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