TWENTE A Prospective Randomized Trial of a Durable-Polymer Zotarolimus-Eluting Stent Versus a

Durable-Polymer Everolimus-Eluting Stent in Patients With Coronary Artery Disease:

Five-Year Outcomes

1 Thoraxcentrum Twente, Medisch Spectrum Twente, Department of Cardiology, Enschede2 Ziekenhuisgroep Twente, Department of Cardiology, Almelo and Hengelo3 Streekziekenhuis Koningin Beatrix, Department of Cardiology, Winterswijk4 Health Technology and Services Research, MIRA – Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede; all centers located in the Netherlands

Clemens von Birgelen, MD, PhD 1,4

on behalf of the TWENTE Investigators 1-4

TWENTE A Prospective Randomized Trial of a Durable-Polymer Zotarolimus-Eluting Stent Versus a

Durable-Polymer Everolimus-Eluting Stent in Patients With Coronary Artery Disease:

Five-Year Outcomes

1 Thoraxcentrum Twente, Medisch Spectrum Twente, Department of Cardiology, Enschede2 Ziekenhuisgroep Twente, Department of Cardiology, Almelo and Hengelo3 Streekziekenhuis Koningin Beatrix, Department of Cardiology, Winterswijk4 Health Technology and Services Research, MIRA – Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede; all centers located in the Netherlands

Clemens von Birgelen, MD, PhD 1,4

on behalf of the TWENTE Investigators 1-4

Disclosure Statement of Financial Interest

• Grant / Research Support• Consulting Fees / Honoraria• Major Stock Shareholder / Equity• Royalty Income• Ownership / Founder• Intellectual Property Rights• Other Financial Benefit

• None*• None / AstraZeneca (lecture)• None• None• None• None• None

Within the past 12 months, I, C. von Birgelen, MD, PhD, have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

Institutional Research Grants* MedtronicBoston ScientificBiotronikAstraZeneca

Source of images: on the left hand side Wikipedia, on the right hand side MST, Enschede, NL.

The Netherlands TWENTE

Twente is the name of a region in the Eastern Netherlands, known for its beautiful landscapes, castles, and technology. The center for cardiac interventions in Twente, Thoraxcentrum Twente, is located in the heart of Enschede, which is the largest city of the region.

Where or What is TWENTE ?

TWENTE Randomized Clinical Trials

BIO-RESORT BIONYX

1st Generation drug-eluting stents (DES)

Basalus MW, von Birgelen C, et al. EuroIntervention 2009; 5: 157-65 EuroIntervention 2009; 5: 505-10EuroIntervention 2010; 6: 141-8 Interventional Cardiology 2010; 2: 159-75 J Interven Cardiol 2011; 24: 149–61 Catheter Cardiovasc Interv 2012; 79: 644-53

Bench Research Performed in Twente

TWENTE: Study Devices

Drug Zotarolimus Everolimus Complete drug elution 180 days 120 days Polymer BioLinx polymer coating Fluoropolymer coating Coating thickness 5.6 µm 7.8 µm Stent platform Driver design Multi-Link Vision design

Cobalt-chromium alloy Cobalt-chromium alloyStrut thickness 91 µm Strut thickness 81 µm

Scanning electron microscopic (SEM) and micro-CT images of stents at bench side generated by C. von Birgelen and co-workers;MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente, Enschede, the Netherlands; processed by M.W.Z. Basalus

Resolute Xience V

Background

• TWENTE trial compared 2nd generation durable-polymer DES in all-comers (except primary PCI):1,2

Resolute zotarolimus-eluting stent Xience V everolimus-eluting stent

• TWENTE enrolled 81.4% of all eligible patients3.• Limited RCT-based data from large, broad patient

populations are available on long-term safety and efficacy of 2nd generation DES.

1 TWENTE (Prim. Outcome) von Birgelen C et al. J Am Coll Cardiol 2012; 59:1350–612 TWENTE (2 Years) Tandjung K et al. J Am Coll Cardiol 2014; 61:2406–163 Non-Enrolled TWENTE Sen H et al. EuroIntervention 2012; 8:664–71

TWENTE Patients with stable angina or non-ST-elevation ACS requiring DES No limit of number of lesions or vessels treated, lesion length, vessel size, or lesion type

(de novo lesion, restenosis, CTO, graft lesion)

Inclusion criteria: Age ≥ 18 yrs and signed informed consent Exclusion criteria: STEMI requiring primary PCI < 48 hrs; planned staged PCI; hemodialysis;

condition limiting compliance to follow-up or life expectancy < 1 year; choice of DES dictated by logistic reasons; participation in another drug or device RCT

Zotarolimus-Eluting RESOLUTE(n=697)

Everolimus-Eluting XIENCE V(n=694)

1391 patients were 1:1 randomized

(gender stratified) in this investigator-initiated,

single-blinded, trial at Thoraxcentrum Twente

From June 2008 to August 2010, 81.4% of all eligible patients at Thoraxcentrum Twente were enrolled (1391/1709). Systematic (serial) assessment of cardiac markers and ECG. Independent external adjudication of clinical events (CEC) by independent external CRO (Cardialysis, Rotterdam, and Diagram, Zwolle, the Netherlands). Analyses were based on

intention-to-treat. Control angiography was performed only if clinically indicated. During 5-year follow-up, 17 patients withdrew consent or refused to participate in the follow-up. Only 4 patients were lost to follow-up. As a consequence, the 5-year follow-up rate is 98.5% (1370 of all randomized 1391 patients).

This investigator-initiated study was funded by Abbott and Medtronic (3 to 5-year follow-up funded by Medtronic).

5-Year Outcomes (Follow-up Rate: 98.5%)

Zotarolimus eluted within < 180 days from a 5.6 µm BioLinx™ polymer coating on a Driver stent platform with 91µm CoCr2 struts

Everolimus eluted within < 120 days from a 7.8 µm fluoropolymer coating on a Multi-Link stent platform with 81µm CoCr2 struts

The primary endpoint Target Vessel Failure (TVF) at 1-year follow-up (TVF = composite of cardiac death, target vessel-related MI, or clinically driven target vessel revascularization) was reached in 8.2 % of patients

of the Resolute arm versus 8.1 % of patients of the Xience V arm (p = 0.94, Pnon-inferiority = 0.001).

TWENTE (Primary Outcome) von Birgelen C et al. J Am Coll Cardiol 2012; 59:1350–61 TWENTE (2 Year Fup) Tandjung K et al. J Am Coll Cardiol 2014; 61:2406–16

TWENTE: Flow Chart

692 Pts. completed3 Yr. follow-up

689 Pts. completed 3 Yr. follow-up

318 Patients treated with Resolute or Xience V were followed in a registry

316 Pts. Completed 1-year follow-up

8 Pts. lost to follow-up 1 Lost to follow-up 1 No participation

697 Pts. allocated toResolute ZES

694 Pts. allocated toXience V EES

695 Pts. completed1 and 2 yr. follow-up*

692 Pts. completed1 and 2 yr follow-up*

0 Lost to follow-up 3 No participation

683 Pts. completed 5-year follow-up

687 Pts. completed 5-year follow-up

0 Lost to follow-up 2 Withdrew consent

0 Lost to follow-up 2 Withdrew consent

0 Lost to follow-up 3 No participation

1709 Eligible patients

1391 Patients enrolled in the TWENTE randomized trial

308 Pts. completed 5-year follow-up

At 5 years, follow-up information was obtained for 98.5% of the TWENTE randomized trial patients and in 96.9% of the Non-Enrolled TWENTE study patients. *No patients were lost or withdrew consent during the 2nd year.

TWENTE RCT

Non-Enrolled TWENTE Study

3 Lost to follow-up 6 No participation

RESOLUTE ZESn = 697 pts.

XIENCE V EESn = 694 pts. P

Age (yrs) 63.9 ± 10.9 64.5 ± 10.7 0.32 Men 505 (72.5) 504 (72.6) 0.94 BMI (kg/m²) 27.7 ± 3.9 27.8 ± 4.0 0.57 Diabetes mellitus (any) 158 (22.7) 143 (20.6) 0.35 Chronic renal failure* 19 (2.7) 19 (2.7) 0.99 Arterial hypertension 386 (55.4) 387 (55.8) 0.89 Hypercholesterolaemia 392/688 (57.0) 411/669 (61.4) 0.10 Current smoker 176 (25.3) 164 (23.6) 0.48 Family history of coronary artery disease 370 (53.1) 370 (53.3) 0.93 Previous myocardial infarction (any) 213 (30.6) 237 (34.1) 0.15 Previous percutaneous coronary intervention 139 (19.9) 149 (21.5) 0.48 Previous coronary arterial bypass surgery 68 (9.8) 80 (11.5) 0.28 Presentation with acute coronary syndrome 362 (51.9) 355 (51.2) 0.77 Clinical indication 0.47

Stable angina 335 (48.1) 339 (48.8)Unstable angina 172 (24.7) 153 (22.0)Non-ST-elevation MI 190 (27.3) 202 (29.1)

Left ventricular ejection fraction < 30% 19/529 (3.6) 13/522 (2.5) 0.30

Patient Characteristics

Data are n (%) or mean ± SD.* Serum creatinine level ≥ 130 μmol/L.

Lesions and Procedures (Patient-Level)

Data are n (%).* Includes CTO (not graft lesions or ISR)

RESOLUTE ZESn = 697 pts.

XIENCE V EESn = 694 pts. P

De novo coronary lesions only* 644 (92.4) 643 (92.7) 0.86

At least one CTO 51 (7.3) 44 (6.3) 0.47

At least one bifurcation 179 (25.7) 183 (26.4) 0.77

At least one bif. with sidebranch treatment 98 (14.1) 115 (16.6) 0.19

At least one in-stent restenosis 36 (5.2) 33 (4.8) 0.73

At least one small-vessel (RVD < 2.75 mm) 445 (63.8) 429 (61.8) 0.43

At least one lesion length > 27 mm 156 (22.4) 137 (19.7) 0.23

Multivessel treatment 174 (25.0) 162 (23.3) 0.48

Total number of lesions treated per patient 0.49

One lesion treated 422 (60.5) 434 (62.7)

Two lesions treated 198 (28.4) 195 (28.1)

Three or more lesions treated 77 (11.0) 64 (9.2)

Glycoprotein IIb/IIIa antagonist use 90 (12.9) 103 (14.8) 0.29

At least one off-label indication 547 (78.5) 530 (76.4) 0.35

Procedural success 667 (95.7) 665 (95.8) 0.91

Lesion Characteristics RESOLUTE ZES

n = 1080 lesionsXIENCE V EESn = 1036 lesions P

Target lesion locationLeft main 26 (2.4) 28 (2.7) 0.67Left anterior descending 441 (40.8) 437 (42.2) 0.53Left circumflex 243 (22.5) 240 (23.2) 0.72Right coronary artery 349 (32.3) 304 (29.3) 0.13Bypass graft 21 (1.9) 27 (2.6) 0.38

ACC-AHA lesion class 0.66A/B1 318 (29.4) 314 (30.4)B2/C 762 (70.6) 722 (69.6)

De novo lesion 1024 (94.8) 975 (94.1) 0.48 Chronic total occlusion 53(4.9) 47 (4.5) 0.69 In stent restenosis 38 (3.5) 37 (3.6) 0.95 Aorta-ostial lesion 76 (7.1) 78 (7.6) 0.66 Severe calcification 192 (17.8) 172 (16.6) 0.47 Bifurcated lesion 258 (23.9) 260 (25.1) 0.52 Thrombus present 33 (3.1) 38 (3.7) 0.43 Total vessel occlusion 109 (10.1) 94 (9.1) 0.43

Data are n (%).

Procedure Characteristics (Lesion-Level)

Data are n (%) or median (IQR) unless otherwise indicated.

RESOLUTE ZESn = 1080 lesions

XIENCE V EESn = 1036 lesions

P

Lesion length (mm) 14.51 (9.85-22.54) 14.30 (9.66-21.83) 0.35 Diameter of reference vessel (mm) 2.65 (2.30-3.05) 2.66 (2.28-3.07) 0.73 Baseline minimum lumen diameter (mm) 0.97 (0.72-1.29) 1.00 (0.73-1.29) 0.39 Baseline stenosis (lumen diameter, %) 62.57 (52.78-71.34) 61.26 (52.67-71.07) 0.31 Postprocedure stenosis (lumen diameter, %) 11.67 (8.93-14.90) 12.00 (9.18-15.64) 0.07 Postprocedure minimum lumen diameter (mm) 2.29 (1.89-2.69) 2.25 (1.88-2.65) 0.37 Acute gain in segment (mm) 1.24 (0.89-1.70) 1.25 (0.83-1.65) 0.22 No. of stents implanted per patient – mean ± SD 2.03 ± 1.19 2.02 ± 1.2 0.91 No. of stents implanted per lesion – mean ± SD 1.31 ± 0.59 1.35 ± 0.6 0.09 Total stent length (mm) per patient – mean ± SD 41.84 ± 27.66 40.09 ± 26.0 0.22 Total stent length (mm) per lesion – mean ± SD 27.00 ± 15.39 26.85 ± 16.0 0.83 Direct stenting 416 (38.5) 408 (39.4) 0.68 Postdilatation 876 (81.1) 848 (82.1) 0.54 Max. stent diameter per lesion (mm) – mean ± SD 2.96 ± 0.45 2.98 ± 0.47 0.37 Implantation of study stents only 1068 (98.9) 1026 (99.0) 0.74 Device success 1063 (98.4) 1011 (97.6) 0.17 Lesion success 1078 (99.8) 1034 (99.8) 0.97

TWENTE 5-Years: Target Vessel Failure (TVF)

Log-Rank P = 0.36

Follow-up (days)

TWENTE 5-Years: CD, TV-MI, CI-TVR, TVF

Clinically Indicated TVR Target Vessel Failure

Cardiac Death TV-Related MI

Log-Rank P = 0.18 Log-Rank P = 0.94

Log-Rank P = 0.36

Log-Rank P = 0.41

MI = myocardial infarction; TV = target vessel; TVF = target vessel failure; TVR = target vessel revascularization

TWENTE 5-Years: Stent Thrombosis

Follow-up (days)132012001080960840720600480360240120600

1

2

3

4

5

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tent

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(%)

Log-Rank P = 0.83

*

*

**

***

****

Cardiac DeathMyocardial InfarctionTarget-Vessel Revascularization

Cardiac DeathMyocardial InfarctionTarget-Vessel Revascularization

Stent thrombosis while being on DAPT

Definite stent thrombosis Probable stent thrombosis

*

1440 1560 1680 1800

*

2.1%

1.9%

Definite stent thrombosis rates for Resolute and Xience V stent groups were also low and showed no significant between-group difference: 1.0 % vs. 0.6 %, Log-Rank P = 0.37.

Data are frequencies (%) and Hazard Ratio (95% Confidence Interval). Target vessel and target lesion revascularizations were clinically indicated.

RESOLUTE ZESn = 697 pts.

XIENCE V EESn = 694 pts.

Hazard Ratio (95% CI)

Log-RankP

Death, any 62 (9.0) 80 (11.6) 0.77 (0.55 – 1.07) 0.12 Cardiac death 25 (3.7) 35 (5.2) 0.71 (0.42 – 1.18) 0.18

Myocardial infarction, any 49 (7.2) 52 (7.7) 0.94 (0.63 – 1.38) 0.73 Target vessel myocardial infarction 46 (6.8) 45 (6.6) 1.02 (0.67 – 1.53) 0.94

Revascularization, any 95 (14.1) 105 (15.9) 0.90 (0.68 – 1.18) 0.43 Target vessel revascularization (TVR) 60 (8.9) 69 (10.5) 0.86 (0.61 – 1.22) 0.41 Target lesion revascularization (TLR) 47 (7.0) 50 (7.7) 0.94 (0.63 – 1.40) 0.77

Target vessel failure (TVF) 110 (16.1) 123 (18.1) 0.89 (0.69 – 1.15) 0.36 Target lesion failure (TLF) 102 (15.0) 110 (16.2) 0.93 (0.71 – 1.21) 0.58 Major adverse cardiac events (MACE) 138 (19.9) 157 (22.7) 0.88 (0.70 – 1.10) 0.26 Patient-oriented composite endpoint (POCE) 176 (25.4) 196 (28.4) 0.89 (0.73 – 1.10) 0.27

Definite-or-probable stent thrombosis 13 (1.9) 14 (2.1) 0.92 (0.43 – 1.96) 0.83 Definite stent thrombosis 7 (1.0) 4 (0.6) 1.74 (0.51 – 5.94) 0.37

TWENTE 5-Years: Clinical Events

RESOLUTE ZES

XIENCE VEES

Hazard Ratio (95% CI)

P PInteraction

TWENTE 5 Years: Subgroup Analysis for TVF

* *

Favors RESOLUTE ZES

Favors XIENCE V EES

Exploratory analysis

TWENTE 5 Years: Patient-Reported Chest Pain

P= 0.91

RESOLUTE = 523

XIENCE V = 514

No or

• TWENTE was performed in a single, high-volume tertiary center for PCI by 5 experienced operators with uniform procedural strategies and liberal use of stent post-dilation. Generalization of the results might be limited in other settings.

• The results may not apply to patients with acute STEMI, as such patients were not studied.

• Due to the limited size of subgroups, results of the subgroup analysis should be interpreted with caution.

Limitations

Conclusion

The 5-year follow-up of the TWENTE randomized trial demonstrates similar long-term safety and efficacy of Resolute ZES and Xience V EES for the treatment of patients with obstructive coronary artery disease, who suffered from stable angina or non-ST-elevation acute coronary syndromes.

Interventional CardiologistsThoraxcentrum Twente Gert van Houwelingen Martin Stoel Frits de Man Hans Louwerenburg Clemens von Birgelen

Principal Investigator Clemens von Birgelen

Referring Hospital Follow-up Gerard Linssen (ZGT, Almelo and Hengelo)

Salah Saïd (ZGT, Almelo and Hengelo)

Miep Kleijne (SKB, Winterswijk)

Patrick Verhorst (MST, Enschede)

Research Team Enschede Mounir Basalus Kenneth Tandjung Hanim Sen Ming Kai Lam Liefke van der Heijden Marlies Kok Marije Löwik

Clinical Event Adjudication CRO Cardialysis (Rotterdam)

CRO Diagram (Zwolle)

Clinical Teams Teams of cath lab, nurse practicioners, A2, E2, CCU of Thoraxcentrum Twente Cees Doelman (Medlon)

Study CenterThoraxcentrum Twente Harald Verheij Jan van Es, on behalf of CRO CardioResearch EnschedeImaging Core Lab Thoraxcentrum Twente Jacqueline Jonge Poerink Ilona Valkenburg Renate Wiggers

Trial Statistician Job van der Palen (MST & University of Twente)

This investigator-initiated randomized trial was equally funded by Medtronic and Abbott Vascular until 2 years, and the 3 to 5-year follow-up was funded by Medtronic.