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CONVENTION
della CARDIOLOGIA LOMBARDA
Induno Olona
27-28/3/2015
Dr Felice Achilli
La terapia cellulare: tra sogno e realtà
05/01/2016 2
(B) Large infarct (MI) in a cytokine-
treated mouse; forming myocardium
(arrowheads) at higher magnification (adjacent panel).
(C) MI in a nontreated mouse.
Healing comprises the entire infarct
(arrowheads). Scarring at higher
magnification (adjacent panel).
FIRST EXPERIMENTAL EVIDENCE: 1
FIRST EXPERIMENTAL EVIDENCE: 2
Orlic PNAS vol.98
Mortality - 68% EF+ 114%
Dose Dipendent TIME Dipendent
4 05/01/2016 4
STEM CELL THERAPY: RATIONALE
The prognosis for patients who are admitted to the hospital
with HF remains poor, with a 5-years mortality of 50%,
wich is worse than that for breast or colon cancer.
Current therapeutic approaches in HF are “palliative” in the
sense that they do not address the the fundamental problem
of the loss of cardiac tissue.
For the first time since cardiac transplantation, the goal is
not damage control but damage elimination,that is, removal
of the underlyng cause of HF.
For this reason stem cell-based therapies have sparked
intense interest.
Bolli R. Circ.Res. 2013; 113;810-834
05/01/2016 5 05/01/2016 5
NYHA II 1.7 Million Patients
NYHA III 1.4 Million Patients
NYHA IV 367,000 Patients
Relieves HF Symptoms
Diuretics
Inotropes
Slow HF Progression
ACE Inhibitors
Beta Blockers
Aldosterone Antagonist
Neprilisina Antagonist
Patient Has Consider
QRS > 150 CRT
3+ / 4+ MR MV Repair
Advanced CAD CABG
Transplant
LVAD
TAH
HEART FAILURE TREATMENT OPTIONS
DRUG THERAPY INTERVENTIONS END STAGE
Source NYHA Class Populations: Health Research International 2004
Progressive
Tissue Damage
Remodelling ?????
Ly and Nattel CIRCULATION 2008
SOME INFERENCES FROM EXPERIMENTAL DATA:
DIRECT AND INDIRECT EFFECTS OF CELL THERAPY
05/01/2016 8 05/01/2016 8
POTENTIAL “CLINICAL GOALS” OF STEM CELLS
Bolli R. Circ.Res. 2013; 113;810-834 mod.
ENDOGENOUS
MOBILIZATION ESOGENOUS
INJECTION
05/01/2016 9
PATHOPHYSIOLOGY AND CLINICAL MODELS:
DIFFERENT STRATEGY
EARLY AFTER STEMI:
CARDIOPROTECTIVE
The goal of therapy include preservation of myocardial architecture. Fibrosis is minimal and cardiac remodelling of the viable myocardium has not yet occurred. Paracrine mechanism that promote cell survival or angiogenesis might be a good strategy for this period.
Citokines:
EPO
G-CSF
LATER STAGES OF STEMI:
CARDIORESTORATIVE
At later stages of florid left ventricular dysfunction, due to necrosis and fibrosis, the goal becomes cardiorestorative (regenerative), i.e. to reverse maladaptive remodelling and
Blood Marrow Stem Cells
(selected and non selected)
Segers and Lee. NATURE 2008; Terzic A. EHJ 2014
05/01/2016 10
CELLS THERAPY IN AMI:
SAFETY
Zimmet et Al. EHJ 2012
NO DIFFERENCE ABOUT : IN STENT RESTENOSIS
THROMBOSIS
Re-AMI
DEATH
HOSPITALIZATION
ARRYTHMIA
SURGICAL REVASCULARIZATION
05/01/2016 11
ENDOGENOUS STRATEGY:
EPO CLINICAL TRIALS IN STEMI
TRIAL POPULATION
DESIGN ENDPOINTS
HEBE IIII Voors et al.
Eur Heart J, 2010
N=529 (1:1)
STEMI after successfull
PCI
- Phase II, prospective,
randomized, open-label.
placebo-controlled.
- Single bolus EPO
- powered to detect
differences in EF
Infarct size/EF =
negative (MR)
Event-free survival
= positive (at 6
weeks)
REVEAL Najjar SS et al.
JAMA, 2011
N=222 (1:1)
STEMI after successfull
PCI
Phase II prospective,
randomized, placebo-
controlled.
- Single bolus EPO (i.v.)
- powered to detect
differences in infarct size
Infarct size =
negative (MR)
Event-free survival
= higher rates of
CV events in EPO
group
(at 12 weeks)
Abdel-Latif et al. META-ANALYSIS - AM HEART J 2008 Abdel-Latif et al. META-ANALYSIS - AM HEART J 2008
Abdel-Latif et al. META-ANALYSIS - AM HEART J 2008
Abdel-Latif et al. META-ANALYSIS - AM HEART J 2008
05/01/2016 16 Achilli F. et Al. Heart 2014
05/01/2016 17
“The final verdict on G-CSF therapy
will emerge not from meta-analyses, but from adequately
powered randomized controlled trials with optimized
study parameters, i.e., dose, duration, timing, patient
population, and outcome parameters”.
G-CSF TREATMENT IN AMI: FUTURE PERSPECTIVE
05/01/2016 18 18
ESOGENOUS INJECTION VARIOUS TYPES OF STEM CELL THERAPIES IN PATIENTS
WITH CARDIOVASCULAR DISEASE
The first study of BMC in experimental MI was published in 2001.
Within a year, this therapy had been applied in patients.
Bolli R. Circ.Res. 2013; 113;810-834
The ACCRUE (Meta-Analysis of Cell-based CaRdiac stUdiEs) is the first
prospectively declared collaborative multinational database including individual data
of patients (IPD) with ischemic heart disease treated with cell therapy.
Safety and efficacy of intracoronary cell therapy after acute myocardial infarction
from 12 randomized trials (ASTAMI, Aalst, BOOST, BONAMI, CADUCEUS,
FINCELL, REGENT, REPAIR-AMI, SCAMI, SWISS-AMI, TIME, LATE-TIME) in
1252 Pt.
This meta-analysis of IPD from randomized trials in patients with recent AMI
revealed that intracoronary cell therapy provided no benefit, in terms of clinical events
or changes in left ventricular function.
ESOGENOUS STRATEGY
What New Information Does This Article Contribute?
• This IPD-based meta-analysis of randomized studies found that
intracoronary administration of autologous reparative cells had
no effect on major adverse cardiac and cerebrovascular events
or on left ventricular performance or remodeling.
• Our results were not influenced by the timing of cell therapy, by
the number of injected cells, or by the baseline cardiac ejection
fraction.
What Is Known?
• Previous meta-analyses of randomized,
cardiac cell-based therapy studies have
shown moderate, but significant
improvements in clinical outcome and left
ventricular function.
• Those meta-analyses suggested that the
beneficial effects were gained by increases
in the numbers of cells delivered, by timing
cell therapy for delivery 5 to 8 days post
myocardial infarction, or by selecting
patients with decreased ejection fraction.
Both BMCs and progenitor cells are known to home to
ischemic myocardium after an injury. Given that endogenous
mechanisms for progenitor cell recruitment already exist, it
may be more important to promote favorable bone marrow
activity than to artificially translocate regenerative cells into
the injured tissue. Therefore, our study may suggest
important therapeutic targets for cardiovascular regenerative
therapies.
05/01/2016 24 05/01/2016 24
PHASE III ongoing CT of Cell Therapy
STEM-AMI OUTCOME
1530 Patients with anterior STEMI (LVEF <45%) >3h <12
Large Phase III, open, randomized,
placebo-controlled, multicenter
nationwide Trial.
Primary combined EP: Death; Re
IMA; HF hospitalization
STEM-AMI OUTCOME
TRIAL
STem cElls Mobilization
in Acute Myocardial Infarction Outcome
Trial
A national, multicentre, randomised, open-label,
Phase III study Principal Investigator
Dr. Felice Achilli
46 Cardiologie Italiane
281 Pazienti con STEMI anteriore
arruolati ad oggi
FEVSx media 39%
Sottoprogetto RMN
per studio endpoint surrogati
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