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
 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
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI with symptom onset ≤12 hours
Aspirin, thienopyridine
R
1:1

UFH + GP IIb/IIIa inhibitor Bivalirudin monotherapy

(abciximab or eptifibatide) (± provisional GP IIb/IIIa)

Emergent angiography, followed by triage to…

CABG – Primary PCI – Medical Rx

3000 pts eligible for stent randomization
R
3:1

Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent

Clinical FU at 30 days, 6 months, 1 year, and then

yearly through 5 years; angio FU at 13 months
 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
 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
 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
 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
 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

 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)
 Statistical Methodology
 Second randomization stratification
i. Results from the first randomization
ii. Presence of medically treated diabetes mellitus
iii. Presence of any lesion >26 mm in length
(requiring overlapping stents by protocol)
iv. 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
 Power Analysis
With 2,850 pts randomized 3:1*
Assumed event rates
One Year Test EXPRESS TAXUS δ Power
Ischemic TLR Superiority 9.0% 5.0% - 95%

Composite
Noninferiority 7.5% 7.5% 3.0% 80%
Safety MACE

With angiographic FU in 1,125 randomized pts (analyzable)

Assumed event rates
13 Months Test EXPRESS TAXUS δ Power
Restenosis Superiority 26.0% 15.6% - 96%

* Assumed 5% withdrew or lost to FU at 1 year → 3000 randomized

 Study Organization
 Sponsor:
 Grant Support:
 Principal Investigator:
 Steering Committee:
 European Steering
Committee:
 Additional Country
Leaders:
 Pharmacology
Committee:
The Cardiovascular Research Foundation
Boston Scientific Corporation (unrestricted)
The Medicines Company
Gregg W. Stone MD
Gregg W. Stone (Chair), Bruce R. Brodie, David
A. Cox, Cindy L. Grines, Barry D. Rutherford
H Bonnier, A Colombo, Eulogio Garcia,
E Grube, G Guagliumi, A Kastrati,
P Serruys, H Suryapranata
Y Almagor, A Banning, J Belardi, D Dudek,
L Grinfeld, K Huber, D Nilsen, G Olivecrona,
L Rasmussen
Deepak Bhatt, George Dangas, Fred Feit,
Magnus Ohman
 Study Organization
 Data Management:
 Clinical Events Committee:
 Site and Data Monitoring:
 Angiographic Core Lab:
 ECG Core Lab:
 IVUS Core lab:
 DSMB:
CRF, Roxana Mehran (Director),
Lynn Vandertie, Louise Gambone
(Ops), Allison Kellock (Programming),
Helen Parise (Stats)
CRF, S. Chiu Wong (Chair)
J. Tyson and Associates (USA),
Premier (Europe), Tango (S.A.)
CRF, Alexandra Lansky (Director),
Ecaterina Cristea (Ops)
CRF, James Reiffel (Director)
CRF, Akiko Maehara (Director)
Bernhard Gersh (Chair), David Faxon,
Spencer King, Stuart Pocock, David
Williams
 Sponsored by CRF
The Cardiovascular Research
Foundation (CRF) HORIZONS-AMI Team
 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)
USA (57) Austria (5)
Israel (10)
(1) Spain
Italy (2)

Argentina (12)
 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
Harmonizing Outcomes with Revascularization and Stents in AMI
UFH + GPI (n=1802)
R
Primary Medical Rx 193 3602 pts with STEMI 1:1
Primary CABG 62 Bivalirudin (n=1800)
Deferred PCI 2
Index PCI, not eligible
- PTCA only 119
- Stented 220

93.1% of all stented

3006 pts eligible for stent rand.
pts were randomized
R
3:1

TAXUS DES EXPRESS BMS

Randomized N=2257 N=749
18 • • • Withdrew • • • 7
53 • • • Lost to FU • • • 27

N=2186 N=715
1 year FU
(96.9%) (95.5%)
 Baseline Characteristics (i)
TAXUS EXPRESS
(N=2257) (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% * 51.9%
Prior MI 9.1% 10.9%
Prior PCI 9.5% 7.7%
Prior CABG 2.2% 1.9%
*P=0.009
 Baseline Characteristics (ii)
TAXUS EXPRESS
(N=2257) (N=749)
Weight (kg) 80 [71, 90] 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% 8.0%
Closure device 30.1% 28.8%
Aspiration catheter 11.4% 10.7%
 Study Drugs
TAXUS EXPRESS
(N=2257) (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%
 Procedural Data (Site Reported)
TAXUS EXPRESS
(N=2257, L=2495) (N=749, L=815)

N lesions treated 1.1 ± 0.4 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: 40.1%, 14.6%, 42.4%, 15.9%,

LAD, LCX, RCA, LM, SVG 45.1%, 0.3%, 0.3% 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] 14.0 [12.0, 16.0]
*P=0.002; **P<0.0001
 Quantitative Coronary Angiography
TAXUS EXPRESS
(L=2642, V=2353) (L=857, V=771)
Pre RVD (mm) 2.89 ± 0.51 2.90 ± 0.50
Pre MLD (mm) 0.35 ± 0.45 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
 Aspirin and Thienopyridine Use
Regular* aspirin use (%) Regular* thieno. use (%)

99.1% 98.5% 99.4% 98.7%

98.3% 97.5% 94.7%
Antiplatelet agent use (%)

98.6% 98.3% 97.5% 98.9% 97.8%

97.1% 73.1%
87.5%

P<0.001
63.9%

P<0.001

*Taken >50% of days since last visit

 Primary Efficacy Endpoint: Ischemic TLR
10 TAXUS DES (n=2257)
Diff [95%CI] =
9 EXPRESS BMS (n=749)
Ischemic TLR (%) -3.0% [-5.1, -0.9]
8 HR [95%CI] =
7 0.59 [0.43, 0.83]
7.5%
6 P=0.002
5
4
4.5%
3
2
1
0
0 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
Secondary Efficacy Endpoint: Ischemic TVR
10 TAXUS DES (n=2257)
Diff [95%CI] =
EXPRESS BMS (n=749)
Ischemic TVR (%) 9 -3.0% [-5.2, -0.7] 8.7%
8 HR [95%CI] =
7 0.65 [0.48, 0.89]
6 P=0.006
5.8%
5
4
3
2
1
0
0 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
 Primary Safety Endpoint: Safety MACE*
10 TAXUS DES (n=2257)
9 EXPRESS BMS (n=749)
Safety MACE (%) 8.1%
8
8.0%
7
6
Diff [95%CI] =
5 0.1% [-2.1, 2.4]
4 HR [95%CI] =
3 1.02 [0.76, 1.36]
2 PNI=0.01
1 PSup=0.92
0
0 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

 One-Year All-Cause Mortality
5 TAXUS DES (n=2257)
EXPRESS BMS (n=749)
4
3.5%
Mortality (%)

3
3.5%

2 HR [95%CI] =
0.99 [0.64,1.55]
1 P=0.98

0
0 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
 One-Year Cardiac Mortality
5 TAXUS DES (n=2257)
EXPRESS BMS (n=749)
Cardiac Mortality (%) 4

3
2.7%
2.4%
2
HR [95%CI] =
1 0.90 [0.54,1.50]
P=0.68
0
0 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
 One-Year Death or Reinfarction
8 TAXUS DES (n=2257)

7
EXPRESS BMS (n=749) 7.0%
6.8%
Death or MI (%)
6

4 HR [95%CI] =
0.97 [0.70,1.32]
3
P=0.83
2

0
0 1 2 3 4 5 6 7 8 9 10 11 12

Time in Months
Number at risk
TAXUS DES 2257 2140 2110 2083 1882
EXPRESS BMS 749 703 689 678 625
Stent Thrombosis (ARC Definite or Probable)
4 TAXUS DES (n=2238)
EXPRESS BMS (n=744)
3.4%
Stent Thrombosis (%)
3 3.1%

2 HR [95%CI] =
0.92 [0.58,1.45]
P=0.72
1

0
0 1 2 3 4 5 6 7 8 9 10 11 12

Time in Months
Number at risk
TAXUS DES 2238 2122 2098 2078 1884
EXPRESS BMS 744 701 694 683 629
 Stent Thrombosis Rates*
TAXUS EXPRESS Hazard ratio P
(N=2238) (N=744) [95%CI] Value

Stent thrombosis, ≤30 days 2.3% 2.7% 0.87 [0.52,1.46] 0.60

- ARC definite 1.9% 2.3% 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] 0.51

- ARC definite 0.9% 0.7% 1.25 [0.47,3.35] 0.65

- ARC probable 0.1% 0% - 0.42

Stent thrombosis, ≤1 year 3.1% 3.4% 0.92 [0.58,1.45] 0.72

- ARC definite 2.6% 3.0% 0.86 [0.53,1.41] 0.55

- ARC probable 0.5% 0.4% 1.33 [0.38,4.73] 0.65

*Kaplan-Meier estimates
One Year Composite Safety Endpoints*
TAXUS EXPRESS P
HR [95%CI]
(N=2257) (N=749) Value
Safety MACE** 8.1% 8.0% 1.02 [0.76,1.36] 0.92
Death, all-cause 3.5% 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% 2.7% 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] 0.55
- 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
 Angiographic Follow-up
1800 consecutive eligible pts assigned to
13 month angiographic FU*

Randomized
TAXUS DES EXPRESS BMS
N=1348 N=452
40 • • • Died before angio FU • • • 11

Eligible N=1308 N=441

366 • Angio FU not performed • 134

Completed N=942 N=307

Angio FU (72.0%) (69.6%)
28 • • Not received/analyzable • • 14
3 • • • • Out of window • • • • 0

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
 Follow-up QCA
TAXUS EXPRESS
P value
(L=1081, V=964) (L=332, V=302)
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 <0.0001
FU %DS in-stent 18.8 ± 22.9 32.6 ± 24.9 <0.0001
FU %DS in-segment 28.8 ± 19.6 37.4 ± 22.0 <0.0001
Aneurysm 0.5% 0.9% 0.40
Ulcerated 0.5% 0.6% 0.67
Ectasia 0.7% 0.9% 0.73
Binary Analysis Segment Restenosis at 13 Months
Patient and Lesion Level Analysis*

RR [95%CI] = RR [95%CI] =
0.44 [0.33, 0.57] 0.44 [0.33, 0.57]
P<0.0001 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
Angiographic Late Loss at 13 Month
Lesions with Stents Implanted

P<0.0001
± 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
Binary Angiographic Restenosis at 13 Months
Lesions with Stents Implanted

RR [95%CI] = RR [95%CI] =
0.39 [0.29, 0.52] 0.42 [0.32, 0.54]
P<0.0001 P<0.0001

P = 0.42 P = 0.13
 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
 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
 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