m. valgimigli, md, phd on behalf of 3t/2r investigators
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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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
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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
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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
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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)
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< 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
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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
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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
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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
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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
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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%
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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
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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
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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
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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
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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
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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
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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
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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%
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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
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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