1. Tailoring Treatment with Tirofiban in patients showing Resistance to
aspirin and/or Resistance to clopidogrel
M. Valgimigli, MD, PhD
On behalf of 3T/2R
Investigators

2. Background i Current treatment strategies for patients with
coronary artery disease ignore the individual
response to antiplatelet agent(s)
This largely contrasts with the existing practice
surrounding many cardiovascular medications
including anti-hypertensive and lipid-lowering
agents where response to therapy, or lack thereof,
drives subsequent treatment decisions

3. Background ii Inhibition of platelet aggregation following aspirin
or clopidogrel intake varies greatly among patients
Previous studies, using a variety of definitions,
have shown that poor response to Aspirin or
Clopidogrel increases up to 10-fold the risk of
thrombotic events, particularly after PCI
Whether this reflects suboptimal platelet inhibition
per se which might benefit from alternative/
more potent antiplatelet agents, is unknown

4. Patients selection Patients scheduled to undergo elective CAG/PCI
Screening
Patients scheduled to undergo elective CAG/PCI
for silent ischemia, stable angina or low risk
NSTEACS
Eligibility
-Undergoing PCI
-CK, CK-MB and Tp I/T persistently –ve
-No controindications to Gp IIb/IIIa blockers
-Aspirin and/or Clopidogrel poor response as
assessed by VerifyNow™ Aspirin and P2Y12
assays (Accumetrics, USA)

5. Response evaluation Aspirin reaction units (ARU) >550
Aspirin Poor Response
Aspirin reaction units (ARU) >550
ASA orally ≥80 mg for at least 5 days
i.v. 500 mg ASA 15 mins or more before
And/Or
Clopidogrel Poor Response
< 40% platelet inhibition
 600 mg clopidogrel LD at least 2 hours before
300 mg clopidgrel LD at least 6 hours before
75 mg clopidogrel MD for at least 7 days Or Or
Valgimigli et al. Cardiovasc Drugs Ther Aug;22(4):313-20

6. Trial Design Aspirin + Clopidogrel UFH or Bivalirudin Tirofiban*
1:1
Double Blind
Tirofiban*
Placebo
Bail-out Placebo
Bail-out Tirofiban
Blood sampling: Hb, PLT, Tp; CK-MB 6, 12, 18 or 24 hrs
Clinical F-UP: 30-d, 4, 8 and 12 months
*: 25 g/kg in 3 mins, followed by an hour infusion at 0.15 g/kg/min

7. Study Endpoints Primary Secondary
Troponin I/T elevation > 3 times ULN in one or more blood sample(s) within 48 hours after PCI
Ho= 45% in placebo vs. 25% in Tirofiban arm; =90% =5%
Target sample size: 240 pts
Secondary
CK-MB mass elevation >1; 3 or 5 times ULN
Major adverse cardiovascular events
Stent thrombosis based on ARC classification
Valgimigli et al. Cardiovasc Drugs Ther Aug;22(4):313-20

8. Study Organization Sponsor: University of Ferrara, Italy
Data Management: Medical Trial Analysis, Switzerland
Site and data monitoring: Medical Trial Analysis, Italy
Clinical Events Committee: S. Curello (Chair), Brescia, Italy
ECG core lab: MTA, C. Arcozzi (Chair)
Angiographic core lab: MTA, P. Malagutti (Chair)
DSMB: G Fucà, (Chair), Italy

9. 3T/2R P.I. and Sites G Campo Ferrara M Sabatè Barcelona
G Percoco Lagosanto M Hamon Caen
N de Cesare Zingonia Brugaletta Barcelona
Meliga/Marra Torino A Repetto Pavia
P Vranckx Hasselt P Agostoni Antwerp
A Furgieri Cotignola C Tumscitz Piacenza

10. 15% 27% 9% 10% 23% 8% 116 Randomised 52 Allocated to Placebo
1277 Patients Assessed for Eligibility
916 screened for Aspirin response
283 were also screened for Clopidogrel response
361 screened for
Clopidogrel response
754 Aspirin
Screening
Failure
204 Clopidogrel
240 Clopidogrel
Screening
failure
754
53 Clopidogrel
Poor Responders
204
15%
162 Aspirin
Poor Responders
26 were also Clopidogrel Poor Responders
Overall 73 pts excluded:
36 Medical Tx
18 CABG
13 Troponin/CK-MB +ve
5 Refused to participate
1 sudden drop of haemoglobin
174 Clopidogrel
Poor Responders
27% 9%
10%
23% 8%
116 Randomised
52 Allocated to Placebo
10 Received bailout tirofiban
64 Allocated toTirofiban
2 Calls for bailout tirofiban
116 Completed 30-d F-UP
147 Randomised
79 Allocated to Placebo
5 Received bailout tirofiban
68 Allocated to Tirofiban
1 Call for bailout tirofiban
147 Completed 30-d F-UP

11. Baseline Characteristics
Tirofiban Placebo P-Value
(n=132) (n=131)
Age (yr) (62-75) (61-75)
Male Sex (%)
BMI (kg/m2) (25-30) (25-29)
Diabetes (%)
Hypertension (%)
CrCl (ml/min)
Prior MI (%)
Prior PCI (%)
Prior CABG (%)
LVEF (%)
Stable CAD (%)
Unstable CAD (%)
1-Vessel Disease (%)
Multi-Vessel Disease (%)
ASA Steady State (%)
Clopid. Steady State (%)

12. Procedural Results Tirofiban Placebo P-Value
(n=132) (n=131)
No treated lesions ± ±
Multivessel PCI (%)
No Stents implanted ± ±
Stent Lenght (mm)
Use of UFH (%)
Use of Bivalirudin (%)
Location of lesion (%)
LMCA
LAD
CFX
RCA
Venous Graft
B2 or C type lesion (%)
Thrombus present (%)
Bifurcation (%)
Stenting (%)

13. Primary Endpoint Tp >3ULN w/in 48 hs
Placebo
Tirofiban
P=0.009 for superiority
P=0.053
8.4 50
RRR: 42% 95%CI: 61-12 45 40
35.1% % 35
2.3 30 25
20.4% 20
Bail-out Tirofiban 15 10 5

14. 1° Endpoint: Subgroup Analysis Tirofiban Better Placebo Better
LOG RISK RATIO
(95% CI)
PRIMARY END POINT
P-VALUE
Tirofiban Placebo
(%)
Overall
< 70 yr
0.68
≥ 70 yr
Male
0.38
Female
No Diabetes
0.51
Diabetes
Aspirin Poor Responders
0.78
Clopidogrel Poor Responders
% Inhibition ≥21
0.35
% Inhibition <21
Poor Responders to Both
Stable Angina
0.47
Unstable Angina
1 Treated lesion
> 1 Treated Lesion
0.87
A/B1 Treated Lesion(s)
0.69
B2/C Treated Lesion(s)
0.1 1 10
Tirofiban Better
Placebo Better

15. Secondary Endpoints
Relative Risk Reduction
62%
50%
70%

16. 48 hour Outcomes Efficacy Endpoints (CEC adjudicated)
Placebo
Tirofiban
40%
P=0.009
P=0.009
25%
10%
MACE
Death MI
uTVR
Definite ST

17. 48 hour/30-day Outcomes Efficacy Endpoints (CEC adjudicated)
Placebo
Tirofiban
40%
1 Type 4a*
1 Type 4b*
1 Type 4a*
Pulmonary
embolism
25%
10% 2 1 1 1 1
MACE
Death MI
uTVR
Definite ST
*: according to universal definition of myocardial infarction

18. 30-Day Outcomes Efficacy Endpoints (CEC adjudicated)
Placebo
Tirofiban
P=0.006
P=0.006
40%
37%
25%
21%
10%
MACE
Death MI
uTVR
Definite ST

19. 30-Day Outcomes Safety Endpoints (DSMB adjudicated)8%
Placebo
Tirofiban 6% 4%
P=0.99 2%
P=0.99 0%
Major
Minor
RBC
Tranfusion
Mild
TIMI-Bleeding
 PLT

20. Summary The tailored intensification of platelet inhibition
through the infusion of tirofiban in poor responders
to aspirin and/or clopidogrel decreased the rate of
myocardial infarction after elective PCI and resulted
in a lower rate of major adverse cardiovascular
events at 30 days
Our study provides proof of concept for a new
treatment strategy in patients with coronary artery
disease which, by assessing response to standard
anti-platelet agents by a point-of-care assay,
modulates intensity of treatment accordingly