Transcript The Detrimental Impact of Chronic Renal Insufficiency

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
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± 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
Test
EXPRESS
TAXUS

Power
Ischemic TLR
Superiority
9.0%
5.0%
-
95%
Composite
Safety MACE
Noninferiority
7.5%
7.5%
3.0%
80%
One Year
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
Study Organization

Sponsor:
The Cardiovascular Research Foundation

Grant Support:
(unrestricted)
Boston Scientific Corporation
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
Committee:
H Bonnier, A Colombo, Eulogio Garcia,
E Grube, G Guagliumi, A Kastrati,
P Serruys, H Suryapranata

Additional Country
Leaders:
Y Almagor, A Banning, J Belardi, D Dudek,
L Grinfeld, K Huber, D Nilsen, G Olivecrona,
L Rasmussen

Pharmacology
Committee:
Deepak Bhatt, George Dangas, Fred Feit,
Magnus Ohman
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
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
USA (57)
Germany (16)
Austria (5)
Israel (10)
(1) Spain
Italy (2)
Argentina (12)
Top 20 Enrolling Sites
1. B. Witzenbichler, Germany
11. H. Suryapranata, Netherlands
2. G. Guagliumi, Italy
12. K. Huber, Austria
3. J. Peruga, Poland
13. J. Wöehrle, Germany
4. B. Brodie, USA
14. C. Metzger, USA
5. R. Kornowski, Israel
15. M. Desaga, Germany
6. F. Hartmann, Germany
16. K. Zmudka, Poland
7. M. Moeckel, Germany
17. J. Kochman, Poland
8. A. Ochala, Poland
18. D. Nilsen, Norway
9. W. Ruzyllo, Poland
19. D. Dudek, Poland
10. V. Guetta, Israel
20. A. Finkelstein, Israel
Harmonizing Outcomes with Revascularization and Stents in AMI
Primary Medical Rx
193
Primary CABG
62
Deferred PCI
2
Index PCI, not eligible
- PTCA only
119
- Stented
220
93.1% of all stented
pts were randomized
Randomized
3602 pts with STEMI
UFH + GPI (n=1802)
Bivalirudin (n=1800)
3006 pts eligible for stent rand.
R
3:1
TAXUS DES
N=2257
18
53
1 year FU
R
1:1
N=2186
(96.9%)
EXPRESS BMS
N=749
• • • Withdrew • • •
• • • Lost to FU • • •
7
27
N=715
(95.5%)
Baseline Characteristics (i)
TAXUS
(N=2257)
Age (years)
EXPRESS
(N=749)
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
*
51.9%
Baseline Characteristics (ii)
TAXUS
(N=2257)
EXPRESS
(N=749)
80 [71, 90]
80 [71, 90]
Killip class 2-4
8.8%
8.0%
Anterior MI
42.2%
44.7%
50 [44, 59]
50 [43, 58]
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%
Weight (kg)
LVEF (%), site
Symptoms – PCI, hrs
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%
Procedural Data (Site Reported)
TAXUS
(N=2257, L=2495)
EXPRESS
(N=749, L=815)
1.1 ± 0.4
1.1 ± 0.4
- ≥ 2 lesions treated
11.1%
9.0%
- ≥ 2 vessels treated
4.5%
3.1%
30.4%
33.7%
N lesions treated
Direct stenting attempted
Stent target lesion:
LAD, LCX, RCA, LM, SVG
40.1%, 14.6%,
42.4%, 15.9%,
45.1%, 0.3%, 0.3% 41.3%, 0.4%, 0.4%
N stents implanted
1.5 ± 0.9
Total stent length**
30.8 ± 17.8
*
**
1.4 ± 0.7
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
(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
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
Antiplatelet agent use (%)
Regular* aspirin use (%)
99.1%
98.5%
98.3%
97.5%
98.6%
98.3%
97.5%
97.1%
*Taken >50% of days since last visit
Regular* thieno. use (%)
99.4%
98.9%
98.7%
94.7%
97.8%
73.1%
87.5%
P<0.001
63.9%
P<0.001
Primary Efficacy Endpoint: Ischemic TLR
10
9
Ischemic TLR (%)
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
Diff [95%CI] =
-3.0% [-5.1, -0.9]
8
7
HR [95%CI] =
0.59 [0.43, 0.83]
6
P=0.002
7.5%
5
4.5%
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
EXPRESS BMS 749
2132
697
2098
675
2069
658
1868
603
Secondary Efficacy Endpoint: Ischemic TVR
10
9
Ischemic TVR (%)
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
Diff [95%CI] =
-3.0% [-5.2, -0.7]
8
7
HR [95%CI] =
0.65 [0.48, 0.89]
6
P=0.006
8.7%
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
EXPRESS BMS 749
2119
695
2078
669
2045
650
1848
598
Primary Safety Endpoint: Safety MACE*
10
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
Safety MACE (%)
9
8.1%
8.0%
8
7
6
Diff [95%CI] =
0.1% [-2.1, 2.4]
5
HR [95%CI] =
1.02 [0.76, 1.36]
4
3
PNI=0.01
PSup=0.92
2
1
0
0
Number at risk
TAXUS DES
EXPRESS BMS
1
2
3
4
5
6
7
8
9
10
11
12
Time in Months
2257
749
2115
697
2086
683
2057
672
* Safety MACE = death, reinfarction, stroke, or stent thrombosis
1856
619
One-Year All-Cause Mortality
5
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
Mortality (%)
4
3.5%
3.5%
3
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
EXPRESS BMS
2257
749
2180
716
2161
712
2147
702
1949
648
One-Year Death or Reinfarction
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
8
7.0%
6.8%
Death or MI (%)
7
6
5
4
HR [95%CI] =
0.97 [0.70,1.32]
3
P=0.83
2
1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Time in Months
Number at risk
TAXUS DES
EXPRESS BMS
2257
749
2140
703
2110
689
2083
678
1882
625
Stent Thrombosis (ARC Definite or Probable)
Stent Thrombosis (%)
4
TAXUS DES (n=2238)
EXPRESS BMS (n=744)
3.4%
3.1%
3
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
EXPRESS BMS
2238
744
2122
701
2098
694
2078
683
1884
629
Stent Thrombosis Rates*
TAXUS EXPRESS
(N=2238)
(N=744)
Stent thrombosis, ≤30 days
Hazard ratio
[95%CI]
P
Value
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
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
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
Stent thrombosis, >30d – 1y
Stent thrombosis, ≤1 year
*Kaplan-Meier estimates
One Year Composite Safety Endpoints*
TAXUS EXPRESS
(N=2257) (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%
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
1.0%
0.7%
1.52 [0.58,4.00]
0.39
Stroke
*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
N=1348
EXPRESS BMS
N=452
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 • • Not received/analyzable • • 14
3
0
• • • • Out of window • • • •
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
(L=1081, V=964) (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
<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*
TAXUS DES (910 patients, 1081 lesions)
EXPRESS BMS (293 patients, 332 lesions)
Binary Restenosis (%)
40
30
RR [95%CI] =
0.44 [0.33, 0.57]
P<0.0001
RR [95%CI] =
0.44 [0.33, 0.57]
P<0.0001
24.9
22.9
20
10.0
10.9
10
0
Major 2 endpoint
Per Lesion
* 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
Per Patient**
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] =
0.39 [0.29, 0.52]
P<0.0001
P = 0.42
RR [95%CI] =
0.42 [0.32, 0.54]
P<0.0001
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