I nuovi antiaggreganti piastrinici: dai trial alla pratica ... didattici/NUOVI ANTIAGGREGANTI... ·...

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Palermo

I nuovi antiaggreganti piastrinici: dai trial alla pratica clinica

12 febbraio 2013

Scuola di Specializzazione in Malattie dell’Apparato Cardiovascolare

Antonino Rotolo

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Palermo Trip MD et al, N Engl J Med 1990;322:1549-1554

A: SPA-negative B: SPA-intermediate C: SPA-positive

SPA: Spontaneous Platelet Aggregation

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Palermo

Antithrombotic Trialists’ Collaboration BMJ 2002;324:71-86

PCI-CURE Investigators, Lancet 2001;358:527-533

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Palermo

Clopidogrel: is it the right

CURE?

Seminari Palermitani di Cardiologia, 2004

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Palermo

Meccanismi della resistenza al clopidogrel

Michos ED et al, Mayo Clin Proc 2006;81:518-526

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Palermo The FAST-MI Investigators, N Engl J Med 2009;360:363-375

CYP2C19

The ELEVATE-TIMI 56 Investigators, JAMA 2011;306:2221-2228

p=0.003

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Palermo Tentzeris I et al, Thromb Haemost 2011;105 (suppl. 1):S60-S66

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PRASUGREL

TICAGRELOR

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Palermo Schömig A, N Engl J Med 2009;361:1108-1111

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Palermo Brandt JT et al, Am Heart J 2007;153:66.e9-66.e16

PRASUGREL

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Palermo Wallentin L et al, Eur Heart J 2008;29:21-30

PRASUGREL

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Palermo Gurbel PA et al, Circulation 2009;120:2577-2585

ADP 20 µmol/L

TICAGRELOR

180 mg ticagrelor 600 mg clopidogrel

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Palermo

VerifyNow P2Y12

Gurbel PA et al, Circulation 2009;120:2577-2585

TICAGRELOR

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Palermo

• TRITON-TIMI 38

Trial to Assess Improvement in Therapeutics Outcomes by Optimizing Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction 38

• PLATO

Study of Platelet Inhibition and Patient Outcomes

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Palermo The TRITON-TIMI 38 Investigators, N Engl J Med 2007;357:2001-2015

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Palermo

TRITON-TIMI 38 Study Design

NSTE-ACS (TIMI score ≥3)

STEMI (primary PCI ≤12 hours or delayed PCI>12 hours – 14 days)

Clopidogrel-naïve; All patients received ASA

randomized within 72 hours of index event

(N = 13,608)

Primary End Point: CV Death, MI, or Stroke

Primary Safety End Point: TIMI Major Bleeding

6-15 month exposure Median 14.5 months

Clopidogrel 300-mg loading dose

then 75-mg once-daily maintenance; (N = 6,795)

Prasugrel 60-mg loading dose

then 10-mg once-daily maintenance (N = 6,813)

The TRITON-TIMI 38 Investigators, N Engl J Med 2007;357:2001-2015

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-18%

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Palermo The TRITON-TIMI 38 Investigators, Lancet 2009;373:723-731

RRR -32% RRR -19%

End point primario End point secondario

RRR -50% RRR -43%

TRITON STEMI

Trombosi di stent Emorragie maggiori non CABG-correlate

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TRITON DIABETE

The TRITON-TIMI 38 Investigators, Circulation 2008;118:1626-1636

End point primario

IM (fatale e non fatale)

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Palermo

TRITON DIABETE

The TRITON-TIMI 38 Investigators, Circulation 2008;118:1626-1636

Trombosi di stent

Emorragie maggiori

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TRITON RECIDIVE

The TRITON-TIMI 38 Investigators, Eur Heart J 2008;29:2473-2479

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Palermo Mega JL et al, Lancet 2010;376:1312-1319

TRITON ANALISI GENETICA

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Palermo The TRILOGY ACS Investigators, N Engl J Med 2012;367:1297-1309

TRILOGY

GRACE risk score: 114-120

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Palermo The PLATO Investigators, N Engl J Med 2009;361:1045-1057

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PLATO Study Design

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)

Clopidogrel-treated or -naïve; All patients received ASA

randomized within 24 hours of index event

(N = 18,624)

Primary End Point: CV Death, MI, or Stroke

Primary Safety End Point: Total Major Bleeding

Clopidogrel 300-mg loading dose unless pre-treated

then 75-mg once-daily maintenance; (additional 300 mg allowed pre-PCI)

(N = 9,291)

Ticagrelor 180-mg loading dose, then

90-mg twice-daily maintenance; (additional 90 mg pre-PCI)

(N = 9,333)

6-12 month exposure Median 9.2 months

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-16%

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Palermo

The PLATO Investigators, N Engl J Med 2009;361:1045-1057 The PLATO Investigators, Circulation 2001;124:244-554

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Palermo The ONSET/OFFSET Investigators, J Am Coll Cardiol 2010;56:185-193

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Palermo Serebruany VL and Atar D, Eur Heart J 2012;31:764-767

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Palermo

PLATO STEMI

The PLATO Investigators, Circulation 2010;122:2131-2141

-13%

-19%

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Palermo

PLATO DIABETE

The PLATO Investigators, Eur Heart J 2010;31:3006-3016

End point primario: -12%; mortalità globale: -18%; trombosi di stent: -35%

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Palermo

PLATO CABG

All-cause mortality CV death

The PLATO Investigators, J Am Coll Cardiol 2011;57:672-684

Intervento entro 7 giorni dall’ultima dose

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Palermo

PLATO CKD

The PLATO Investigators, Circulation 2010;122:1056-1067

-21%

-11%

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Palermo The PLATO Investigators, Circ Cardiovasc Qual Outcomes 2012;5:680-688

PLATO ANZIANI

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Palermo James SK et al, BMJ 2011;342:d3527

PLATO STRATEGIA NON INVASIVA

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PLATO ANALISI GENETICA

The PLATO Investigators, Lancet 2010;376:1320-1328

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Palermo

TRITON PLATO

Pazienti (n) 13.608 18.624

Età mediana (anni) 61 62

Età >75 anni (%)

Sesso femminile (%)

13

26

15,5

28

STEMI (%) 26 38

UA/NSTEMI (%) 74 59

Diabete (%) 23 25

Insufficienza renale (GFR<60) (%) 11 21

PCI (%) 99 62

CABG (%) 1 10

Trattamento conservativo (%) 0 28

Inibitori GP IIb/IIIa (%) 55 27

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TRITON PLATO

PRA CLO p TIC CLO p

End point primario (%) 9,9 12,1 <0,001 9,8 11,7 <0,001

Mortalità cardiovascolare (%) 2,1 2,4 NS 4,0 5,1 0,001

Mortalità totale (%) 3,0 3,2 NS 4,5 5,9 <0,001

Infarto miocardico (%) 7,3 9,5 <0,001 5,8 6,9 0,005

Ictus (%) 1,0 1,0 NS 1,5 1,3 NS

Trombosi di stent (%) 1,1 2,4 <0,001 5,3 5,8 NS

Sanguin. maggiori CABG (%) 13,4 3,2 <0,001 5,3 5,8 NS

Sanguin. maggiori non CABG (%) 2,4 1,8 0,03 2,8 2,2 0,03

Sanguin. maggiori o minori TIMI (%) 5,0 3,8 0,002 11,4 10,9 NS

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Palermo

Nei pazienti ad alto rischio, HR confrontabili per prasugrel e ticagrelor

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Palermo ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST segment elevation, 2011

NSTEMI

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Palermo ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST segment elevation, 2012

STEMI

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Palermo Jukema JW et al, Curr Med Res Opin 2012;28:203-211

TAO

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Palermo Schiele F and Meneveau N, Eur Heart J ACC 2012;1:170-176

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Palermo

40

386

758

1084

0

200

400

600

800

1000

1200

ASA Ticlopidina

generico

Tiklid Plavix

Pre

zzo

(e

uro

)Costo annuale per singolo paziente dei farmaci antipiastrinici

ASA 325 mg/die Ticlopidina 250 mg/12 ore Clopidogrel 75 mg/die

2004

1147

587

876

0

100

200

300

400

500

600

700

800

900

1000

ASA Clopidogrel Efient Brilique

Pre

zzo

(eu

ro)

ASA 100 mg/die (1 c = 0,03 euro) Clopidogrel 75 mg/die (1 c = 0,13 euro) Prasugrel 10 mg/die (1 c = 1,61 euro) Ticagrelor 90 mg x 2/die (1 c = 1,20 euro)

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Palermo

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