Κωνσταντίνος Τριανταφύλλου,

Επιμελητής A´A´ Καρδιολογικό Τμήμα

Γ.Ν.Α. «Ευαγγελισμός»

Αναστολείς GPIIb/IIIa (GPIs) :

ποια είναι η θέση τους σήμερα.

Πιθανή σύγκρουση συμφερόντων

Ομιλητής: Κωνσταντίνος Τριανταφύλλου.

Δεν υπάρχει πιθανή σύγκρουση συμφερόντων σχετική

με την παρουσίαση αυτή.

Ανενεργό αιμοπετάλιο.

Αδρανείς υποδοχείς GPIIb/IIIa

Ενεργοποιημένο αιμοπετάλιο.

Ενεργοί υποδοχείς GPIIb/IIIa

Fibrinogen / Fibrin

GPIIb/IIIa inhibitor

GP IIb/IIIa υποδοχείς και αναστολείς

GPIIb/IIIa R:

integrin, heterodimer,

aIIβ & β3 subunits.

Αbciximab Eptifibatide Tirofiban

Molecule Fab 7E3 Synthetic peptide Nonpeptide mimetic

Binding Noncompetitive Competitive Competitive

Half-life

Plasma: 10 - 15 hr Plasma: 2 -2.5 hr Plasma: 2 -2.5 hr

Biologic: 12 - 24 hr Biologic = plasma Biologic = plasma

PCI dosing

Bolus: Bolus: Bolus:

0.25mg/kg 180µg/kg (10min) + 180µg/kg 25µg/kg

Infusion: Infusion: Infusion:

0.125µg/kg/min (12hr)

Max:10μg/min

2µg/kg/min (24 to 48 hr) 0.15µg/kg/min (18hrs)

*Renal adjustment No

Bolus: Bolus:

180µg/kg 12.5µg/kg

Infusion: Infusion:

1µg/kg/min (24 to 48 hr) 0.075 µg/kg/min (18hs)

Aναστολείς GP IIb/IIIa

2014 ESC/EACTS Guidelines on myocardial revascularization

Stable CAD

Recent trials did not demonstrate additional benefit from GPIs

after a clopidogrel loading dose of 600 mg.

Biondi-Zoccai et al. Am Heart J 2012;163:835 e1-7. (eptifibatide).

Kastrati et al. N Engl J Med 2004;350:232-8. (abciximab).

Valgimigli et al. J Am Coll Cardiol 2004;44:14-9. (tirofiban).

Windecker et al. Eur Heart J 2014;35:2541-619.

Tirofiban as adjunctive therapy for ACS and PCI:

a meta-analysis of RCTs

Valgimigli et al. Eur Heart J 2010;31:35-49.

14 RCTs, 3424 pts.

After pretreatment with clopidogrel.Does clopidogrel help tirofiban effect?

GPI use in contemporary ACS trials

NSTE ACS

Era before DAPT, patients undergoing PCI (POBA or with stents):

lower incidence of MACE in favour of UFH+GP IIb/IIIa treatment vs UFH alone,

primarily through a reduction in MI.

Boersma et al. Lancet 2002;359:189-98 (Metanalysis).

Era after DAPT, ISAR REACT 2 (Clopidogrel 600 mg LD)

Lower incidence of MACE in favour of UFH+GPIIb/IIIa (abciximab) vs UFH maintained:

- In NSTEMI (13.1% vs. 18.3%; RR 0.71, p = 0.02),

- Not in UA (4.6% vs. 4.6%, p= 0.98).

Kastrati et al. JAMA 2006;295:1531-8.

NSTE ACS - ACUITY study

Stone et al. N Engl J Med 2006;355:2203-16.

NSTE ACS – ISAR REACT 4

Kastrati et al. N Engl J Med 2011;365:1980-9.

NACE:NS Major bleeding:

bivalirudin safer

MACE: NS

NSTEMI patients undergoing PCI (n=1721).

All 600mg clopidogrel.

UFH+abciximab vs bivalirudin.

Early versus delayed, provisional eptifibatide in NSTE ACS.

Guiliano et al. N Engl J Med 2009;360:2176-90.

Pts in the early eptifibatide group :

significantly higher rates of bleeding and red-cell transfusion.

(TIMI major bleeding 2.6% vs 1.8%, OR 1.42, p=0.02).

NSTE ACS – EARLY ACS

Ticagrelor & Prasugrel

Wiviott et al. N Engl J Med 2007;357:2001-15.Wallentin et al. N Engl J Med 2009;361:1045-57.

PLATO TRITON -TIMI 38

NSTE ACS

TRITON -TIMI 38

O’ Donongue et al. J Am Coll Cardiol 2009;54:678-85.

- Prasugrel significantly reduces MACE in ACS pts after PCI regardless of GPI use.

- GPIs do not accentuate bleeding RR with prasugrel as compared with clopidogrel.

NSTE ACS – ISAR REACT 3

Stable or unstable angina (Tn - ) patients undergoing PCI. (n=4570).

All 600 mg clopidogrel, > 2hrs before.

UFH vs bivalirudin.

NACE:NS MACE:NS

Kastrati et al. N Engl J Med 2008;359:688-96.

- Bivalirudin did not provide a net clinical benefit compared to UFH.

- However, it reduced the incidence of major bleeding: 3.1 vs 4.6%, p=0.008.

2014 ESC/EACTS Guidelines on myocardial revascularization

NSTE ACS

Windecker et al. Eur Heart J 2014;35:2541-619.

De Luca et al. JAMA 2005;293:1759-65.

Abciximab in primary PCI metanalysis

- 8 RCTs, 3949 STEMI pts randomized

- Primary PCI (7 RCTs) or rescue PCI (1 RCT).

STEMI - pPCI

Era before

thienopyridine preloading

Vaglimili

EVA-AMI

MULTISTRATEGY

FATA

Gurm et al. Circ Cardiovasc Interv 2009;2:230-6.

STEMI pPCI: Abciximab vs small molecule GPIs metanalysis

STEMI - pPCI

No difference in outcome (mortality, NACE, MACE, bleeding).

STEMI - pPCI

Ellis et al. N Engl J Med 2008;358:2205-17.

“Neither facilitation of PCI with reteplase plus abciximab nor facilitation with abciximab

alone significantly improved the clinical outcomes, as compared with abciximab given at the

time of PCI, in patients with ST-segment elevation myocardial infarction.”

FINESSE study -2452 pts randomized

STEMI - pPCI

On-TIME study -1398 pts.

ASA/UFH/600mg clopidogrel.

Randomized to HBD tirofiban in ambulance - upstream vs provisional – downstream.

MACE at 30 days: 5.8% vs. 8.6%, p= 0.043.

Mortality 30d (2.2% vs. 4.1%, p=0.051) & 1-year (3.7% vs. 5.8%, p=0.08).

No clinically relevant difference in bleeding (3.4% vs 2.9%, p=0.58)

Ten Berg et al. J Am Coll Cardiol 2010;55:2446-55.

De Luca et al. J Thromb Haemost 2011;9:2361-70.

.

Early GPIs in primary angioplasty - abciximab long-term results

(EGYPT-ALT) cooperation: individual patient's data meta-analysis.

INFUSE-AMI:Intracoronary abciximab and aspiration thrombectomy

in patients with large anterior STEMI.

Stone et al. JAMA 2012;307:1817-26.

.

STEMI - pPCI

STEMI - pPCI

Thiele et al. Lancet 2012;379:923-31.

Death, MI, CHF Death

Reinfarction New CHF

AIDA STEMI: 2065 pts.

IC vs IV abciximab in STEMI < 12 hrs.

Stone et al. N Engl J Med 2008;358:2218-30.

HORIZONS-AMI:

Bivalirudin during primary PCI in acute myocardial infarction.

*But increased acute ST :

1.3% vs 0.3%, p<0.001).

STEMI - pPCI

STEMI - pPCI

EUROMAX (2218 pts).

STEMI transferred:

Bivalirudin vs UFH+provisional GPI (69.1%)

*Acute ST higher with bivalirudin (1.1% vs. 0.2%; RR, 6.11, P=0.007).

Death or non CABG major bleeding. Death, re-MI or non CABG major bleeding.

Steg et al. N Engl J Med 2013;369:2207-17.

STEMI - pPCI

Shahzad et al. Lancet 2014;384:1849-58

HEAT-PPCI1491 of 1812 pts did PCI,

1 center RCT, open label.

UFH vs bivalirudin in pPCI.

Contemporary practice:

-Restriction of GPIs for bail-out (15%)

- Novel P2Y12 inhibitors: 89%

- Radial approach: 81%

- DES implantation

Primary efficacy EP:

-Death, CVA, recurrent MI, TLR @ 28d: 5.7% vs 8.7%, p=0.01.

* ST: 0.9% vs 3.4%, p=0.001,

* Mortality: 4.3% vs 5.1%, p=NS.

Primary safety EP:

Major BARC 3-5 bleeding: 3.1% vs 3.5%, p=NS.

Bivalirudin vs heparin with or without tirofiban during pPCI in STEMI.

Han et al. JAMA 2015;313:1336-46.

NACE

MACCE Any BARC bleeding

STEMI - pPCI

BRIGHT RCT

Bivalirudin ctd 3hrs post PCI.

***No acute ST increase.

Bivalirudin versus heparin in patients planned for PCI: a meta-analysis of RCTs.

Bleeding decreased with bivalirudin only with routine GPI use in UFH arm.

No difference in mortality (contrast with HORIZONS – AMI).

Increased early ST/MI with bivalirudin.

Prolonged bivalirudin infusion (full dose) 4 hours post procedure may prevent ST.

Cavender MA, Sabatine MS. Lancet 2014;384:599-606.

STEMI - pPCI

Bivalirudin versus UFH with or without GPIs

in patients with STEMI undergoing pPCI

Stone et al. J Am Coll Cardiol 2015;65:27-38.

STEMI - pPCI

Comprehensive M/A of safety and efficacy of bivalirudin versus UFH with

or without routine GPI in ACS pts (study-level data).

Navarese et al. JACC Cardiovasc Interv 2015;8:201-13.

STEMI - pPCI

Bivalirudin or UFH in Acute Coronary Syndromes

7213 pts randomized.

MATRIX study

MACE and NACE:

not significantly lower with bivalirudin .

Urgent TVR/definite ST/ NACE:

not significantly lower with a post-PCI bivalirudin infusion.

MACE NACE

NACE/urgent TVR, definite ST

Valgimigli et al. N Engl J Med 2015;373:997-1009.

Death (any): 1.7% vs 2.3%, p=0.04.

Death (cardiac): 1.5% vs 2.2%, p=0.03.

Definite ST: 1% vs 0.6%, p=0.048.

Major bleeding (BARC 3-5): 1.4% vs 2.5%, p<0.001)

!

Use of GPIs as bail-out

on bivalirudin arms of RCTs :

~ 1:10 pts

STEMI - pPCI

2014 ESC/EACTS Guidelines on myocardial revascularization

Windecker et al. Eur Heart J 2014;35:2541-619.

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

Randomized assessment of ticagrelor versus prasugrel

antiplatelet effects in patients with STEMI.

STEMI - pPCI

FABOLUS PRO:

Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without

concomitant prasugrel administration in patients with myocardial infarction undergoing

coronary stenting.

Valgimigli et al. JACC Cardiovasc Interv 2012;5:268-77.

Prasugrel administration leads to a suboptimal IPA for at least 2 hrs in STEMI patients.

Prasugrel, given in association with a bolus only GPI obviates the need of post-bolus infusion and

almost abolishes residual variability of IPA after treatment.

Cangrelor ?

“Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural

thrombotic complications, at the expense of increased mild bleeding.”

Steg et al. Lancet 2013;382:1981-92.

24910 pts

STEMI – 11.6%

NSTEMI - 57.4%

SCAD – 31%

Death, MI, IDR, ST at 48hrs:

3.8% vs 4.7% (-19%)

*ST at 48hrs:

0.5 vs 0.8% (-42%)

*GUSTO maj/mod bleeding:

No difference

*GUSTO mild bleeding:

16.8% vs 13%

Safley et al. JACC Cardiovasc Interv 2015;8:1574-82.

Period : July 2009 and September 2011.

970,865 pts included - 326,283 (33.6%) received a GPI.

Multivariable logistic regression, propensity-matched and instrumental variable analysis.

Impact of Glycoprotein IIb/IIIa Inhibition in Contemporary PCI for ACS.

Insights From the National Cardiovascular Data Registry.

GPIs

Heavy thrombotic burden.

Intraprocedure thrombus formation.

Slow flow / no-reflow.

Threatened vessel closure.

? No preloading with P2Y12 antagonists.

? Complex lesions / High risk patients.

Prevent bleeding!

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