The Zotarolimus-eluting Endeavor sprint stent in

Uncertain DES candidates (ZEUS)

M. Valgimigli, MD, PhD

Erasmus MC, Rotterdam

The Netherlands

On behalf of the ZEUS Investigators

I, Marco Valgimigli, have received:

• honoraria for lectures/advisory board from Merck, Correvio, Eli Lilly, Astra Zeneca, The Medicines Company, St Jude, Abbott Vascular, CID and Terumo.

• Institutional research grant from Medtronic (current study), The Medicines Company, Terumo

Background

• Drug-eluting stents (DES) per se are currently regarded as more efficacious but also more thrombogenic than BMS

• In order to restore safety to a level comparable

to BMS, a prolonged course of dual antiplatelet

therapy (DAPT) has been recommended after DES

• As a consequence, the use of DES instead of BMS remains controversial in selected patient/lesion subsets:

• Pts at high bleeding risk

– in whom long-term DAPT poses safety concerns

• Pts at high thrombosis risk

– whose risk for coronary events may be higher after DES

• Pts at low risk for in-stent restenosis

– the need for prolonged DAPT and the long-term risk for

adverse events after DES implantation may outweigh their

benefit in terms of low re-intervention rates

Background

Systematically Excluded from RCTs

EuroInterv.2007;3:50-53

ZES (PC-Coating) 100% Eluted at 14 days

No detectable drug in arterial tissue beyond 28

days

100

80

60

40

20

0 0 0.5 1 2 3 5 7 14 28 60

Days 90 180

Other 1 or 2 gen DES

E-ZES

Dru

g R

ele

ase

(%

)

Drug Elution Kinetics

30

20

15

10

5

0 0 0.5 1 2 3 5 7 14 28 60

Days 90 180

E-ZES

Zo

taro

lim

us (

ng

/m

L)

Zotarolimus in Arterial Tissue (in Stent)

25

Other 1 or 2 gen DES

Zotarolimus-eluting Endeavor Sprint: hydrophilic polymer-based second-generation device with unique

drug fast-release profile

Study Design

High Bleeding Risk High Thrombotic Risk Low Restenosis Risk Need for OACs Intolerance to ASA Planned stent ≥3.0 mm, Previous Relevant Bleeding Intolerance to any P2Y12 apart from LMCA and Age > 80 y/o Planned surgery w/in 1 year SVG intervention or for Bleeding diathesis Cancer-life expectancy >1 Y ISR lesions Known Anemia (Hb

Study Design

High Bleeding Risk High Thrombotic Risk Low Restenosis Risk Need for OACs Intolerance to ASA Planned stent ≥3.0 mm, Previous Relevant Bleeding Intolerance to any P2Y12 apart from LMCA and Age > 80 y/o Planned surgery w/in 1 year SVG intervention or for Bleeding diathesis Cancer-life expectancy >1 Y ISR lesions Known Anemia (Hb

Study Design

High Bleeding Risk High Thrombotic Risk Low Restenosis Risk Need for OACs Intolerance to ASA Planned stent ≥3.0 mm, Previous Relevant Bleeding Intolerance to any P2Y12 apart from LMCA and Age > 80 y/o Planned surgery w/in 1 year SVG intervention or for Bleeding diathesis Cancer-life expectancy >1 Y ISR lesions Known Anemia (Hb

Ferrara—Sponsor and study site with an unrestricted grant from Medtronic

Lisbon— H. M. Gabriel; Szeged— A. Thury, I. Ungi;

Torino—S. Colangelo; R. Garbo

Baggiovara —S. Tondi

Parma—A. Menozzi

Zingonia—N. de Cesare

Torino—E. Meliga

Milano— L. Testa, F. Bedogni

Milano—F. Airoldi

Pavia—M. Ferlini

Arezzo—F. Liistro

Savigliano—A. Dellavalle

Napoli—C. Briguori

Ravenna—M. Acquilina

Bergamo—G. Musumeci

Geneva—M. Roffi

Lisbon— H. M. Gabriel

Szeged— A. Thury, I. Ungi

Clinical Event Committee

P. Vranckx, Chair

S. Curello

G. Guardigli

Data Management and Monitoring

Medical Trial Analysis

Eustrategy Research Coordination

A. Patialiakas, Chair

Angiographic Core-lab

Key baseline or angiographic features

of the study population (N=1,606) BMS (N=804) E-ZES (N=802)

Age, median (IQR) 74 (64-81) 74 (64-81) Females (%) 29 30

Diabetes (%) 26 27

Prior MI/PCI/CABG (%) 24/19/7 24/19/7

Mild to Severe CKD (%) 41 42

ACS/STEMI (%) 63/19 63/ 19

MVD (%) 61 59

LAD/LMCA treated (%) 51/5 53/5

≥1 B2/C treated lesion (%) 73 73 MI: myocardial infarction; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; CKD: chronic kidney dysfunction; Lad: left anterior descending, LMCA: left main coronary artery; ACS: acute coronary syndrome; STEMI: ST-segment elevation myocardial infarction

High Bleeding Risk 828 (52%)

High Thrombosis Risk 285 (17%)

Low Restenosis Risk

-Unstable- 604 (38%)

454 (28%)

140 (9%)

29 (2%)

14 (1%)

173 (11%)

388 (24%) 22

(1%)

9 (1%)

71 (4%)

107 (7%)

199 (12%)

Low Restenosis Risk

-Stable- 337 (21%)

Study Population

ZEUS: Truly high risk patient population

11.3

8

2.1 1.5

3.3

2.5

1.1 0.4

1 0.5

0

2

4

6

8

10

12

Death CV Death

ZEUS

RESOLUTE AC

LEADERS

SPIRIT IV

SIRIUS

Event rates at 1 year across stent trials

%

≈30% of the screened patient population

0 30 60 90 120 150 180 210 240 270 300 330 360

Days of DAPT duration to first discontinuation

0

10

20

30

40

50

60

70

80

90

100

Cum

ula

tive f

requency (

%)

E-ZES

BMS

4.6%

43.6%

62.5%

77.3%

Duration of DAPT* in stent groups (ITT)

*: to first planned permanent discontinuation

Median: 33 days (IQR: 30-180)

Median: 31 days (IQR: 30-180)

37.5% on DAPT

24.7% on DAPT

2 Months 6 Months

Major Adverse Cardiovascular events primary endpoint

0 50 100 150 200 250 300 350 400

25.0

23.0

21.0

19.0

17.0

15.0

13.0

11.0

9.0

7.0

5.0

3.0

1.0

No. at Risk BMS 804 752 716 689 668 651 639 628 E-ZES 802 761 747 723 705 685 673 664

22.1%

17.5%

BMS

E-ZES %

2 pts, one in each group, were lost to follow-up after hospital discharge

HR: 0.76 (0.61-0.95), P=0.011

Target Vessel Revascularization

0 50 100 150 200 250 300 350 400

15.0

14.0

13.0

12.0

11.0

10.0

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0

10.7%

5.9%

No. at Risk BMS 804 759 721 694 675 657 645 636 E-ZES 802 765 751 729 712 693 682 675

HR: 0.53 (0.37-0.75) P

Myocardial infarction

0 50 100 150 200 250 300 350 400

10.0

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0

No. at Risk BMS 804 757 730 709 695 684 675 666 E-ZES 802 762 750 733 726 713 698 684

8.1%

2.9%

HR: 0.35 (0.22-0.56), P

An application of the Classification System from the Universal MI Definition

1.5

0.1 0

0.4

0.9

4.2

0

0.4

1

2.5

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Type 1 Type 2 Type 3 Type 4a Type 4b

E-ZES BMS

%

P=0.001 P=0.009

P=0.11

P=0.13

Definite or Probable Stent Thrombosis

0 50 100 150 200 250 300 350 400

5.0

4.0

3.0

2.0

1.0

0.0

2.0%

4.1%

No. at Risk BMS 804 763 739 723 712 701 692 685 E-ZES 802 767 758 741 733 721 713 708

HR: 0.48 (0.27-0.88), P=0.019

E-ZES

BMS

%

Bleeding events in the two groups

5.1

0.5

2.2 2.4

6.6

0.9

2.2

3.5

0

1

2

3

4

5

6

7

Type 5, 3, 2 Type 5 Type 3 Type 2

E-ZES BMS

BARC scale

P=N.S. for all comparisons

Overall

≤ 75 yr

> 75 yr

Male

Female

Diabetes

No diabetes

Stable coronary disease

Unstable coronary disease

Protocol mandated no or up to 30 day DAPT

Low restenosis risk criteria yes

HAZARD RATIO (95% CI)

HAZARD RATIO (95% CI)

P-VALUES

BMS better E-ZES better

0.76 (0.61-0.95)

0.74

0.18

0.99

0.15

0.30

0.41

0.12

0.87

High bleeding risk criteria yes

High thrombotic risk criteria yes

0.85 (0.65-1.10)

0.58 (0.38-0.88)

0.82 (0.62-1.10)

0.68 (0.48-0.96)

0.80 (0.54-1.19)

0.74 (0.56-0.96)

0.97 (0.63-1.49)

0.69 (0.53-0.89)

0.75 (0.58-0.96)

0.78 (0.49-1.23)

0.74 (0.50-1.09)

0.74 (0.57-0.97)

1.02 (0.64-1.64)

0.70 (0.54-0.90)

0.67 (0.48-0.93)

0.85 (0.63-1.15)

Interaction

Protocol mandated > 30 day DAPT

High bleeding risk criteria no

High thrombotic risk criteria no

Low restenosis risk criteria no

No. of patients

1,606

473

1,133

741

865

420

1,186

590

1,016

1,077

529

828

778

285

1,321

941

665

1 0.2 1.8

Subgroup Analysis for the Primary Endpoint

Conclusions

• In patients at high bleeding, thrombotic or low restenosis risk, E-ZES implantation followed by a personalized duration of DAPT, including no or a 30-day course of therapy, resulted in a lower risk of major adverse cardiovascular events as compared to BMS

• Our study suggests that E-ZES may become the new gold standard coronary device in pts who cannot, or refuse to, tolerate (long-term) DAPT