M valgimigli md phd on behalf of 3t 2r investigators
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T ailoring T reatment with T irofiban in patients showing R esistance to aspirin and/or R esistance to clopidogrel. M. Valgimigli, MD, PhD On behalf of 3T/2R Investigators. Background i. Current treatment strategies for patients with coronary artery disease ignore the individual

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M. Valgimigli, MD, PhD On behalf of 3T/2R Investigators

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M valgimigli md phd on behalf of 3t 2r investigators

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


M valgimigli md phd on behalf of 3t 2r investigators

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


M valgimigli md phd on behalf of 3t 2r investigators

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


M valgimigli md phd on behalf of 3t 2r investigators

Patients selection

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)


M valgimigli md phd on behalf of 3t 2r investigators

Response evaluation

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

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


M valgimigli md phd on behalf of 3t 2r investigators

Trial Design

Aspirin + Clopidogrel

UFH or Bivalirudin

1:1

Double Blind

Tirofiban*

Placebo

Bail-out Tirofiban

Blood sampling: Hb, PLT, Tp; CK-MB mass @ 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 14-24 hour infusion at 0.15 g/kg/min


M valgimigli md phd on behalf of 3t 2r investigators

Study Endpoints

Primary

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

Troponin I/T elevation > 1 or 5 times ULN

CK-MB mass eevation >1; 3 or 5 times ULN

Major adverse cardiovscular events

Stent thrombosis based on ARC classification


M valgimigli md phd on behalf of 3t 2r investigators

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


M valgimigli md phd on behalf of 3t 2r investigators

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


M valgimigli md phd on behalf of 3t 2r investigators

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 failure

501

253

204

240

9%

4

132

26

53

121

15%

27%

Coronary Angiography

26 Poor Responders

to both agents

136 Aspirin Poor Responders

174 Clopidogrel Poor Responders

27

5

4

Medical Tx

CABG

Troponin/CK-MB +ve

Refused to participate

Medical Tx

CABG

Troponin/CK-MB +ve

Refused to participate

At risk for bleeding

1

1

3

7

6

7

1

2

3

1

3

1

1

PCI

10%

8%

23%

93 Randomised

40 allocated to/received Placebo

5 received bailout tirofiban

1 Died

53 allocated to/received Tirofiban

2 calls for bailout tirofiban

0 Died

92 completed 30-d F-UP

23 Randomised

12 allocated to/received Placebo

0 Died

11 allocated to/received Tirofiban

tirofiban

0 Died

23 completed 30-d F-UP

147 Randomised

79 allocated to/received Placebo

5 received bailout tirofiban

0 Died

68 allocated to/received Tirofiban

0 Died

1 call for bailout tirofiban

147 completed 30-d F-UP

30 day F-UP


M valgimigli md phd on behalf of 3t 2r investigators

Baseline Characteristics

TirofibanPlaceboP-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 (%) 24 280.57

Hypertension(%) 67 760.10

CrCl (ml/min) 75.6 74.50.77

Prior MI (%) 47.7 38.20.13

Prior PCI (%) 38.9 38.90.99

Prior CABG (%) 6.8 6.10.99

LVEF (%) 56.5 580.98

Stable CAD (%) 65 690.78

Unstable CAD (%) 35 310.51

1-Vessel Disease (%) 27 280.78

Multi-Vessel Disease (%) 73 720.99

ASA Steady State (%) 1001000.99

Clopid. Steady State (%) 1001000.99


M valgimigli md phd on behalf of 3t 2r investigators

Procedural Results

TirofibanPlaceboP-Value

(n=132)(n=131)

No treated lesions 1.5±0.6 1.5±0.70.96

Multivessel PCI (%) 24 19 0.37

No Stents implanted 1.6±0.9 1.6±1.00.96

Stent Lenght (mm) 27 270.59

Use of UFH (%) 98 980.99

Use of Bivalirudin (%) 2 20.99

Location of lesion (%)

LMCA 2.6 1.60.72

LAD 40.9 34.00.17

CFX 21.8 25.00.47

RCA 65 690.78

Venous Graft 2.1 0.50.37

B2 or C type lesion (%) 58 560.86

Thrombus present (%) 5.7 4.30.64

Bifurcation (%) 25 180.13

Stenting (%) 92 940.82


Primary endpoint tp 3 uln w in 48 hs

Primary EndpointTp >3ULN w/in 48 hs

Tirofiban

Placebo

P=0.053

P=0.009 for superiority

8.4

50

RRR: 42% 95%CI: 61-12

45

40

35.1%

%

35

2.3

30

20.4%

25

20

Bail-out Tirofiban

15

10

5

0


M valgimigli md phd on behalf of 3t 2r investigators

1° Endpoint:

Subgroup Analysis

PRIMARY END POINT

P-VALUE

LOG RISK RATIO

(95% CI)

TirofibanPlacebo

(%)

20.4 35.1

Overall

< 70 yr

21.4 38.5

0.68

20.3 30.6

≥ 70 yr

21.4 40.0

Male

0.38

17.6 22.2

Female

22.1 39.3

No Diabetes

0.51

Diabetes

16.2 21.8

21.9 40.4

Aspirin Poor Responders

0.78

16.5 30.8

Clopidogrel Poor Responders

% Inhibition ≥21

17.1 25.5

0.35

15.9 37.5

% Inhibition <21

0 25.0

Poor Responders to Both

22.1 34.1

Stable Angina

0.47

Unstable Angina

18.3 37.5

1 Treated lesion

15.2 26.7

0.87

> 1 Treated Lesion

28.3 51.1

A/B1 Treated Lesion(s)

8.1 20.3

0.69

B2/C Treated Lesion(s)

27.7 45.4

10

0.1

1

Placebo Better

Tirofiban Better


M valgimigli md phd on behalf of 3t 2r investigators

Secondary Endpoints

Relative Risk Reduction

62%

50%

70%


M valgimigli md phd on behalf of 3t 2r investigators

48 hour OutcomesEfficacy Endpoints (CEC adjudicated)

Tirofiban

Placebo

40%

P=0.009

P=0.009

25%

10%

Definite ST

uTVR

MACE

Death

MI


M valgimigli md phd on behalf of 3t 2r investigators

48 hour/30-day OutcomesEfficacy Endpoints (CEC adjudicated)

Tirofiban

Placebo

40%

1 Type 4a*

1 Type 4b*

1 Type 4a*

Pulmonary

embolism

25%

10%

2

1

1

1

1

Definite ST

uTVR

MACE

Death

MI

*: according to universal definition of myocardial infarction


M valgimigli md phd on behalf of 3t 2r investigators

30-Day OutcomesEfficacy Endpoints (CEC adjudicated)

Tirofiban

Placebo

P=0.006

P=0.006

40%

37%

25%

21%

10%

Definite ST

uTVR

MACE

Death

MI


M valgimigli md phd on behalf of 3t 2r investigators

30-Day OutcomesSafety Endpoints (DSMB adjudicated)

8%

Tirofiban

Placebo

6%

4%

P=0.99

P=0.99

2%

0%

Major

Minor

RBC

Tranfusion

Mild

 PLT

TIMI-Bleeding


M valgimigli md phd on behalf of 3t 2r investigators

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


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