Sindrome Coronarica Acuta

Antiaggreganti: quale molecola, quale paziente, quale durata?

Alessandra Chinaglia

Antiaggreganti piastrinici

Quale molecola ?

ASPIRINA

+

P2Y12 receptor inhibitor

Quale molecola ?Caratteristiche degli antagonisti del recettore piastinico P2Y12 orali

SerebruanySerebruany, JACC 2005, JACC 2005

Quale molecola ?Caratteristiche degli antagonisti del recettore piastinico P2Y12 orali

SerebruanySerebruany, JACC 2005, JACC 2005

Variability in plateletresponsiveness to clopidogrel

Ticagrelor ha maggiore attività antipiastrinica rispetto a clopidogrel ?

Clopidogrel-nonresponsive patients Clopidogrel-responsive patients

* P < 0.0001, † P < 0.001, ‡ P < 0.05* P < 0.0001, † P < 0.001, ‡ P < 0.05

Gurbel, Circulation. 2010;121:1188-1199

Quale paziente ?

Età avanzataAlto rischio emorragico

Insufficienza renaleDiabete mellito

SCA

NSTEMI STEMI

PCI PPCI FibrinolisiChirurgia Terapia medica

SCA

STEMI nSTEMI

PCI Non PCI

N Engl J Med 2001;345: 494-502

SCA

STEMI nSTEMI

PCI Non PCI

N Engl J Med 2007;357:2001-15

SCA

STEMI nSTEMI

PCI Non PCI

SCA

STEMI nSTEMI

PCI Non PCIX

N Engl J Med 2012;367:1297-309N Engl J Med 2009;361:1045-57

CLOPIDOGREL PRASUGREL TICAGRELOR

Triton TIMI 38PRASUGREL vs CLOPIDOGREL

Primary study endpoint: cardiovascular death, myocardial infarction, stroke

Wiviott, NEJM 2007; 357; 20: 2001

Unstable angina or NSTEMI : 74%

PCI: 99% STENT 94%

CV DeathNonfatal MI

Nonfatal Stroke All Cause Death UTVR Stent Thrombosis

Wiviott SD et al. New Engl J Med 2007;357:2001-2015

TRITONTRITON--TIMI 38: TIMI 38: Major Efficacy End Points at 15 Months (All ACS)Major Efficacy End Points at 15 Months (All ACS)

HR 0.76 P<0.001

HR 0.89 P=0.31

HR 1.02 P=0.93

HR 0.95 P=0.64

(n=6,795)

(n=6,813)

End

Poin

t (%

)

HR 0.66 P<0.001

HR 0.48 P<0.001

2.12.4

7.3

9.5

1.01.0

3.03.2

2.5

3.7

1.1

2.4

TRITON-TIMI 38: Non-CABG TIMI Major Bleeds at 15 Months (All ACS)

Non-CABGTIMI Major

TIMI Major Spontaneous

TIMI Major Related to Instrumentation

TIMI Major Trauma

(n=6,716)

(n=6,741)

Subsets of Non-CABG TIMI Major

1.8%n=111

P=0.032.4%n=146

0.6%n=38

0.7%n=45

0.2%n=12

0.2%n=9

1.1%n=61

1.6%n=92

P=0.45

P=0.01

P=0.51

Wiviott SD et al. New Engl J Med 2007;357:2001-2015

Endp

oint

(%)

PLATOTicagrelor vs clopidogrel

Morte cardiovascolare,infarto miocardico, stroke

9.8%11.7%

N Engl J Med 2009;361:1045-57

Unstable angina or NSTEMI : 62%

PCI: 61%

PLATOACS (37% STEMI – NSTEMI)

Ticagrelor vs clopidogrel

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

Total major bleeding

NS

NS

NS

NS

NS

0

K-M

est

imat

ed ra

te (%

per

yea

r)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

13

TIMI major bleeding

Red cell transfusion *

PLATO life-threatening/

fatal bleeding

Fatal bleeding

TicagrelorClopidogrel

Major bleeding and major or minor bleeding according to TIMI criteria refer to nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with definition described in (Wiviott SD et al. NEJM. 357:2001-2015); *Proportion of patients (%); NS = not significant

11.611.2

7.9 7.7

8.9 8.9

5.8 5.8

0.3 0.3

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57

Non-CABG and CABG-related major bleeding

p=0.0264

p=0.0246

NS

NS

9K

-M e

stim

ated

rate

(%

per

yea

r)

Non-CABGPLATO major

bleeding

8

7

6

5

4

3

2

1

0Non-CABGTIMI major bleeding

CABGPLATO major

bleeding

CABG TIMI major bleeding

TicagrelorClopidogrel

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57

NSTEMI sottoposto a PCI ?

Cannon, Lancet 2010

Cardiovascular death, myocardial infarction, or stroke

p=0·0025

PCI: 77 %

NSTEMI sottoposto a PCI ?

Cannon, Lancet 2010

All cause death p=0·0025

PCI: 77 %

Cannon, Lancet 2010

Quale paziente ?

Età avanzataAlto rischio emorragico

Insufficienza renaleDiabete mellito

SCA

NSTEMI STEMI

PCITICAGRELORPRASUGREL

PPCI FibrinolisiChirurgia0 Terapia medica

N Engl J Med 2012;367:1297-309

Hazard ratio 0.75, 0.61 to 0.93; P=0.01

James, BMJ 2011;342

Quale paziente ?

Età avanzataAlto rischio emorragico

Insufficienza renaleDiabete mellito

SCA

NSTEMITICAGRELOR STEMI

PCITICAGRELORPRASUGREL

PPCI FibrinolisiChirurgia0

Terapia medicaTICAGRELOR

CLOPIDOGREL

NSTEMI ad alto rischio (anziani) ?

Husted, Circ Cardiovasc Qual Outcomes, 2012 Sep 1;5(5):680-8

Cardiovascular death/MI/stroke All cause mortality

Husted, Circ Cardiovasc Qual Outcomes, 2012 Sep 1;5(5):680-8

Major bleeding Non-CABG-related bleeding

26

RRR 38%

RRR 19%

James, Circulation published online May 9, 2012

NSTEMI con pregresso TIA/stroke ?

27James, Circulation published online May 9, 2012

Quale paziente ?

Età avanzata: TICAGRELOR, CLOPIDOGRELAlto rischio emorragico: TICAGRELOR, CLOPIDOGRELInsufficienza renaleDiabete mellito

SCA

NSTEMI STEMI

PCITICAGRELORPRASUGREL

PPCI FibrinolisiChirurgia0

Terapia medicaTICAGRELOR

CLOPIDOGREL

Circulation. 2010;122:1056-1067

HR 0.77; 95% CI 0.65 to 0.90

17%

22%

7,9%

8,9%

HR, 0.72; 95% CI,0.58 to 0.89

10%

14%

Circulation. 2010;122:1056-1067

15.1%

14.3%;

HR, 1.07; 95% CI, 0.88 to 1.30

8.5%

7.3%

HR, 1.28; 95% CI, 0.97 to 1.68

Quale paziente ?

Età avanzata: TICAGRELOR, CLOPIDOGRELAlto rischio emorragico: CLOPIDOGREL, TICAGRELORInsufficienza renale: TICAGRELORDiabete mellito:

SCA

NSTEMI STEMI

PCITICAGRELORPRASUGREL

PPCI FibrinolisiChirurgia0

Terapia medicaTICAGRELOR

CLOPIDOGREL

Wiviott, Circulation. 2008;118:1626-1636

NNT : 13 DM on insulin, 26 DM not on insulin, 71 no DM

Cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke

Wiviott, Circulation. 2008;118:1626-1636

James, EurHJ, August 29, 2010

NSTEMI ad alto rischio (diabete) ?

James, EurHJ, August 29, 2010

Quale paziente ?

Età avanzata: TICAGRELOR, CLOPIDOGRELAlto rischio emorragico: CLOPIDOGREL, TICAGRELORInsufficienza renale: TICAGRELORDiabete mellito: PRASUGREL

SCA

NSTEMI STEMI

PCITICAGRELORPRASUGREL

PPCI FibrinolisiChirurgia0

Terapia medicaTICAGRELOR

CLOPIDOGREL

SCA

STEMI nSTEMI

PCI Non PCI

N Engl J Med 2001;345: 494-502

SCA

STEMI nSTEMI

PCI Non PCI

N Engl J Med 2007;357:2001-15

SCA

STEMI nSTEMI

PCI Non PCI

SCA

STEMI nSTEMI

PCI Non PCIX

N Engl J Med 2012;367:1297-309N Engl J Med 2009;361:1045-57

CLOPIDOGREL PRASUGREL TICAGRELOR

Cardiovascular death, non-fatal myocardial infarction, non-fatal stroke cardiovascular death, non-fatal myocardial infarction, urgent target vessel revascularisation

Stent thrombosis TIMI major bleeding unrelated to CABG surgery

Lancet 2009; 373: 723–31

3534 pazientiPCI 97%

7544 pazientiPCI 82%

HR, 1.63; 95% CI, 1.07 to 2.48; P<0.02

HR, 0.87; 95% CI, 0.75 to 1.01; P<0.07

HR, 0.83; 95% CI, 0.67 to 1.02; P0.07

HR, 0.80; 95% CI, 0.65 to 0.98; P0.03

Quale paziente ?

Età avanzata: TICAGRELOR, CLOPIDOGRELAlto rischio emorragico: CLOPIDOGREL, TICAGRELORInsufficienza renale: TICAGRELORDiabete mellito: PRASUGREL

SCA

NSTEMI STEMI

PCITICAGRELORPRASUGREL

PPCIPRASUGRELTICAGRELOR

FibrinolisiChirurgia0

Terapia medicaTICAGRELOR

CLOPIDOGREL

Quanto è rapida l’inibizione piastrinica dopo il carico ?

Am Heart J 2007;153:66.e9266.e16 Circulation. 2009;120:2577-2585

Parodi, JACC 2013;61:1601–6

Alexopoulos Circ Cardiovasc Interv. 2012;5:797-804

Pre-hospital vs In-hospital Initiation of Ticagrelor Therapy in STEMI PatientsPlanned for Percutaneous Coronary Intervention (ATLANTIC) study

Bhatt, N Engl J Med, March 10 2013

Death from any cause,myocardial infarction, ischemia-driven revascularization, stent thrombosisat 48 hours after randomization

Quale durata ?CLOPIDOGREL

PRASUGREL

TICAGRELOR

30 day and 31–365 day mortality after first time hospitalisation for myocardial infarction between 1984 and 2008

in a Danish nationwide cohort study

Schmidt et al. BMJ 2012

Mortalità complessiva al fup a 6 mesiInH su tutti i pz, a 30 gg e a 6 mesi su quelli con dato disponibile

8,2% 7,5%

Quale molecola ?Caratteristiche degli antagonisti del recettore piastinico P2Y12 orali

reversibileNOTicagrelor

2-4 ore75-85%irreversibileSIPrasugrel

2 ore40-60%irreversibileSIClopidogrel

Tempo dal caricoIPA massimaLEGAMEProfarmaco

Variability in platelet responsiveness to clopidogrel

SerebruanySerebruany, JACC 2005, JACC 2005

Coronarografia: 43.7 %CABG 16.5 %PCI 21.2 %

CUREDeath from Cardiovascular Causes, Nonfatal Myocardial Infarction, Stroke

N Engl J Med 2001;345: 494-502

COMMIT Lancet 2005;366:1607-21

COMMIT: CLOPIDOGREL 75 mg (non carico)45852 pazienti trattati con aspirina e fibrinolisi (54%) o non riperfusi

Morte, Re-IMA o Stroke

CLARITY: clopidogrel 300 vs placebo3491 pazienti < 75 anni trattati con fibrinolisi + aspirina

End Point: Death from Cardiovascular causes, Recurrent Myocardial Infarctionor Recurrent Ischemia Leading to the Need for Urgent Revascularization.

Sabatine, NEJM, 352;12; 2005: 1179

14.1%

11.6%

P=0.03

58

EventTicagrelor,%

(n=2601)Clopidogrel, %

(n=2615) p valueCV death, MI or stroke 12.0 14.3 0.045

MI 7.2 7.8 0.555

CV death 5.5 7.2 0.019

All-cause death 6.1 8.2 0.010

Non-CV death 0.6 1.0 0.252

Stroke 2.1 1.7 0.162

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; NSTEMI, non-ST-segment elevated myocardial infarction; UA, unstable angina.James S, et al. BMJ 2011;342:d3527.

[James 2011:K]

Clopidogrel betterTicagrelor better

1.0 2.00.2

HR (95% CI)

NSTEMI sottoposto a PCI ?PLATO intent for non-invasive management

NSTEMI

STRATEGIA CONSERVATIVA

PRASUGREL

PCI

TICAGRELORCLOPIDOGREL

DiabeteGiovane

Alto rischioInsufficienza renale

Età avanzataPeso<60 kg

TICAGRELOR

Alto rischioemorragico

TAOPeso<60 kg

CLOPIDOGREL

TICAGRELORCLOPIDOGREL