Safety of Drug-Eluting Stents in Acute Coronary Syndromes

Safety of Drug-Eluting Stents in

Acute Coronary Syndromes

Rotterdam, June 11th 2012

Stephan Windecker

Department of Cardiology

Swiss Cardiovascular Center and Clinical Trials Unit Bern

Bern University Hospital, Switzerland

Scientific Advances and

Cardiovascular MortalityNabel and Braunwald. N Engl J Med 2012;366:54-63

1958

Coronary

arteriography

(Sones)

2002

19771977

Coronary

angioplasty

(Grüntzig)1993

Superiority of

primary PCI vs.

fibrinolysis in

acute MI

2002

Efficacy of

drug-eluting

vs. bare-

metal stents

MortalityMortality andand Repeat Repeat RevascularizationRevascularization withwith

Early Generation DES versus Bare Early Generation DES versus Bare MetalMetal StentsStents

Mortality Repeat Revasc

SES vs BMS

PES vs BMS

SES vs PES

1.00 (0.82-1.25)

1.03 (0.84-1.22)

0.96 (0.83-1.24)

SES vs BMS

PES vs BMS

SES vs PES

0.30 (0.24-0.37)

0.42 (0.33-0.53)

0.70 (0.56-0.84)

HR (95% CI) HR (95% CI)

Stettler C et al. Lancet 2007;370:937-48

10·2 2 50·5

SES vs PES 0.96 (0.83-1.24)

10·2 2 50·5

SES vs PES 0.70 (0.56-0.84)

0

10

20

30

40

50

SES vs BMS PES vs BMS SES vs PES

NNT=7(CI 6-8)

NN

T

NNT=8(CI 7-10)

NNT=35(CI 23-65)

Drug-Eluting vs. Bare Metal Stent in Acute MIMauri L et al. N Engl J Med 2008;359:1330-42

Propensity Score Matched Pair Comparison of DES and BMS in Patients Undergoing PCI for acute myocardial infarction in Massachusetts

N=7,217 Patients (04/2003-09/2004)

Mortality Recurrent MI

DES 8.5%BMS 11.6%

∆ 3.1%↓↓↓↓ 27%

DES 7.0%BMS 8.0%

∆ 1.0%↓↓↓↓ 13%

14,1

15,7 15,415

20

RR 1.08 (0.82-1.43)

P=0.46

RR 0.51 (0.43-0.61)

P<0.001

RR 0.94(0.78-1.14)

P=0.98

RR 1.01 (0.73-1.40)

P=0.90

RR 0.91 (0.71-1.15)

P=0.63

15 RCTs Comparing DES and BMS in 7,843 STEMI Patients

Early Generation Drug-Eluting Stents versus

Bare Metal Stents in Patients With STEMIKalesan B et al. Eur Heart J 2012

14,1

7,5

9,2 8,7

4,1

7,99,1

3,2

0

5

10

15

Death Cardiac death

MI TVR Definite ST

DES BMS

%

Stent Choice

Newer Generation

DES and ACS

Thrombus Burden in

ACS

Vessel Size in ACS

Stent Choice in ACS

Vessel Remodelling

and Inflammation

in ACS

Discontinuation of Antiplatelet

Therapy

Impact of Vessel Diameter

and Late Loss on Restenosis

RVD 4.0 mm 3.5 mm 3.0 mm 2.5 mm 2.0 mm

Late loss (BMS) 0.9 mm 0.9 mm 0.9 mm 0.9 mm 0.9 mm

Diameter stenosis 23% 26% 30% 36% 45%

Late loss (DES) 0.2 mm 0.2 mm 0.2 mm 0.2 mm 0.2 mm

Diameter stenosis 5% 6% 7% 8% 10%

2,93,2 3,2

2,9 2,9 2,93

4

mm

Mean Reference Vessel Diameter (mm)

Vessel Size in Patients With

Acute Myocardial Infarction

0

1

2

3

0,8

1

In-Stent In-Segment

Lo

ss (

mm

) 0.82 0.70

P<0.001

0,8

1

La

te L

um

en

Lo

ss (

mm

)

P<0.001

Paclitaxel-Eluting Stents versus Bare-Metal

Stents in Acute Myocardial Infarction: HORIZONS-AMIStone G et al. N Engl J Med 2009;360:1946-59

0

0,2

0,4

0,6

PES BMS

La

teL

um

en

Lo

ss (

mm

)

N=1081 N=332

0.41 0.64

0

0,2

0,4

0,6

DES BMS

La

te L

um

en

Lo

ss (

mm

)

0.30 0.56

0.59 0.64

N=1081 N=332

Drug-Eluting Stent Safety in Large Vessels

BASKET-PROVE: DES vs BMSKaiser C et al. N Engl J Med 2010

Death or MI Repeat Revasc

2,314 Patients 2,314 Patients

NewerNewer GenerationGeneration DrugDrug--ElutingEluting StentsStents versus versus

BareBare Metal Metal StentsStents in in PatientsPatients withwith STEMISTEMI

Target Lesion Revascularization

EXAMINATIONEES versus BMS

COMFORTABLE AMIBES versus BMS

Stent Choice

Vessel Size in ACS

Newer Generation

DES and ACS

Thrombus Burden in

ACS

Stent Choice in ACS

Vessel Remodelling

and Inflammation

in ACS


Therapy

10

15 OR=12.4(1.7-89.7)

OR=2.3(1.3-4.0)

OR=1.8(1.1-2.7)

Odds/H

azard

Ratio

Acute Coronary Syndrome

as Predictor of Stent Thrombosis

HR=2.6(1.3-4.9)

0

5

10

Park et alAm J Card 2006

Daemen et alLancet 2007

Urban et alCirculation 2006

Odds/H

azard

Ratio

De la Torre et alJACC 2008

Impact of Thrombus Burden on Risk of StentThrombosis With DES in Patients With STEMI

Sianos G et al. J Am Coll Cardiol 2007;50:573-83

Variable Hazard Ratio 95% CI

Age 0.6 0.4-0.8

Independent Predictors of ST

Age 0.6 0.4-0.8

Index ST 6.2 2.1-18.9

Bifurcation 4.1 1.6-10.0

Thrombectomy 0.1 0.01-0.8

Large thrombus 8.7 3.4-22.5

15 RCTs Comparing DES and BMS in 7,843 STEMI Patients

RiskRisk of of IschemicIschemic Events and Events and StentStent ThrombosisThrombosis StratifiedStratified

AccordingAccording toto Time and Time and StentStent Type (DES Type (DES vsvs BMS) in STEMIBMS) in STEMI

Favors SES/PES Favors BMS Kalesan, Windecker

Stent Choice

Vessel Size in ACS

Newer Generation

DES and ACS

Thrombus Burden in

ACS

Stent Choice in ACS

Vessel Remodelling

and Inflammation

in ACS


Therapy

Correlation between fibrous cap

thickness and % uncovered struts

ArterialArterial HealingHealing atat CulpritCulprit Sites after DES Sites after DES

Implantation in Patients Implantation in Patients withwith AcuteAcute MI MI andand

StableStable Angina Angina –– An An AutopsyAutopsy StudyStudyNakazawa et al. Circulation 2008; 118:1138-1145

Stent Malapposition/Vessel Remodeling

Cook S et al. Circulation 2007

Neointimalthickness

Struts withfibrin

Struts withinflammation

Uncoveredstruts

P=0.008 P=0.008 P=0.003 P=0.01

Arterial Healing at Culprit Sites after DES

Implantation in Patients with Acute MI and

Stable Angina – An Autopsy StudyNakazawa et al. Circulation 2008; 118:1138-1145

0

0,02

0,04

0,06

0,08

0,1

0,12

Acute MI culprit site

Stable Angina culprit site

63

36

0

10

20

30

40

50

60

70



35

17

0

5

10

15

20

25

30

35

40



49

9

0

10

20

30

40

50

60



0.04

(0.02–0.09)

0.11

(0.07–0.21)

mm % % %

Acute MI culprit site (N=25) Stable angina culprit site (N=26)

Association of Eosinophilic Infiltrates ofThrombus Aspirates With Vessel Remodeling

Cook S, Ladich E, Virmani R, Windecker S. Circulation 2009

Eosinophilic Infiltrates Vessel Remodeling

2924,2

46,8

20,9

30.8

20

30

40

50

%

Late Acquired Stent Malapposition in HORIZONS-AMIGuo N et al. Circulation 2010;122:1088-84

P=0.007 P=0.02P=0.63

LASM: 75% positive remodeling25% thrombus resolution

8,1

0

10

20

Late Stent Malapposition Persistent Stent Malapposition

Late Acquired Stent Malapposition

BMS PES

Independent predictors of LASM:

-plaque/thrombus protrusion at baseline (OR=5.6, 95% CI 2.3-13.5)

-PES use (OR=6.3, 95% CI 2.2-18.6)

OCT 5 yrs after STEMI

Stent Thrombosis @ 5.5 yrsSTEMI @ BL

Courtesy Räber/Windecker, SIRTAX OCT

5,76.3

6

8

%

Strut Coverage, Malapposition and Protrusion

in HORIZONS-AMI – OCT Substudy @ 13 MonthsGuagliumi G et al. Circulation 2010;123:274-81

P=0.0003 P<0.0001P<0.0001

0,1

1,1 10,9

0

2

4

6

Malapposed and Uncovered Struts

Uncovered Struts Protruding Struts

BMS PES

Stent Choice

Vessel Size in ACS

Newer Generation

DES and ACS

Thrombus Burden in

ACS

Stent Choice in ACS

Vessel Remodelling

and Inflammation

in ACS


Therapy

HR=19.2(5.6-65.5)

HR=13.7(4.0-46.7)

OR=4.8(2.0-11.1)

Odds/H

azard

Ratio

Discontinuation of Antiplatelet Therapy as Predictor of Stent Thrombosis

HR=13.8(8.8-21.6)

HR=4.6(1.4-15.35)

Odds/H

azard

Ratio

%

Premature Discontinuation of Thienopyridine Therapy After DES Implantation

Spertus JA et al. Circulation 2006;113:2803-9

Mortality Between

30 Days and 1 Year

HR=1.5

P=0.08

Multicenter, prospective PREMIERregistry in patients admitted with myocardial infarction-500 DES patients enrolled at 19 sites-68 (14%) patients d/c thienopyridine

7,5

23

0,7

14

0

5

10

15

20

25

Death Rehosp.

Off Thienopyridine On Thienopyridine

%

HR=9.0

P<0.001

P=0.08

Factors associated with prematureThienopyridine discontinuation-older age-lower socioeconomic status-preexisting cardiovascular disease-inadequate discharge instructions-lack of referral to cardiac rehab

-68 (14%) patients d/c thienopyridine

REAL / ZEST(N=2,701)

PRODIGY(N=2,701)

Overall(N=4,671)


PRODIGY(N=2,701)

Overall(N=4,671)

1.73 (0.99-3.00)

1.02 (0.78-1.35)

1.25 (0.76-2.07)

Death, MI, or Stroke Bleeding

2.93 (0.31-28.46)

2.17 (1.44-10.00)

2.19 (1.46-3.28)

>1 Year vs. ≤1 Year

DAPT DAPT Following DESFollowing DES

10·2 2 50·5

(N=4,671)

10·2 2 50·5

(N=4,671)

10·2 2 50·5


PRODIGY(N=2,701)

Overall(N=4,671)

10·2 2 50·5

1.12 (0.77-1.67)

1.02 (0.78-1.35)

1.05 (0.85-1.31)

2.56 (0.79-8.33)

2.17 (1.44-10.00)

2.21 (1.50-3.25)

Adapted from Kastrati A. ESC Congress 2011, Paris

>6 Months vs. ≤6 Months


PRODIGY(N=2,701)

Overall(N=4,671)

LOG HAZARD RATIO (95% CI)

ENDEAVOR SPRINT

BMS

TAXUSXIENCE V

From 6 up to 24 months

6-mo Landmark Death/MI/CVA

Pt oriented Outcome stratified by stent

HAZARD RATIO (95% CI) P-VALUES

Superiority

0.05

0.90

0.88

1.04 (0.56-1.95)

2.55 (1.19-5.47)

0.63 (0.35-1.14)

1.06 (0.53-2.11)

Interaction

0.18

0.002

24-month DAPT better 6-month DAPT better

110

ENDEAVOR SPRINTTAXUSXIENCE V

XIENCE VTAXUS

BMS

BMSENDEAVOR SPRINT

6-mo Landmark Death/MI

6-mo CV Death/MI

0.10

0.03

0.57

0.07

0.61

0.28

0.20

0.83 (0.43-1.58)

2.07 (0.94-4.53)

0.59 (0.30-1.14)

1.18 (0.52-2.68)

0.86 (0.49-1.51)

2.33 (1.20-4.53)

0.73 (0.49-1.31)

0.58 (0.26-1.33)

0.014

0.12

0.70

Courtesy: M Valgimigli

Stent Choice

Vessel Size in ACS

Thrombus Burden in

ACS

Newer Generation

DES and ACS

Stent Choice in ACS

Vessel Remodelling

and Inflammation

in ACS


Therapy

34.3 %

30

40

Lesions With >10% Uncovered Struts

Struts Coverage 9 Months After Implantation of

Everolimus- and Sirolimus-Eluting StentsChoi et al. Int J Cardiovasc Imaging 2011

10 %

0

10

20

30

EES(N=40)

SES(N=70)

EES SES

Trials EES SES RR (95% CI)

EES vs SES EES vs PES

Trials EES PES RR (95% CI)

EverolimusEverolimus--ElutingEluting StentStent versus versus

Early Generation DESEarly Generation DESDES Safety – Risk of Stent Thrombosis

Overall (I-squared = 0.0%, p = 0.579)

RESET

ISAR-TEST 4

Burzotta et al.

ESSENCE-DIABETES

SORT-OUT 4

BASKET-PROVE

5/1597

4/652

0/75

0/149

2/1390

2/774

6/1600

9/652

0/75

0/151

9/1384

3/775

0.51 (0.26, 0.99)

0.83 (0.26, 2.73)

0.44 (0.14, 1.44)

(Excluded)

(Excluded)

0.22 (0.05, 1.02)

0.67 (0.11, 3.98)

0.83 (0.26, 2.73)

0.44 (0.14, 1.44)

(Excluded)

(Excluded)

0.22 (0.05, 1.02)

0.67 (0.11, 3.98)

1.1 .2 .5 1 2 5 10

Risk ratio

N = 11,167 N = 6,789

Overall (I-squared = 34.6%, p = 0.205)

SPIRIT II

SPIRIT IV

SPIRIT III

COMPARE

1/223

8/2458

6/669

5/897

2/77

12/1229

2/333

24/903

0.35 (0.16, 0.77)

0.17 (0.02, 1.88)

0.33 (0.14, 0.81)

1.49 (0.30, 7.36)

0.21 (0.08, 0.55)

0.17 (0.02, 1.88)

0.33 (0.14, 0.81)

1.49 (0.30, 7.36)

0.21 (0.08, 0.55)

1.1 .2 .5 1 2 5 10

Risk ratio

Favors EES Favors SES Favors EES Favors PES

Kalesan, Windecker

3

4

5

incid

en

ce

(%)

EES vs. SES HR* = 0.33, 95% CI 0.15 – 0.72,

P=0.006

EES vs. PES HR* = 0.24, 95% CI 0.13-0.47,

P <0.0001

BernBern--Rotterdam Rotterdam CohortCohort Study Study Very Late Definite ST (1-4 yrs)

Paclitaxel Stent 2.4%

Räber et al. Circulation 2012; 125:1110-21

0

1

2

Cu

mu

lative

incid

en

ce

0 6 12 18 24 30 36 42 48Months after index PCI

Sirolimus Stent 1.6%

Everolimus Stent 0.6%

Paclitaxel Stent 2.4%

*from Cox proportional hazards model

50,5

40

50

60-45.5

(-76.9 to –14.3)P<0.01

Biolimus Eluted from Biodegradable Polymer

versus Sirolimus Eluted from Durable Polymer Barlis P et al. Eur Heart J 2010

Lesions With At Least5% Uncovered Struts

3,5

0

10

20

30

40

Biolimus Stent Sirolimus Stent

(%)

29 Lesions 35 LesionsBiolimus

N=29Sirolimus

N=35

BP-DES DP-SES RR (95% CI)

Definite STMeta-Analysis

Definite STLEADERS trial @ 4 years

BiodegradableBiodegradable Polymer DES versus Durable Polymer DES versus Durable

Polymer Polymer SirolimusSirolimus ElutingEluting StentsStentsStefanini G et al. Lancet 2011

DES Safety – Risk of Stent Thrombosis

1 to 4 year*

RR 0.20 (95% CI 0.06-0.67)

p=0.004

* RR 0-1 vs RR 1-4 p for interaction=0.017

Overall (I-squared = 0·0%, p=0·92)

LEADERS

ISAR-TEST 4

ISAR-TEST 3

20/857

9/1299

1/202

32/850

9/652

2/202

0·58 (0·37, 0·93)

0·62 (0·36, 1·08)

0·50 (0·20, 1·26)

0·50 (0·05, 5·47)

10·1 0·2 2 50·5

Favours

biodegradable

polymer DES

Favours

durable

polymer SES

Risk ratio

0 to 1 year*

RR 0.99 (95% CI 0.51-1.95)

p=0.98

Cardiac death, MI, or ci-TVR 0·70

≤1 year 78/857 87/850 0·89 (0·65-1·20) 0·44

1 to 4 years 67/749 79/738 0·81 (0·59-1·12) 0·21

Cardiac death or MI 0·43

≤1 year 48/857 47/850 1·02 (0·68-1·53) 0·94

1 to 4 years 43/779 52/781 0·80 (0·54-1·21) 0·30

Clinically-indicated TVR 0·64

≤1 year 37/857 45/850 0·81 (0·52-1·25) 0·33

BES SES RR (95% CI) P P-interNOT ASSOCIATED with ST

Biodegradable Polymer BES vs Durable Polymer SES

Stefanini G et al. Lancet 2011

Association of Cardiac Events With Definite ST

≤1 year 37/857 45/850 0·81 (0·52-1·25) 0·33

1 to 4 years 39/776 40/760 0·94 (0·60-1·45) 0·77

Cardiac death, MI, or ci-TVR 0·049

≤1 year 13/857 15/850 0·86 (0·41-1·80) 0·68

1 to 4 years 2/749 11/738 0·17 (0·04-0·78) 0·009

Cardiac death or MI 0·08

≤1 year 11/857 11/850 1·00 (0·43-2·30) 0·99

1 to 4 years 3/779 11/781 0·27 (0·08-0·95) 0·029

Clinically-indicated TVR 0·07

≤1 year 13/857 15/850 0·85 (0·41-1·80) 0·68

1 to 4 years 2/776 10/760 0·19 (0·04-0·87) 0·017

0·1 0·2 0·5 1 2 4 6

ASSOCIATED with ST

Favours BES Favours SES

≤1 year

1 to 4 years

2,0

1,6

2,0

2,5

Early Generation DES Newer Generation DES

DES Thrombosis in Perspective

Very Late Definite ST in All-Comers Trials @ 3 Years

1,6

1,4

0,9

0,7

0,40,3

0,2

0,0

0,5

1,0

1,5

PES

SIRTAX

PES

COMPARE

SES

SIRTAX

SES

LEADERS

EES

COMPARE

EES

RESOLUTE

R-ZES

RESOLUTE

BES

LEADERS

%

Definite Stent Thrombosis among Patients

with Stable Coronary Artery Disease and

Acute Coronary Syndromes @ 4 YearsBern-Rotterdam Cohort Study

5 5

Stable CAD ACS

P=0.0001 P=0.0001

% %

2,31,8

0,4

0

1

2

3

4

PES SES EES

3,73,2

1,4

0

1

2

3

4

PES SES EES

N=5,138 N=7,201

P=0.0001 P=0.0001

Clinical Outcomes With Everolimus- and

Paclitaxel-Eluting Stents in Patients With ACSPlaner D et al. J Am Coll Cardiol Intv 2011;4:1104–15

8,7

11

7,78

10

12%

P=0.04 P=0.01 P=0.38 P=0.01 P=0.04

A Pooled Analysis of SPIRIT II, III, IV, and COMPARE Trials @ 2 Years

5,2

1,4

4

4,7

7,7

1,9

6,2 6,2

0

2

4

6

8

Cardiac death, MI, TLR

Cardiac death or MI

Cardiac death MI TLR

EES (N=1393) PES (N=988)

2,9

4

5%

P=0.01 P=0.0002

StentStent ThrombosisThrombosis WithWith EverolimusEverolimus-- andand

PaclitaxelPaclitaxel--ElutingEluting StentsStents in in PatientsPatients WithWith ACSACSPlaner D et al. J Am Coll Cardiol Intv 2011;4:1104–15

A Pooled Analysis of SPIRIT II, III, IV, and COMPARE Trials @ 2 Years

0,40,7

2,2

2,9

0

1

2

3

Definite ST Definite or Probable ST

EES (N=1393) PES (N=988)

EXAMINATION Trial - Everolimus-Eluting Stents

vs Bare Metal Stents in STEMI @ 12 Months

12

14,4

12

14

16%

P=0.003P=0.16

Sabaté M. Presented at ESC Congress 2011

P=0.01P=0.01

2,2

0,5 0,9

5,1

1,92,6

0

2

4

6

8

10

12

Death, MI, any Revasc

TLR Definite ST Definite/Probable ST

EES - Xience BMS - Vision(N=751) (N=747)

Definite/Probable Stent ThrombosisEXAMINATION trialEXAMINATION trial

p = 0.01p = 0.01

Sabaté M. ESC Congress 2011

4

6

8

10

MA

CE

(%

) BMS 8.7 %

1 yr HR

0.49 (0.30-0.80)

P=0.004

COMFORTABLE AMI TrialBiolimus-Eluting Stent vs Bare Metal Stent in STEMI

Primary Endpoint – MACE

@ 1 Year

0

2

4MA

CE

(%

)

575 543 541 540 537 534 530BES582 546 539 531 525 519 514BMS

No at risk

0 60 120 180 240 300 365Days since index procedure

BES 4.3 %

MACE= Cardiac death, TV-MI, ci-TLR – Clinical outcomes were adjudicated by an independent and blinded CEC

COMFORTABLE AMI Trial - Biolimus-Eluting Stents

vs Bare Metal Stents in STEMI @ 12 Months

8,7

8

9

10%

P=0.53P=0.004

Räber L Presented at EuroPCR 2012

P=0.10P=0.01 P<0.001

4,2

2,9

0,5

1,60,9

3,52,7

5,7

2,1

0

1

2

3

4

5

6

7

Cardiac Death, TV-MI, TLR

Cardiac Death TV-MI TLR Definite ST

BES-BioMatrix BMS - Gazelle(N=575) (N=582)

BMSBESBMSBES

Target vessel MI up to 30 days

Nu

mb

er

of

eve

nts

Stent thrombosisRestenosis

BMSBESBES BMS

Target vessel MI between 30 days and 1 year

Nu

mb

er

of

eve

nts

Stent thrombosisRestenosis

StentStent ThrombosisThrombosis WithWith EverolimusEverolimus--ElutingElutingStentsStents andand Bare Bare MetalMetal StentsStents

A Network Meta-AnalysisPalmerini T. et al. Lancet 2012

0 to 1 Year

Death MI

Short and LongShort and Long--Term Outcomes with Term Outcomes with Drug Eluting and Bare Metal Stents Drug Eluting and Bare Metal Stents

A Mixed Treatment Comparison of 77 RCTs and 117,762 Patient-Years Fup

Bangalore S et al. Circulation 2012, in press

Long Term

0 to 1 Year

Definite or Probable ST Target Lesion Revasc

Bangalore S et al. Circulation 2012, in press

Short and LongShort and Long--Term Outcomes with Term Outcomes with Drug Eluting and Bare Metal Stents Drug Eluting and Bare Metal Stents

A Mixed Treatment Comparison of 77 RCTs and 117,762 Patient-Years Fup

Long Term

Eur Heart J 2010

Use of Drug-Eluting Stents

• No safety concerns

• Consistent reduction in repeat revascularization with the use of DES

Eur Heart J 2011

� Improved safety in all-comers• Reduced risk of stent thrombosis

• Reduced risk of cardiac death or MI associated with ST

Newer Generation Drug-Eluting

Stents…What Have We Achieved?

� Improved efficacy in all-comers• Reduced risk of TLR

� Improved efficacy and safety in STEMI compared with BMS

• Reduced risks of TLR and ST, translating into a lower risk of MI at 1 year

• Are newer generation DES safer than BMS during long-term follow-up?

• Are biodegradable polymer based DES superior to newer generation durable polymer based DES?

Questions for Tomorrow

based DES?

• Will BVS outperform newer generation DES?

Documents

Safety of Drug-Eluting Stents in Acute Coronary Syndromes