Leonardo De Luca, M.D., Ph.D., F.A.C.C.

Department of Cardiovascular SciencesInterventional Cardiology UnitEuropean HospitalRome, Italyleo.deluca@libero.it

Conflict of interest: none

The Italian Network ofCardiac Care Units and the STEMI System of Care

2010 Annual Chapter MeetingNemacolin Woodlands ResortFarmington, PA

Pittsburgh, PA. October 16th 2010

* Percentages refer to pts with complete data receiving reperfusion TxANC=Australia, New Zeland, CanadaAB=Argentina, Brazil

Reperfusion Therapy by Geographic Region*:Findings From the GRACE Registry

Eagle KA, et al. Lancet 2002;359:373

Single χ2 test, p<0.001 for each four-by-four comparison

%

Hospitalized STEMI Treatment in Europe**data from national registries or surveys

Widimsky P, et al. Eur Heart J 2010;31: 943

Countries abbreviations: CZ, Czech Republic; SLO, Slovenia; DE, Germany; CH, Switzerland; PL, Poland; HR, Croatia; SE, Sweden; HU, Hungary; BE, Belgium; IL, Israel; IT, Italy; FIN, Finland; AT, Austria; FR, France; SK, Slovakia; LAT, Latvia; UK, United Kingdom; BG, Bulgaria; PO, Portugal; SRB, Serbia; GR, Greece; TR, Turkey; RO, Romania

Improving Patient Care by Linking Evidence-Based Medicine and Evidence-Based Management

Two components

Advances in evidence-based medicine (EBM)

Knowledge of how to put this content into routine practice (EBMgt)

EBMgt focuses on the underlying organizational issues that influence how care is delivered.

Advances in EBMgt identify the organizational strategies, structures, and management practice that enable to provide

evidence-based care, i.e., the context of providing care.

Managed Clinical Networks

Linked groups of health professionalsand organizations from primary, secondary, and tertiary care working in a coordinated manner, unconstrained by existing professionals and organisational boundaries to ensure equitable provision of high quality effective services

The Scottish Office, Department of Health. Introduction of managed ClinicalNetworks within the NHS in Scotland. Leeds: NHS Executive, 1999.

Practical Limitations of Primary PCI as a Universal Reperfusion Strategiy

Time delays (DBT, transfer time, waiting time for next available ambulance etc.)

Availability of invasive facilities

Operators’ skillness and cath lab volume load

Reorganization of EMS systems not conducive to making PPCI

EMS lacking 12-lead ECG capabilitiesNot all patients having STEMI are transported by EMSMandates to transport patients to the nearest facility

Transport in STEMI Networks:a Continous Odissey

Organization of ambulance systems, prehospital management, and adequate PCI capacity appear now to be the key issues in providing

reperfusion therapy for AMI.

Terkeisen et al. J Electrocardiology 2005; 36: 187

0

50

100

150

200

250

300

Sym

ptom

ons

et to

bal

loon

infla

tion

(min

utes

)

No prehospital diagnosisAdmission to local hospitalSubsequently transferredto interventional hospital

Prehospital diagnosisAdmission to local hospitalSubsequently transferredto interventional hospital

Prehospital diagnosisLocal hospital bypassed.Patients rerouted directlyto interventional hospital

PRAGUE-1PRAGUE-2MAASTRICTDANAMI-2Terkelsen et al.Aashein et al.

Clinical impact of direct referral to primary PCI following pre-hospital diagnosis of STEMI

Is Possible to Apply These Findings in a “Real World” Setting?

66%

86.6%

PRE POST PRE POST

16%

9.5%

Implementation of Guidelines Improve the Standard of Care

The Vienna STEMI RegistryREPERFUSION THERAPY MORTALITY

Kalla K, et al. Circulation 2006;113:2398

%

EMS coordinated with 5 Heart Hospitals Rotated 24 hr PCI availability Evaluated frequency of PCI and Lytics Evaluated Mortality

Ting HH et al. Circulation 2007; 116:729*Bradley EH, et al. N Engl J Med 2006;355:2308

28 regional hospitals without PCI capability located up to 150 miles away across 3 states

The Mayo Clinic STEMI Protocol

A Regional System to Provide Timely Access to PPCI Centers

ACC D2B Alliance*• emergency medicine physicians activate catheterization laboratory; • single phone call activates catheterization laboratory; • catheterization laboratory staff arrive at hospital within 20 min after activation; • real-time data feedback given to emergency medicine and cardiology staff

0

10

20

30

40

50

60

70

80

90

37.5%

51%

85.7%

EMS12 LeadPre-Arrival Activation

No EMS12 Lead

EMS12 Lead

Prehosp Emerg Care 2006;10:374-377

Door to Balloon Time < 90 min

Establishing Infarct NetworksMedical Response Delay

The Ottawa Hospital Institute STEMI Regional Program

DTB<90 min DTB<120 min

%

Le May RM et al. N Engl J Med 2008;358:231

Field transfInter-hosp. transf

Interhospitaltransfers

Fieldtransfers

P<0.001

Minutes

ECG

to B

allo

on T

ime

Prop

ortio

n of

Pat

ient

s (%

)The Citywide Ottawa ProgramTime to Treatment

p<0.001 p<0.001

ThrombolysisPTCA shock and ctd. to TBLThrombolysis and transfer to HubHigh risk PCIHigh and not high risk PCI

2002 2004

2003

AMI Network and Reperfusion Strategies in STEMI. Health Care Agency of the Italian region Emilia-Romagna

January 2003ESC Guidelines:

Primary PCIGold standard for

STEMI

Network implementation(transition) Saia F. et al, Heart 2008

Reperfusion TreatmentPatients with STEMI < 12h (85%)

Saia F. et al, Heart 2008

58,876,3

41,223,7

0

20

40

60

80

100

2002 2004

%

No reperfusionReperfusion

AMI Network and Reperfusion Strategies in STEMI. Health Care Agency of the Italian region Emilia-Romagna

In-hospital mortality

17

12,3

0

5

10

15

20

2002 2004

%

4.7 % ARR

p = 0.00528 % RRR

Saia F. et al, Heart 2008

AMI Network and Reperfusion Strategies in STEMIHealth Care Agency of the Italian region Emilia-Romagna

Clinical Impact of an Interhospital Transfer Strategy in Patients with STEMI Undergoing Primary PCI

The Emilia-Romagna STEMI network

Manari A et al. Eur Heart J 2008;29:1834

0

2

4

6

8

10

12

14

16

18

20

0 1 2 3 4 5 6 7 8 9 10 11 12

On-site p-PCITransfer p-PCI

9.2%

7.4%

HR: 0.8295% CI: 0.62 – 1.08; P=0.16

Months

1-Ye

ar

Car

diac

Mor

talit

y (%

)

47,90%

29,00%23,10%

ECG senza teletrasmissione

ECG con teletrasmissione

No ECG sul territorio

ECG and TNK

other combinationsECG and TNK sul territorio

ECG with teletransmission

ECG without teletransmission

No ECG

White: No ECGLight Blue:ECG without teletransmissionDark Blue:ECG with teletransmission

Pre-Hospital ECGand Teletransmission

Areas >60’ from Hub PPCI all ptsPPCI all pts (except for low risk <3h)PPCI for pts at high riskPPCI for pts at high risk >3hPPCI in case of shock or contraindications to TBLNo ECG transfer to ER

Reperfusion Strategiesby 118 Areas

1,6%4,1%

41,6%

6,8%

14,2%

31,8%

Sempre PPCIPPCI (TBL basso rischio <3h) Mix PPCI/TBLPPCI solo alto rischio > 3hSempre TBLSolo trasporto al PS

Strategie di Riperfusioneby 118 areas

Missing data (0)PCI for all patients (47)

PCI for all patients (except low risk, <3h) (16)PCI for all high risk patients (9)

PCI for high risk patients >3h (1)Thrombolysis; PCI only for shock or counterindication TBL (7)

No ECG / Direct Transport (54)

Percentage of STEMI Patients Arriving to the First Hospital via EMS Services

Widimsky P, et al. Eur Heart J 2010;31: 943

Italy

Primary PCIs per Year per Million Inhabitantsin European Countries

Widimsky P, et al. Eur Heart J 2010;31: 943

23

Primary PCIIn Italy (year 2009)

2007 2008 ∆% 2009 ∆%

22.421 24.101 7,5% 25.697

6,6%

7.601

5.200

4.6364.984

8.175

5.366

4.705

5.855

8.270

5.499

5.065

6.863

Nord Ovest Nord Est Centro Sud e Isole

2007 2008 2009

www.gise.it

24

Italiy tot. primary PCI./mlninhabitants 2009: 428(404 in 2008)

0

100

200

300

400

500

600

700

800

Abru

zzo

Alto A

dig

e

Basi

licata

Cala

bria

Cam

pania

Em

ilia R

.

Friuli

V.G

.

Lazi

o

Lig

uria

Lom

bard

ia

Marc

he

Molis

e

Pie

monte

Puglia

Sard

egna

Sic

ilia

Tosc

ana

Tre

ntino

Um

bria

V. d'A

ost

a

Veneto

2007 2008 2009

www.gise.it

Primary PCI /millions Inhabitants (year 2009)

Incidence

STEMINSTEMIUA

Epidemiology of ACS in Italy

6 months mortality

www.istat.it

411 CCUs in Italy2005

De Luca L, et al. G it Cardiol 2008;9(Suppl. 1)

728 Hospitals with a Cardiology Unit

CCUs

Cath LabPCI

Cardiac Surg

CCU+Cath lab

CCU+Cath +Cardiac Surg

Nuclear medicine

E.P.Ablations

North (%) Center (%) South (%)

CCUs in Italy2005

De Luca L, et al. G it Cardiol 2008;9(Suppl. 1)

Population/CCU Bed1 CCU bed/21816 inhabitants – 1 CCU/136577 inhabitants

•1888 patients, 257 centers, May 2003 (3 weeks)

•ACS admitted within 24 hours from last episode of chest pain, and biochemical evidence of myocardial necrosis a/o ECG changes, w/o ST elevation

•1959 patients, 296 centers, October 2001 (2 weeks)

•Patients with AMI (STEMI and NSTEMI) within 48 hours from symptoms onset (biochemical evidence of myocardial necrosis a/o acute ischemic ECG changes

IN ACS

Outcome

•5869 patients, 41 centers, 2006-2007 (12 months)

•ACS admitted within 48 hours from symptoms onset, with biochemical a/o ECG changes a/o known CAD/MI

ANMCO Registrieson ACS

BackgroundThe BLITZ History

Katz JN, et al. J Am Coll Cardiol 2007;49:1279

BackgroundCardiology and the Critical Care Crisis

0 10 20 30 40 50 60 70

Acute Coronary Syndromes

Acute Renal Failure

Ischemic Cardiomyopathy

Vasopressors/Inotropes used

PCI Performed

Respiratory Failure

Invasive Mechanical Ventilation

Chronic Kidney Disease/ESRD

STEMI

Acute Decompensated Heart Failure

Pneumonia

Sepsis/Septic shock

VT/VF

IABP Used

Gastrointestinal Bleed

Nonischemic Cardiomyopathy

Cardiogenic Shock

Thrombolytics Given

Infective Endocarditis

Pulmonary Embolism

Jul-06 Jul-01 Jul-96

Prevalence (%)

To Describe in Italian CCUs :

• epidemiology of admissions• main management aspects • most used resources for diagnosis, therapy and

management • in-CCU patients outcomes • organizing pathways • frequency of the most important co-morbidities

Blitz-3Aims of the Study

N° of Invited CCUs: 409N° of Partecipating CCUs: 332 (81%)

Blitz-3Results

80 79 84

0

20

40

60

80

100

North Central South

79 85 81

0

20

40

60

80

100

CCU CCU+Cath Lab CCU+CathLab+Cardiac

Surgery

% %

Blitz-3Diagnosis at Discharge from CCUs

%

21

31

13

7 7 6

2 2 2 2 1 1 1 1 0,5 0,4 0,3 0,3 0,20

20

40

STE ACS

NSTE ACS

Heart f

ailure

AF/SVT

Bradya

rrhyth

mias

Chest p

ainVT/VF

Synco

pe

Post-PCI/s

urgery

Other con

ditions

Pulmona

ry Embolis

m

Out-ho

spita

l Arre

st

Shock no ACS

Myo-peri

carditis

Post-PM-A

blatio

n

Tampo

nade

Aortic Diss

ectio

n

Stable

CAD

Endocarditis

Blitz-3Resources Use

79

3524

105 5 3 2 2 1

8

0

20

40

60

80

100

Echo

Coro

PCI

Pacem

aker CT

Ventila

tion

CVETEE

IABP

Ultrafi

ltrati

onNon

e

%

Number of procedures/patient

1 42%2 26%≥3 24%

Overall Population

Overall Mortality in CCU: 3.34 %

Blitz-3Complications in CCU

6

4

23

0,9 0,5

9

3

0,81,5

66,9

0

5

10

15

Supraven

tricular

arrhyth

Major v

entric

ular ar

rhth

AV Block

Angina

Re-IMA

Stroke

HF or worse

ning

Cardiac arre

st

Sepsis

Cardiogenic

Shock

Major B

leeding

Other

%

Hospital-based quality improvement initiative created by the ANMCO to improve the care as suggested by

current guidelines of patients with ACS admitted in CCUs

Aimand Methods

• Survey• Performance measures• Rapid feedback to partecipating centers• Snapshot on actual management of ACS pts

admitted to CCUs in Italy

PartecipatingCCUs (n=163)

The ANMCO Network

Nearly 5500 cardiologists N. 754 hospitals

N. 871 cardiological centers N. 403 CCUs

Cardiology Centers involved in ANMCO research projects

(total number 549)

> 5 projects 21 3 projects 78

5 projects 38 2 projects 147

4 Projects 49 1 project 216

Further, 60 Internal Medicine Divisions, 40 diabetologycenters, nearly 300 GPs are collaborating in ANMCO

projects

ANMCO Research Center

Epidemiology (E) Clinical Trial (RCT) Outcomes Research (OR)

IN-CHF (E)Survey Acute HF (E)

AREA IN-CHF (RCT)GISSI-HF (RCT)

CandHeart * (RCT)EVEREST* (RCT)

ALOFT* (RCT)

BLITZ 2 (E)OAT (RCT)•

Diabete e SCA# (RCT)G-CSF ISS# (RCT)Eplerenone* (RCT)

IN-ACS Outcome (OR)

IN-CP# (E)HEART Survey (E)•

DYDA (E)GOSPEL (RCT)

CARDIO-SIS (RCT)ORIGIN * (RCT)SCOUT * (RCT)

ONTARGET* (RCT)BEAUTIFUL* (RCT)

Total: 24 projects

Euro Heart Surveys, Osservatorio MinSal, Censimento

ACTIVE * (RCT)GISSI-AF (RCT)

• In collaborazione* Endorsement # Forthcoming

Heart FailureArrhythmiasCHDCV Prevention

The GISSI-1 Trial

GISSI Responsibilities

Study Design

Protocol Development + CRFsSelection of CommitteesImplementation of study protocolCentral RandomizationInvestigator’s Meetings Communication with CentersRecruitmentMonitoring Database set up + Data ManagementStatistical AnalysisSubstudies & Core LabEvent Adjudication ProcessPrimary Publication and Approval of secondary publications

The GISSI Collaboration

The enduring lessons of GISSI provide us with guidance about how to proceed:

- Focus trials aimed at drug development on questions that willinform clinical practice.

- Keep the mechanisms and bureaucracy of trials to a minimum.

- The spirit of the GISSI organization must be replicated to provide a mechanism that can deliver the evidence for thepractice of evidence-based medicine.

Califf RM Circulation. 1998;98:2649

Am Heart J 2004;148:187-193

…………The Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardio (GISSI) trial was the first megatrial (commonly defined as a trial enrolling10,000 patients) in STEMI and provided an unambiguous, affirmative answer. GISSI 1 (the number 1 was added later, when the group wisely decided to conduct additional trials) was more than a landmark trial—it was a bombshell. Like the development of thecoronary care unit 2 decades earlier, it immediatelyimproved the treatment of these patients……

Am Heart J 2004;148:187.

Continuity and Consistency:the Main Result of GISSI

GISSI 1 GISSI 2 GISSI 3 GISSI P

Enrollment 1984-85 1988-89 1991-93 1993-96

Publication 1986 1990 1993 1998

No Centers 176 223 200 172

No Patients 11,806 12,490 19,394 11,379

Total costs 350,000 € 4,000,000 € 6,000,000 € 4,000,000 €

Cost per pt Reg Auth

30 € SK by FDA

320 € 309 € Lisinopril by FDA

350 € n-3 PUFA by IMH and EMEA

GISSI-1 GISSI-2 GISSI-3 GISSI-P

GISSI-HF : 2002-2007A large randomized multi-center double blind, placebo controlled clinical trial testing the effects of n-3 PUFA (fish oil) and a statin on mortality and morbidity of patients with symptomatic Congestive Heart Failure.

GISSI: Recent Clinical Trials

GISSI-AF : 2005-2008Randomized, multi-center double blind, placebo controlled clinical trial on the use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of Atrial Fibrillation recurrence.

GISSI-HF Study Design

At each visit, the following assessments were performed: CV examination, vital signs, 12-lead electrocardiogram, compliance check, serious adverse events assessment and blood chemistryNYHA=New York Heart Association; R1=randomization 1; R2=randomization 2; D=drug distribution

Rosuvastatin 10 mg q.d.(n=2285)

Placebo (n=2289)

Median follow-up 3.9 years

Visit:

Month: 101 2

33

D

64

D

125

D

186

D

247

D

308

D

369

D

R1, R2

Placebo (n=3481)

n-3 PUFA 1 g q.d.(n=3494)

R1 (n=6975)

R2 (n=4574)

Adapted from: Tavazzi et al. Eur J Heart Fail 2004;6: 635.GISSI-HF Investigators. Lancet 2008; 372(9645):1231

GISSI-HF (n 3 PUFA)Co-primary End Points

Adapted from GISSI-HF Investigators. Lancet 2008; 372(9645):1223

HR = hazard ratio; CI = confidence interval*adjusted HR

0.90

0.94

P value

[99% CI 0.91-1.11]

[95.5% CI 0.90-1.12]

CI

1.01

1.00

HR*

1283 (56)1305 (57)All-cause mortality or CV hospitalizations

644 (28)657 (29)All-cause mortalityPrimary end points

Placebo(n=2289)

n (%)

Rosuvastatin(n=2285)

n (%)

(i) All-cause mortality and (ii) all-cause mortality or hospitalizations for CV reasons

GISSI-HF (Rosuva)Co-primary End Points

Adapted from GISSI-HF Investigators. Lancet 2008; 372(9645):1231

Visit 1 2

Week Days-5 to -1

Day 0

Randomization

3

2

4

4

5

8

6

24

7

52

Study Drug Treatment

placebo

placebo

placebo

80 mg valsartan160 mg valsartan

320 mg valsartan

GISSI-AFStudy Design

All patients have been provided with a transtelephonic monitoring tool N Engl J Med. 2009;360:1606

TRATTAMENTO A B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

timefirstFA

0 30 60 90 120 150 180 210 240 270 300 330 360

Time to first recurrence of AF(n. 1442)

Valsartan: 371/722 (51.4%)Placebo: 375/720 (52.1%)

Adjusted* HR 0.9996%CI 0.85-1.15P value 0.84

Pts at riskValsartanPlacebo* Adjusted for ACE-I, amiodarone use, cardioversion, PAD, CAD

722 586 524 491 465 445 423 398 383 368 356 343 260720 589 520 484 454 435 407 387 377 359 344 334 254

Days

N Engl J Med. 2009;360:1606

Focus of Innovative Research: From Lumpers to Splitters

not treated

treated

MAC

E %

0102030405060708090

100

Time

70% event-freewithout treatment

18% MACEwith treatment

40% MACEreduction

Maseri A, Circulation 2006

GISSI OUTLIERSProjects

1. Post-MI LV Remodelling

2. Risk Factors for Atherosclerosis

3. Determinants of coronary instability and healing

4. Idiopathic Heart Failure

5. Biomolecular Research in Cardiac Surgery