1. When, how & why GP IIb/IIIa inhibitors
Luca Testa, MD, PhD
Istituto Clinico S. Ambrogio
IRCCS San Donato, Milano

2. Abciximab 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.

3. Tirofiban & Eptifibatide
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.

4. When? STEMI UA/NSTEMI PCI when high thombus burden is present
“Bridge Therapy”

5. When? STEMI UA/NSTEMI PCI when high thombus burden is present
“Bridge Therapy”

6. ESC 2012 STEMI Guidelines (When & How)

7. Patients with estimated CrCl<60ml/min

8. WHY??? ¯ ¯ ¯ ¯ ¯ % of Patients 1.Circulation 1998; 98:734-741
59%
48%
52%
57%
% of Patients
34%
p=0.03
p=0.04
p=0.01
p=0.01
p=0.02 1 2 3 4 5
1.Circulation 1998;
98:
2.JACC 2000;
35:
3.NEJM 2001;
344:
4.Circulation 2003;
108:
5.JACC 2003;
42:

9. Primary PCI: 30-Day Composite Endpoint
59%
48%
52%
57%
% of Patients
34%
p=0.03
p=0.04
p=0.01
p=0.01
p=0.02 1 2 3 4 5
1.Circulation 1998;
98:
2.JACC 2000;
35:
3.NEJM 2001;
344:
4.Circulation 2003;
108:
5.JACC 2003;
42:

10. ACE, ADMIRAL and ISAR-2 Meta-Analysis: Outcomes through 3 Years Follow-Up
Primary endpoint: Composite of Death or Re-MI up to 3 years follow-up
Meta-analysis of
PCI Trials (N=1101):
ISAR-2.JACC 2000;35:915-21
ADMIRAL.NEJM 2001;344:
ACE.JACC 2003;42:
% of Patients
P=0.013
For the primary endpoint
Number Needed to Treat = 19
p=0.008
p=0.052
Adapted from Montalescot et al. EHJ 2007; 28: 443-9

11. Short and Long Term Mortality Reduction
Primary endpoints: Mortality at 30 days and at long-term follow-up
Meta-analysis of
PCI Trials (N=3949):
RAPPORT.Circulation 1998;98:734-41
ISAR-2.JACC 2000;35:915-21
ADMIRAL.NEJM 2001;344:
CADILLAC.NEJM 2002;346:
Petronio et al.AHJ 2002;143:
Zorman et al.AJC 2002;90:
Petronio et al.EHJ 2003;24:67-76
ACE.JACC 2003;42:
% of Patients
p=0.047
p=0.01
*At long-term follow-up, N=1996 for the abciximab group and N=1916 for the group without abciximab
Adapted from De Luca et al. JAMA 2005; 293:

12. ESC 2012 STEMI Guidelines (When & How)

13. FINESSE Results: Safety (Bleeding) Endpoints
Primary PCI (%)
Abciximab-facilitated (%)
Combination (abciximab/ reteplase)- facilitated (%)
Combination- facilitated vs primary PCI (P)
Combination- facilitated vs abciximab- facilitated (P)
TIMI major bleeding
2.6
4.1
4.8
0.025 NS
TIMI minor bleeding
4.3
6.0
9.7
<0.001
0.006
TIMI major or minor bleeding
6.9
10.1
14.5
0.008
Ellis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, Austria

14. On-TIME 2: Study Design and Flowchart
STEMI patients diagnosed in ambulance or referral center
ASA mg clopidogrel + UFH
Open-label phase
June 2004-June 2006, N=414
Double-blind phase
June 2006-Nov. 2007, N= 984
HDB Tirofiban* (N=709)
Placebo (N=689)
Transportation
This slide has gone through quality review; 27Aug2013
Angiogram (N=681)
PCI center
Angiogram (N=696)
Primary PCI (N=601)
HDB Tirofiban bailout
Primary PCI (N=602)
Tirofiban Infusion*
PCI
*Bolus: 25 µg/kg; Infusion: 0.15 µg/kg/min for 18 hours
Ten Berg et al, JACC 2010; 55:
*Bolus: 25 µg/kg and 0.15 µg/kg/min infusion.
van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46

15. On-TIME 2: Study End Points
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 PCI
Combined occurrence of death, recurrent MI, urgent TVR, or thrombotic bailout at 30 days follow-up
This slide has gone through quality review; 27Aug2013

16. On-TIME 2 Pooled Analysis: Short- and Long-Term Efficacy
Total Pooled Cohort (n=1398)
n=656
n=670
This slide has gone through quality review; 27Aug2013
n=662
n=677
n=662
n=677
Primary Endpoint
Secondary Endpoint
Ten Berg et al JACC 2010; 55:

17. On-TIME 2: 30 Day-MACE and 1 Year-Mortality in Patients Undergoing Primary PCI (86%)
Pooled Cohort Primary PCI Subgroup (n=1203)
n=515
n=477
n=583
n=586
This slide has gone through quality review; 27Aug2013

18. On-TIME 2 Pooled Analysis: 1 Year-Survival
Pooled Cohort Primary PCI Subgroup (n=1203)
100 99
Tirofiban (N=577) 98 97
3.1% ARR
p=0.007 96
Event-free Survival (%) 95 94
Placebo (N=578) 93
This slide has gone through quality review; 27Aug2013 92 91 90 30 60 90
120
150
180
210
240
270
300
330
360
Time (days)

19. Thus

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

21. Summary of Study Design
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.

22. Analyses
Primary Analysis
Bleedings occurring until hospital discharge.
Secondary Analyses
Information 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

23. Analyses (2)
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.

24. When? STEMI UA/NSTEMI PCI when high thombus burden is present
“Bridge Therapy”

25. ESC 2012 UA/NSTEMI Guidelines (When & How)

26. Mortality according to GRACE score

27. CRUSADE in-hospital MB score

28. Risk of MB across the scpectrum of CRUSADE score

29. ESC 2012 UA/NSTEMI Guidelines (When & How)

32. When? STEMI UA/NSTEMI PCI when high thombus burden is present
“Bridge Therapy”

33. Thrombus formation during PCI
Inadequate anticoagulation
Coronary dissection (Flow limiting?)

34. Thrombus formation during PCI

35. When? STEMI UA/NSTEMI PCI when high thombus burden is present
“Bridge Therapy”

36. Bridge Therapy
For pts on DAPT waiting for undelaydable surgery  ASA + small molecules after stopping ADP receptor inhibitors
Physiopathologically “logic”
Different schemes
Not yet standardised
Just mentioned in the GL
Under investigation

37. Thanks for the attention Luca Testa, MD, PhD Istituto clinico S
Thanks for the attention Luca Testa, MD, PhD Istituto clinico S. Ambrogio, IRCCS San Donato Milano