Stefano De ServiDipartimento CardiovascolareAzienda Ospedaliera Ospedale Civile di Legnano

1910 1960

2010

CONFLICT OF INTEREST :

ELI LILLY- DAICHII SANKYO , MERCK, MEDICINES COMPANY, ASTRA ZENECA: Advisory Board Meetings , Speaker’s fees

EmploYEd antithrombotic therapies in patients with acute

coronary Syndromes HOspitalized in iTalian CCUs

Registry

EYESHOT

EYESHOTRegistry

EYESHOT

è un registro nazionale, prospettico, multicentrico ed osservazionale, su pazienti ricoverati consecutivamente con diagnosi di Sindrome Coronarica Acutanelle UTIC italiane , ubicate in ospedali con e senza laboratorio di emodinamica e cardiochirurgia, durante un periodo di 3 settimane , che rispondano ai criteri di inclusione

EYESHOTRegistry

Obiettivi (1)

• Ottenere una serie completa di dati al fine di migliorare le conoscenze sulle varie terapie antitrombotiche comunemente impiegate (da sole o in combinazione), dal momento del ricovero alla dimissione, in pazienti con SCA con differenti profili di rischio ischemico/emorragico e sottoposti a differenti strategie terapeutiche (PCI, CABG, strategia conservativa);

EYESHOTRegistry

Obiettivi (2)

•Valutare i fattori che determinano le scelte delle strategie di gestione delle terapie antitrombotichenella fase acuta dell'evento indice;

• Determinare la frequenza di eventi clinici intra-ospedalieri (ischemici ed emorragici) in un’ampia popolazione del mondo reale di pazienti con SCA ricoverati in UTIC, trattati con diverse strategie di rivascolarizzazione e differenti combinazioni di agenti antitrombotici.

BLITZ

2001

1959

ACS patients

296 centres

4 Italian ANMCO Registries

BLITZ-2

2003

1888

NSTE-ACS patients

275 centres

BLITZ-4

2009-2010

5854

ACS patients

163 centres

EYESHOT

2013

?

ACS patients

243 centres

BLITZ

2001

1959

ACS patients

296 centres

4 Italian ANMCO Registries

BLITZ-2

2003

1888

NSTE-ACS patients

275 centres

BLITZ-4

2009-2010

5854

ACS patients

163 centres

EYESHOT

2013

?

ACS patients

213 centres

In-hospital treatment

Treatment at discharge

BLITZ

2001

1959

ACS patients

296 centres

4 Italian ANMCO Registries

BLITZ-2

2003

1888

NSTE-ACS patients

275 centres

BLITZ-4

2009-2010

5854

ACS patients

163 centres

EYESHOT

2013

?

ACS patients

213 centres

2001, anno cruciale nella storia della Cardiologia moderna

Clopidogrel in non-STE ACS

ESC Guidelines 2002

- Once diagnosed, ACS without persistent ST-segment elevation requires an initial medical treatment including aspirin 75 to 150 mg daily, clopidogrel , LMWH or unfractionated heparin , betablocker and oral or intravenous nitrates in cases of persistent or recurrent chest pain.

ESC Guidelines for nonESC Guidelines for non--STE ACSSTE ACSStrategies accoding to risk stratificationStrategies accoding to risk stratification

Patients with recurrent ischemiaRecurrent chest pain

Dynamic ST-segment changes(ST-segment depression or transient

ST segment elevation)Early post infarction unstable angina

Elevated troponin levelsDiabetes

Hemodynamic instabilityMajor arrhythmias (VF, VT) h

Patients with recurrent ischemiaPatients with recurrent ischemiaRecurrent chest painRecurrent chest pain

Dynamic STDynamic ST--segment changessegment changes(ST(ST--segment depression or transient segment depression or transient

STST segment elevationsegment elevation))Early post infarction unstable anginaEarly post infarction unstable angina

Elevated troponin levelsElevated troponin levelsDiabetesDiabetes

Hemodynamic instabilityHemodynamic instabilityMajor arrhythmias Major arrhythmias (VF, VT)(VF, VT) hh

GpIIB/IIIA blockersGpIIB/IIIA blockers

andand

Coronary angiographyCoronary angiography

Bertrand M et al, Eur Heart J 2002;Bertrand M et al, Eur Heart J 2002;Bertrand M et al, Eur Heart J 2002; 23:1809

BLITZ

2001

1959

ACS patients

296 centres

4 Italian ANMCO Registries

BLITZ-2

2003

1888

NSTE-ACS patients

275 centres

BLITZ-4

2009-2010

5854

ACS patients

163 centres

EYESHOT

2013

?

ACS patients

213 centres

BLITZ

2001

1959

ACS patients

296 centres

4 Italian ANMCO Registries

BLITZ-2

2003

1888

NSTE-ACS patients

275 centres

BLITZ-4

2009-2010

5854

ACS patients

163 centres

EYESHOT

2013

?

ACS patients

213 centres

EYESHOTRegistry

Data Entry

3 settimane: 2-22 Dicembre

Diagnosi iniziale e finaleCaratteristiche clinicheValori di laboratorio e caratteristiche dell’ECGProfilo di rischio (ischemico/emorragico)Modalità del ricovero e durata della permanenza in U TICProcedure diagnostiche e terapeutiche (PCI, CABG o nessuna) Variabili proceduraliEventi clinici intra-ospedalieri (morte, infarto mi ocardico, sanguinamenti maggiori eminori).

Differenti terapie antitrombotiche, comprese le combin azioni, con la loro tempistica, via di somministrazione e dosaggio, dal momento del ricovero alla dimissione, con particolare attenzione a lle modifiche del tipo di farmaco, e/o alla via di somministrazione ed al suo dosaggio nei differenti contesti clinici

Disegno dello Studioe Raccolta Dati

Choices Impacting Anti-Thrombotic Therapy

Cath S

trategy

UFH Biva LMWH

ASA Clopidogrel Prasugrel

NoneAbciximab

Eptifibatide/Tirofiban

New Direct Xa Inhibitors

Cangrelor

Ticagrelor

Fondap.

Timing of Administration

Ris

k P

rofil

e

Aspirin (81-325 mg)

Clopidogrel → Novel P2Y12 inhibitors

LMWH → UFH → Bivalirudin

GP IIb/IIIa inhibitors

Routine post-PCI LMWH

Chronic oral anticoagulation

Stacking: An Unappreciated Enemy

2012

NSTE-ACS

Pre-HospED

CCU

Cath Lab

PCI Post-PCIChronic

Oral Tx

Unknown Anatomy Known Anatomy

Clopidogrel Ticagrelor

When to StartAntiplatelet Rx?

Prasugrel

Upstream Downstream

Prasugrel 30 mg

Prasugrel 60 mg Prasugrel 30 mg

Prasugrel 10 mg or 5 mg (based on weight and age) f or 30 days

PCI

1°Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailo ut, at 7 days

Placebo

CoronaryAngiography

n~4100 (event driven)

CoronaryAngiography

PCI

CABG or

MedicalManagement(no prasugrel)

CABG or

MedicalManagement

(no more prasugrel)

Montalescot G et al. Am Heart J 2011;161:650

Randomize 1:1Double-blind

NSTEMI + Troponin ≥ 1.5 times ULN local lab valueClopidogrel naive or on long term clopidogrel 75 mg

ACCOAST Design Schema

Days From First Dose0 5 10 15 20 25 30

End

poin

t (%

)

0

5

10

15

19962037

17881821

17751809

17691802

17621797

17521791

CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout

16211616

No. at Risk, PrimaryEfficacy End Point:No pre-treatmentPre-treatment

Pre-treatment10.810.0

Pre-treatment

Hazard Ratio, 0.997 (95% 0.83, 1.20)P=0.98P=0.81

(95% 0.84, 1.25) Hazard Ratio, 1.02

No Pre-treatment10.8

9.8No Pre-treatment

1° Efficacy End Point @ 7 + 30 days

Montalescot G, et al. N Engl J Med 2013;369:999

All TIMI (CABG or non-CABG) Major Bleeding

Days From First Dose0 5 10 15 20 25 30

End

poin

t (%

)

0

1

2

3

4

5

All TIMI Major Bleeding

Pre-treatment2.9

Pre-treatment2.6

No Pre-treatment1.5

No Pre-treatment1.4

19962037

19471972

13281339

12971310

12881299

12841297

12631280

No. at Risk, All TIMI Major Bleeding:No pre-treatmentPre-treatment

Hazard Ratio, 1.97 (95% 1.26, 3.08)P=0.002

Hazard Ratio, 1.90(95% 1.19, 3.02) P=0.006

Montalescot G, et al. N Engl J Med 2013;369:999

OLD PARADIGM

NEW PARADIGM

CAG + PCI

CAG + PCI *

UFH, ASA, upstream GPIIB IIIA blockers,

UPSTREAM P2Y12 INHIBITOR

ASA, LMWH ( Bivalirudin, UFH) GPIIB IIIA blockers ( selective use),

PRASUGREL ( 60 mg LD ), TICAGRELOR (180 mg LD ) bef ore PCI according to clinical characteristics ( diabetes , risk stent thrombosis, low CrCl, age…)

“ Cooling-off strategy ”

DAYS

HOURS

“ Early invasive approach”

Antithrombotic therapy in NSTE-ACS with planned invas ive strategy

* Immediate or early surgery may be an additional a vailable option

EYESHOT (EmploYE d antithrombotic therapies

in patients with acute coronary S yndromes HOspitalized in iT alian CCUs) Registry

Strategies in NSTE-ACS

Conservative strategy :

ASA + TICAGRELOR on admission

Invasive strategy :

ASA + CLOPIDOGREL 300 mg LD on admission

Switch to PRASUGREL , if PCI in diabetics, or high risk of stent thrombosis

Switch to TICAGRELOR , if CrCl <60 ml/min, Age >74 y, “no option” for revascularization

ESC 2013

Switching of P2Y12 inhibitor in patients with ACS:Insights from the GReek AntiPlatElet Registry (GRAP E)

N = 1280 ACS patients (53.5% STEMI)

N= 434 (91%)UPGRADEClop →→→→Pra/Tica

N= 25 (5%)DOWNGRADEPra/Tica →→→→Clop

N= 18 (4%)CHANGETica↔↔↔↔Pra

Conclusions : In-hospital switching of P2Y12 inhibitor is frequent and mostly represents upgrade from clopidogrel to prasugrel or ticagrelor.

477 (37.3%) SWITCHING

EYESHOTRegistry

250 UTIC rappresentative della realtà italiana (ospedali di ogni livello, in aree metropolitane e

rurali, nel nord, nel centro e nel sud della nazione)

Studio Periodo arruolamento

Popolazione N UTIC n

BLITZ 1 2 settimane STEMI/NSTEMI 296 1959

BLITZ-2 3 settimane NSTEACS 275 1888

BLITZ-3 2 settimane Ricoveri UTIC 332 3636 (solo SCA)

BLITZ-4 10 settimane (fase 1)

STEMI/NSTEMI 163 5915 (fase 1)

n stimato= 2500 pazienti

Influence of Timing of Clopidogrel Treatment on theEfficacy and Safety of Bivalirudin in the ACUITY Tri al

Lincoff AM, et al. J Am Coll Cardiol Intv 2008;1:63 9

Risk ratio: 1.66, 95% CI: 1.05 to 2.63; p=0.03*Death, MI, urgent TVR at 30 days

Guidelines on myocardial revascularizationWijns W, et al. Eur Heart J 2010;31:2501

Guidelines for the management of NSTE-ACSHamm CW, et al. Eur Heart J. 2011 Sep 21. [Epub ahead of print]

ESC Recommendations for Oral Antiplatelet Agents

Rates of Definite Acute ST in Recent Clinical Trial s without Pre-Treatment with APLT

Wiviott SD, et al.N Engl J Med 2007

Bhatt DL, et al.N Engl J Med 2013

Stone GW, et al.N Engl J Med 2007

Comparator ArmsNew Drug

Clopidogrel and Pre-Treatment in PCI: A Meta-Analysis

8608 patients out of 7 RCTs undergoing PCI, including NSTEACS, STEMI, and elective PCI

PCI Cure

Relative Weight, % 43.1 49.7

Bellemain-Appaix A, et al. JAMA. 2012;308:2507

Ab

solu

te r

isk

, %

OR: 0.80P=0.17

OR: 0.77P<0.001NNT: 40

VN

-P2Y

12 P

RU

0

100

200

300

400

clop 600 mg/pras 60 mg

clop 600 mg/pras 30 mg

median

placebo/pras 60 mg

Pharmacodynamic

Endpoints

Primary Endpoint:

PRU at 6 hrs

n= 43 n= 38 n= 45

P=0.188

Diodati J and Angiolillo DJ. Circ Cardiovasc Interv 2013 (in press)

Prasugrel LD Alone vs. Clopidogrel + Prasugrel LDs

PRASUGREL (AM) CLOPIDOGREL (AM)

PRASUGREL LD ALONE CLOPIDOGREL + PRASUGREL LDs

Platelet P2Y12 Receptor

Diodati J and Angiolillo DJ. Circ Cardiovasc Interv 2013 (in press)AM=Active Metabolite; LD=Loading Dose, PD=Pharmacodynamic

4 French AMI registries

30-day mortality in whole AMI population and NSTEMI

USIK 1995 USIC 2000 FAST-MI 2005 FAST-MI 2010Courtesy of N.Danchin

30-day mortality by age in NSTEMI

4 French AMI registries

Courtesy of N.Danchin

NSTEMI:changing characteristics

1995 2000 2005 2010 P value

Age (years) 68.5 ± 14.2 68.9 ± 13.5 70.2 ± 13.4 68.6 ± 13.6 0.71

Diabetes mellitus 20.1 25.8 29.1 27.1 0.002

Current smoking 26 21.9 22.2 24.5 0.74

Obesity 13.4 22.5 21 23.9 <0.001

Previous MI 27.4 28.4 23.8 22.8 0.006

Peripheral artery disease 12 14.7 13.6 11.8 0.57

4 French AMI registries

Courtesy of N.Danchin

Use of PCI during hospital stayNSTEMI

4 French AMI registries

Courtesy of N.Danchin

Use of coronary angiography : 2000 - 2010 NSTEMI

4 French AMI registries

Courtesy of N.Danchin

In-hospital switching in real-life patients with ACS

Alexopoulos A, et al. JACC 2013

Data from GRAPE registry

Alexopoulos A, et al. International Journal of Cardiology 2013

Contemporary use of oral antiplatelet agentsThe GRAPE registry

Bleeding events with new P2Y12 inhibitors in real-life patients

The GRAPE registry

Alexopoulos A, et al. JACC 2013

NSTEMI: antithrombotic therapy in first 48 hours

Courtesy by Danchin

4 French AMI registries

30-day mortality by PCI use

% with PCI: 12.5 44 51 65

Mean age: 68.5 68.9 70.2 68.6

Mean age: 68.5/62.7 72.0/64.9 73.6/67.0 72.3/66.6

NSTEMI

4 French AMI registries

Courtesy of N.Danchin

3-year-survival according to the strategy used

Puymirat E, et al. J AM Coll Cardiol Intv 2012;5:893-902

FAST-MI Registry

3-year-outcomes according to invasive strategy

Puymirat E, et al. J AM Coll Cardiol Intv 2012;5:893-902

FAST-MI Registry

5-year-outcome in elderly by management strategy

Roe MT, et al. Circ Cardiovasc Qual Outcomes 2013;6:323-32

CRUSADE Registry

Puymirat E, et al. J AM Coll Cardiol Intv 2012;5:893-902

Invasive Strategy according to GRACE scoreFAST MI Registry

Ryan JW, et al. Circulation 2005;112:3049-57

CRUSADE registry

Timing of coronary angiography

Bakhai A, et al. Eurointervention 2011;6:992-6

The APTOR observational study

Time from hosp-admission to PCI in NSTEMI

Zeymer U, et al. Eur J Prev Cardiol 2012;20:218-28

Data from 14 european countries

Timing of clopidogrel in ACS undergoing PCI

EYESHOTRegistry

Saranno inclusi tutti i pazienti con diagnosi inizi ale di SCA (NSTE-SCA o STEMI) ricoverati consecutivamente in UTIC nel periodo di osservazione stabilito, sottoposti a rivascolarizzazione miocardica (PCI o CABG) o a trattamento conservativo, che avranno firmato il consenso informato.

Criteri di Inclusione/Esclusione

Bakhai A, et al. Eurointervention 2011;6:992-6

Cumulative frequency of days

from hospital admission to clopidogrel LD in NSTEMI

The APTOR study

Valenti R, et al. Am J Cardiol . In press

Prasugrel vs Clopidogrel

in unprotected left main-PCI using DES

Clopidogrel Prasugrel p value

n=104 n=148

�Age (yrs) 72 ± 11 72 ± 10 .811

� Male 78 (75) 112 (76) .902

� Diabetes 23 (22) 36 (24) .684

� Pre MI 20 (19) 36 (24) .338

� Peripheral Vascular disease 20 (19) 32 (22) .644

� Recent MI (<30 days) 11 (12) 14 (14) .595

� Acute coronary syndrome 61 (59) 103 (70) .073

� LVEF < 0.40 34 (33) 51 (34) .770

� Creatinine > 150 µmol/L 9 (9) 23 (15) .106

� EuroSCORE > 6 55 (53) 84 (57) .553

� EuroSCORE > 13 24 (23) 48 (32) .106

FLORENCE LEFT MAIN-PCI REGISTRY

Valenti R, et al. Am J Cardiol . In press

Prasugrel vs Clopidogrel in unprotected left main-PCI using DES

FLORENCE LEFT MAIN-PCI REGISTRY

One-year clinical outcomes

Invasive Strategy according to risk levelGRACE Registry

Jedrzkiewicz S, et al. Can J Cardiol 2009;25:e370-e376

Gyenes GT, et al. Can J Cardiol 2013

Canadian Global Registry of Acute Coronary Events

Timing of coronary angio by admission day

Mon Tue Wed Thu Fri Sat Sun

Tim

e fr

om

ad

mis

sio

n t

o a

ng

iog

rap

hy,

ho

urs

Day of admission

51,0 49,6 46.6

92.7

71.3

58.9

94.7

Gyenes GT, et al. Can J Cardiol 2013

Canadian Global Registry of Acute Coronary Events

Frequency and timing of coronary angiography by risk status

0

20

40

60

80

100

Weekday

54 h

Co

ron

ary

ang

iog

rap

hy,

per

cen

t

1812 753 756 307 2568 1060

Weekday

70 h

Weekend

69 h

Weekend

72 h

Overall

61 h

Overall

71 h

Low-to intermediate-risk gorup (GRACE score < 141), overall n = 3701

High-risk group (GRACE score ≥ 141), overall n = 2378

P < 0.0001

Time to angiography

69.7

44.7

69.6

45.2

69.7

44.8

Bakhai A, et al. Eurointervention 2011;6:992-6

The APTOR observational study

Location of first clopidogrel LD in ACS patients

Boggon R, et al. Eur Heart J 2011

HR 2.65 (95% CI, 2.17-3.17) for death or MI in the first year post hospital

discharge in case of premature clopidogrel discontinuation

MINAP-GPRD COHORT

Clopidogrel discontinuation after ACS

NSTEMI:NSTEMI:

tra best practice e registritra best practice e registri

Le nuove evidenze della terapia antipiastrinicaLe nuove evidenze della terapia antipiastrinica

Alberto MenozziAzienda Ospedaliero-Universitaria di Parma

Napoli, 2 ottobre 2013

Incidence of myocardial infarction

- Steg PG, et al. Eur Heart J 2012; 33:2569–2619

- Hamm CW, et al. Eur Heart J 2011;32:2999-3054

- Yeh RW, et al. N Engl J Med 2010;362:2155-65

Generalised use of

troponin measurement

STEMI

NSTEMI

5-year-mortality in NSTEMI and STEMI

FAST-MI Registry

Puymirat E, et al. J AM Coll Cardiol Intv 2012;5:893-902

NSTEMIConundrum of clinical situations

Conclusioni• I dati di registro mostrano che, negli anni più recenti, le

raccomandazioni di “best practice” vengono sempre più estesamente

adottate nella pratica clinica, ed in particolare è in aumento la quota di

pazienti sottoposti a strategia invasiva, con inerente beneficio clinico

• Per quanto concerne il timing all’angiografia è verosimile che a

seguito delle linee guida ESC del 2011 vi sia un progressivo

accorciamento delle tempistiche, per lo meno nei centri dotati di

emodinamica

• I dati riguardanti la terapia antiaggregante mostrano discreta adesione

alle linee guida e, per quanto concerne i nuovi antiaggreganti orali e

prasugrel in particolare, mostrano anche nella popolazione “real-

world” dati di efficacia e sicurezza consistenti con quelli degli studi

clinici

Objectives:

- To obtain a complete national data set in order to improve our knowledge on different

antithrombotic therapies commonly employed from admission to discharge in ACS patients

undergoing different therapeutical strategies (PCI, CABG, conservative).

-To assess the rate of in-hospital clinical events (ischemic and hemorrhagic) in a wide real-

world setting of ACS patients admitted in CCUs treated with different revascularization

strategies and combinations of antithrombotic agents.

EYESHOT