Everolimus-eluting Bioresorbable Vascular Scaffolds in Patients with Coronary Artery Disease: The...

Everolimus-eluting Bioresorbable Vascular Scaffolds in Patients with

Coronary Artery Disease: The ABSORB III trial

Dean J. Kereiakes, MD, Stephen G. Ellis, MD, D. Christopher Metzger, MD, Ronald P. Caputo, MD, David G. Rizik, MD, Paul S.

Teirstein, MD, Marc R. Litt, MD, Annapoorna Kini, MD, Ameer Kabour, MD, Steven O. Marx, MD, Jeffrey J. Popma, MD, Robert McGreevy, PhD, Zhen Zhang, PhD, Charles Simonton, MD and

Gregg W. Stone, MD for the ABSORB III Investigators

• Modest Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Significant Consulting Fees• Major Stock Shareholder/Equity

• HCRI• Boston Scientific• Abbott Vascular• Svelte Medical Systems, Inc.• Janssen Research & Development LLC• Sanofi-Aventis U.S. LLC• Ablative Solutions, Inc.

Affiliation/Financial Relationship Company

Disclosure Statement of Financial Interest

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Everolimus/PDLLA (1:1) matrix coating

• 7 µm

• Conformal coating

• Controlled drug release similar to Xience CoCr-EES

PLLA Backbone

• Semi-crystalline

• Circumferential sinusoidal rings connected by linear links

• Strut thickness 150 µm

• Platinum markers in each end ring

FullyBioresorbable

Absorb BVS

Drug Elution

Mechanical Support

Mass loss

Oberhauser JP et al. EuroInt 2009;5:F15-22

1 6 243

Revascularization Restoration Resorption

Months

Phases of Absorb Functionality

1Atherosclerosis 2014;237:23e292 Images courtesy of S Windecker, ABSORB Cohort B 5 Yrs

Metallic DES1 Absorb-Treated Artery2

Metallic DES vs. Absorb BVSRepresentative Human images at 5 Years

Absorb Program ObjectivesA Series of Randomized Trials Designed to:

• Demonstrate similar (non-inferior) results with ABSORB BVS compared to Xience CoCr-EES at 1 year

• Demonstrate superior results with ABSORB BVS compared to Xience CoCr-EES between 1 and 5 years

7

30 d

6 mo

12 mo

24 mo

36 mo

48 mo

60 mo

Clinical follow-up:

Prospective, multicenter, single-blind, trial~2,000 patients randomized

2:1 Absorb BVS vs. Xience CoCr-EES

ABSORB III Study Design

No routine angiographic follow-up

U.S.

Australia

193 Enrolling Centers

1. Dr. Metzger (76)Holston Valley Wellmont Medical

Center

8. Dr. DeGregorio (38)Englewood Hospital and Medical

Center

15. Dr. Waksman (26)MedSTAR Washington Hospital

Center

2. Dr. Caputo (52)St. Joseph's Hospital Health

Center

9. Dr. Cannon (36)Northern Michigan Hospital

16. Dr. Abbas (24)William Beaumont Hospital

3. Dr. Rizik (49)Scottsdale Healthcare

10. Drs. Cambier & Stein (35)Morton Plant Hospital,

17. Dr. Zidar (24)Rex Hospital, Inc

4. Dr. Teirstein (45)Scripps Green Hospital

11. Dr. Newman (34)WakeMed

18. Dr. Dearing (24)Thomas Hospital

5. Dr. Litt (42)Baptist Medical Center

12. Dr. Feldman (31)Munroe Regional Medical Center

19. Dr. Williams (23)Presbyterian Hospital

6. Dr. Kini (41)Mount Sinai Medical Center

13. Dr. Broderick (28)The Christ Hospital

20. Dr. Choi (23)Baylor Jack and Jane Hamilton

Heart and Vascular Hospital

7. Dr. Kabour (41)Mercy St. Vincent Medical Center

14. Dr. Jain (28)Washington Hospital, Fremont, CA

21. Dr. Moses (23)Columbia University Medical Center

Top Enrollers (N patients)

• Principal InvestigatorsDean Kereiakes, MD, The Christ Hospital, Cincinnati, OHStephen G. Ellis, MD, Cleveland Clinic, Cleveland, OH

• Study ChairmanGregg W. Stone, MD, Columbia University Medical Center, NY, NY

• Clinical Events CommitteeCardiovascular Research Foundation, New York, NY

Steven Marx, MD, chair

• Angiographic Core LaboratoryBeth Israel Deaconess Medical Center, Boston, MA

Jeff Popma, MD, director

• Data Safety Monitoring Board Axio Research, Seattle, WA; Robert N. Piana, MD, chair

• SponsorAbbott Vascular, Santa Clara, CA

Study Leadership

Primary Endpoint: Target Lesion Failure (non-inferiority)

• Cardiac death, or

• Myocardial infarction attributed to the target vessel (TV-MI), or

• Peri-procedural MI: CK-MB >5x ULN w/i 48 hours

• Ischemia-driven target lesion revascularization (ID-TLR)

Powered Secondary Endpoints (superiority)

• Angina

• All revascularization

• Ischemia-driven target vessel revascularization (ID-TVR)

Major Endpoints at 1 Year

Non-inferiority analysis for TLF at 1 year with the following assumptions:

1-year TLF rate of 7%

Non-inferiority margin of 4.5%

“Putative placebo”, preserving ≥ 50% of the treatment effect of Xience vs. BMS

1-sided alpha of 0.025 (equivalent to 2-sided 0.05)

95% 1-year follow-up

2000 subjects → 96% power

Maximum observed difference in order to pass non-inferiority = 2%

Primary Endpoint

Statistical Design

• >18 years old

• Evidence of myocardial ischemia (stable/unstable/post-infarction angina or silent ischemia)

• No elevation of CK-MB

• 1 or 2 de novo target lesions in up to 2 native coronary arteries (max 1 lesion per artery)

• Diameter stenosis ≥50% and <100% with TIMI flow ≥1

If <70%, abnormal functional test (including FFR ≤0.80), unstable angina or post-infarct angina

• RVD ≥2.50 mm and ≤3.75 mm (site-determined)

• Lesion length ≤24 mm (site-determined)

Key Patient Eligibility Criteria

Randomized 2:1N=2008 (ITT)

ABSORB N=1322

ABSORBN=1312

Xience N=677

99.2% Complete 98.7% Complete

N=4 lost to follow-upN=6 withdrew consent

N=6 lost to follow-upN=3 withdrew consent

XienceN=686

12-month Follow-up

Study Flow and Follow-up

CharacteristicAbsorb

(N=1322)Xience

(N=686) p-value

Age (mean) 63.5 ±10.6 63.6±10.3 0.75

Male 70.7% 70.1% 0.80

Race (Caucasian) 87.1% 88.3% 0.44

Current tobacco use 21.3% 20.7% 0.77

Hypertension 84.9% 85.0% 0.95

Dyslipidemia 86.2% 86.3% 0.97

Diabetes 31.5% 32.7% 0.60

Insulin-treated 10.5% 11.2% 0.60

Prior MI 21.5% 22.0% 0.79

Prior coronary intervention 38.7% 38.0% 0.75

Stable angina 57.3% 60.8% 0.13

Unstable angina 26.9 % 24.5% 0.25

Silent ischemia 10.0% 10.2% 0.88

Single vessel disease 69.5% 67.2% 0.29

Baseline Characteristics

Characteristic

Absorb(N=1322)(L=1385)

Xience(N=686)(L=713) p-value

ACC/AHA lesion class B2/C 68.7% 72.5% 0.08

# of target lesions treated 1.0 ± 0.2 1.0 ± 0.2 0.38

One 95.1% 96.1% 0.32

Two 4.8% 3.9% 0.36

Target lesion

LAD 44.5% 42.2% 0.31

RCA 29.2% 27.2% 0.35

Circumflex 26.2% 30.6% 0.03

Lesion length, mm 12.60 ± 5.41 13.12 ± 5.82 0.05

RVD, mm 2.67 ± 0.45 2.65 ± 0.46 0.36

RVD <2.25 mm 18% 19% 0.39

MLD, mm 0.92 ± 0.37 0.90 ± 0.34 0.11

%DS 65.3 ± 12.5 65.9 ± 11.7 0.24

Baseline Lesion Characteristics (QCA)

N= number of subjectsL= number of lesions

Characteristic

Absorb(N=1322)(L=1385)


Per Subject

Bivalirudin use 60.7% 58.7% 0.39

GP IIb/IIIa inhibitor use 10.1% 12.4% 0.11

Only unassigned devices implanted 4.4% 0.6% <0.001

Unplanned overlapping devices 6.2% 8.5% 0.06

Post-dilatation performed 65.5% 51.2% <0.001

Intravascular imaging guidance 11.2% 10.8% 0.81

Procedure duration (min) 42.2 ± 23.1 38.3 ± 20.9 <0.001

Per Lesion

Total study device length (mm) 20.5 ± 7.2 20.7 ± 9.0 0.56

Max device/balloon diameter (mm) 3.18 ± 0.43 3.12 ± 0.45 0.007

Max device/balloon to vessel diameter ratio 1.21 0.15 1.19 0.14 0.05

Maximum device/balloon pressure (atm.) 15.4 ± 3.0 15.4 ± 3.2 0.83

Procedural Characteristics


Measurement

Absorb(N=1322)(L=1385)


RVD 2.70 ± 0.45 2.68 ± 0.47 0.33

In-Device

MLD 2.37 ± 0.40 2.49 ± 0.40 <0.0001

Acute gain 1.45 ± 0.45 1.59 ± 0.44 <0.0001

%DS 11.6 ± 8.77 6.4 ± 8.91 <0.0001

In-Segment

MLD 2.15 ± 0.41 2.14 ± 0.43 0.58

Acute gain 1.23 ± 0.46 1.24 ± 0.44 0.50

%DS 20.0 ± 7.94 19.8 ± 8.20 0.55

Post-procedural QCA


Absorb(N=1322)(L=1385)


Device Success 94.3% 99.3% <0.0001

Procedural Success 94.6% 96.2% 0.12

• Device Success (lesion basis) Successful delivery and deployment of study scaffold/stent at intended target lesion Successful withdrawal of delivery system and final in-scaffold/stent DS <30% (QCA)

• Procedure Success (patient basis) Successful delivery and deployment of at least one study scaffold/stent at intended

target lesion Successful withdrawal of delivery system and final in-scaffold/stent DS <30% (QCA) No in-hospital (maximum 7 days) TLF

Acute Success

Absorb(N=1322)

Xience(N=686) p-value

At index procedure

P2Y12 inhibitor 99.0% 98.8% 0.70

Clopidogrel 62.6% 64.7% 0.34

Prasugrel 21.8% 19.5% 0.24

Ticagrelor 14.8% 14.9% 0.94

Aspirin 99.3% 99.3% 1.00

At 30 days

P2Y12 inhibitor 99.0% 99.1% 0.81

Clopidogrel 68.3% 72.0% 0.09

Prasugrel 20.7% 17.5% 0.08

Ticagrelor 11.8% 10.6% 0.44

Aspirin usage 98.6% 99.0% 0.43

At 1 year

P2Y12 inhibitor 94.4% 95.0% 0.55

Clopidogrel 67.5% 72.2% 0.03

Prasugrel 17.9% 14.0% 0.03

Ticagrelor 9.0% 8.9% 0.94

Aspirin usage 95.8% 95.8% 0.94

Antiplatelet Agent Usage

-1 0 1 2 3 4 5

Non-inferiority margin = 4.5%

Difference = 1.7% [-0.5%, 3.9%]PNI = 0.007

% Difference (ABSORB - Xience)

Primary Endpoint1 Year TLF

1-Year TLFABSORB vs. Xience

7.8% (102/1313) vs. 6.1% (41/677)

No. at Risk:Absorb

TL

F (

%)

Xience

Months Post Index Procedure

20%

100%

80%

60%

40%

0%

0 1 2 3 4 5 6 7 8 9 10 11 12

1322686

1254661

1230651

1218643

1196634

13

Absorb BVS (n=1322)Xience CoCr-EES (n=686)

Diff [95% CI] =1.7% [-0.5% to 3.9%]

Psuperiority=0.16

20%

15%

10%

5%

0%0 1 2 3 4 5 6 7 8 9 10 11 13

7.7%6.0%

12

Target Lesion Failure

SubgroupAbsorb

(N=1322)Xience

(N=686)RR

(95% CI)Relative Risk

(95% CI)p-value

(interaction)Age ≥64 years 8.1% 5.9% 1.37 (0.84-2.23)

0.69Age <64 years 7.4% 6.2% 1.19 (0.72-1.97)

Female 8.5% 7.4% 1.16 (0.64-2.08)0.68

Male 7.4% 5.5% 1.36 (0.88-2.10)

Diabetes 10.7% 9.1% 1.18 (0.71-1.95)0.68

No diabetes 6.3% 4.6% 1.38 (0.85-2.24)

Unstable angina/recent MI 6.5% 6.6% 0.98 (0.50-1.90)0.35

Stable CAD 8.3% 5.8% 1.42 (0.94-2.15)

Single TL/TV treated 7.7% 5.8% 1.32 (0.92-1.89)0.50

Dual TL/TV treated 9.4% 11.5% 0.81 (0.22-3.01)

Clopidogrel 8.0% 6.8% 1.17 (0.77-1.78)0.43

Prasugrel or ticagrelor 7.1% 4.3% 1.63 (0.82-3.25)ACC/AHA class A or B1 6.8% 2.2% 3.05 (1.08-8.60)

0.07ACC/AHA class B2 or C 8.2% 7.5% 1.10 (0.75-1.61)

Lesion length <11.75 mm 7.9% 4.8% 1.64 (0.95-2.83)0.23

Lesion length ≥11.75 mm 7.7% 7.3% 1.06 (0.67-1.67)

RVD <2.63 mm 9.8% 7.8% 1.27 (0.82-1.94)0.90

RVD ≥2.63 mm 5.7% 4.3% 1.34 (0.73-2.44)

0.1 1 10Favors Absorb Favors Xience

1-Year TLF: Subgroup analysis

1.0

1-Year TLF Components

TLF Cardiac death TV-MI ID-TLR0

2

4

6

8

10

7.8

0.6

6.0

3.0

6.1

0.1

4.6

2.5

Absorb (N=1322)Xience (N=686)

1-Y

ea

r T

LF

(%

)

P=0.16

P=0.29

P=0.18

P=0.50

All MI All Q-MI All NQ-MI TV MI TV Q-MI TV NQ-MI0

2

4

6

8

10

6.9

0.8

6.1 6.0

0.7

5.35.6

0.4

5.24.6

0.3

4.3

Absorb (N=1322)

Xience (N=686)

1-Y

ea

r M

I (%

)

P=0.18

P=0.35

P=0.31

P=0.28

P=0.56

P=0.40

Myocardial Infarction to 1 Year

CK-MB thresholdAbsorb

(N=1322)Xience

(N=686) Difference p-value

>3x ULN 6.8% 6.6% 0.2 0.89

>5x ULN (protocol) 3.0% 2.8% 0.2 0.75

>8x ULN 1.3% 1.3% 0.0 0.96

>10x ULN 0.9% 1.2% -0.3 0.58

SCAI definition* 0.9% 1.2% -0.3 0.58

Peri-Procedural MI by Definition

*>10x ULN or >5x ULN with new Q waves or new persistent LBBB J Am Coll Cardiol 2013;62:1563-70

Absorb(N=1322)


Device Thrombosis (def*/prob) 1.54% 0.74% 0.13

- Early (0 to 30 days) 1.06% 0.73% 0.46

- Late (> 30 to 1 year) 0.46% 0.00% 0.10

- Definite* (1 year) 1.38% 0.74% 0.21

- Probable (1 year ) 0.15% 0.00% 0.55

*One “definite ST” in the Absorb arm by ITT was in a pt that was treated with Xience

Device Thrombosis to 1 Year

1-Year Device Thrombosis

SubgroupAbsorb

(N=1322)Xience

(N=686)RR

(95% CI)Relative Risk

(95% CI)p-value

(interaction)Age ≥64 years 1.8% 0.6% 3.22 (0.73-14.32

0.38Age <64 years 1.2% 0.9% 1.33 (0.36-4.99)

Female 1.6% 2.0% 0.79 (0.23-2.78)0.07

Male 1.5% 0.2% 7.21 (0.95-54.63)

Diabetes 3.2% 1.4% 2.34 (0.67-8,13)0.78

No diabetes 0.8% 0.4% 1.79 (0.37-8.56)

Unstable angina/recent MI 1.0% 0.6% 1.88 (0.21-16.74)0.91

Stable CAD 1.7% 0.8% 2.16 (0.73-6.42)

Single TL/TV treated 1.6% 0.8% 2.09 (0.79-5.55)n/a

Dual TL/TV treated 0.0% 0.0% -

Clopidogrel 1.8% 0.7% 2.69 (0.78-9.24)0.33

Prasugrel or ticagrelor 0.8% 0.9% 0.96 (0.18-5.20)

ACC/AHA class A or B1 0.8% 0.6% 1.36 (0.14-12.98)0.67

ACC/AHA class B2 or C 1.9% 0.8% 2.32 (0.79-6.87)

Lesion length <11.75 mm 1.4% 0.9% 1.58 (0.43-5.78)0.56

Lesion length ≥11.75 mm 1.7% 0.6% 2.82 (0.63-12.67)

RVD <2.63 mm 2.3% 0.9% 2.65 (0.77-9.07)0.48

RVD ≥2.63 mm 0.8% 0.6% 1.28 (0.25-6.54)

0.1 1 10 100Favors Absorb Favors Xience

Absorb(N=1322)


Angina 18.3% 18.4% 0.93

All Revascularization 9.1% 8.1% 0.50

ID-TVR 5.0% 3.7% 0.21

Powered Secondary Endpoints

• ABSORB III eligibility criteria included vessels with RVD 2.5 mm – 3.75 mm (visual estimation)

• The thicker struts of ABSORB may be of particular concern in very small vessels

• Subgroup analysis was therefore performed in vessels with QCA RVD <2.25 mm vs. ≥2.25 mm (correlates with visual estimate ~2.5 mm)

• ~19% of patients had a target lesion with RVD <2.25 mm by QCA

ABSORB III Very Small Vessel Analysis

TLF ST TLF ST

-5%

0%

5%

10%

15%

20%

12.9%

4.6%6.7%

0.9%

8.3%

1.5%

5.5%

0.6%

Absorb Xience

RVD <2.25 mm(median 2.09 mm)

1-Y

ear

Eve

nts

(%

)

Median based on pooled Absorb and Xience

RVD ≥2.25 mm(median 2.74 mm)

Outcomes by QCA RVD 2.25 mm

# Events: 31 11 11 2 71 30 9 3

# Risk: 241 133 238 133 1067 542 1058 540

TLF: Pint diff = 0.31ST: Pint diff = 0.12

• ABSORB III enrolled patients with stable ischemic heart disease and stabilized ACS, and excluded specific complex lesions (e.g. CTO, LM, large bif); results may therefore not be generalizable to higher-risk patients and more complex disease

• Underpowered for low frequency events

• Results should be viewed in context that Xience was the control device which has been associated with the lowest rates of ST and other events

• BVS is a first generation device and was used for the first time by most operators within this trial

Limitations

• ABSORB BVS was non-inferior to Xience CoCr-EES for TLF at 1 year (primary endpoint met)

• TLF components (cardiac death, TV-MI, ID-TLR) were not significantly different between devices

• Angina, all revascularization and ID-TVR were similar between devices

• No statistically significant differences in device thrombosis were present

Summary and Conclusions (1)

• The ABSORB III trial has demonstrated safety and efficacy of Absorb BVS at 1 year in patients with stable CAD and stabilized ACS

• Longer term evaluation is ongoing to determine if ABSORB improves late outcomes compared to Xience

Summary and Conclusions (2)

Everolimus-eluting Bioresorbable Vascular Scaffolds in Patients with Coronary Artery Disease: The...

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