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 ?????

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From Reverse Remodeling to Myocardial Recovery

Ly and Nattel CIRCULATION 2008

SOME INFERENCES FROM EXPERIMENTAL DATA:

DIRECT AND INDIRECT EFFECTS OF CELL THERAPY

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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)

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ENDOGENOUS STRATEGY

G-CSF TRIALS IN STEMI

05/01/2016 13

ENDOGENOUS STRATEGY

G-CSF TRIALS IN STEMI

Zimmet et Al. EHJ 2012

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

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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

05/01/2016 19

ESOGENOUS STRATEGY :

METANALYSIS ??

(BONAMI, HEBE, and REGENT trials excluded)

05/01/2016 20

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.

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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