On behalf of the TRILOGY ACS Investigators
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
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 P2Y12 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
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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
ITT Population
N = 9326
Primary Population
Age < 75
N = 7243
Triaged after Angiography*
N = 3085 (43%)
Randomized to Prasugrel
N = 1524
Randomized to Clopidogrel
N = 1561
Trigaged without Angiography*
N = 4158 (57%)
Randomized to Prasugrel
N = 2096
Randomized to Clopidogrel
N = 2062
Age ≥ 75
N = 2083
Prespecified Analysis of Angiographic Cohort
*For angiography vs no angiography comparisons — p-values unadjusted, for prasugrel vs clopidogrel — p-value adjusted for clopidogrel stratum
Baseline Characteristics
Age < 75 Years (N = 7243)
Angiography(N = 3085)
No Angio(N = 4158)
P-Value
Age—yr 62 (56–68) 63 (57–68) 0.0007
Female sex—% 33.3 37.8 < 0.0001
Body weight < 60 kg—% 8.9 16.0 < 0.0001
Disease classification—% < 0.0001
NSTEMI 78.7 59.2
Unstable angina 21.3 40.8
Medical history—%
Diabetes mellitus 39.3 38.6 0.56
Current/recent smoking 29.3 19.2 < 0.0001
Prior myocardial infarction 42.6 45.2 0.03
Prior PCI 33.9 23.7 < 0.0001
Prior CABG 21 11.3 < 0.0001
Baseline risk assessment
GRACE risk score 112 (99–124) 117 (102–131) < 0.0001
Creatinine clearance—mL/min 86 (68–109) 77 (59–98) < 0.0001
Regional Differences in Angiography Pre-randomization
NA WE AU/NZ/SA Med Basin LA EA IND C/E E0%
25%
50%
75%
100%
84% 80% 76%
56%47%
32%24% 21%
16% 20% 24%
44%53%
68%76% 79%
Angio No Angio
995 630 106 527 968 571 1021 2429
Baseline Characteristics: Angiographic Results (>50% Stenosis)
Non-obstructive17.1%
1-vessel41.5%
2-vessel21.5%
3-vessel19.9%
Notes:
1. Non-obstructive = 30 - <50% stenosis
2. LM disease - 6.2% of subjects
CVD/MI/
Stroke
CVD MI Stroke Death TIMI_x000d_Major
TIMI_x000d_Major/
Minor
0%
5%
10%
15%
20%
12.8%
4.7%
8.7%
1.5%
5.8%
2.0%
3.2%
16.5%
8.2%
9.9%
2.1%
9.6%
1.6%2.3%
Angio No Angio
P = 0.11
P = 0.47
P < 0.001
P = 0.04
Incidence of Outcomes by Angiography Status(Age < 75 years)
P < 0.001
P < 0.001
P = 0.09
Primary Efficacy Endpoint to 30 Months(Age < 75 years)
P interaction = 0.08
10.7% vs 14.9%P = 0.031
HR (95% CI): 0.77 (0.61, 0.98)
AngioN=3085
No AngioN=4158
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)
Angiography No Angiography
Pras Clop Pras Clop
≥ 1 event 137 168 262 261
≥ 2 events 23 45 59 69
3–7 events 6 10 13 15
HR (CI) 0.75 (0.58–0.98) 0.91 (0.74–1.11)
Lower risk of multiple recurrent ischemic events suggested with prasugrel in the angiography group using the pre-specified Andersen-Gill model
* Pre-specified evaluation of all CV death, MI, or stroke events by treatment
P interaction = 0.26
P interaction = 0.12
7.2% vs 10.3%P = 0.042
HR (95% CI): 0.74 (0.55, 1.00)
Angio No Angio
9.2% vs 10.6%P = 0.989
HR (95% CI): 1.00 (0.79, 1.26)
Myocardial Infarction
Stroke
P interaction = 0.02
0.6% vs 2.4%P = 0.004
HR (95% CI): 0.30 (0.13,0.71)
Angio No Angio
2.2% vs 2.0%P = 0.933
HR (95% CI): 1.03 (0.58,1.83)
P interaction = 0.90
4.2% vs 5.2%P = 0.626
HR (95% CI): 0.91 (0.61,1.34)
Angio No Angio
8.4% vs 7.9%P = 0.569
HR (95% CI): 0.93 (0.73,1.20)
CV Death
P interaction = 0.90
4.2% vs 5.2%P = 0.626
HR (95% CI): 0.91 (0.61,1.34)
Angio No Angio
8.4% vs 7.9%P = 0.569
HR (95% CI): 0.93 (0.73,1.20)
CV Death
P interaction = 0.85
Angio:HR (95% CI):
0.98 (0.69,1.38)
No Angio:HR (95% CI):
0.94 (0.75,1.18)
All-Cause Death
TIMI Major Bleeding
P interaction = 0.16
2.7% vs 1.4%P = 0.074
HR (95% CI): 1.84 (0.93, 3.63)
Angio No Angio
1.6% vs 1.5%P = 0.851
HR (95% CI): 0.92 (0.47, 1.83)
TIMI Major Bleeding
P interaction = 0.16
2.7% vs 1.4%P = 0.074
HR (95% CI): 1.84 (0.93, 3.63)
Angio No Angio
1.6% vs 1.5%P = 0.851
HR (95% CI): 0.92 (0.47, 1.83)
P interaction = 0.65
Angio:HR (95% CI):
1.68 (1.00, 2.83)
No Angio:HR (95% CI):
1.42 (0.83, 2.41)
TIMI Major or Minor Bleeding
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.