When, how & why GP IIb/IIIa inhibitorsLuca Testa, MD, PhDIstituto Clinico S. AmbrogioIRCCS San Donato, Milanoluctes@gmail.com

Derived from a murine monoclonal antibody.

It interacts with the GP IIb/IIIa receptor and several integrins.

The majority of the drug cleared from plasma within 25 minutes, but much slower clearance from the body, with a catabolic half-life up to 7 hours.

Yet platelet-associated abciximab can still be detected in the circulation for more than 14 days after cessation of infusion, in part related to its high affinity for the receptor.

Stoichiometry of 1.5 molecules of abciximab for each receptor.

Abciximab

They are specific for GP IIb/IIIa. Because of their small size, these drugs are also much less likely to induce an antibody response than abciximab.

They have a high affinity for GP IIb/IIIa, but not as strong as abciximab, and are rapidly eliminated from the circulation once the infusion is stopped (+ 4 hours).

The stoichiometry of both eptifibatide and tirofiban needed to achieve full platelet inhibition is greater than 100 molecules of drug per GP IIb/IIIa receptor. Tirofiban & Eptifibatide

When?

STEMI

UA/NSTEMI

PCI when high thombus burden is present

Bridge Therapy

When?

STEMI

UA/NSTEMI

PCI when high thombus burden is present

Bridge Therapy

ESC 2012 STEMI Guidelines(When & How)

Patients with estimated CrCl

WHY???12435p=0.03p=0.04p=0.01p=0.01p=0.021.Circulation 1998; 98:734-7412.JACC 2000; 35:915-9213.NEJM 2001; 344:1895-19035.JACC 2003; 42:1879-18854.Circulation 2003; 108:1316-132348%52%59%34%57%% of Patients

Primary PCI: 30-Day Composite Endpoint12435p=0.03p=0.04p=0.01p=0.01p=0.021.Circulation 1998; 98:734-7412.JACC 2000; 35:915-9213.NEJM 2001; 344:1895-19035.JACC 2003; 42:1879-18854.Circulation 2003; 108:1316-132348%52%59%34%57%% of Patients

ACE, ADMIRAL and ISAR-2 Meta-Analysis: Outcomes through 3 Years Follow-UpMeta-analysis of PCI Trials (N=1101):

ISAR-2.JACC 2000;35:915-21ADMIRAL.NEJM 2001;344:1895-1903ACE.JACC 2003;42:1879-1885 Adapted from Montalescot et al. EHJ 2007; 28: 443-9p=0.008p=0.052Primary endpoint: Composite of Death or Re-MI up to 3 years follow-upP=0.013% of PatientsFor the primary endpoint

Number Needed to Treat = 19

Short and Long Term Mortality ReductionMeta-analysis of PCI Trials (N=3949):

RAPPORT.Circulation 1998;98:734-41ISAR-2.JACC 2000;35:915-21ADMIRAL.NEJM 2001;344:1895-1903CADILLAC.NEJM 2002;346: 957-66Petronio et al.AHJ 2002;143: 334-341Zorman et al.AJC 2002;90: 533-36Petronio et al.EHJ 2003;24:67-76ACE.JACC 2003;42:1879-1885 Adapted from De Luca et al. JAMA 2005; 293:1759-1765*At long-term follow-up, N=1996 for the abciximab group and N=1916 for the group without abciximabp=0.047p=0.01Primary endpoints: Mortality at 30 days and at long-term follow-up% of Patients

ESC 2012 STEMI Guidelines(When & How)

FINESSE Results: Safety (Bleeding) EndpointsEllis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, Austria

EndpointPrimary PCI (%)Abciximab-facilitated (%)Combination (abciximab/ reteplase)- facilitated (%)Combination- facilitated vs primary PCI (P)Combination- facilitated vs abciximab- facilitated (P)TIMI major bleeding2.64.14.80.025NSTIMI minor bleeding4.36.09.7

TransportationPCI centerPCI*Bolus: 25 g/kg and 0.15 g/kg/min infusion.van t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46 Ten Berg et al, JACC 2010; 55:2446-55*Bolus: 25 g/kg; Infusion: 0.15 g/kg/min for 18 hoursOn-TIME 2: Study Design and Flowchart

Pooled Analysis (Double blind & open label phase) Primary:MACE (death, recurrent MI, or uTVR at 30-days) Key Secondary:Mortality at 1-year Safety (TIMI bleeding, transfusions, stroke, thrombocytopenia, serious AEs)

Double Blind Phase Primary Endpoint:Residual ST segment deviation (>3 mm) 1 hour after PCIKey Secondary:Combined occurrence of death, recurrent MI, urgent TVR, or thrombotic bailout at 30 days follow-upSafety (TIMI bleeding, transfusions, stroke, thrombocytopenia, serious AEs)

On-TIME 2: Study End Points

Total Pooled Cohort (n=1398)n=662n=662n=677n=677On-TIME 2 Pooled Analysis: Short- and Long-Term EfficacyTen Berg et al JACC 2010; 55:2446-2455Primary EndpointSecondary Endpoint

On-TIME 2: 30 Day-MACE and 1 Year-Mortality in Patients Undergoing Primary PCI (86%)

3.1% ARRp=0.007On-TIME 2 Pooled Analysis: 1 Year-SurvivalPooled Cohort Primary PCI Subgroup (n=1203)Event-free Survival (%)909297981009909695949391306090120150180210240270300330360Time (days)Placebo (N=578)Tirofiban (N=577)

Thus

The Favorite Approach to Safe and Effective Treatment for Early Reperfusion (FASTER) Registry

This registry will include patients undergoing primary PCI with tirofiban administered as a bolus plus up to 18 hours infusion according to ESC guidelines:

with or without early use of P2Y12 oral inhibitors,

with or without concomitant or previous use of bivalirudin,

procedures performed with a radial or femoral approach.

Summary of Study Design

Primary AnalysisBleedings occurring until hospital discharge.Secondary AnalysesInformation on bleedings, death, MI, urgent TVR and stent thrombosis after end of PCI up to hospital discharge, final TIMI flow and TMBG and ST segment resolution 1 hour after PCI will be collected and analyzed in all patients enrolled and in the following subgroups: Patients presenting between 0 to 3, 3 to 6 and 6 to 12 hours after symptom onset P2Y12 oral inhibitors administered or not prior to arrival to cath lab Males and females Below and above 75 years of age Diagnosis of diabetes or not Anterior and non-anterior MI Killip > 2 or not TIMI flow grade before PCI > 1 or not Radial or femoral approach Thromboaspiration or not

Analyses

In a subset of patients with or withouth pre-cathlab administration of P2Y12 blockers and enrolled in sites where device is available, inhibition of platelet reactivity (PRU) will be tested upon arrival to cathlab by means of VerifyNow, repeated after administration of tirofiban bolus or administration of P2Y12.

Analyses (2)

When?

STEMI

UA/NSTEMI

PCI when high thombus burden is present

Bridge Therapy

ESC 2012 UA/NSTEMI Guidelines(When & How)

Mortality according to GRACE score

CRUSADE in-hospital MB score

Risk of MB across the scpectrum of CRUSADE score

ESC 2012 UA/NSTEMI Guidelines(When & How)

When?

STEMI

UA/NSTEMI

PCI when high thombus burden is present

Bridge Therapy

Inadequate anticoagulation

Coronary dissection (Flow limiting?)

Thrombus formation during PCI

Thrombus formation during PCI

When?

STEMI

UA/NSTEMI

PCI when high thombus burden is present

Bridge Therapy

Bridge TherapyFor pts on DAPT waiting for undelaydable surgery ASA + small molecules after stopping ADP receptor inhibitorsPhysiopathologically logicDifferent schemesNot yet standardisedJust mentioned in the GLUnder investigation

Thanks for the attention

Luca Testa, MD, PhDIstituto clinico S. Ambrogio,IRCCS San DonatoMilanoluctes@gmail.com

*This slide has gone through quality review; 27Aug2013

*This slide has gone through quality review; 27Aug2013

*This slide has gone through quality review; 27Aug2013*This slide has gone through quality review; 27Aug2013This slide has gone through quality review; 27Aug2013

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