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