Five-Year Follow-up of Safety and Efficacy of the Resolute Zotarolimus-Eluting Stent: Insights

from the RESOLUTE Global Clinical Trial Program in Approximately 8000 Patients

Prof. Sigmund Silber, MD, PhDFESC, FACC, FAHA

Cardiology Practice and Heart Center at the Isar, Munich, Germany

on behalf of the RESOLUTE Global Clinical Program Investigators

euroPCR 2015

Potential conflicts of interest

Speaker's name: Sigmund Silber

Research Grant from Medtronic for the RESOLUTE All Comers Randomized Trial

Background

• Individual trials, while powered for composite endpoints of various parameters, are often underpowered to show real and truly evidence based differences for low-frequency but important adverse clinical events such as stent thrombosis.

• Objective of the current analysis is to assess the long-term safety and efficacy outcomes of the Resolute™ zotarolimus-eluting stent (R-ZES) in nearly 8000 patients enrolled in the RESOLUTE Global Clinical Trial Program.

RESOLUTE Pooled – 5 Years

Methods

• This pooled analysis includes all trials within the RESOLUTE Global Clinical Program, including regulatory trials with 100% monitoring, all with high rates of follow-up.

• Patient level data of all 7618 Resolute patients were pooled, including data to the latest available follow-up of each trial.

• Kaplan Meier cumulative incidence out to 5 year follow-up was calculated.

• Strengths: All trials were prospectively performed and event definitions across studies were consistent. The independent clinical event adjudication was harmonized across all studies.

• Limitations: post-hoc analysis

RESOLUTE Pooled – 5 Years

The RESOLUTE Global Clinical Program:7618 Patients Included in this Pooled Analysis

1 Meredith IT, et al. EuroIntervention. 2010;5:692-7. 2 Serruys PW, et al. N Engl J Med. 2010;363:136-46. 3 Silber S, et al. Lancet. 2011;377:1241-47. 4 Neumann FJ, et al. EuroIntervention. 2012;7(10):1181-8. 5 Belardi JA, et al. J Interv Cardiol. 2013;26(5):515-23. 6 Yeung AC, et al. JACC. 2011;57:1778-83.7 Lee M, et al. Am J Cardiol. 2013;112(9):1335-41. 8 Xu B, et al. JACC Cardiovasc Interv. 2013;6(7):664-70. 9 Qiao S, et al. Am J Cardiol. 2014;113(4):613-20.

RESOLUTE1 Non-RCT First-in-Human (R=139)Non-RCT First-in-Human (R=139) 5 yr

RESOLUTE AC2,3 1:1 RCT vs. Xience V™ EES (R=1140; X=1152)1:1 RCT vs. Xience V™ EES (R=1140; X=1152) 5 yr

2.25 – 4.0 mm Non-RCT vs. Hx Control (R=1402)2.25 – 4.0 mm Non-RCT vs. Hx Control (R=1402) 5 yrRESOLUTE US6

2.5 – 3.5 mm Non-RCT (R=100) vs. Hx Control2.5 – 3.5 mm Non-RCT (R=100) vs. Hx ControlRESOLUTE Japan 5 yr

1:1 RCT vs. Taxus™ PES (R=200; T=200)1:1 RCT vs. Taxus™ PES (R=200; T=200)R-China RCT8 3 yr

Non-RCT Observational (R=2349)Non-RCT Observational (R=2349) 3 yr RESOLUTE Int4,5

R-China Registry9 Non-RCT Observational (R=1800)Non-RCT Observational (R=1800) 2 yr

R-Japan SVS 2.25 Non-RCT vs. PG (R=65)2.25 Non-RCT vs. PG (R=65) 3 yr

38 mm sub-study Non-RCT vs. PG (R=114)38 mm sub-study Non-RCT vs. PG (R=114) 3 yrRESOLUTE US7

Available follow-up

RESOLUTE Asia7 Non-RCT Observational (R=312)Non-RCT Observational (R=312) 2 yr

% N = 7618 Pts

Age (yr) 63.0 ± 11.0Male 75.4Diabetes mellitus 30.4 IDDM 6.7Hypertension 71.0Hyperlipidemia 62.3Current smoker 26.4Family history 29.1Prior MI 29.2Prior PCI 25.8Prior CABG 6.3Cardiac Status: Stable angina 33.0

Unstable angina 38.1All myocardial infarction 25.9Acute coronary syndrome 52.4

Baseline Patient CharacteristicsRESOLUTE Pooled – 5 Years

% N = 7618 Pts,10186 Lesions

LAD 53.2

LCx 29.0

RCA 34.4

Left Main 1.8

Bypass graft 1.1

B2/C lesion 67.5

Reference Vessel Diameter (mm) 2.8 ± 0.5

Minimum Lumen Diameter (mm) 0.6 ± 0.5

Percent Diameter Stenosis 77.5 ± 16.2

Lesion length (mm) 18.2 ± 11.3

No. of lesions treated per patient 1.3 ± 0.6

No. of stents per patient 1.6 ± 1.0

Total stent length per patient (mm) 33.10 ± 22.59

Multi-vessel treament (%) 20.5

Complex patient1 46.7

1Complex patient definition: bifurcation, bypass grafts, ISR, AMI <72 hr, LVEF <30%, unprotected LM, >2 vessels stented, renal insufficiency or failure (creatinine >140 µmol/L), lesion length >27 mm, >1 lesion per vessel, lesion with thrombus or total occlusion (preprocedure TIMI = 0).

Lesion and Procedure CharacteristicsRESOLUTE Pooled – 5 Years

Definition of Composite Endpoints

Device Oriented Composite EndpointTarget Lesion Failure (TLF)

Cardiac Death

Target Vessel Myocardial Infarction (TV-MI)

Target Lesion Revascularization (clinically indicated, TLR)

Patient Oriented Composite Endpoint

(POCE)

All Deaths

All Myocardial Infarctions

All Revascularizations

Cutlip DE, et al. Circulation. 2007; 115: 2344-2351

RESOLUTE Pooled – 5 Years

Individual Components of the Device-Oriented Endpoint

0

30

0 1 2 4 5

Time After Initial Procedure (years)

3

Cum

ulati

ve In

cide

nce

(%)

Cardiac Death 7618 7616 7375 6714 4542 24650.0% 1.0% 1.9% 2.8% 4.0% 5.0%

RESOLUTE Pooled – 5 Years

Cardiac Death

5.0

15

20

25

10

5

Individual Components of the Device-Oriented Endpoint

0

30

0 1 2 4 5

Time After Initial Procedure (years)

3

Cum

ulati

ve In

cide

nce

(%)

Cardiac Death 7618 7616 7375 6714 4542 24650.0% 1.0% 1.9% 2.8% 4.0% 5.0%

TV-MI 7618 7538 7179 6506 4386 23771.0% 2.8% 3.2% 3.6% 3.9% 4.4%

RESOLUTE Pooled – 5 Years

Cardiac Death

5.0

15

20

25

10

5

Target Vessel MI (TV-MI)

4.4

Individual Components of the Device-Oriented Endpoint

0

30

0 1 2 4 5

Time After Initial Procedure (years)

3

Cum

ulati

ve In

cide

nce

(%)

Cardiac Death 7618 7616 7375 6714 4542 24650.0% 1.0% 1.9% 2.8% 4.0% 5.0%

TV-MI 7618 7538 7179 6506 4386 23771.0% 2.8% 3.2% 3.6% 3.9% 4.4%

TLR 7618 7608 7191 6444 4318 23270.1% 2.6% 4.0% 4.5% 5.1% 6.3%

RESOLUTE Pooled – 5 Years

Cardiac Death

5.0

15

20

25

10

5

Target Vessel MI (TV-MI)

4.4

Target Lesion Revascularization (TLR)

6.3

Device Oriented = Target Lesion Failure (TLF)

00 1 2 4 5

Time After Initial Procedure (years)

3

Cum

ulati

ve In

cide

nce

(%)

TLF 7618 7532 7027 6280 4196 22571.1% 5.7% 8.1% 9.5% 11.4% 13.4%

RESOLUTE Pooled – 5 Years

Device-Oriented Endpoint (TLF): Cardiac Death, TV-MI, TLR

20

50

30

40

10 5.713.4

Device- vs. Patient-Oriented Endpoint

00 1 2 4 5

Time After Initial Procedure (years)

3

Cum

ulati

ve In

cide

nce

(%)

TLF 7618 7532 7027 6280 4196 2257POCE 7618 7530 6661 5801 3746 1926

RESOLUTE Pooled – 5 Years

Device-Oriented Endpoint (TLF): Cardiac Death, TV-MI, TLR

20

50

30

40

10 5.713.4

Patient-Oriented Endpoint (POCE): All Deaths, All MI, All Revascularizations

29.5

11.2

Note for reference: POCE in RESOLUTE All-Comers was not statistically significant between Resolute ZES and Xience V EES.

1 6 12 24 36 48 600

25

50

75

10091.0 %

47.3%

37.0% 34.4%

DAPT Usage - overall

Patie

nts

Rece

ivin

g DA

PT (%

)

Time After Initial Procedure (months)

31.9%

R-Pooled (N=7618)

RESOLUTE Pooled – 5 Years

1 6 12 24 36 48 600

10

20

30

40

50

60

70

80

90

100

DAPT Usage - Individual Trials

Patie

nts

Rece

ivin

g DA

PT (%

)

Time After Initial Procedure (months)

R-US (N=1402)R-All Comers (N=1140)R-International (N=2349)

11.0% (Europe + Israel)

46.6% (US)

RESOLUTE FIM (N=139)R-Japan (N=100)R-Japan SVS (N=65)

62.5% (Japan)

R-38mm (N=223)R-Asia Dual vessel (N=202)R-China RCT (N=200)

R-China Registry (N=1800)

20.1% (China)

39.4% (ANZ)

R-Pooled (N=7618)

1 6 12 24 36 48 600

25

50

75

100

34.6% (Intern.)

66.1% (Japan)65.6% (Asia + US)

51.0% (China)

65.8% (Asia)

31.9%

RESOLUTE Pooled – 5 Years

Definite Stent Thrombosis (ARC)

0

2

5

3

0.78

4

0 1 2 4 5

Time After Initial Procedure (years)

1

3

Cum

ulati

ve In

cide

nce

ofAR

C D

efini

te S

T (%

)

0.46

No. at risk 7618 7611 7347 6680 4516 2450

% CI 0.07 0.46 0.56 0.62 0.66 0.78

RESOLUTE Pooled – 5 Years

Definite/Probable Stent Thrombosis

0

2

5

3

4

0 1 2 4 5

Time After Initial Procedure (years)

1

3

Cum

ulati

ve In

cide

nce

ofAR

C D

efini

te/P

roba

ble

ST (%

)

No. at risk 7618 7610 7344 6676 4511 2443

% CI 0.08 0.67 0.84 0.95 1.07 1.20

RESOLUTE Pooled – 5 Years

1.200.67

Very Late Stent Thrombosis (Definite / Probable)

0

2

5

3

0.54

4

1

Time After Initial Procedure (years)

1

Cum

ulati

ve In

cide

nce

of A

RCVe

ry L

ate

Defi

nite

/Pro

babl

e ST

(%)

No. at risk 7618 7375 6706 4533 2456

% CI 0.00 0.18 0.29 0.41 0.54

2 3 54

RESOLUTE Pooled – 5 Years

Conclusions

• The current analysis of 7618 patients is the largest and longest dataset to date of Resolute patients evaluated. While the complexity of patients varied by study, approximately half of all patients had one or more complex patient characteristics.

• Significant differences were observed in DAPT duration between trials and geographies, reflective of different clinical practices around the world.

• The event rates were stable through long-term follow-up. In particular, the rate of very late ST (>1 yr, definite/probable) is low at 0.5% out to 5 years.

• Long-term follow-up of current generation DES remains critically important to evaluate if there is any increased risk over time of low frequency events. In this pooled analysis, we did not observe any concerns of long term safety associated with the Resolute stent.

• Over 5 years, more than half of the adverse events were not device (= stent) related, indicating that we still need better general treatment options for patients with coronary artery disease - even after stenting the culprit lesion(s).

RESOLUTE Pooled – 5 Years