Stefano De Servi

UO Cure Intensive Coronariche e LRSC

Fondazione IRCCS Policlinico San Matteo, PAVIA

CONFLICTS OF INTEREST :

- ELI LILLY- DAICHII SANKYO : Advisory Board Meetings , Speaker’s feesASTRA ZENECA : Speaker’s fees

UPSTREAM vs DOWNSTREAM NELLA TERAPIA ANTIAGGREGANTE PIASTRINICADELLE SINDROMI CORONARICHE ACUTE

2014

NSTENSTE--ACSACS

Primary Endpoint MeasuresPrimary Endpoint Measures

11.7%

7.1%6.1%

4.9%

11.7%

7.9%

Net clinical

outcome

Ischemic composite Major bleeding

30 d

ay e

ven

ts (

%)

Routine Upstream IIb/IIIa (N=4605) Deferred PCI IIb/IIIa (n=4602)

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIaRoutine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

PNI <0.0001

PSup = 0.93

PNI = 0.044

PSup = 0.13

PNI < 0.0001

PSup = 0.009

0 1 2

Actual ManagementActual ManagementRoutine Upfront IIb/IIIa vs. Deferred PCI IIb/IIIaRoutine Upfront IIb/IIIa vs. Deferred PCI IIb/IIIa

Deferred PCI GPI betterDeferred PCI GPI better Routine Upstream GPI betterRoutine Upstream GPI better

P Pint

0.34

1.06 (0.93-1.22)0.38

0.85 (0.65-1.12)0.25

0.96 (0.72-1.29)0.80

0.15

1.19 (1.00-1.42)0.05

0.88 (0.65-1.18)0.39

1.39 (0.91-2.12)0.13

0.74

0.84 (0.69-1.02)0.08

0.74 (0.40-1.34)0.33

Deferred

IIb/IIIa

14.5%

15.8%

5.5%

9.5%

13.5%

3.3%

6.5%

3.3%

2.6%

Upstream

IIb/IIIa

13.7%

18.5%

5.8%

8.0%

15.3%

2.4%

7.8%

4.5%

3.7% 0.70 (0.47-1.05)0.09

RR (95% CI)

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

Major Bleeding

Risk ratio

±95% CI

Risk ratio

±95% CINet Clinical Outcome

Composite Ischemic

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

96-Hour Primary Efficacy Results

Death, MI, RIUR, TBO 9.3% 10.0% 0.92 0.23

(0.80-1.06)

Death 0.8% 0.9% 0.96 0.87

(0.62-1.50)

Death or MI 7.5% 8.3% 0.89 0.13

(0.77-1.04)

Death, MI, RIUR 8.4% 9.4% 0.89 0.11

(0.77-1.03)

DelayedProvisional Eptifibatide

(n=4684)

Routine Early

Eptifibatide(n=4722)

OR(95% CI)

P

MI, myocardial infarction; RIUR, recurrent ischemia requiring urgent revascularization; TBO, thrombotic bailout

Kaplan-Meier Curves for 30-day Death or MI

De

ath

or

MI (%

)

0

5

10

15

Time Since Randomization (Days)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

12.4%

11.2%

P = 0.079

(stratified for intended early

clopidogrel use)

Delayed provisional eptifibatide

Routine early eptifibatide

9.3

13.6

0

5

10

15

PROCEDURAL COMPLICATIONS§

EARLY EPTIFIBATIDE

LATE EPTIFIBATIDE

§ Loss of side branch; abrupt vessel closure ; distal embolization; no reflow

Conclusioni (1)

L’uso upstream di GPI ( piccole molecole ) non

ha indicazione in tutta la popolazione dei pazienti con NSTE-ACS.

In pazienti ad alto rischio , in cui vi e’indicazione a trattamento invasivo precoce il pretrattamento con GPI puo’ ridurre le complicanze ischemiche periprocedurali.

Tale beneficio deve essere sempre rapportato all’aumento di complicanze emorragiche nel

singolo paziente.

STEMISTEMI

16-10-2001

GPI: does bailout make sense ? ON-TIME

16-10-2001

GPI: does bailout make sense ?

Blinded bail-out use of study medication was used in 24.2% of patients, with a

significantly higher use in patients pretreated with placebo 29% (HDT bail-out) vs.

20% (placebo bail-out), P=0.002).

© 2012 Correvio Confidential

1313

On-TIME 2 Pooled Analysis: 30-day MACE Subgroup Analysis

Adapted from Ten Berg et al JACC 2010; 55:2446-2455

Odds Ratio and 95% Confidence Interval

All subjects (N=1339) 0.65 (0.43 - 0.99)

Gender

Female 1.24 (0.56 - 2.77)

Male 0.51 (0.31 - 0.84)

Age

< 61.5 years 0.62 (0.30 - 1.26)

≥ 61.5 years 0.66 (0.39 - 1.13)

Diabetes Mellitus

No 0.62 (0.39 - 1.00)

Yes 0.72 (0.28 - 1.86)

Infarct location

Anterior MI 0.74 (0.39 - 1.40)

Non-anterior MI 0.50 (0.26 - 0.95)

Killip class > 1

No 0.60 (0.35 - 1.03)

Yes 0.64 (0.29 - 1.45)

TIMI flow grade before PCI

0-2 0.59 (0.36 - 0.97)

3 0.86 (0.24 - 3.03)

Time start study medication to angio

≤ 55 min 0.52 (0.26 - 1.05)

> 55 min 0.63 (0.36 - 1.13)

Time symptom onset to diagnosis

≤ 75 min 0.51 (0.26 - 0.99)

> 75 min 0.88 (0.50 - 1.57)

Primary PCI

No 1.58 (0.60 - 4.19)

Yes 0.50 (0.31 - 0.82)

0.1 0.2 0.5 1.0 2.0 5.0

Tirofiban better Placebo better

ISO 9001

Time-to-Tx and

Myocardial Salvage

Time from symptom onset to reperfusion (h)

0 4 6 1 2

4

Mo

rta

lity r

ed

uctio

n (

%)

100

80

60

40

20

0Extent of Myocardial Salvage

Mod from Gersh B et al. JAMA 2005; 293: 979

On-TIME 2

FINESSE

BRAVE 3

© 2012 Correvio Confidential

15

Acute Stent Thrombosis (< 24 hours)

Reduction of acute stent thrombosis by pre-hospital tirofiban

in primary PCI for STEMI

N=1073

On-TIME 2 Pooled Analysis: Acute Stent Thrombosis

Heestermans et al. J Thromb Haemost. 2009; 7:1612-1618

p<0.001

Conclusioni (2)

L’uso upstream di GPI nello STEMI non e’supportato dalle Linee Guida , che ne avallano l’utilizzo solo in “bail-out” in caso di fenomeni di “no-reflow” ( peraltro senza evidenza provata da studi specifici ) .

Alcuni dati della letteratura tuttavia mostrano come in casi selezionati ( ampia area a rischio , utilizzo precoce ) tali farmaci potrebbero essere molto utili , anche per ridurre l’incidenza di trombosi acuta dello stent.

De Servi

2011

2014

NSTENSTE--ACSACS

4774 patients = PCI-CURE (n=2658) + CREDO (n=2116 , of whom 66% had UA or recent MI )

NSTE-ACS

EYESHOTRegistry

NSTE-ACS:Strategies and Timing

HU

B

Coro

Medical

Rx

PCI

CABG

Medical

Rx

1258

(82.8%)

n=1519

261(17.2%)

832(54.8%)

39

(2.6%)

387

(25.5%)

648

(42.6%)

54.4±66.3 hrs

25th -75

th perc:

17.6-69.0 hrs

SP

OK

E

All TIMI (CABG or non-CABG) Major

Bleeding

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

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

PRE-TREATMENT WAS ONLY 4 HOURS IN PLATO !

Conclusioni (3)

L’uso upstream di inibitori del recettore piastrinico P2Y12 deriva dallo stdio PCI-CURE , in cui la PCI veniva eseguita ad una mediana di 10 giorni dopo il ricovero .

L’attuale standard di cura prevede uno studio coronarografico piu’ precoce , come dimostrato dallo studio EYESHOT.

In tali circostanze non vi e’ alcuna evidenza di un beneficio clinico dall’utilizzo upstream di tali farmaci.

2014 ESC Myocardial Revascularisation

Guidelines: Primary PCI

\\

Potential benefits of early use of ADP receptor

blockers in STEMI patients undergoing

primary PCI

• Improved patency rate before PCI

• Increased number of patients with effective

reperfusion

• Reduced acute stent thrombosis

Potential benefits of early use of ADP receptor

blockers in STEMI patients undergoing

primary PCI

• Improved patency rate before PCI ?

• Increased number of patients with effective

reperfusion

• Reduced acute stent thrombosis

2nd Co-primary endpointNo TIMI 3 flow in infarct-related artery

Potential benefits of early use of ADP receptor

blockers in STEMI patients undergoing

primary PCI

• Improved patency rate before PCI

• Increased number of patients with effective

reperfusion ?

• Reduced acute stent thrombosis

1st Co-primary endpointNo ST-segment resolution (≥70%)

Potential benefits of early use of ADP receptor

blockers in STEMI patients undergoing

primary PCI

• Improved patency rate before PCI

• Increased number of patients with effective

reperfusion

• Reduced acute stent thrombosis ?

Definite stent thrombosis

up to 10 days

Non-CABG-related bleeding events (TIMI, STEEPLE, GUSTO and ISTH definitions) - Safety population

Conclusioni (4)

L’uso upstream di inibitori del recettore piastrinico P2Y12 nello STEMI non si associa ad una piu’rapida o piu’ efficace riperfusione .

E’ verosimile tuttavia che una precoce

somministrazione di questi farmaci possa ridurre la trombosi acuta dello stent .

Non essendo gravato da un incremento significativo di emorragie, l’uso upstream appare clinicamente giustificabile.

Speaker

Median pretreatment time = 3 days

6.1

0

5

10

3.4

No pretreatment, n=4320

Clopidogrel pretreatment, n=1625

In-hospital mortality

Clinical endpoints at 30 days

OLD PARADIGM

NEW PARADIGM

CAG + PCI

CAG + PCI *

UFH, ASA, UPSTREAM P2Y12 INHIBITOR

Upstream GPIIB IIIA blockers ( selective use)

ASA, LMWH ( Bivalirudin, UFH, NO UPSTREAM P2Y12 INHIBITOR

P2 Y12 INHIBITOR before PCI ( PRASUGREL if diabetes, risk of stent thrombosis; TICAGRELOR if CKD, age >75; “no option” for revascularization )

“ Cooling-off strategy ”

DAYS

HOURS

“ Early invasive approach ”

Antithrombotic therapy in NSTE-ACS with early planned invasive strategy

* Immediate or early surgery may be an additional available option