Complex Coronary Intervention in the DrugEluting Stent Era

1
Complex Coronary Intervention in theDrug-Eluting
Stent Era
2
Two Very Different Drugs

• Sirolimus
• Antibioticanti-inflammatory
• Cytostatic
• Local toxicitynon issue

• Paclitaxel
• Chemotherapeutic
• Cytotoxic
• Dose-relatedlocal toxicity

3
The Lower the Late Loss, the BetterLess
Neointimal Hyperplasia Is Better
Stent A vs Stent B
Amount of obstruction drives clinical outcomes
0.40 mm ? 0.50
0.20 mm ? 0.50
B
A
LL B
LL A
Late Loss (LL)
Percentage of patients with significant
obstruction
Perin E. J Invasive Cardiol. 2004 16 (Suppl F).
4
CYPHER and Taxus In-Stent Late Loss 6- to
9-Month Follow-Up
83
83
58
100
61
1.0
1.2
1.04
1.00
0.80
0.79
1.0
0.92
0.8
0.8
0.6
Control
mm
0.6
DES
0.4
0.39
0.4
0.31
0.2
0.18
0.17
0.2
0.0
0
0
SIRIUS
NEW SIRIUS
TAXUS IV
RAVEL
TAXUS II
6 MO F/U
8/9 MO F/U
Pooled data from E-SIRIUS C-SIRIUS Trials,
9-month follow-up.
Perin E. J Invasive Cardiol. 200416 (Suppl F).
5
CYPHER and TaxusPercent Volume Obstruction
97
98
59
95
66
40
40
36.7
34.2
35
35
29.4
28.6
30
30
25
25
23.2
Control
Percent ()
DES
20
20
15
15
12.2
10
10
7.8
5
5
2.6
1.2
1.4
0
0
SIRIUS
NEWSIRIUS
TAXUS IV
RAVEL
TAXUS II
6 MO F/U
8/9 MO F/U
Pooled data from E-SIRIUS C-SIRIUS Trials,
9-month follow-up.
Perin E. J Invasive Cardiol. 200416 (Suppl F).
6

• MACE Rates AcrossAll Major DES Stent Trials

12 Months
9 Months
9 Months
18
16.4
16
14
12
10.9
10.8
10
MACE Rates ()
8.3
8.0
7.9
8
5.8
6
4.9
4
2
0
DIRECT
TAXUS IV
TAXUS II
SIRIUS
NewSIRIUS
RAVEL
TAXUS VI
SVELTE
n225
n533
n120
n225
n131
n662
n219
n101
Taxus Moderate Release not commercially
available.
vs 22.5 control not statistically significant
(P0.12)
Zidar J. TCT. 2004.
7
Relationship Between Late Loss andVessel
Diameter Determines Restenosis Rate
100
90
80
70
60
Constant Late Loss
Restenosis Rate ()
50
40
30
20
10
0
1.5
2
2.5
3
3.5
4
Post-procedure MLD (mm)
Presented at American College of Cardiology 52nd
Annual Scientific Session March 30April 2,
2003 Chicago, IL. Kuntz R.
8
Small Vessels In-Stent Late Loss
1.2
1.01
0.99
0.97
0.93
1.0
0.91
0.85
0.8
In-Stent Late Loss (mm)
0.6
0.35
0.4
0.22
0.21
0.20
0.16
0.2
0
RAVEL
SIRIUS
New SIRIUS8 mos
SES-SMART8 mos
SVELTE
TAXUS IV
6 mos
8 mos
8 mos
8 mos
Smallest Tercile
Bare-metal Control
Perin E. J Invasive Cardiol. 200416 (Suppl F).
9
Diabetes Is a Predictor of Late LossFollowing
Stenting
Late Loss vs of Diabetics inBare (non-DES)
Stent Study
30
1.00
0.98
25
0.97
0.83
1.19
0.93
0.8
20
0.9
Percent of Diabetics in the study
15
0.6
0.54
0.7
10
5
0
0
0.5
1
1.5
Late Loss (mm)
Kuntz R. Personal communication.
10
Percent Reduction in 12-Month TLR with CYPHER vs
Bx Velocity by Lesion Length, Vessel Size, and
Diabetic Status
SIRIUS Trial
Lesion Length lt12 mm 12 - 15 mm gt15
mm Non-Diabetics RVD gt3.0
mm 78.5 78.1 77.5 2.5 mm RVD lt3.0
mm 77.6 77.1 76.2 RVD lt2.5 mm 76.6 76.0 74.7 Di
abetics RVD gt3.0 mm 77.2 76.7 75.6 2.5
mm RVD lt3.0 mm 75.8 75.0 73.4 RVD lt2.5
mm 74.1 73.1 71.0
RVD, reference-vessel diameter.
Holmes D et al. Circulation. 2004109634.
11
DIRECT Diabetic Analysis Target Lesion
Revascularization

12
DIRECT
10
SCAC
8.0
8
P0.51
P1.00
Percent ()
6
3.8
3.7
4
P1.00
2
1.0
0.6
0.0
0
Non DM
Non-insulin-dependentdiabetics
Insulin-dependentdiabetics
n 155 307 54 80 16 25
Presented at the American College of Cardiology
Annual Scientific Session March 7-10, 2004 New
Orleans, LA. Moses JW for DIRECT Pis.
12
DIABETES Trial9-Month Follow-Up 92 Compliance
CYPHER
BMS
P value
All Diabetics
In-stent Late Loss (mm)
0.08 mm
0.66 mm
lt0.0001
In-segment Restenosis ()
7.7
33
lt0.0001
MACE()
36.3
lt0.0001
11.3
TLR ()
7.5
31.3
lt0.0001
Insulin-Dependent Diabetics
In-stent Late Loss (mm)
0.0 mm
0.5 mm
lt 0.0001

• Study Conclusions
• CYPHER is effective in significantly reducing
  late loss and restenosis in diabetics, as
  compared to BMS
• IDDMs had the same degree of reduction as
  compared to those treated with oral agents

Cardiac death, MI, and TLRSabate. TCT. 2004.
13
Integrated Analysis of CYPHER Trials Diabetics
Control233
Sirolimus292
Plt0.0001
Plt0.0001
24.0
63
74
22.3
9-Month Event ()
8.9
5.8
TVR
TLR
Integrated analysis of SIRIUS, New SIRIUS,
DIRECT, SVELTE, RAVEL Trials. Control is
bare-metal stents.
Moussa. TCT. 2004.
14
BRIDGE Diabetic Registry CYPHER 360-Day
Adverse Events
n479 Patients (83 Follow-Up Compliance)
12
10.2
10
8
6.2
Percent ()
6
3.1
4
2
0
MACE (n49)
Death (n15)
Cardiac Death(n9)
Non-Cardiac Death(n6)
MI(n6)
QMI(n3)
NonQMI (n3)
TLR(n30)
CABG(n6)
Commeau. TCT. 2004.
15
e-CYPHERSM Registry Diabetics
6-Month Follow-Up in Diabetes n3171 / 3669
Eligible Patients (86)
10
8
6
4.60
4
1.77
1.67
2
0.95
0.54
0.48
0.47
0
Card
Other
Q AMI
NQ AMI
TLR
TVR
MACE
Death
Death
All cases with reported death, AMI, TLR or stent
thrombosis were reviewed and adjudicated by CEC
Guagliumi. TCT. 2004.
16
Long DES Study CYPHER vs Taxus
Plt0.001
Plt0.001
1.00
25
21.3
0.90
0.78
0.80
20
0.70
15
0.60
0.50
0.40
10
7.4
0.27
0.30
0.20
5
6 mos
6 mos
0.10
0.00
0
In-stent Late Loss (mm)
In-Segment Restenosis
P0.387
P0.140
8
6
5.4
7
5
6.0
6
4
5
2.7
4
3
3.4
3
2
2
1
1
7 mos
7 mos
0
0
MACE
TLR
CYPHER Stent
Taxus Stent
Park. TCT. 2004.
17
Long Lesions 30-Day MI Rates in DES Trials
TAXUS VI moderate release
Long lesion tercile analysis of CYPHER Stent
trials
30-Day MI Rates
8.2
8
6
5.1
MI Rates ()
4
1.3
1.3
2
0.0
0
TAXUS VI
SVELTE
DIRECT
New SIRIUS
SIRIUS
n219
n34
n75
n75
n175
LL 20.6 mm
LL 22.5 mm
LL 19.0 mm
LL 20.9 mm
LL 20.7 mm
Longest tercile Taxus Moderate Release used in
TAXUS VI not commercially available. Zidar J.
TCT. 2004.
18
Covariate Adjusted Predictors of Mortality
Following MultivesselCoronary Revascularization
0 1.0 2.0 3.0 4.0 5.0
872 PCI vs 5161 CABG Brener SJ et al.
Circulation. 20041092290.
19
ARTS II MACE-Free Survival
Serruys. TCT. 2004.
20
ARTS II Revascularization-Free Survival
100
ARTS II CYPHER
97.3
95
94.5
ARTS I CABG
90
85
84.7
ARTS I PCI
Event-free survival ()
80
75
70
65
60
0
30
60
90
120
150
180
Time (days) since procedure
Serruys. TCT. 2004.
21
e-CYPHERSM Registry SVG6-Month MACE
6.40
CEC-Adjudicated Events
5
4
3.10
3
2.46
Percent ()
1.97
2
1.23
1.06
0.99
0.99
0.95
1
0.49
0.36
0.33
0
MACE
Cardiac
Non Cardiac
MI
QMI
TLR
Death
Death
Non SVG (10,956)
SVG (203)
Gershlick. TCT. 2004.
22
The RESEARCH RegistryCYPHER Acute MI Sub-Study
Cumulative Incidence of Death, MI, or TVR
Lee. ESC. 2003.
23
The STENT Registry
3-Month Outcomes
STEMI
20
15.3
PNS
DES (n137)
15
BMS (n196)
10.9
of Patients
10
PNS
5
2.0
1.0
0.7
0
0
Stent Thrombosis
MACE
TVR
MACE death, MI, CABG, TVR Simonton. TCT. 2004.
24
e-CYPHERSM Registry AMI 6-Month MACE
4.90
5
CEC-Adjudicated Events
4
3.10
3
2.25
Percent ()
2
1.62
1.50
1.23
0.96
0.93
0.75
1
0.37
0.34
0
0
MACE
Cardiac
Non Cardiac
MI
QMI
TLR
Death
Death
Non AMI (10,358)
AMI (801)
Gershlick. TCT. 2004.
25
HORIZONS Taxus AMI Trial
3400 Randomized Patients Undergoing Primary PCI
Use of bivalirudin bail-out IIb/IIIa will
reduce the composite rate of death, reinfarction,
TVR, disabling stroke and major bleeding at
30-days
Anti-thrombotic therapy
Randomize 11
UFH IIb/IIIa inhibitor
Bivalirudin bail-out IIb/IIIa
Use of the Taxus PTx-eluting Liberté stent will
safely reduce the 1-year rate of ischemia-driven
TVR
Target vessel stenting
Randomize 12
Uncoated Liberté stent
Taxus Liberté stent
Immediate stenting of all diseased vessels will
safely reduce the 1-year rate of any
revascularization and re-hospitalization
Complete revascularization
Randomize 11
SponsorBoston Scientific Co-sponsor The
Medicines Co.
Standard staged DES
Immediate multivessel DES
26
SICTO CYPHER Events to 12 Months
27
e-CYPHERSM Registry CTO 6-Month MACE
Other (n11,159)
CTO (n362)
4
3.3
3.2
3
Percent ()
2
1.5
1.4
1.4
1.3
1.0
0.8
1
0
MACE
Death
MI
TLR
CTO was defined as chronic total occlusion gt3
months. Lotan. TCT. 2004.
28
TAXUS III Clinical TrialIn-Stent Restenosis
Feasibility
28 out of 30 patients available for follow-up
Preliminary Results 30-day 6-month 12-month MACE 3
.6 28.6 28.6 MI (Q nonQ-wave) 3.6 3.6 3.6
TVR (non-target lesion) 0 0 0 TLR 0 21.4 21.
4 CABG 0 3.6 3.6 Death 0 0 0 Stent
Thrombosis 0 0 0
29
TROPICALCYPHER Clinical Outcome at 270 Days
Plt0.0001
35
TROPICAL
Plt0.001
29.7
GAMMA I/II
30
25.0
25
20
P0.001
Non-Hierarchical Event Rate ()
15
10.9
P0.041
P0.660
10
6.2
4.7
4.9
5
2.3
1.9
1.2
0.6
0
Clinically-drivenTLR
Death
MI
Stent
Total MACE
thrombosis
Neumann. TCT. 2004.
30
ISAR-DESIRE TrialCYPHER vs Taxus
P0.006
Taxus
CYPHER
56
0.6
0.48
0.5
0.4
50
0.3
0.21
0.2
40
Pn/s
0.1
6 mos
30
Percent ()
22
0
Late Loss (mm)
20
14
P0.02
25
10
6 mos
19
20
58
0
Restenosis
15
Percent ()
10
8
5
9 mos
0
TVR
Kastrati. ESC. 2004.
31
e-CYPHERSM RegistryIn-Stent Restinosis
6-Month MACECEC-Adjudicated Events (N10,962
86)
4.00
4
3.10
Non-ISR (n9563)
3
ISR (n1399)

2.07
Percent ()
2
1.14
1.11
0.98
1
0.71
0.63
0.36
0.37
0.38
0.14
0.14
0.14
0
Cardiac
Other
Q MI
NQ MI
TLR PCI
TLR
MACE
Death
Death
CABG
P0.0005 Urban. ESC. 2004.
32
Low Repeat Revascularization RatesFollowing
Drug-Eluting Stent Implantationin De Novo
Bifurcation Lesions
Treatment with SES period 04/02-04/03
Treatment with PES period 03/03-09/03
MACE-free
100
60
55
90
48
CYPHER n123
38
40
Percent ()
80
28
27
27
Percent ()
18
TAXUSTM n71
20
14
8
70
4
0
60
P0.03
Crush
Crush
T-stent
T-stent
Culotte
Culotte
Kissing Balloon post
Kissing balloon post
Kissing stent
Kissing stent
0
3
6
9
Stenting technique
Follow-up (months)
Both the SES and PES used for de novo
bifurcation lesions demonstrate a low rate of
target vessel revascularization (TVR). Ensuring
complete lesion coverage with drug-eluting stents
may further reduce restenosis, particularly at
the ostium of the side branch
Presented at American College of Cardiology 53rd
Annual Scientific Session March 710, 2004 New
Orleans, LA. Hoye A, Lemos PA, Tanabe K, et al.
33
Overlapping CYPHER Stents
TLR
100

• 28.5 of patients in SIRIUS received overlapping
  stents
• 35 of patients in New SIRIUS received
  overlapping stents
• SAT comparable to control (0.6 in each arm)

Sirolimus
Control
80
60
Percent ()
93
85
38.0
40
?
?
26.4
20
3.9
2.5
0
SIRIUS (2 yr)
New SIRIUS (1 yr)
Moses JW et al for the DIRECT Investigators.
Presented at American College of Cardiology
Annual Scientific Session March 7-10, 2004 New
Orleans. LA.
34
Morphologic Differences in Surface
Endothelialization, Percentage of Struts
Surrounded by Fibrin, and InflammationOverlappin
g Segment in Rabbit Iliac Arteries at 28 Days
Greater inflammation and less endothelialization
with Taxus stentat overlap site
Vermani R. EuroPCR. 2004.
35
Overlapping Stents 30-Day MI Rates in DES Trials

• Taxus Stent (slow release)
• No data available
• awaiting TAXUS V

• CYPHER Stent
• SIRIUS
• New SIRIUS
• SVELTE
• DIRECT

30-Day MI Rates
9.0
7.9
All bare-metal control groups ?4.2
7.0
5.0
3.5
MI Rates ()
3.0
CTRL
1.6
1.4
1.0
0.0
0.0
TAXUS VI
SIRIUS
New SIRIUS
DIRECT
SVELTE
-1.0
n15
n79
n70
n173
n63
LL 17.6 mm
LL 17.9 mm
LL 17.5 mm
LL 18.3 mm
LL 25.1 mm
Taxus is slow release formulation. Taxus
Moderate Release used in TAXUS VI not
commercially available.Control is bare-metal
stents. J Zidar. TCT. 2004.
36
Conclusions

• Sirolimus and paclitaxel show lower late loss,
  less neointimal hyperplasia, superior results
• SVELTE 1-year results SES in small arteries
  excellent(3.0 of TLR) proper technique
  minimizes neointimal hyperplasia and restenosis
  rate implantation may lead to less variability
  in neointimal response significantly reduces
  late loss and restenosis in diabetics compared to
  BMS
• DESs safe, with less in-segment and in-stent late
  loss (paclitaxel) lower late loss (sirolimus)
  and lower restenosis rate (for sirolimus compared
  with paclitaxel) despite smaller post-procedure
  MLD

37
Conclusions

• SES safe for unselected pts w/STEMI compared to
  conventional stents (RESEARCH Registry)
• SICTO showed SES effective in treatment of CTO
  with low rates of TLR, MACE, TVR compared to
  historical data on bare stents and signficantly
  inhibits intimal hyperplasia in CTO
• TROPICAL demonstrated in-stent restenosis SES
  highly efficacious, reducing angiographic
  restenosis and TLR substantially
• ISAR-DESIRE showed strategy based on DESs in
  ptsw/in-stent restenosis superior to plain
  balloon angioplastyfor reduction of recurrent
  restenosis
• DESs in AMI promising in CTO lesions with
  typically longer, more complex morphologies
  appear to have unprecedented long-term patency
  (larger registries needed)