13 (48) 0.60 Family history of CAD, n (%) 12 (41) 9 (33) 0.73
STEM-AMI TRIAL: Biochemical characteristics of study population Blood analysis G-CSF (n 29) Placebo (n 27) p CRP (mg/dl) 1.4 ± 3.2 0.89 ± 1.00 0.39 Pro-BNP (pg/ml) 2094 ± 3969 1749 ± 2039 0.69 WBCs count (x10 3 /mm 3 ) 13 ± 5 12 ± 2 0.33 Platelets count (x10 3 /mm 3 ) 196 ± 49 211 ± 51 0.28 Creatinine (mg/dl) 0.87 ± 0.21 0.94 ± 0.22 0.23
STEM-AMI TRIAL: Medication of study population Medication at discharge % G-CSF (n 29) Placebo (n 27) p Aspirin 100 100 1.0 Clopidogrel 100 100 1.0 Statin 100 100 1.0 ACE inhibitors 100 100 1.0 Beta-blockers 100 100 1.0 Diuretics 35 37 0.93 Medication at 6 months of f.u. Statin, % 100 100 1.0 Atorvastatin median dose, mg 35.0 ± 9.00 27.5 ± 11.4 0.12 ACE inhibitors, % 100 100 1.0 Ramipril median dose, mg 6.6 ± 3.5 7.4 ± 3.0 0.62 Betablockers, % 100 100 1.0 Carvedilol median dose, mg 25.4 ± 12.8 23.0 ± 14.7 0.63 Diuretics, % 40 25 1.0 Furosemide median dose, mg 31.2 ± 22 28.1 ± 15.7 0.81
STEM-AMI TRIAL: Angiographic and infarction-related characteristics VARIABLE G-CSF (n. 29) Placebo (n. 27) P ECG involved leads, n (% ) Pts > 5 leads 14 (48) 13 (48) 0.79 Medium ST elevation (mm) 6 ± 4 5 ± 2 0.30 Creatine kinase max U/L 4207 ± 2767 3052 ± 1721 0.09 Troponin I peak 205 ± 265 117 ± 83 0.11 EF % 39.1 ± 6.2 38.6 ± 7.4 0.85 Killip class, n (%) Pts 3 7 (24) 3 (11) 0.29 IABP, n (%) 6 (21) 1 (4) 0.10 Onset of AMI to PCI, min 277 ± 166 238 ± 124 0.32 TIMI flow 0 pre PCI, n(%) 22 (76) 15 (56) 0.18 TIMI flow III post PCI, n(%) 24 (83) 25 (93) 0.47 PCI plus stent, n(%) 29 (100) 27 (100) 1.0 Drug eluting stent, n(%) 10 (35) 5 (19) 0.29 Multivessel disease, n(%) 15 (52) 8 (30) 0.15 PCI to G-CSF administration, min 553 ± 166 /
STEM-AMI SAFETY : Clinical Events over six months of follow-up EVENTS G-CSF (n 29) Placebo (n 27) p In hospital events, n Events from discharge to 6 months, n Death 0 0 1.0 Reinfarction 2 0 0.49 Ventricular arrhythmia 0 0 1.0 AHF 9 3 0.10 Stroke 0 0 1.0 Death 1 1 1.0 Reinfarction/ischemia 0 0 1.0 Late stent thrombosis 0 0 1.0 Target vessel restenosis 12 9 0.73 Ventricular arrhythmia 0 0 1.0 Heart failure 4 1 0.35 Stroke 1 0 1.0 Urgent revascularization 0 1 0.48 MACE, n 6 3 0.47
STEM-AMI TRIAL: Effects of the G-CSF treatment on mobilization of SCs Data are expressed as cells/μl of peripheral blood. *=p<0.001
STEM-AMI TRIAL: Changes of LVEF by Echo and MRI ECHO MRI * Increase of LVEF from enrolment to baseline for G-CSF (p=0.006) and placebo (p=0.013); Increase of LVEF from enrolment to 6-months for G-CSF (p=0.016).
STEM-AMI TRIAL: Changes of LV volumes by MRI Panel A: Changes of normalized LVEDV Changes of normalized LVEDV from baseline to 6-months for placebo (p=0.00005); Panel B: Changes of normalized LVESV # Changes of normalized LVESV from baseline to 6-months for placebo (p=0.016);
Scatterplots of the change of LVEDV from baseline to 6-months (Δ LVEDV) vs. time-toreperfusion in placebo (open square) and G- CSF (solid circles) groups. Solid lines represent the median of Δ LVEDV (9,3 ml) and time-toreperfusion (180 min.). * Upper right panel: patients with time-toreperfusion (T-to-R) > 180 min and Δ LVEDV > 9,3 ml. (p=0.0123).
STEM-AMI TRIAL: Infarct size: mean number of segments with LGE > 75% by MRI * Changes of mean number of segments with late gadolinium enhancement > 75% for G-CSF (p=0.04).
STEM-AMI TRIAL: Perfusion by SPECT: mean signal intensity (MSI) * Changes of MSI for G-CSF (p=0.005) and placebo (p=0.008).
STEM-AMI: Conclusions In patients with large anterior STEMI, EF 45% after reperfusion and a symptom-to-balloon time 2-12 hours, early administration (<12 hours) of G-CSF s.c. may attenuates 6-months unfavourable remodelling The analysis of the relationship between extent of remodelling and time-to-reperfusion has shown that the protective effect of G-CSF seems even more relevant when reperfusion time exceeds 3 hours About the possible mechanism involved in the G-CSF protective effect on LV remodelling, we observed a reduction in infarct size, suggesting that cells homing into the infarct zone may have played a role in reducing scar dimensions through the release of factors promoting infarct healing Large scale trials are now necessary to verify these hypothesis