1. For the HORIZONS-AMI Investigators
A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Metal Stents During Primary Angioplasty in Acute Myocardial Infarction
– One Year Results –
Gregg W. Stone MD
For the HORIZONS-AMI Investigators

2. Background
No consensus exists regarding the safety and efficacy of drug-eluting stents in pts with STEMI undergoing primary PCI
TLR and restenosis rates tend to be lower in STEMI vs. elective PCI patients because of less plaque burden and non viable myocardium
The safety of implanting DES in ruptured plaques with thrombus has been questioned
Outcomes from registry studies of DES vs. BMS in STEMI have been conflicting, and no large-scale randomized trials have been performed

3. Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI with symptom onset ≤12 hours
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Aspirin, thienopyridine R
1:1
Emergent angiography, followed by triage to…
Primary PCI
CABG –
Medical Rx
3000 pts eligible for stent randomization R
3:1
Bare metal EXPRESS stent
Paclitaxel-eluting TAXUS stent
Clinical FU at 30 days, 6 months, 1 year, and then
yearly through 5 years; angio FU at 13 months

4. Stent Randomization Hypotheses
In patients with STEMI undergoing primary PCI, the use of paclitaxel-eluting TAXUS stents rather than bare metal EXPRESS stents will be:
Efficacious, as evidenced by reduced rates of ischemia-driven target lesion revascularization at 1-year and angiographic binary restenosis at 13 months; and
Safe, with non-inferior rates of the composite measure of death, reinfarction, stent thrombosis or stroke at 1-year

5. Clinical Inclusion Criteria
STEMI >20 mins and <12 hours in duration
ST-segment elevation of 1 mm in 2 contiguous leads; or
Presumably new left bundle branch block; or
True posterior MI with ST depression of 1 mm in 2 contiguous anterior leads
Patients with cardiogenic shock, left main disease, etc., were not excluded
Age ≥18 years
Written, informed consent

6. Principal Clinical Exclusion Criteria
Contraindication to any of the study medications
Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed)
Current use of coumadin
History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions
History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm3 or hgb <10 g/dL
Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment

7. Angiographic Inclusion Criteria
The presence of least 1 acute infarct artery target vessel* in which:
a) ALL significant lesions are eligible for stenting with study stents, and
b) ALL such lesions have a visually estimated reference diameter ≥2.25 mm and ≤4.0 mm
Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal tortuosity or severe calcification)
Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked calcification)
*Arteries containing multiple lesions may be randomized if all lesions are study stent eligible; multiple vessels may be randomized if all lesions in each vessel are study stent eligible

8. Angiographic Exclusion Criteria
Bifurcation lesion definitely requiring implantation of stents in both the main vessel + side branch
Infarct related artery is an unprotected left main
>100 mm of study stent length anticipated
Infarction due to stent thrombosis, or infarct lesion at the site of a previously implanted stent
High likelihood of CABG within 30 days anticipated

9. Study Medications (i) Unfractionated heparin Bivalirudin
60 U/kg IV*; subsequent boluses titrated by nomogram to ACT secs; terminated at procedure end unless prolonged antithrombin needed
Bivalirudin
Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)
Glycoprotein IIb/IIIa inhibitors
Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm
Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abcx) or 12-18 (eptif)
* If pre randomization UFH administered, ACT is checked first
** If pre randomization UFH administered, started 30’ after last bolus

10. Study Medications (ii)
Aspirin
324 mg chewed non enteric coated or 500 mg IV in the ER, followed by mg/day in-hospital and mg/day as out patient indefinitely
Thienopyridines
Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended)
Ticlopidine load + daily dose permissible if clopidogrel is unavailable or patient is allergic
Other
Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF <40%; Statin if LDL >100 mg/dl

11. 2 Primary Stent Endpoints (at 12 Months)
1) Ischemia-driven TLR*
and
2) Composite Safety MACE = All cause death, reinfarction, stent thrombosis (ARC definite or probable)**, or stroke
Major Secondary Endpoint (at 13 Months)
Binary angiographic restenosis
* Related to randomized stent lesions (whether study or non study stents were implanted);
** In randomized stent lesions with ≥1 stent implanted (whether study or non study stents)

12. Statistical Methodology
Second randomization stratification
Results from the first randomization
Presence of medically treated diabetes mellitus
Presence of any lesion >26 mm in length (requiring overlapping stents by protocol)
U.S. vs. non-U.S. site
Primary analysis conducted in the ITT cohort using Kaplan-Meier methodology, with the groups compared by log-rank
1-sided α=0.025 for NI; 2-sided α=0.05 for Sup

13. With angiographic FU in 1,125 randomized pts (analyzable)
Power Analysis
With 2,850 pts randomized 3:1*
Assumed event rates
One Year
Test
EXPRESS
TAXUS 
Power
Ischemic TLR
Superiority
9.0%
5.0% -
95%
Composite Safety MACE
Noninferiority
7.5%
3.0%
80%
With angiographic FU in 1,125 randomized pts (analyzable)
Assumed event rates
13 Months
Test
EXPRESS
TAXUS 
Power
Restenosis
Superiority
26.0%
15.6% -
96%
* Assumed 5% withdrew or lost to FU at 1 year → 3000 randomized

14. Study Organization Sponsor: The Cardiovascular Research Foundation
Grant Support: Boston Scientific Corporation (unrestricted) The Medicines Company
Principal Investigator: Gregg W. Stone MD
Steering Committee: Gregg W. Stone (Chair), Bruce R. Brodie, David A. Cox, Cindy L. Grines, Barry D. Rutherford
European Steering H Bonnier, A Colombo, Eulogio Garcia, Committee: E Grube, G Guagliumi, A Kastrati, P Serruys, H Suryapranata
Additional Country Y Almagor, A Banning, J Belardi, D Dudek, Leaders: L Grinfeld, K Huber, D Nilsen, G Olivecrona, L Rasmussen
Pharmacology Deepak Bhatt, George Dangas, Fred Feit, Committee: Magnus Ohman

15. Study Organization
Data Management: CRF, Roxana Mehran (Director), Lynn Vandertie, Louise Gambone (Ops), Allison Kellock (Programming), Helen Parise (Stats)
Clinical Events Committee: CRF, S. Chiu Wong (Chair)
Site and Data Monitoring: J. Tyson and Associates (USA), Premier (Europe), Tango (S.A.)
Angiographic Core Lab: CRF, Alexandra Lansky (Director), Ecaterina Cristea (Ops)
ECG Core Lab: CRF, James Reiffel (Director)
IVUS Core lab: CRF, Akiko Maehara (Director)
DSMB: Bernhard Gersh (Chair), David Faxon, Spencer King, Stuart Pocock, David Williams

16. The Cardiovascular Research Foundation (CRF) HORIZONS-AMI Team
Sponsored by CRF
The Cardiovascular Research Foundation (CRF) HORIZONS-AMI Team

17. Horizons Enrollment - Centers
3,602 pts randomized at 123 centers in 11 countries
between March 25th, 2005 and May 7th, 2007
(2) Norway
(3) Netherlands
Poland (9)
(6) UK
Germany (16)
Austria (5)
USA (57)
Israel (10)
(1) Spain
Italy (2)
Argentina (12)

18. Top 20 Enrolling Sites 1. B. Witzenbichler, Germany
2. G. Guagliumi, Italy
3. J. Peruga, Poland
4. B. Brodie, USA
5. R. Kornowski, Israel
6. F. Hartmann, Germany
7. M. Moeckel, Germany
8. A. Ochala, Poland
9. W. Ruzyllo, Poland
10. V. Guetta, Israel
11. H. Suryapranata, Netherlands
12. K. Huber, Austria
13. J. Wöehrle, Germany
14. C. Metzger, USA
15. M. Desaga, Germany
16. K. Zmudka, Poland
17. J. Kochman, Poland
18. D. Nilsen, Norway
19. D. Dudek, Poland
20. A. Finkelstein, Israel

19. Harmonizing Outcomes with Revascularization and Stents in AMI
UFH + GPI (n=1802)
Bivalirudin (n=1800)
3602 pts with STEMI R
1:1
Primary Medical Rx 193
Primary CABG 62
Deferred PCI 2
Index PCI, not eligible
- PTCA only 119
- Stented 220
3006 pts eligible for stent rand.
TAXUS DES
N=2257
EXPRESS BMS
N=749
Randomized
1 year FU
N=2186
(96.9%)
N=715
(95.5%)
• • • Withdrew • • •
• • • Lost to FU • • • 18 53 7 27 R
3:1
93.1% of all stented pts were randomized

20. Baseline Characteristics (i)
TAXUS
(N=2257)
EXPRESS
(N=749)
Age (years)
59.9 [52.4, 69.4]
59.3 [51.8, 69.2]
Male
77.0%
76.0%
Diabetes
16.1%
15.2%
Hypertension
51.2%
51.9%
Hyperlipidemia
42.2%
41.1%
Current smoking
46.3%
Prior MI
9.1%
10.9%
Prior PCI
9.5%
7.7%
Prior CABG
2.2%
1.9% *
*P=0.009

21. Baseline Characteristics (ii)
TAXUS
(N=2257)
EXPRESS
(N=749)
Weight (kg)
80 [71, 90]
Killip class 2-4
8.8%
8.0%
Anterior MI
42.2%
44.7%
LVEF (%), site
50 [44, 59]
50 [43, 58]
Symptoms – PCI, hrs
3.7 [2.7, 5.5]
3.8 [2.7, 5.8]
Femoral a. access
93.6%
92.9%
Venous access
8.5%
Closure device
30.1%
28.8%
Aspiration catheter
11.4%
10.7%

22. Study Drugs TAXUS (N=2257) EXPRESS (N=749) Aspirin at home 22.7% 20.5%
Aspirin load pre PCI
97.0%
97.2%
Thienopyridine at home
2.1%
2.5%
Thienopyridine loading dose
98.9%
98.3%
- clopidogrel 300 mg
34.2%
35.5%
- clopidogrel 600 mg
63.3%
61.3%
- clopidogrel other
1.2%
1.3%
- ticlopidine
0.5%
0.3%
UFH pre randomization
65.2%
65.8%
UFH as the procedural antithrombin
49.8%
50.1%
Bivalirudin administered
50.7%
50.9%
GP IIb/IIIa inhibitor administered
52.0%
51.5%

23. Procedural Data (Site Reported)
TAXUS
(N=2257, L=2495)
EXPRESS
(N=749, L=815)
N lesions treated
1.1 ± 0.4
- ≥ 2 lesions treated
11.1%
9.0%
- ≥ 2 vessels treated
4.5%
3.1%
Direct stenting attempted
30.4%
33.7%
Stent target lesion:
LAD, LCX, RCA, LM, SVG
40.1%, 14.6%, 45.1%, 0.3%, 0.3%
42.4%, 15.9%, 41.3%, 0.4%, 0.4%
N stents implanted
1.5 ± 0.9
1.4 ± 0.7
Total stent length**
30.8 ± 17.8
27.3 ± 14.9
Max balloon dia. (mm)
3.00 [2.75, 3.50]
3.00 [2.90, 3.50]
Max pressure (atm.)
14.0 [12.0, 16.0] * **
*P=0.002; **P<0.0001

24. Quantitative Coronary Angiography
TAXUS
(L=2642, V=2353)
EXPRESS
(L=857, V=771)
Pre RVD (mm)
2.89 ± 0.51
2.90 ± 0.50
Pre MLD (mm)
0.35 ± 0.45
Pre %DS
87.6 ± 15.4
87.4 ± 15.4
Pre lesion length (mm)
17.5 ± 10.1
16.2 ± 8.8
Pre TIMI 0/1, 2, 3
60.6%, 13.6%, 25.7%
57.4%, 15.2%, 27.4%
Post RVD (mm)
2.93 ± 0.51
2.95 ± 0.50
Post MLD (mm)*
2.36 ± 0.55
2.37 ± 0.52
Post %DS*
19.9 ± 11.6
19.5 ± 11.1
Acute gain (mm)**
2.04 ± 0.64
2.05 ± 0.62
Post TIMI 0/1, 2, 3
1.7%, 10.7%, 87.6%
0.9%, 9.3%, 89.8% †
*Analysis segment, all lesions, whether stented or not; **stented lesions only; †P=0.006

25. Aspirin and Thienopyridine Use
Regular* aspirin use (%)
Regular* thieno. use (%)
99.1%
98.5%
99.4%
98.3%
98.7%
97.5%
94.7%
98.6%
98.3%
98.9%
97.5%
97.8%
97.1%
73.1%
87.5%
P<0.001
Antiplatelet agent use (%)
63.9%
P<0.001
*Taken >50% of days since last visit

26. Primary Efficacy Endpoint: Ischemic TLR10
Diff [95%CI] =
-3.0% [-5.1, -0.9]
HR [95%CI] =
0.59 [0.43, 0.83]
P=0.002
TAXUS DES (n=2257) 9
EXPRESS BMS (n=749) 8
7.5% 7 6
Ischemic TLR (%) 5
4.5% 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
TAXUS DES
2257
2132
2098
2069
1868
EXPRESS BMS
749
697
675
658
603

27. Secondary Efficacy Endpoint: Ischemic TVR10
Diff [95%CI] =
-3.0% [-5.2, -0.7]
HR [95%CI] =
0.65 [0.48, 0.89]
P=0.006
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
8.7% 9 8 7 6
5.8%
Ischemic TVR (%) 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
TAXUS DES
2257
2119
2078
2045
1848
EXPRESS BMS
749
695
669
650
598

28. Primary Safety Endpoint: Safety MACE*10
TAXUS DES (n=2257) 9
EXPRESS BMS (n=749)
8.1% 8
8.0% 7 6
Diff [95%CI] =
0.1% [-2.1, 2.4]
HR [95%CI] =
1.02 [0.76, 1.36]
PNI=0.01
PSup=0.92
Safety MACE (%) 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
TAXUS DES
2257
2115
2086
2057
1856
EXPRESS BMS
749
697
683
672
619
* Safety MACE = death, reinfarction, stroke, or stent thrombosis

29. One-Year All-Cause Mortality5
TAXUS DES (n=2257)
EXPRESS BMS (n=749) 4
3.5%
3.5% 3
Mortality (%) 2
HR [95%CI] =
0.99 [0.64,1.55]
P=0.98 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
TAXUS DES
2257
2180
2161
2147
1949
EXPRESS BMS
749
716
712
702
648

30. One-Year Death or Reinfarction
Death or MI (%) 1 2 3 4 5 6 7 8
Time in Months 9 10 11 12
2257
2140
2110
2083
1882
749
703
689
678
625
Number at risk
TAXUS DES
EXPRESS BMS
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
7.0%
6.8%
HR [95%CI] =
0.97 [0.70,1.32]
P=0.83

31. Stent Thrombosis (ARC Definite or Probable)
2238
2122
2098
2078
1884
744
701
694
683
629
Number at risk
TAXUS DES
EXPRESS BMS
Stent Thrombosis (%) 1 2 3 4
Time in Months 5 6 7 8 9 10 11 12
TAXUS DES (n=2238)
EXPRESS BMS (n=744)
3.4%
3.1%
HR [95%CI] =
0.92 [0.58,1.45]
P=0.72

32. Stent Thrombosis Rates*
TAXUS
(N=2238)
EXPRESS
(N=744)
Hazard ratio
[95%CI]
P Value
Stent thrombosis, ≤30 days
2.3%
2.7%
0.87 [0.52,1.46]
0.60
- ARC definite
1.9%
0.83 [0.47,1.45]
0.51
- ARC probable
0.5%
0.4%
1.11 [0.31,4.05]
0.87
Stent thrombosis, >30d – 1y
1.0%
0.7%
1.39 [0.52,3.68]
0.9%
1.25 [0.47,3.35]
0.65
0.1% 0% -
0.42
Stent thrombosis, ≤1 year
3.1%
3.4%
0.92 [0.58,1.45]
0.72
2.6%
3.0%
0.86 [0.53,1.41]
0.55
1.33 [0.38,4.73]
*Kaplan-Meier estimates

33. One Year Composite Safety Endpoints*
TAXUS
(N=2257)
EXPRESS
(N=749)
HR [95%CI]
P Value
Safety MACE**
8.1%
8.0%
1.02 [0.76,1.36]
0.92
Death, all-cause
3.5%
0.99 [0.64,1.55]
0.98
- Cardiac
2.4%
2.7%
0.90 [0.54,1.50]
0.68
- Non cardiac
1.1%
0.8%
1.32 [0.54,3.22]
0.55
Reinfarction
3.7%
4.5%
0.81 [0.54,1.21]
0.31
- Q-wave
2.0%
1.9%
1.07 [0.59,1.94]
0.83
- Non Q-wave
1.8%
0.68 [0.39,1.17]
0.16
Stent thrombosis†
3.1%
3.4%
0.92 [0.58,1.45]
0.72
- ARC definite
2.6%
3.0%
0.86 [0.53,1.41]
- ARC probable
0.5%
0.4%
1.33 [0.38,4.73]
0.65
Stroke
1.0%
0.7%
1.52 [0.58,4.00]
0.39
*Kaplan-Meier estimates; **Primary safety endpoint; †ARC definite or probable

34. Angiographic Follow-up
1800 consecutive eligible pts assigned to 13 month angiographic FU*
TAXUS DES
N=1348
EXPRESS BMS
N=452
Randomized 40
• • • Died before angio FU • • • 11
Eligible
N=1308
N=441
366
• Angio FU not performed •
134
Completed
Angio FU
N=942
(72.0%)
N=307
(69.6%) 28 3
• • Not received/analyzable • •
• • • • Out of window • • • • 14
Analyzed
N=911
1081
• • • Lesions • • •
332
N=293
* Randomized in stent arm; stent procedure successful (DS <10%, TIMI-3 flow, ≤NHLBI type A peri-stent dissection); no stent thrombosis or CABG w/i 30 days

35. Follow-up QCA TAXUS (L=1081, V=964) EXPRESS (L=332, V=302) P value
TIMI flow
- 0/1
2.8%
3.6%
0.45
- 2
7.0%
5.0%
0.22
- 3
90.2%
91.4%
0.55
FU RVD (mm)
2.91 ± 0.49
2.90 ± 0.48
0.97
FU MLD in-stent (mm)
2.36 ± 0.75
1.98 ± 0.82
<0.0001
FU MLD in-segment (mm)
2.08 ± 0.69
1.84 ± 0.76
FU %DS in-stent
18.8 ± 22.9
32.6 ± 24.9
FU %DS in-segment
28.8 ± 19.6
37.4 ± 22.0
Aneurysm
0.5%
0.9%
0.40
Ulcerated
0.6%
0.67
Ectasia
0.7%
0.73

36. Binary Analysis Segment Restenosis at 13 Months Patient and Lesion Level Analysis*
RR [95%CI] =
0.44 [0.33, 0.57]
P<0.0001
RR [95%CI] =
0.44 [0.33, 0.57]
P<0.0001
Major 2 endpoint
* ITT: Includes all stent randomized lesions, whether or not a stent was implanted, and whether or not non study stents were placed
** Any lesion with restenosis  per pt restenosis

37. Angiographic Late Loss at 13 Month Lesions with Stents Implanted
± 0.70
P<0.0001
± 0.64
P = 0.07
± 0.64
P = 0.18
± 0.56
± 0.50
± 0.47
± 0.54
± 0.42

38. Binary Angiographic Restenosis at 13 Months Lesions with Stents Implanted
RR [95%CI] =
0.39 [0.29, 0.52]
P<0.0001
RR [95%CI] =
0.42 [0.32, 0.54]
P<0.0001
P = 0.42
P = 0.13

39. Limitations Open label design
Potential bias was mitigated by high protocol procedure compliance and use of blinded clinical event adjudication committees and core laboratories
Underpowered for stent thrombosis and death
The virtually identical rates of MACE in the TAXUS and EXPRESS groups makes it unlikely that major safety differences exist favoring either stent type at 1-year

40. Conclusions
In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary stenting, the implantation of paclitaxel-eluting TAXUS stents compared to bare metal EXPRESS stents resulted in:
A significant 41% reduction in the 1-year primary efficacy endpoint of ischemia-driven TLR, and a significant 56% reduction in the 13 month major secondary efficacy endpoint of binary restenosis
Non inferior rates of the primary composite safety endpoint of all cause death, reinfarction, stent thrombosis or stroke at 1-year

41. Conclusions
The long-term safety and efficacy profile of paclitaxel-eluting TAXUS stents compared to bare metal EXPRESS stents in STEMI will be determined by the ongoing 5 year follow-up of patients randomized in the HORIZONS-AMI trial