Transcript Instent Restenosis and Late Stent Thrombosis

Instent Restenosis and Late
Stent Thrombosis
Larry S. Dean, MD, FACC, FSCAI
Professor of Medicine and Surgery
University of Washington School of
Medicine
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Instent Restenosis and Late Stent
Thrombosis
Larry S. Dean MD, FSCAI
The following relationships exist related to this presentation: None
Off label use of products will be discussed in this presentation.
The PTCA Result
The Interventional Tool Box
The Restenosis Cascade
Angioplasty
Vascular Injury
Mechanical Stretch
Thrombus Formation
Endothelial
Disruption
Growth
Factors
SMC Activation
Thrombus Organization
Recoil &
Remodeling
Migration
DNA Synthesis
Proliferation
Restenosis
Modified, Heldman, TCT 2002
Extracellular
Matrix Formation
BMS and Lower Restenosis
Rates
• Intracoronary stents:
o Maximize the geometric result
o Eliminate elastic recoil
o Eliminate negative remodeling
o Promote smooth muscle cell
proliferation
Stenting for Elastic Recoil
Rodriguez, et el. Circulation 1995;91:1397-402
The STRESS Trial: QCA
Stent
PTCA
RD (mm)
3.03
2.99
% Stenosis
75+9
75+8
Post MLD (mm)
2.49
1.99*
F/U MLD (mm)
1.74
1.56*
F/U % Stenosis
42+18
49+19*
Restenosis
31.6%
42.1%*
NEJM. 331;496, 1994
*P<0.05
In-Stent Restenosis
Patterns and Recurrence Rates
Type I
<10mm lesions
Type II
>10mm Intra-stent lesions
Type III
>10mm proliferative lesions
Type IV
Total occlusions
Mehran R et al. Circulation 1999;100:1872-8.
Repeat TVR
BMS Restenosis
Patient Factors
Diabetes mellitus
Vessel Factors
Chronic occlusion
Restenosis after PTCA
Lesion location = LAD
Chronic renal failure
Lesion location = SVG
High serum CRP
High serum IL-6
Small vessel (diameter < 3
mm)
Long lesion (length > 20 mm)
Low serum IL-10
Bifurcation lesion
CCS Class IV angina
Ostial location
Procedure Factors
Smaller post-stent MLD
(diameter < 3 mm)
Multiple stents
Suboptimal stent apposition
and/or stent underexpansion
Stent fracture
Type C lesion
Kim MS, Dean LS, In-Stent Restenosis, Cardiovascular Therapeutics In Press
Management of Instent
Restenosis (ISR)
• POBA
• Atheroablative technology
• Brachytherapy
• Drug eluting stents
Placebo
The
START
Trial
45.2%
 36%
41.2%
8 Month
Angiographic
Restenosis
Sr-90
 66%
28.8%
14.2%
p < 0.001
Popma JJ, et al. Circulation. 2002;106:1090-1096
p = 0.001
Drug Eluting Stents
Control
Paclitaxel
SIRIUS: 9 Month Overall
Outcomes
%
Moses JW, et al. NEJM 2003;349:1315
TAXUS IV Clinical Trial Restenosis at 9 Months
Restenosis (%)
RR=0.23 [0.13, 0.38]
P<0.0001
Stone GS, et al. NEJM 2004;350:221-31.
RR=0.30 [0.19, 0.46]
P<0.0001
DES Restenosis
Patient Factors
Vessel Factors
Procedure Factors
Female gender
Chronic occlusion
Smaller post-stent MLD
Diabetes mellitus
In-stent restenosis
Stent under expansion
CRF on hemodialysis
Bifurcation lesion
Prior MI
Lesion location = LAD
Overdilation of an undersized
stent
Stent fracture
Prior PCI
Small vessel (< 2.75 mm)
Drug resistance or
hypersensitivity
Long lesion (length > 20 mm)
Severe calcification or
tortuosity
Type C lesion
Kim MS, Dean LS In-Stent Restenosis. Cardiovascular Therapeutics In Press
Nonuniform stent expansion
(i.e., altered drug deposition)
TAXUS V ISR Trial: Study Design
396 patients > 18 years with stable or unstable angina or inducible ischemia
undergoing percutaneous coronary intervention (PCI) of a single bare-metal
in-stent restenosis (ISR) lesion in a native coronary artery.
Randomized.
34% female, median age 63 years, mean follow-up 9 months
Angiography (Baseline)
VBT using a beta-source
radiation
n=201
PCI with paclitaxel-eluting
stents
n=195
Repeat Angiography (9 months)
170 in VBT group and 172 in Paclitaxel
group
Primary Endpoint: Ischemia-driven target vessel revascularization at 9
months
Stone GW, et al. JAMA 2006;295:1253
TAXUS V ISR Trial: 9 month Angiography
Binary Restenosis at 9 months
p<0.001
Final post-procedure diameter stenosis
in the analysis segment
Diameter stenosis (%)
Binary restenosis (%)
p<0.001
Management Strategies for
Restenosis
• Class IIA
o It is reasonable to consider that patients who develop
restenosis after PTCA or PTCA with atheroablative devices
are candidates for repeat coronary intervention with
intracoronary stents if anatomic factors are appropriate.
(Level of Evidence: B)
o It is reasonable to perform repeat PCI for ISR with a DES or
a new DES for patients who develop ISR if anatomic factors
are appropriate. (Level of Evidence: B)
o Brachytherapy can be useful as a safe and effective
treatment for ISR. (Level of Evidence: A)
Smith SC, et al. ACC/AHA/SCAI 2005 guideline
update for percutaneous coronary intervention
Stent Thrombosis
How Could this Ever Work?
N = 105
35
32
One Site = 39%
30
24
25
20
%
15
10
7.6
5
0
Death
Serruys, et al. NEJM 1991;324:13
Occluded
Restenosis
Early Stent Outcomes with
Aggressive Anticoagulation
20
18
18
16
15
14
12
10
8.5
8
6
4
5
5
2.5
2
0
0.6
ASA/dipyridamole
Schatz, et al. Circ 1991;83:148
1
0
0.6
ASA/dipyridamole/warfarin
SAT
MI
ECABG
MACE
Bleeding
Intracoronary Stenting:
Standard (Old) Anticoagulation
• ASA 325 mg QD
• Dipyridamole 75 mg TID
• IV heparin until INR 3 to 4 on warfarin
• Dextran 40 for 12 to 24 hours
Associated with: Hospital stay of 5 to 7 days
A Novel Idea Stenting without
Anticoagulation: 6 Month Outcome
7
6.4
5.7
6
5
4
3
1.9
2
1.6
1
0
CABG
MI
Colombo, et al. Circ 1995;91:1676
Death
Stent
Thrombosis
BMS History of Stent thrombosis
16%
16
Stent thrombosis (%)
14
12
Coumadin
High-pressure balloons and
ticlopidine
10
8
6
3.5%
4
1.6%
0.8%
2
0.6%
0
PS1
1991
STRESS2
1993
Colombo3
1995
1. Schatz et al. Circulation.1991;83:148; 2. Fischman et al. N Engl J
Med. 1994;331496; 3. Colombo et al. Circulation.1995;91:1676;
4. Schömig et al.Circulation.1994,90:2716; 5. Leon et al. N Engl J Med.
1998;339:1665;
ISAR4
1996
STARS5
1997
DES: Early Discontinuation of Anti-platelet
Therapy is the Strongest Risk Factor for ST
Incidence (%)
N=2229
Overall stent thrombosis = 1.3%
HR 90
Case fatality rate: 45%
Unstable Thrombus
angina
Diabetes
Iakovou et al. JAMA. 2005;293:2126.
Unprotected left Bifurcation
main
Renal
failure
Prior
brachy Rx
Premature
antiplatelet
discont’d
Post MI Premature Discontinuation
of Clopidogrel: N = 500
100
90
80
86.4
70
60
% at 30 Days
Death at 12 Months
50
40
30
20
10
13.6
7.5
0.7
0
Compliant
Non Compliant
Spertus, et al. Circ 2006;113:2803
Nordmann Meta-analysis of DES
vs. BMS ESC Sept 2006
Non-Cardiac Mortality
Odds Ratio (95% CI)
Cypher® Stent
1 year
n=8*
0.94 (0.44-2.00)
2 year
n=5
2.74 (1.22-6.13)
3 year
n=4
2.04 (1.00-4.15)
4 year
n=2
1.65 (0.88-3.10)
TAXUS®
Express2™ Stent
1 year
n=10
1.11 (0.58-2.15)
2 year
n=7
1.21 (0.59-2.45)
3 year
n=5
Favors DES
* studies
Favors BMS
1
0.5
2
Odds Ratio
TAXUS® Express® Stent
Modified. Nordmann, et al EHJ 2006;27:2784
Cypher™ Stent
1.17 (0.67-2.05)
10
Millions face risk from
drug-coated stents
“Millions of Americans could be walking around with tiny time bombs in their hearts”
“Potentially lethal heart devices a frightening problem for patients, doctors”
“The FDA panel might recommend they not be used at all”
By Robert Bazell
Chief science correspondent
NBC News
Nov 2006 – March 2007
December 2006 FDA Findings
•
•
The panel was in general agreement that DES, when
used in accordance to their FDA approved labeled
indications, are associated with a clinically important
numerical excess of late stent thromboses (after 1 year
post-implantation) compared to BMS; however, the
magnitude of this excess is uncertain and additional data
are needed.
The panel reached consensus that the DES safety
concerns do not outweigh their benefits compared to
BMS when used within the limits of the approved
labeling.
December 2006 FDA Findings
•
•
•
The Panel recognized that with more complex patients,
there is an expected increased risk in adverse events in
these subsets . The panel generally agreed that off-label
use of DES is associated with an increased risk of stent
thrombosis, death and MI when compared to on-label
use of DES.
The labeling for both approved DES should include
reference to the ACC/AHA/SCAI PCI Practice
Guidelines, which recommend that patients receive
aspirin indefinitely plus a minimum of 3 months (for
Cypher patients) or 6 months (for TAXUS patients) of
clopidogrel, with therapy extended to 12 months in
patients at a low risk of bleeding.
The panel agreed that at least 12 months of dual
antiplatelet therapy should be recommended for off-label
uses of DES.
Stent Thrombosis
• ARC definitions:
Definite
Probable
Possible
• Timing:
Acute: 0 to 24 hours
Subacute: > 24 to 30 days
Late: > 30 to 1 year
Very Late: > 1 year
VLST BMS vs DES
Lemesle G, et al. Cardiol Clin 2010;28:97
AHA/ACC/SCAI/ACS/ADA/ACP
Scientific Advisory
1. Healthcare providers who perform invasive or surgical procedures on
patients who have had coronary stents placed should contact the
patient’s cardiologist to discuss optimal management of the patient’s
antiplatelet therapy.
2. Elective procedures where discontinuation of dual antiplatelet therapy
is felt necessary should be deferred for 1 month in the case of bare
metal stents and 12 months for drug eluting stents.
3. Patients treated with drug eluting stents that undergo procedures that
mandate discontinuation of the thienopyridine (clopidogrel or
ticlopidine) should remain on aspirin if at all possible with the
thienopyridine restarted as soon as possible post procedure.
Grines, et al. Circulation 2007;115:813-818