Unresolved issues with Drug-eluting Stents

Stent Thrombosis

Advanced Angioplasty 2007

Dan BlackmanYorkshire Heart Centre

Conflicts of Interest

• Speakers Honoraria– Boston Scientific

– St Jude

– Nycomed

• Advisory Boards– St Jude

– Nycomed

– Lilly

Investigator-led meta-analyses ‘The ESC Firestorm’

• Camenzind• 5 Taxus and 4 Cypher RCTs. All published data to latest available f/up

3.9

2.3

6.3

2.6

0123456789

10

Cypher Taxus

Dea

th o

r Q

-wav

e M

I (%

) BMS

DES

P=0.03

P=0.68

Investigator-led meta-analyses ‘The ESC Firestorm’

• Nordman• 16 RCTs (5 Taxus, 4 Cypher,

2 Cook, 5 independent*)

• Increased non-cardiac mortality with Cypher alone

• No difference in cardiac mortality or stent thrombosis

* BASKET-LATE, ASPECT, SES-SMART,

DIABETES, SCANDSTENT

Eur Heart J 2006;27:2784-2814

TCT ResponseIndependent patient-level meta-analysis

TCT ResponseIndependent patient-level meta-analysis

TCT ResponseIndependent patient-level meta-analysis

TCT ResponseIndependent patient-level meta-analysis

TCT ResponseIndependent patient-level meta-analysis

ARC Definition patient level meta-analysesDefinite or probable

0.5 0.5 0.50.3 0.4

1.20.4

0.20.1

0.9

0.2

0.2

0.2

0.9

0.5

0.1

0.6

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Taxus(n=1400)

Cypher(n=878)

Endeavour(n=1318)

Ste

nt

thro

mb

os

is (

%)

Very late

Late

Early

1.5%

0.9%

1.5%

1.8%

0.7%

1.4%

BMS (n=1397)

BMS (n=870)

BMS (n=594)

Off-label/Real-world DES thrombosisWashington Hospital Data

• 12 month outcome with ‘on-label’ (n=1773, 55%) vs ‘off-label’ (n=1365, 45%) DES use

• Off-label = >33mm, ISR, SVG, AMI, LMS, CTO

Waksman R. FDA Hearing 12/06

Off-label/Real-world DES thrombosisRotterdam/Bern Registry

• 8,146 consecutive (ALL) DES cases in Bern/Rotterdam 2002 - 2005• Angiographically proven ST• 90% of all DES patients complete clinical follow-up

Wenaweser

FDA Hearing 12/06 Lancet in press

Off-label/Real-world DES outcomeBASKET-LATE

1.3 1.3

7.5

4.9

2.6

8.4

0

1

2

3

4

5

6

7

8

9

V.Late D/MI V.Late ST Overall D/MI

%

BMS

DES

• 746 patients; 1133 lesions• Randomised 2:1 DES:BMS in

BASKET trial• Event-free patients at 6/12

followed up to 18/12• ‘Real-world’ population

– 84% of all PCIs included

– 67% MVD; 58% STEMI/UA

– 27% ≤2,5mm; 2 stents/pt

• Increased late death/MI, though not all due to ST

• Overall death/MI equivalent

J Am Coll Cardiol 2006;2584-91

Off-label/Real-world DES outcomeSwedish PCI Registry

• 13,738 BMS + 6033 DES implanted in 2003-2004• Complete long-term f/up from National registry of MI, CABG, and death• DES use in Sweden 62% → 26% from Jan 06 to Oct 06

Wallentin. FDA Hearing 12/06

Absolute excess mortality 0.3%

Off-label/Real-world DES outcomeDuke Registry

• 3165 BMS implanted 2000-2005 + 1501 DES implanted 2003-2005• Median follow-up 3.1 years

Eisenstein.

FDA Hearing. 12/06

Independent predictors of DES thrombosisOR1 OR2 OR3 ST incidence

PATIENT FACTORS

Premature d/c antiplatelets 90 11.1 2.1

STEMI 7.5 3.8%

Renal failure 6.5 3.8

Reduced LVEF 3.3 (<30%) 1.1/10%

Diabetes 3.7

LESION FACTORS

Bifurcation 6.4 4.4 4.3% (Crush)

Vein graft 6.3

In-stent restenosis 4.5

LAD 3.9

Stent length 1.06/mm

PROCEDURAL FACTORS

Final atmospheres 0.28

Stent underexpansion p=0.03

Incomplete lesion coverage p=0.02

Reduced Aspirin and clopidogrel responsiveness are associated with stent thrombosis and worse outcome after PCI

Study Platelet function Clinical Outcome

1. Barragan P2Y12 reactivity ratio Stent thrombosisCathet Cardiovasc Interven 2003

2. Ajzenberg shear-induced platelet aggregation Stent thrombosisJ Am Coll Cardiol 2005

3. Gurbel P2Y12 reactivity ratioJ Am Coll Cardiol 2005 ADP-induced aggregation Stent thrombosis

4. Matzesky ADP-induced aggregation MACE post PCICirculation 2005

5. Gurbel peri-procedural platelet aggregation Myonecrosis post PCIJ Am Coll Cardiol 2006

6. Bliden platelet aggregation pre-PCI 1 year MACE post PCIJ Am Coll Cardiol in press

7. Cuisset platelet aggregation 30 day MACE post PCIJ Thromb Haemost 2006

8. Lev Clopidogrel/aspirin resistance Myonecrosis post PCIJ Am Coll Cardiol 2006

9. Hochholzer platelet aggregation 30 day MACE post PCIJ Am Coll Cardiol 2006

How long should patients have clopidogrel after DES?

• Milan/Siegburg/Naples registry

• 3021 patients with 5389 lesions treated with DES

• Incidence of definite stent thrombosis assessed according to whether patient was on or off clopidogrel

0.9

0.3 0.4 0.4

4.2

0.8

0.2 0.10

1

2

3

4

5

< 30/7 30/7 - 6m 6-12 m 12-18 m

Ste

nt

thro

mb

os

is (

%)

On clopidogrel Off clopidogrel

Conclusions

• DES are associated with a small increase in very late stent thrombosis

• ‘On-label’ this increased risk of stent thrombosis is not associated with an increased risk of death or MI

• In more complex patients data are limited, but indicate that the risk of stent thrombosis is higher, and may be associated with an increase in death/MI

• The balance between restenosis risk and thrombosis risk should be considered when determining treatment, and stent, choice in individual patients

• Optimising stent expansion and lesion coverage is essential to minimise risk

• Ensuring compliance with clopidogrel for 12 months is vital. Longer-term clopidogrel is not supported by the evidence, but may be justified in the highest risk patients

• Platelet aggregation studies ± an increase in the dose of clopidogrel to 150mg/day should be considered in the highest risk patients

• Further studies are underway which will provide more information to guide future strategies