Transcript Primary Results of Testing platelet Reactivity In patients underGoing elective stent placement on clopidogrel to Guide alternative thErapy with pRasugrel TRIGGER-PCI Study TCT 2011 Dietmar Trenk,

Primary Results of
Testing platelet Reactivity In patients underGoing
elective stent placement on clopidogrel
to Guide alternative thErapy with pRasugrel
TRIGGER-PCI Study
TCT 2011
Dietmar Trenk, PhD
On behalf of the TRIGGER-PCI Investigators
Disclosures
Consulting fees/honoraria: Eli Lilly, Daiichi Sankyo,
sanofi-aventis, AstraZeneca
Speaker Honoraria: Eli Lilly, Daiichi Sankyo, sanofiaventis, AstraZeneca
Off-label use of prasugrel and VerifyNow P2Y12 test will
be discussed in this presentation
Death or myocardial infarction (%)
Prognostic impact of on-treatment platelet
reactivity in EXCELSIOR
RPA > 14%
RPA ≤ 14%
8
6
Log-RankP = 0.004
4
2
0
0
120
240
Days after PCI
360
Trenk et al., J Am Coll Cardiol 2008; 51: 1925
High dose vs. standard dose Clopidogrel:
Primary Endpoint: CV death, MI, stent thrombosis
n=1109
n=1105
Price et al., JAMA 2011; 305: 1097
Pharmacodynamic effect of high- and standarddose Clopidogrel in patients with high OTR
Standard-Dose
500
P = 0.98
High-Dose
P < 0.001
400
PRU
value
Persistently high
reactivity @ 30
days: 62% vs 40%,
p<0.001
300
200
100
0
N=1105 N=1013 N=940
Post-PCI 30 d
ITT population
6 mo
N=1109 N=1012 N=944
Post-PCI 30 d
6 mo
Price et al., JAMA 2011; 305: 1097
Study objective
… to assess whether the outcome of patients with high onclopidogrel platelet reactivity after elective PCI with drugeluting stents can be improved by switching from clopidogrel
to prasugrel.
Primary efficacy endpoint: Cardiovascular death or
myocardial infarction
Key safety endpoint:
Non-CABG TIMI major bleeding
Flow-chart TRIGGER-PCI Study
Successful PCI with DES without major complication and NO GPIIb/IIIa use
Post-PCI VerifyNow P2Y12 Assay (PRU)
2 - 7 hours after MD of clopidogrel 75 mg at day 1 post-PCI
N ~6500
Non-Responder
A
N = 1075
B
Yes
PRU > 208
No
Responder
C
N = 1075
“Prasugrel arm”
“Clopidogrel arm”
Prasugrel LD 60 mg
Prasugrel MD 10 mg QD
+ Clopidogrel placebo
Placebo LD
Clopidogrel MD 75 mg QD
+ Prasugrel placebo
N = 4350
“Standard
Therapy”
Clopidogrel MD 75 mg QD
N = 2,150
 33%
Non-interventional
study (Registry)
Clinical Follow-up and blinded VerifyNow Assessment at 90 days, 180 days
Primary Endpoint: 6 month CV Death or MI
Key inclusion and exclusion criteria
Major inclusion criteria
 Successful DES-PCI in patients with stable CAD and
clinical indication for PCI
 Clopidogrel 600-mg LD between 24 hours before, and
the time of PCI + 75-mg MD in the morning after PCI.
Major exclusion criteria
 Patients with STEMI / NSTEMI
 Patients with known major complications after PCI
Sample size and power calculation
 6-month incidence of the composite endpoint of
cardiovascular death or MI (including minor infarctions
with elevated troponin) expected as 4.7%.
 Randomization of 2,150 patients to provide 93% power to
detect a 50 % relative risk reduction on prasugrel.
Disposition of patients in TRIGGER-PCI
3,525 patients screened
33 No test result
3,492 VerifyNow testing
209 Invalid test result
No
PRU >208?
2,658 pts. with PRU ≤208
Yes
625 patients with PRU >208
202 patients declined
423 patients randomized
212 prasugrel
211 clopidogrel
210 received ≥1 dose prasugrel
210 received ≥1 dose clopidogrel
74 study discontinuations
73 study discontinuations
15 Subject decision
1 Consent revoked
58 Early termination of study
9 Subject decision
4 Consent revoked
60 Early termination of study
136 completed study
137 completed study
Number of patients
Frequency distribution of VerifyNow P2Y12 PRU
after loading with Clopidogrel 600mg and 1st MD
208
600
500
400
300
200
81.0%
PRU ≤208
19.0%
PRU >208
Total n=3,283
patients
100
0
0
50 100 150 200 250 300 350 400>400
VerifyNow P2Y12 PRU
Early termination of TRIGGER-PCI at
March 18, 2011
 236 patients completed 6 months follow-up
 Only 1 clinical endpoint (peri-procedural MI) observed
→ rate 0.4%
 Upper 95 %-confidence limit 1.25 %
Baseline demographic and clinical characteristics
of the randomized patients
Prasugrel
N=212
Clopidogrel
N=211
245
249
(225 - 273)
(225 - 277)
66 ± 8
66 ± 9
Male gender
Body mass index (median)
72%
73%
29.1
29.6
Current smoker
16%
14%
Diabetes mellitus
Hypertension
41%
43%
89%
89%
Prior myocardial infarction
30%
25%
Prior PCI
Prior CABG
44%
45%
12%
14%
Proton pump inhibitor
Prior clopidogrel use
21%
22%
2%
1%
Residual platelet reactivity (PRU),
median (IQR)
Age, mean ± SD
Procedural characteristics of the randomized
patients
Prasugrel
N=212
Clopidogrel
N=211
1.9 ± 1.2
1.8 ± 1.1
51%
50%
2 stents
≥ 3 stents
25%
27%
23%
23%
Stent length, mean±SD, mm
18.7 ± 7.9
18.5 ± 8.0
Stent diameter, mean±SD, mm
3.0 ± 0.5
3.0 ± 0.5
- Native artery
95%
97%
- Saphenous vein graft
- Arterial graft
2%
2%
1%
1%
28%
29%
Total no. of DES, mean±SD
Pts. with 1 stent
Vessel type stented
Overlapping stents
Stents used in TRIGGER-PCI patients
Prasugrel
N=212
Clopidogrel
N=211
Total no, of stents used
395
389
XIENCE V / PROMUS
195 (49%)
207 (53%)
CYPHER
119 (30%)
101 (26%)
ENDEAVOR
49 (12%)
24 ( 6%)
TAXUS
10 ( 3%)
6 ( 2%)
Endeavor Resolute / Resolute
Integrity
8 ( 2%)
31 ( 8%)
Others
14 ( 4%)
20 (5%)
Platelet reactivity by VerifyNow P2Y12 assay:
Prasugrel 10mg QD vs. Clopidogrel 75mg QD
ITT - population
p=0.644
p<0.001
p<0.001
Clopidogrel
Prasugrel
300
208
200
100
V3
P
V3
Day 176
C
V2
V2
C
P
C
Prasugrel
Clopidogrel
Day 90
P
At random.
V1
0
V1
VerifyNow P2Y12 PRU
400
(IQR 88-94)
(IQR 171-182)
187
189
139
144
n=210
n=206
Median with interquartile range; 10-90% percentile
Proportion of pts. with high on-treatment platelet
reactivity by VerifyNow P2Y12 assay (PRU >208)
p<0.001
80
p<0.001
70.8%
70.4%
Clopidogrel
Prasugrel
60
% 40
20
5.9%
0
90
P
Day 90
D
Prasugrel
Clopidogrel
ay
(IQR 88-94)
n=187
n=189
5.8%
Day 176
(IQR 171-182)
139
144
Summary of primary and secondary
CEC-adjudicated efficacy endpoints
Prasugrel Clopidogrel
p
N=212
N=211
HR (95% CI)
Days on study treatment(median)
Primary composite efficacy EP:
CV death or MI
174
174
-
0
1 (0.5%)
-
0
1 (0.5%)
-
2 (0.9%)
4 (1.9%)
0.992
0.99 (0.14-7.03)
2 (0.9%)
1 (0.5%)
-
Definite ST
0
0
-
Stroke
0
1 (0.5%)
-
CV death
0
0
-
All cause death
0
1 (0.5%)
-
Key secondary efficacy EPs:
MI
Rehospitalization for cardiac
ischemic event
Urgent TVR
Summary of CEC-adjudicated bleeding events
Prasugrel Clopidogrel
p
N=212
N=211
HR (95% CI)
Key safety EP:
Non-CABG TIMI Major Bleeding
Secondary bleeding events:
Non-CABG TIMI fatal bleeding
Non-CABG TIMI life-threatening
bleeding
Non-CABG TIMI major or minor
bleeding
Non-CABG TIMI major, minor, or
minimal bleeding
3 (1.4%)
1 (0.5%)
-
0
0
0
1 (0.5%)
-
3 (1.4%)
2 (1.0%)
.
6 (2.9%)
4 (1.9%)
0.516
1.52 (0.42-5.38)
Non-CABG TIMI major, minor or minimal bleeding
4.0
Event rate, %
3.5
3.0
Prasugrel
2.5
2.0
Clopidogrel
1.5
Hazard Ratio 1.517
(95% CI, 0.428-5.376)
p=0.516
1.0
0.5
0.0
0
30
60
90
120 150 180 210 240
Days from randomization
Summary and conclusion: Effectiveness of
Prasugrel vs Clopidogrel after elective PCI
 High on-clopidogrel platelet reactivity (>208 PRU by
VerifyNow P2Y12 test) was observed less frequently than
expected.
 Compared with standard-dose clopidogrel 75 mg QD,
prasugrel 10 mg QD substantially decreased platelet
reactivity in patients with high on-clopidogrel platelet
reactivity after elective PCI.
 Given the low event rate in elective PCI patients without
peri-procedural complications it was not possible to
assess the risk – benefit ratio with prasugrel treatment.
Therefore, the study was terminated prematurely for
futility.
Study organization
Trial Leadership:
Franz-Josef Neumann (Chair), Dietmar Trenk, Adnan Kastrati,
Meinrad Gawaz, Gregg W. Stone (US PI), Dominick J. Angiolillo,
Joseph A. Jakubowski
Sponsor:
Eli Lilly and Company, Daiichi Sankyo Co., Ltd.
Data Center and Site Management:
Quintiles
Data Safety and Monitoring Board:
Hanjörg Just (chair), Jochen Senges, Kurt Ulm
Principal Investigators
F.-J. Neumann (Bad Krozingen, GER)
R. Zimmermann (Pforzheim, GER)
G. Schuler (Leipzig, GER)
E. Dogu (Bremen, GER)
M. Gawaz (Tuebingen, GER)
M. Bergmann (Hamburg, GER)
A. Kastrati (Munich, GER)
C. Toma (Pittsburgh, PA, US)
G. Richardt (Bad Segeberg, GER)
S. V. Manoukian (Nashville, TN, US)
J. Yu (Bad Berka, GER)
T. J. Gluckman (Portland, OR, US)
W. Jung (Villingen-Schwenningen, GER)
D. J. Spriggs (Clearwater, FL, US)
B. Witzenbichler (Berlin, GER)
D. J. Angiolillo (Jacksonville, FL, US)
H. Heuer (Dortmund, GER)
J. C. Merritt (Rome, GA, US)
S. Genth-Zotz (Mainz, GER)
M. Haude (Neuss, GER)
B. Goldmann (Hamburg,GER)
V. Schaechinger (Fulda, GER)
M. Moser (Freiburg, GER)
H. Schuehlen (Berlin, GER)
U. Sechtem (Stuttgart, GER)
D. A. Purdy (Rapid City, SD, US)
D. Boese (Essen, GER)
S. Puri (Moline, IL, US)
H. Mudra (Munich, GER)
K. Garatt (New York, NY, US)