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.