When, how & why GP IIb/IIIa inhibitors

Luca Testa, MD, PhDIstituto Clinico S. AmbrogioIRCCS San Donato, Milano

luctes@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<60ml/min

WHY???

11,2 10,5

14,6

7

10,5

5,8 56

4,6 4,5

0

5

10

15

20

RAPPORT ISAR-2 ADMIRAL CADILLAC ACE

No Abciximab Abciximab

1 2 43 5

p=0.03 p=0.04 p=0.01 p=0.01 p=0.02

1.Circulation 1998; 98:734-741

2.JACC 2000; 35:915-921

3.NEJM 2001; 344:1895-1903

5.JACC 2003; 42:1879-1885

4.Circulation 2003; 108:1316-1323

48% 52%

59%

34% 57%

% o

f Pati

ents

Primary PCI: 30-Day Composite Endpoint

11,2 10,5

14,6

7

10,5

5,8 56

4,6 4,5

0

5

10

15

20

RAPPORT ISAR-2 ADMIRAL CADILLAC ACE

No Abciximab Abciximab

1 2 43 5

p=0.03 p=0.04 p=0.01 p=0.01 p=0.02

1.Circulation 1998; 98:734-741

2.JACC 2000; 35:915-921

3.NEJM 2001; 344:1895-1903

5.JACC 2003; 42:1879-1885

4.Circulation 2003; 108:1316-1323

48% 52%

59%

34% 57%

% o

f Pati

ents

ACE, ADMIRAL and ISAR-2 Meta-Analysis: Outcomes through 3 Years Follow-Up

19

14,3

5,5

12,910,9

2,3

0

5

10

15

20

25

Death/Re-MI Death Reinfarction

No Abciximab (N=551) Abciximab (N=551)

Meta-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: 443-9

p=0.008 p=0.052

Primary endpoint: Composite of Death or Re-MI up to 3 years follow-up

P=0.013

% o

f Pati

ents

For the primary endpoint

Number Needed to Treat = 19

Short and Long Term Mortality Reduction

3,4

6,2

2,4

4,4

0

1

2

3

4

5

6

7

8

30-Day 6-12 Months

No Abciximab (N=1933)* Abciximab (N=2016)*

Meta-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 abciximab

p=0.047 p=0.01

Primary endpoints: Mortality at 30 days and at long-term follow-up

% o

f Pati

ents

ESC 2012 STEMI Guidelines(When & How)

FINESSE Results: Safety (Bleeding) Endpoints

Endpoint 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 <0.001 0.008

Ellis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, AustriaEllis S. European Society of Cardiology Congress 2007; September 3, 2007; Vienna, Austria

Angiogram (N=696)

HDB Tirofiban* (N=709)Placebo (N=689)

Transportation

PCI centerAngiogram (N=681)

Primary PCI (N=601)HDB Tirofiban bailout

Primary PCI (N=602)Tirofiban Infusion*PCI

*Bolus: 25 µg/kg and 0.15 µg/kg/min infusion.

STEMI patients diagnosed in ambulance or referral centerASA + 600 mg clopidogrel + UFH

van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46 Ten Berg et al, JACC 2010; 55:2446-55

*Bolus: 25 µg/kg; Infusion: 0.15 µg/kg/min for 18 hours

Open-label phaseJune 2004-June 2006, N=414

Double-blind phaseJune 2006-Nov. 2007, N= 984

On-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-up• Safety (TIMI bleeding, transfusions, stroke, thrombocytopenia, serious AEs)

On-TIME 2: Study End Points

Total Pooled Cohort (n=1398)

n=656 n=670n=662 n=662n=677 n=677

On-TIME 2 Pooled Analysis: Short- and Long-Term Efficacy

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

Primary Endpoint Secondary Endpoint

Pooled Cohort Primary PCI Subgroup (n=1203)

n=515 n=477n=583 n=586

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

3.1% ARRp=0.007

On-TIME 2 Pooled Analysis: 1 Year-Survival

Pooled Cohort Primary PCI Subgroup (n=1203)Ev

ent-

free

Sur

viva

l (%

)

90

92

97

98

100

99

0

96

95

94

93

91

30 60 90 120 150 180 210 240 270 300 330 360

Time (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 DesignSummary 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

AnalysesAnalyses

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 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

Thanks for the attention

Luca Testa, MD, PhDIstituto clinico S. Ambrogio,

IRCCS San DonatoMilano

luctes@gmail.com