instent restenosis and late stent thrombosis larry s. dean, md, facc, fscai professor of medicine...
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Instent Restenosis and Late Stent Thrombosis
Larry S. Dean, MD, FACC, FSCAIProfessor of Medicine and SurgeryUniversity 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
Angioplasty
Vascular Injury
EndothelialDisruption
SMC Activation
Thrombus Organization
ExtracellularMatrix Formation
DNA SynthesisProliferation
Migration
Mechanical Stretch
Recoil &Remodeling
Restenosis
Growth Factors
Thrombus Formation
The Restenosis Cascade
Modified, Heldman, TCT 2002
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
% R
este
nos i
s
Rodriguez, et el. Circulation 1995;91:1397-402
The STRESS Trial: QCA
*P<0.05NEJM. 331;496, 1994
In-Stent Restenosis Patterns and Recurrence Rates
Repeat TVR
Mehran R et al. Circulation 1999;100:1872-8.
Type I
<10mm lesions
Type II
>10mm Intra-stent lesions
Type III
>10mm proliferative lesions
Type IV
Total occlusions
BMS Restenosis
Kim MS, Dean LS, In-Stent Restenosis, Cardiovascular Therapeutics In Press
Management of Instent Restenosis (ISR)
• POBA
• Atheroablative technology
• Brachytherapy
• Drug eluting stents
Sr-90Sr-90PlaceboPlacebo
14.2%
45.2%
28.8%
41.2%
p < 0.001p < 0.001p < 0.001p < 0.001
66%66% 66%66%
36%36% 36%36%
p = 0.001p = 0.001p = 0.001p = 0.001
TheTheSTARTSTARTTrial Trial
8 Month8 MonthAngiographicAngiographicRestenosisRestenosis
Popma JJ, et al. Circulation. 2002;106:1090-1096
Drug Eluting Stents
ControlControl PaclitaxelPaclitaxel
SIRIUS: 9 Month Overall Outcomes
%
Moses JW, et al. NEJM 2003;349:1315
TAXUS IV Clinical Trial Restenosis at 9 Months
RR=0.23 [0.13, 0.38]
P<0.0001
RR=0.30 [0.19, 0.46]
P<0.0001
Res
ten
osi
s (
%)
Stone GS, et al. NEJM 2004;350:221-31.
DES Restenosis
Kim MS, Dean LS In-Stent Restenosis. Cardiovascular Therapeutics In Press
Angiography (Baseline)Angiography (Baseline)
TAXUS V ISR Trial: Study Design
Primary Endpoint: Ischemia-driven target vessel revascularization at 9 months
Primary Endpoint: Ischemia-driven target vessel revascularization at 9 months
VBT using a beta-source radiation
n=201
VBT using a beta-source radiation
n=201
PCI with paclitaxel-eluting stentsn=195
PCI with paclitaxel-eluting stentsn=195
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
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
Repeat Angiography (9 months)
170 in VBT group and 172 in Paclitaxel group
Repeat Angiography (9 months)
170 in VBT group and 172 in Paclitaxel group
Stone GW, et al. JAMA 2006;295:1253Stone GW, et al. JAMA 2006;295:1253
TAXUS V ISR Trial: 9 month Angiography
Dia
met
er s
teno
sis
(%)
Dia
met
er s
teno
sis
(%)
Final post-procedure diameter stenosis Final post-procedure diameter stenosis in the analysis segment in the analysis segment
p<0.001
Binary Restenosis at 9 months p<0.001
Bin
ary
rest
enos
is (
%)
Bin
ary
rest
enos
is (
%)
Management Strategies for Restenosis
• Class IIAo 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 guidelineupdate for percutaneous coronary intervention
Stent Thrombosis
How Could this Ever Work?
7.6
24
32
0
5
10
15
20
25
30
35
Death Occluded Restenosis
%
Serruys, et al. NEJM 1991;324:13
One Site = 39%
N = 105
Early Stent Outcomes with Aggressive Anticoagulation
18
0.6
5
12.5
0
15
0.6
5
8.5
0
2
4
6
8
10
12
14
16
18
20
ASA/dipyridamole ASA/dipyridamole/warfarin
SAT
MI
ECABG
MACE
Bleeding
Schatz, et al. Circ 1991;83:148
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
6.45.7
1.91.6
0
1
2
3
4
5
6
7
CABG MI Death StentThrombosis
Colombo, et al. Circ 1995;91:1676
BMS History of Stent thrombosis
0
2
4
6
8
10
12
14
16
PSPS11
19911991STRESSSTRESS22
19931993ColomboColombo33
19951995STARSSTARS55
19971997
Ste
nt
thro
mb
osi
s (%
)S
ten
t th
rom
bo
sis
(%)
16%16%
3.5%3.5%
1.6%1.6%0.6%0.6%0.8%0.8%
ISARISAR44
19961996
CoumadinCoumadinHigh-pressure balloons and High-pressure balloons and
ticlopidineticlopidine
1. Schatz et al. Circulation.1991;83:148; 2. Fischman et al. N Engl J 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; 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. 4. Schömig et al.Circulation.1994,90:2716; 5. Leon et al. N Engl J Med. 1998;339:1665; 1998;339:1665;
DES: Early Discontinuation of Anti-platelet Therapy is the Strongest Risk Factor for ST
Unstable angina
Thrombus Diabetes Unprotected left main
Bifurcation Renal failure
Prior brachy Rx
Premature antiplateletdiscont’d
Inci
denc
e (%
)
Iakovou et al. JAMA. 2005;293:2126.
N=2229 Overall stent thrombosis = 1.3%
HR 90Case fatality rate: 45%
Post MI Premature Discontinuation of Clopidogrel: N = 500
86.4
13.6
0.77.5
0
10
20
30
40
50
60
70
80
90
100
Compliant Non Compliant
% at 30 Days
Death at 12 Months
Spertus, et al. Circ 2006;113:2803
Modified. Nordmann, et al EHJ 2006;27:2784
TAXUS® Express® Stent Cypher™ Stent
Nordmann Meta-analysis of DES vs. BMS ESC Sept 2006
Odds Ratio (95% CI)Non-Cardiac Mortality
Favors DES Favors BMS
TAXUS® Express2™ Stent
1 year n=10
2 year n=7
3 year n=5
Cypher® Stent
1 year n=8*
2 year n=5
3 year n=4
4 year n=2
0.94 (0.44-2.00)
2.74 (1.22-6.13)
2.04 (1.00-4.15)
1.65 (0.88-3.10)
1.11 (0.58-2.15)
1.21 (0.59-2.45)
1.17 (0.67-2.05)
0.5 1 2 10
Odds Ratio* studies
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 BazellChief science correspondent NBC NewsNov 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:DefiniteProbablePossible
• Timing:Acute: 0 to 24 hoursSubacute: > 24 to 30 daysLate: > 30 to 1 yearVery 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