Prasugrel versus clopidogrel for patients with UA/NSTEMI medically managed after angiographic triage —
Results from the TRILOGY ACS Trial
Stephen D. Wiviott, MD, Harvey D. White, MB, ChB, DSc, E. Magnus Ohman, MB, ChB,
Keith A. A. Fox, MB, ChB, Paul W. Armstrong, MD, Dorairaj Prabhakaran, MD, DM, MSc,
Gail Hafley, MS, William E. Boden, MD, Christian Hamm, MD, Peter Clemmensen, MD, DMSc,
Jose C. Nicolau, MD, PhD, Alberto Menozzi, MD, PhD, Witold Ruzyllo, MD,
Petr Widimsky, MD, DSc, Ali Oto, MD, Jose Leiva-Pons, MD, Gregory Pavlides, MD,
Matthew T. Roe, MD, MHS, and Deepak L. Bhatt, MD, MPH
On behalf of the TRILOGY ACS Investigators www.clinicaltrials.gov Identifier: NCT00699998

Authors and Disclosures*
The TRILOGY ACS Trial was funded by Eli Lilly & Company and
Daiichi Sankyo.
Stephen D. Wiviott —grant/research support from Eli Lilly & Company,
AstraZeneca,Merck, Eisai; Consulting fees/honoraria from Eli Lilly & Company, Daiichi
Sankyo, AstraZeneca, BMS, Sanofi-Aventis, Eisai.
Petr Widimsky
—consulting fees/honoraria from Lilly, Ali Raif Ilac Sanayi, Bayer,
Daiichi Sankyo, Medtronic, Boehringer Ingelheim, Abbott, AstraZeneca, Sanofi.
Deepak L. Bhatt
—honoraria and travel expenses from the Duke Clinical Research
Institute; serving as a board member for Medscape Cardiology, Boston VA Research
Institute, Society of Chest Pain Centers; grant funding from Amarin, AstraZeneca,
Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, The Medicines
Company; payment for developing educational presentations from WebMD; serving on clinical trial steering committees for the Duke Clinical Research Institute; serving as an editor for the American College of Cardiology and chief medical editor for Slack
Publications.
Gail Hafley and Witold Ruzyllo
—nothing to report.
*For all other authors, see MT Roe et al, NEJM 2012

Angiography Background
 The proportion of ACS (UA/NSTEMI) patients worldwide who are managed medically without revascularization (PCI or CABG) is 40 –60%.
This includes 2 distinct sets of patients:
• triaged to medical therapy after angiography
• for whom angiography is not performed
 Prasugrel, a thienopyridine P2Y
12 inhibitor, improved ischemic outcomes in ACS patients undergoing PCI in the TRITON-TIMI 38 trial, with an increase in major bleeding.
Wiviott SD et al NEJM 2007

Inclusion Criteria (Main Trial)
 Randomization within 10 days of a UA/NSTEMI event
•
NSTEMI: CK-MB or troponin > ULN
•
UA: ST depression > 1 mm in 2 or more leads
 Medical management strategy decision determined
 Angiography not required , but if performed, had to be done before randomization, and evidence of coronary disease in a major vessel ( 1 lesion > 30% or prior PCI/CABG )
 At least 1 of 4 enrichment criteria:
•
Age > 60 years
•
Diabetes mellitus
•
Prior MI
•
Prior revascularization (PCI or CABG)

Primary Efficacy Endpoint and
TIMI Major Bleeding Through 30 Months
(Age < 75 years; 7243)
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
HR (95% CI):
1.31 (0.81, 2.11)
P = 0.27
Roe MT et al NEJM 2012

Overall TRILOGY ACS Results: Summary
(Age < 75 years)
 No statistical differences in cardiovascular events or major bleeding
 Lower risk multiple recurrent ischemic events suggested with prasugrel using the pre-specified Andersen-Gill model
(HR = 0.85, 95% CI: 0.72
–1.00, P = 0.04)
 Significant interaction with treatment and time (HR for > 12 mos = 0.64, 95% CI: 0.48
–0.86, Interaction P = 0.02)
Roe MT et al NEJM 2012

Objectives of TRILOGY-ACS Prespecified
Angiography Sub-Study
 Within the TRILOGY ACS trial, to:
•
Assess clinical characteristics and outcomes of subjects triaged to medical therapy with or without preceding angiography
•
Assess effects of prasugrel vs. clopidogrel in these two groups and whether there is any differential effect based on how subjects entered the trial

Prespecified Analysis of Angiographic Cohort
ITT Population
N = 9326
Primary Population
Age < 75
N = 7243
Triaged after
Angiography*
N = 3085 (43%)
Trigaged without
Angiography*
N = 4158 (57%)
Age ≥ 75
N = 2083
Randomized to Prasugrel
N = 1524
Randomized to
Clopidogrel
N = 1561
Randomized to
Prasugrel
N = 2096
Randomized to Clopidogrel
N = 2062
*For angiography vs no angiography comparisons — p-values unadjusted, for prasugrel vs clopidogrel — p-value adjusted for clopidogrel stratum

Baseline Characteristics
Age —yr
Female sex —%
Body weight < 60 kg —%
Disease classification —%
NSTEMI
Unstable angina
Medical history —%
Diabetes mellitus
Current/recent smoking
Prior myocardial infarction
Prior PCI
Prior CABG
Baseline risk assessment
GRACE risk score
Creatinine clearance —mL/min
Age < 75 Years (N = 7243)
Angiography
(N = 3085)
62 (56 –68)
33.3
8.9
No Angio
(N = 4158)
63 (57 –68)
37.8
16.0
78.7
21.3
39.3
29.3
42.6
33.9
21
112 (99 –124)
86 (68 –109)
59.2
40.8
38.6
19.2
45.2
23.7
11.3
P-Value
0.0007
< 0.0001
< 0.0001
< 0.0001
0.56
< 0.0001
0.03
< 0.0001
< 0.0001
117 (102 –131) < 0.0001
77 (59 –98) < 0.0001

100%
75%
Regional Differences in
Angiography Pre-randomization
Angio No Angio
16%
20%
24%
44%
53%
68%
76%
50%
84%
80%
76%
56%
25%
47%
32%
0%
NA
995
WE
630
AU/NZ/SA Med Basin
106 527
LA
968
EA
571
79%
24%
IND
1021
21%
C/E E
2429

Baseline Characteristics:
Angiographic Results (>50% Stenosis)
3-vessel
19,9%
Nonobstructive
17,1%
2-vessel
21,5%
1-vessel
41,5%
Notes:
1. Non-obstructive = 30 - <50% stenosis
2. LM disease - 6.2% of subjects

Incidence of Outcomes by Angiography Status
(Age < 75 years)
20%
P < 0.001
16,5%
15%
12,8%
10%
P = 0.11
P < 0.001
8,2%
8,7%
9,9%
P < 0.001
9,6%
Angio No Angio
5%
4,7%
P = 0.47
5,8%
1,5%
2,1%
P = 0.04
P = 0.09
2,0%
1,6%
3,2%
2,3%
0%
CVD/MI/Stroke CVD MI Stroke Death TIMI
Major
TIMI
Major/Minor

Primary Efficacy Endpoint to 30 Months
(Age < 75 years)
Angio
N=3085
No Angio
N=4158
10.7% vs 14.9%
P = 0.031
HR (95% CI):
0.77 (0.61, 0.98)
P interaction = 0.08
16.3% vs 16.7%
P = 0.954
HR (95% CI):
1.01 (0.84, 1.20)

Evaluation of All Ischemic
Events over Time*
(Age < 75 years)
 Lower risk of multiple recurrent ischemic events suggested with prasugrel in the angiography group using the pre-specified Andersen-Gill model
≥
1 event
≥
2 events
3 –7 events
HR (CI)
Angiography
Pras Clop
137
23
168
45
6 10
0.75 (0.58
–0.98)
No Angiography
Pras Clop
262 261
59 69
13 15
0.91 (0.74
–1.11)
* Pre-specified evaluation of all CV death, MI, or stroke events by treatment
P interaction = 0.26

Myocardial Infarction
Angio No Angio
7.2% vs 10.3%
P = 0.042
HR (95% CI):
0.74 (0.55, 1.00)
P interaction = 0.12
9.2% vs 10.6%
P = 0.989
HR (95% CI):
1.00 (0.79, 1.26)

Stroke
Angio
0.6% vs 2.4%
P = 0.004
HR (95% CI):
0.30 (0.13,0.71)
No Angio
2.2% vs 2.0%
P = 0.933
HR (95% CI):
1.03 (0.58,1.83)
P interaction = 0.02

CV Death
Angio No Angio
4.2% vs 5.2%
P = 0.626
HR (95% CI):
0.91 (0.61,1.34)
P interaction = 0.90
8.4% vs 7.9%
P = 0.569
HR (95% CI):
0.93 (0.73,1.20)

CV Death
Angio
All-Cause Death
Angio:
HR (95% CI):
0.98 (0.69,1.38)
No Angio:
HR (95% CI):
0.94 (0.75,1.18)
P interaction = 0.85
4.2% vs 5.2%
P = 0.626
HR (95% CI):
0.91 (0.61,1.34)
No Angio
8.4% vs 7.9%
P = 0.569
HR (95% CI):
0.93 (0.73,1.20)
P interaction = 0.90

TIMI Major Bleeding
Angio
2.7% vs 1.4%
P = 0.074
HR (95% CI):
1.84 (0.93, 3.63)
No Angio
1.6% vs 1.5%
P = 0.851
HR (95% CI):
0.92 (0.47, 1.83)
P interaction = 0.16

TIMI Major Bleeding
Angio
2.7% vs 1.4%
P = 0.074
HR (95% CI):
1.84 (0.93, 3.63)
No Angio
TIMI Major or Minor
Bleeding
Angio:
HR (95% CI):
1.68 (1.00, 2.83)
No Angio:
1.6% vs 1.5%
P = 0.851
HR (95% CI): HR (95% CI):
P interaction = 0.65
P interaction = 0.16

Limitations
 Reason for pursuing strategy not fully known:
•
Angiography
•
Medical Therapy
 Cannot make direct comparisons between angiography and no angiography and infer causality
 Subgroup analysis of a neutral trial
•
Prespecified
•
Pre-randomization variable
•
Large sample size
 Interaction testing is underpowered

Conclusions
 Substantial differences in baseline characteristics exist among patients triaged for medical therapy with or without angiography from TRILOGY-ACS.
•
Geographically, subjects from North America,
Western Europe, Australasia, South Africa, and the
Mediterranean region had higher rates of angiography pre-randomization
•
Patients with angiography more often were enrolled with NSTEMI, and had prior history of PCI or CABG
 Patients with angiography had lower composite endpoint event (CVDeath, MI, or Stroke), particularly CV death.

Conclusions
 Overall, in the TRILOGY ACS Trial prasugrel did not reduce cardiovascular events among patients managed medically for ACS.
 When treated with prasugrel compared to clopidogrel , patients triaged to medical therapy following angiography tended to have:
•
Lower rates of the combined endpoint of CVD/MI/CVA
•
Lower rates of MI, CVA alone, and recurrent ischemic events
•
A trend to higher rates of TIMI major bleeding.
 Though hypothesis generating, these results are consistent with previous trials and suggest that when angiography is performed and coronary disease is confirmed, the benefits and risks of intensive antiplatelet therapy exist whether medical therapy or PCI is elected.