M. Valgimigli, MD, PhDOn behalf of 3T/2R

Investigators

Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel

Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel

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 medicationsincluding anti-hypertensive and lipid-lowering agents where response to therapy, or lack thereof, drives subsequent treatment decisions

Background iBackground i

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

Background iiBackground ii

Patients scheduled to undergo elective CAG/PCIfor silent ischemia, stable angina or low riskNSTEACS

Patients selectionPatients selection

Screening

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 asassessed by VerifyNow™ Aspirin and P2Y12 assays (Accumetrics, USA)

< 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

Aspirin reaction units (ARU) >550 ASA orally ≥80 mg for at least 5 days i.v. 500 mg ASA 15 mins or more before

Response evaluationResponse evaluation

Aspirin Poor Response

Clopidogrel Poor Response

or

or

or

Aspirin + Clopidogrel UFH or Bivalirudin

Aspirin + Clopidogrel UFH or Bivalirudin

Tirofiban*Tirofiban*Tirofiban*Tirofiban* PlaceboPlaceboPlaceboPlacebo

Trial DesignTrial Design

1:11:1

*: 25 g/kg in 3 mins, followed by an 14-24 hour infusion at 0.15 g/kg/min

Blood sampling: Hb, PLT, Tp; CK-MB mass @ 6, 12, 18 or 24 hrs Clinical F-UP: 30-d, 4, 8 and 12 months

Bail-out Tirofiban

Double Blind

Study EndpointsStudy Endpoints

PrimaryTroponin I/T elevation > 3 times ULN in one or more blood sample(s) within 48 hours after PCIHo= 45% in placebo vs. 25% in Tirofiban arm; =90% =5%

Target sample size: 240 pts

SecondaryTroponin I/T elevation > 1 or 5 times ULNCK-MB mass eevation >1; 3 or 5 times ULNMajor adverse cardiovscular eventsStent thrombosis based on ARC classification

Study OrganizationStudy OrganizationSponsor: 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

3T/2R P.I. and Sites3T/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

1277 Patients Assessed for Eligibility

1277 Patients Assessed for Eligibility

633 screened for

Aspirin response

283 screened for Aspirin and Clopidogrel

response

361 screened for

Clopidogrel response

Aspirin Screening failure

Clopidogrel Screening failure501 253 240204

132 1214 26 53

Medical Tx

CABG

Troponin/CK-MB +ve

Refused to participate

27

Coro

nary

A

ngio

gra

phy

PC

I

4

7

7

1

1

1

Medical Tx

CABG

Troponin/CK-MB +ve

Refused to participate

At risk for bleeding

1

1 3

2

1

3

5

6

3

26 Poor Responders

to both agents

23 Randomised

12 allocated to/received Placebo

0 Died11 allocated

to/received Tirofiban tirofiban0 Died

23 completed 30-d F-UP

30

day F

-UP

93 Randomised40 allocated to/received Placebo

5 received bailout tirofiban1 Died

53 allocated to/received Tirofiban2 calls for bailout tirofiban

0 Died

92 completed 30-d F-UP

147 Randomised79 allocated to/received Placebo

5 received bailout tirofiban0 Died

68 allocated to/received Tirofiban0 Died

1 call for bailout tirofiban

147 completed 30-d F-UP

136 Aspirin Poor Responders 174 Clopidogrel Poor Responders

15% 27%9%

10% 8% 23%

Baseline CharacteristicsBaseline Characteristics Tirofiban Placebo P-Value (n=132) (n=131)

Age (yr) 69 (62-75) 69 (61-75) 0.84

Male Sex (%) 74.2 72.5 0.78

BMI (kg/m2) 28 (25-30) 27 (25-29) 0.27

Diabetes (%) 24 28 0.57

Hypertension (%) 67 76 0.10

CrCl (ml/min) 75.6 74.5 0.77

Prior MI (%) 47.7 38.2 0.13

Prior PCI (%) 38.9 38.9 0.99

Prior CABG (%) 6.8 6.1 0.99

LVEF (%) 56.5 58 0.98

Stable CAD (%) 65 690.78

Unstable CAD (%) 35 31 0.51

1-Vessel Disease (%) 27 28 0.78

Multi-Vessel Disease (%) 73 72 0.99

ASA Steady State (%) 100 100 0.99

Clopid. Steady State (%) 100 100 0.99

Tirofiban Placebo P-Value (n=132) (n=131)

Age (yr) 69 (62-75) 69 (61-75) 0.84

Male Sex (%) 74.2 72.5 0.78

BMI (kg/m2) 28 (25-30) 27 (25-29) 0.27

Diabetes (%) 24 28 0.57

Hypertension (%) 67 76 0.10

CrCl (ml/min) 75.6 74.5 0.77

Prior MI (%) 47.7 38.2 0.13

Prior PCI (%) 38.9 38.9 0.99

Prior CABG (%) 6.8 6.1 0.99

LVEF (%) 56.5 58 0.98

Stable CAD (%) 65 690.78

Unstable CAD (%) 35 31 0.51

1-Vessel Disease (%) 27 28 0.78

Multi-Vessel Disease (%) 73 72 0.99

ASA Steady State (%) 100 100 0.99

Clopid. Steady State (%) 100 100 0.99

Tirofiban Placebo P-Value

(n=132) (n=131)

No treated lesions 1.5±0.6 1.5±0.7 0.96

Multivessel PCI (%) 24 19 0.37

No Stents implanted 1.6±0.9 1.6±1.0 0.96

Stent Lenght (mm) 27 27 0.59

Use of UFH (%) 98 980.99

Use of Bivalirudin (%) 2 2 0.99

Location of lesion (%)

LMCA 2.6 1.6 0.72

LAD 40.9 34.0 0.17

CFX 21.8 25.0 0.47

RCA 65 69 0.78

Venous Graft 2.1 0.5 0.37

B2 or C type lesion (%) 58 560.86

Thrombus present (%) 5.7 4.3 0.64

Bifurcation (%) 25 18 0.13

Stenting (%) 92 94 0.82

Tirofiban Placebo P-Value

(n=132) (n=131)

No treated lesions 1.5±0.6 1.5±0.7 0.96

Multivessel PCI (%) 24 19 0.37

No Stents implanted 1.6±0.9 1.6±1.0 0.96

Stent Lenght (mm) 27 27 0.59

Use of UFH (%) 98 980.99

Use of Bivalirudin (%) 2 2 0.99

Location of lesion (%)

LMCA 2.6 1.6 0.72

LAD 40.9 34.0 0.17

CFX 21.8 25.0 0.47

RCA 65 69 0.78

Venous Graft 2.1 0.5 0.37

B2 or C type lesion (%) 58 560.86

Thrombus present (%) 5.7 4.3 0.64

Bifurcation (%) 25 18 0.13

Stenting (%) 92 94 0.82

Procedural ResultsProcedural Results

Primary Endpoint Tp >3ULN w/in 48 hsPrimary Endpoint

Tp >3ULN w/in 48 hs

Placebo Tirofiban

0

5

10

15

20

25

30

35

40

45

50

35.1%

20.4%

P=0.009 for superiority

RRR: 42% 95%CI: 61-12RRR: 42% 95%CI: 61-12

Bail-out Tirofiban

2.3

8.4

%

P=0.053

Overall

< 70 yr≥ 70 yr

MaleFemale

No DiabetesDiabetes

Stable AnginaUnstable Angina

1 Treated lesion> 1 Treated Lesion

A/B1 Treated Lesion(s)B2/C Treated Lesion(s)

Aspirin Poor Responders

PRIMARY END POINT

Tirofiban Placebo

P-VALUE

(%)

Tirofiban BetterTirofiban Better Placebo BetterPlacebo Better

LOG RISK RATIO(95% CI)

Clopidogrel Poor Responders

Poor Responders to Both

0.1 1 10

% Inhibition ≥21% Inhibition <21

20.4 35.1

21.4 38.5 20.3 30.6

21.4 40.0 17.6 22.2

22.1 39.3 16.2 21.8

21.9 40.4 16.5 30.8 17.1 25.5 15.9 37.5 0 25.0

22.1 34.1 18.3 37.5

15.2 26.7 28.3 51.1

8.1 20.3 27.7 45.4

0.68

0.38

0.51

0.78

0.47

0.87

0.69

0.35

1° Endpoint:1° Endpoint:Subgroup AnalysisSubgroup Analysis

Secondary EndpointsSecondary Endpoints

0

5

10

15

20

25

30

35

40PlaceboTirofiban

>1 >3 >5

p=0.09

p<0.001

p=0.05

Pati

ents

wit

h C

K-M

Bele

vati

on (

%)

62%

50%70%

Relative Risk Reduction

48 hour Outcomes Efficacy Endpoints

(CEC adjudicated)

48 hour Outcomes Efficacy Endpoints

(CEC adjudicated)

-5

1 0

2 5

4 0

MACEMACE DeathDeath MIMI Definite STDefinite ST

P=0.009P=0.009

P=0.009P=0.009

Placebo Tirofiban

40%

10%

25%

uTVRuTVR

48 hour/30-day Outcomes Efficacy Endpoints

(CEC adjudicated)

48 hour/30-day Outcomes Efficacy Endpoints

(CEC adjudicated)

-5

1 0

2 5

4 0

-5

1 0

2 5

4 0

MACEMACE DeathDeath MIMI Definite STDefinite ST

Placebo Tirofiban

40%

10%

25%

uTVRuTVR

1 2 1 11

Pulmonaryembolism

Pulmonaryembolism

1 Type 4a*

1 Type 4b*

1 Type 4a*

1 Type 4b*

1 Type 4a*

1 Type 4a*

*: according to universal definition of myocardial infarction

30-Day Outcomes Efficacy Endpoints

(CEC adjudicated)

30-Day Outcomes Efficacy Endpoints

(CEC adjudicated)

-5

1 0

2 5

4 0

MACEMACE DeathDeath MIMI Definite STDefinite ST

P=0.006P=0.006

Placebo Tirofiban

40%

10%

25%

uTVRuTVR

P=0.006P=0.006

37%37%

21%21%

30-Day Outcomes Safety Endpoints

(DSMB adjudicated)

30-Day Outcomes Safety Endpoints

(DSMB adjudicated)

- 2

0

2

4

6

8

MajorMajor MinorMinor RBC Tranfusion

RBC Tranfusion

MildMild

PLT PLT

P=0.99P=0.99

Placebo Tirofiban

TIMI-BleedingTIMI-Bleeding

2%

6%

4%

8%

0%

P=0.99P=0.99

The tailored intensification of platelet inhibitionthrough the infusion of tirofiban in poor respondersto aspirin and/or clopidogrel decreased the rate ofmyocardial infarction after elective PCI and

resultedin a lower rate of major adverse cardiovascularevents at 30 days

Our study provides proof of concept for a newtreatment strategy in patients with coronary arterydisease which, by assessing response to standardanti-platelet agents by a point-of-care assay,modulates intensity of treatment accordingly

SummarySummary