Intervention Cardiology/Research for Cardiology Trainees Weds Presentations/H2 1100... · 2017. 11. 12. · 21/07/2017 1 Alan C. Yeung, M.D. Li Ka Shing Professor of Medicine Chief,

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1

Alan C. Yeung, M.D.

Li Ka Shing Professor of Medicine Chief, Division of Cardiovascular Medicine

Director, Cardiovascular Health

Intervention Cardiology/Research for

Cardiology Trainees

DISCLOSURES

Research Grant (Interventional Cardiology)

Medtronic

Boston Scientific Corp

Abbott Vascular

In-kind Support (software development)

Apple, Inc.

Scientific Advisors

Medtronic

Boston Scientific Corp

Abbott Vascular

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2

TOPICS

Major trends in Interventional Cardiology

Structural Heart: TAVR

PCI: Bioabsorbable Scaffolds

PCI: FFR

How to have a successful fellowship in research

0

10

20

30

40

POBA early POBA late Stent early Stent late DES

Eve

nt R

ate

%

1977 1985 1997 1994 2003-present

Evolution of PCI: The Dominant Coronary Revascularization Therapy

Failure

Em CABG

Restenosis

Stent thrombosis

VLST

Innovations over time

Progressive improvements in success, safety, and durability,

as serial new technologies have been launched.

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(2010-2017 )

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PCI Volumes

-

10,000

20,000

30,000

40,000

50,000

60,000

Q1FY12

Q2FY12

Q3FY12

Q4FY12

Q1FY13

Q2FY13

Q3FY13

Q4FY13

Q1FY14

Q2FY14

Q3FY14

Q4FY14

Q1FY15

Q2FY15

Q3FY15

Q4FY15

Asia Pacific PCIs

8

Presentation Title (Edit on Slide Master) | June 1, 2015 |

Confidential, for Internal Use Only

# Cath

Labs Population Cath Lab Per Million Population per Cathlab

Japan 1335 127,817,277

10.44

95,743.28

US 2000 311,587,816

6.42

155,793.91

Germany 521 81,797,673

6.37

157,001.29

Australia 80 22,323,900

3.58

279,048.75

Singapore 17 5,183,700

3.28

304,923.53

Korea 133 49,779,000

2.67

374,278.20

Malaysia 50 28,758,968

1.74

575,179.36

Thailand 50 66,576,332

0.75

1,331,526.64

China 1000 1,344,130,000

0.74

1,344,130.00

India 820 1,221,156,319

0.67

1,489,215.02

Vietnam 41 87,840,000

0.47

2,142,439.02

Pakistan 77 176,166,353

0.44

2,287,874.71

Sri Lanka 9 20,869,000

0.43

2,318,777.78

Indonesia 80 243,801,639

0.33

3,047,520.49

Bangladesh 48 152,862,431

0.31

3,184,633.98

Phillipines 22 95,053,437

0.23

4,320,610.77

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9

FY15 PCIs Population PCI per million

US 922,906 311,587,816 2,962

China 613,696 1,344,130,000 457

Australia 47,218 22,323,900 2,115

Canada 75,116 35,344,962 2,125

Japan 251,269 127,817,277 1,966

Korea 60,657 49,779,000 1,219

Malaysia 16,805 28,758,968 584

Singapore 8,801 5,183,700 1,698

India 250,000

1,221,000,000

Myanmar 1,204 52,350,763 23

Thailand 36,382 66,576,332 546

Indonesia 15,025 243,801,639 62

Vietnam 13,865 87,840,000 158

Phillipines 4,748 95,053,437 50

Balloon-expandable THV

Sapien 3 (Cobalt frame, bovine pericardium, outer

skirt, precise positioning)

Self-expandable THV,

REPOSITIONABLE

Medtronic EvolutR (Nitinol frame, porcine pericardium, longer skirt)

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Estimated Global TAVR Growth

SOURCE: Credit Suisse TAVI Comment –January 8, 2015. ASP assumption for 2024 and 2025 based on analyst model. Revenue split assumption in 2025 is 45% U.S., 35% EU, 10% Japan, 10% ROW

In the next 10 years, TAVR growth will increase X4!

Historically, Our Understanding of Aortic Stenosis was Based on Surgical Experience

(1) Nkomo 2006, Iivanainen 1996, Aronow 1991, Bach 2007, Freed 2010, Iung 2007, Pellikka

2005, Brown 2008, Thourani 2015,

Age

Pa

tie

nts

2015 Severe Symptomatic AS Patients in the U.S.1

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The TAVR Experience Has Changed Our Understanding of Aortic Stenosis

Age

Pa

tie

nts




A Large Population of Severe Symptomatic AS Patients Remain Undiagnosed and Untreated

Age

Pa

tie

nts




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2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

Trained US Sites 300 360 420 480 530 560 590 610 630 650

0

100

200

300

400

500

600

700

Trained US Sites

SOURCE: Industry estimates

480

650

Evolution of US TAVR Sites (disciplined, strategic, heart team based,

center-of-excellence approach, soon to reach a plateau )

1 TAVR site per 677,000 people in 2016

TAVR “Underutilization” is Largely Driven by Variation in Health Policy and Reimbursement

16

SOURCE: Eurostat, U.S. Census Bureau, Industry estimates

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79.9%

13.9%

6.2%

Intermediate risk

(STS 4-8%)

Low risk

(STS <4%)

High risk

(STS > 8%)

STS database 2002-2010 (141,905 pts)

Since 2007, in the U.S., >15,000 patients

have been enrolled in FDA studies

(including 6 RCTs) with multiple generations of

two TAVR systems!

N = 179

N = 358 Inoperable

Standard

Therapy

ASSESSMENT:

Transfemoral

Access

Not In Study

TF TAVR

Primary Endpoint: All-Cause Mortality

Over Length of Trial (Superiority)

Co-Primary Endpoint: Composite of All-Cause Mortality

and Repeat Hospitalization (Superiority)

1:1 Randomization

VS

Yes No

N = 179

TF TAVR AVR

Primary Endpoint: All-Cause Mortality at 1 yr

(Non-inferiority)

TA TAVR AVR VS

VS

N = 248 N = 104 N = 103 N = 244

PARTNER Study Design

Symptomatic Severe Aortic Stenosis

ASSESSMENT: High-Risk AVR Candidate

3,105 Total Patients Screened

Total = 1,057 patients

2 Parallel Trials:

Individually Powered

N = 699 High Risk

ASSESSMENT:

Transfemoral

Access

Transapical (TA) Transfemoral (TF)

1:1 Randomization 1:1 Randomization

Yes No

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PARTNER 5-year FU in Lancet (March, 2015)


The risk of all-cause mortality at 5 years was 71·8% in the TAVR group versus

93·6% in the standard treatment group (hazard ratio 0·50, 95% CI 0·39–0·65;

p<0·0001).

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The risk of all-cause mortality at 5 years was 71·8% in the TAVR group versus

93·6% in the standard treatment group (hazard ratio 0·50, 95% CI 0·39–0·65;

p<0·0001).

At 5 years, risk of death was 67·8% in the TAVR group compared with 62·4% in

the SAVR group (hazard ratio 1·04, 95% CI 0·86–1·24; p=0·76).

44.22

10.93

10.79 11.31 10.90 10.59

0.64

1.61 1.56

1.50 1.46 1.52

0.5

1.0

1.5

2.0

2.5

0

10

20

30

40

50

60

70

Mean G

radie

nt

(mm

Hg)

Valv

e A

rea (c

m²)

N =

EOA

Mean Gradient Error bars = ± 1 Std Dev

Mean Gradient & Valve Area (AT) P1B - All Patients

0.0

Baseline 1 Year 2 Years 3 Years 4 Years 5 Years

159 86 70 44 31 15

163 91 71 46 31 15

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43.4

11.5 11.0 10.3

9.9 10.6

43.1

10.0 10.2 9.8

10.8 10.7

0.0

10.0

30.0

20.0

40.0

50.0

p < 0.0001

60.0

70.0

Mean

Gra

die

nt

(mm

Hg

)

SAVR TAVR Error bars = ± 1 Std Dev

No structural valve deterioration that

required re-intervention

Aortic Valve Mean Area (AT) P1A - All Patients

Baseline 1 Year 2 Year 3 Year 4 Year 5 Year

TAVR 310 219 156 106 79 56

SAVR 299 158 123 86 61 48

2343 Patients in Italian Registry

• The rates of mild and moderate PVL did not change from discharge (53.8% and 14.1%) to last available follow up (51% and 16%), p=0.65.

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Primary Endpoint: All-Cause Mortality or Disabling Stroke at Two Years

Randomized Patients

n = 2032


ASSESSMENT by Heart Valve Team

Operable (STS ≥ 4%)

The PARTNER 2A Trial Study Design

TF TAVR

(n = 775)

Surgical AVR

(n = 775) VS. VS.

ASSESSMENT:

Transfemoral Access

Transapical (TA) / TransAortic (TAo) Transfemoral (TF)

1:1 Randomization (n = 482) 1:1 Randomization (n = 1550)

TA/TAo TAVR

(n = 236) Surgical AVR

(n = 246)

Yes No

The PARTNER 2A and S3i Trial The NEJM and Lancet On-line

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1

762 717 708 685 663 652 644 634 612

722 636 624 600 591 573 565 555 537

p (log rank) = 0.04

HR: 0.78 [95% CI: 0.61, 0.99]

16.3%

20.0%

0 0 3 6 9 12 15 18 21 24

0

10

20

30

40

50

15.8%

7.5%

11.7%

4.5%

TF Primary Endpoint (AT) All-Cause Mortality or Disabling Stroke

All

-Cau

se M

ort

ali

ty o

r D

isab

lin

g S

tro

ke (

%)

TF TAVR

TF Surgery

Months from Procedure Number at risk:

TF TAVR

TF Surgery

Events (%)

30 Days 2 Years

TAVR

(n = 1011)

Surgery

(n = 1021) p-value*

TAVR

(n = 1011)

Surgery

(n = 1021) p-value*

Rehospitalization 6.5 6.5 0.99 19.6 17.3 0.22

MI 1.2 1.9 0.22 3.6 4.1 0.56

Major Vascular

Complications 7.9 5.0 0.008 8.6 5.5 0.006

Life-Threatening /

Disabling Bleeding 10.4 43.4 <0.001 17.3 47.0 <0.001

AKI (Stage III) 1.3 3.1 0.006 3.8 6.2 0.02

New Atrial Fibrillation 9.1 26.4 <0.001 11.3 27.3 <0.001

New Permanent

Pacemaker 8.5 6.9 0.17 11.8 10.3 0.29

Re-intervention 0.4 0.0 0.05 1.4 0.6 0.09

Endocarditis 0.0 0.0 NA 1.2 0.7 0.22

Other Clinical Endpoints (ITT) At 30 Days and 2 Years

*Event rates are KM estimates, p-values are point in time

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Evolution of the Edwards Balloon-Expandable Transcatheter Valves

2002

Cribier-Edwards

2006

SAPIEN

2009

SAPIEN XT

2013

SAPIEN 3

* Sheath compatibility for a 23 mm valve

Bovine pericardial tissue • Scalloped leaflet shape

• CE ThermaFix* process is

intended to minimize the

risk of calcification

Outer skirt • PET outer skirt designed to

reduce paravalvular leak

Low frame height • Respects the

cardiac anatomy

Frame design • Enhanced frame geometry

for low delivery profile

• High radial strength for

circularity

Inner Skirt • Polyethylene

terephthalate (PET)

SAPIEN 3 THV

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Intermediate Risk

Operable

(PII S3i)

High Risk Operable /

Inoperable

(PII S3HR)


ASSESSMENT by Heart Valve Team

n = 1076

Patients

n = 583

Patients

ASSESSMENT:

Optimal Valve

Delivery Access

ASSESSMENT:

Optimal Valve

Delivery Access

SAPIEN 3

2 Single Arm Non-Randomized

Historical-Controlled Studies

Transfemoral (TF)

TF TAVR

SAPIEN 3 TAA TAVR

SAPIEN 3

Transapical /

Transaortic (TAA)

TF TAVR

SAPIEN 3

PI A

SAPIEN

PII A

SAVR

Transfemoral (TF)

TAA TAVR

SAPIEN 3

Transapical /

Transaortic (TAA)

The PARTNER II S3 Trial Study Design

Baseline Patient Characteristics S3HR Patients (n=583 at 29 sites)

Average STS =

8.6% (Median 8.4%)

TF, 84%

TA, 10%

TAo, 6% N = 583

1.9%

34.3% 38.9% 24.9%

20 mm 23 mm 26 mm 29 mm

Average Age =

82.6yrs

Male 58%

Female 42%

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Mortality and Stroke: S3HR At 30 Days (As Treated Patients)

2.2 1.4 0

20

40

60

80

100

S3HR

All-Cause Cardiovascular

% O:E = 0.26

(STS 8.6%)

1.5 0.9 0

20

40

60

80

100

S3HR

All Stroke Disabling

Mortality Stroke

%

Baseline Patient Characteristics S3i Patients (n=1076 at 51 sites)

Average STS =

5.3% (Median 5.2%)

TF, 89%

TA, 7%

TAo, 4% N = 1076

4.1%

32.2% 43.7%

20.0%

20 mm 23 mm 26 mm 29 mm

Average Age =

81.9yrs

Male 62%

Female 38%

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Mortality and Stroke: S3i At 30 Days (As Treated Patients)

1.1 0.9 0

20

40

60

80

100

S3i

All-Cause Cardiovascular

O:E = 0.21

(STS 5.3%)

2.6 1.0 0

20

40

60

80

100

S3i

All Stroke Disabling

Mortality Stroke

% %

6.3%

5.2%

3.7% 4.5%

3.5%

2.2% 1.6%

1.1% 1.1%

0%

5%

10%

15%

20%

P1B (TF) P1A (All) P1A (TF) P2B (TF) P2B XT (TF) S3HR (All) S3HR (TF) S3i (All) S3i (TF)

175 344 240 271 282 583 491 1072 947

SAPIEN SXT SAPIEN 3

PARTNER I and II Trials Overall and TF Patients

All-Cause Mortality at 30 Days Edwards SAPIEN Valves

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All Strokes at 30 Days Edwards SAPIEN Valves

6.7%

5.6%

4.1% 4.3%

1.5%

2.6%

0%

5%

10%

15%

20%

P1B (TF) P1A (Overall) P2B (TF) P2B XT (TF) S3HR (Overall) S3i (Overall)

179 344 276 284 583 1076

SAPIEN SAPIEN XT SAPIEN 3

Neurologist evaluations (pre- and post)

PARTNER I and II Trials Overall and TF Patients

Stanford Heart Team

Interventionalists •• William Fearon, MD

•• Alan Yeung, MD

Cardiac Surgeons • Michael Fischbein, MD

• William Hiesinger, MD

• Anson Lee, MD

• D. Craig Miller, MD

Echocardiologists • Rajesh Dash, MD

• David Liang, MD

Radiologist (Cardiovascular) • Dominic Fleischmann, MD

THV Nurse Practitioners • Mykl Morrissey, NP

• Martina Speight, NP

THV Clinic Coordinators • Sandy Cardoza, RN

• Zoe Magee, RN

• Cheryl McWard, RN

• Danna Salvaleon-Cua, LVN

Patient-focused

Multidisciplinary Heart

Team

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Stanford Heart Team Meeting

Stanford Experience with TAVR

22 41

59 77

107

139 153

221 234

2009 2010 2011 2012 2013 2014 2015 2016 2017*

Yearly Volume

# T

AV

R

*Projected

Fiscal Year

21/07/2017

21

Stanford Experience with TAVR

35 61 66

108

177

222

21 40

54

41

34

69

30

44

12

0

20

40

60

80

100

120

140

160

180

200

220

240

260

2009 2010 2011 2012 2013 2014 2015 2016 2017*

Commercial Study

# T

AV

R

139 15

In the past 3 months…

14%

86%

CoreValve Evolut-R

Sapien 3

Valve # of

Cases

Sapien 3 61

CoreValve Evolut R 10

Complications n (71)

PPM/ ICD 7%

Death (TA) 1%

Major Vasc 3%

Stroke 0%

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Description January February March Total

Number of Cases 19 22 19 60

Average PPLOS 3 3 2 2.73

No. ICU Pts 4 3 5 12

Average ICU Pt PPLOS 6 3 2.8 4.8

No. Non-ICU Pts 15 19 14 48

Average Non-ICU Pt

PPLOS 2 2 2 2

2017 Year to Date:

• 80% Fast Track

• PPLOS down from 3 to 2.73

• Counter measure: Readmission rate ???

In the past 3 months…

TAVR Clinical Evidence

Capodanno D and Leon MB. EuroIntervention 2016;12:Y1-Y5.

19 Studies

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Simplifying TAVR DIRECT EASY TAVI

Optimizing Outcomes ACTIVATION REDUCE AKI SENTINEL REFLECT Expanding Indications

NOTION 2 EARLY TAVR

19 Additional Studies!



Anti-thrombotic Therapy ARTE POPULAR TAVI AUREA AVATAR GALILEO ATLANTIS

Valve Leaflet Thickening/ Thrombosis RESOLVE SAVORY EVOLUT R Low Risk PARTNER 3 PORTICO IDE

19 Additional Studies!

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• Bioprosthetic valve failure (aortic and mitral)

Expand the use of surgical bioprothesis, less mechanical

• Bicuspid AV disease

Better imaging, avoiding high risk morphology

Expanding TAVR Clinical Indications

Future Goals

Cerebral Protection?

Low Risk Patients

Asymptomatic Patients

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TOPICS

Major trends in Interventional Cardiology

Structural Heart: TAVR

PCI: Bioabsorbable Scaffolds

PCI: FFR

How to have a successful fellowship in research

Ferrarotto Hospital A.O.U. Policlinico-Vittorio Emanuele

Catania, Italy

D. Capodanno ECM Catania – February 2, 2017 – Slide 50

The Comparator (1) - 5-Year ST of G2 DES

Von Birgelen C et JAMA Cardiology 2017 [ePub ahead of print]

1,370 patients treated with second-generation EES or ZES from the TWENTE trial

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Cu

mu

lative

in

cid

en

ce

(%

)

0

5

10

15

20

25

Days since initial procedure

0 180 360 540 720 900 1080 1260 1440 1620 1800

BES

EES

CI-TVR @ 5 year

Plogrank = 0.36

3.0 %

2.2 %

RR: 1.35 (0.81 – 2.24)

P = 0.25 6.4 %

5.8 %

RR: 1.09 (0.80 – 1.50)

P = 0.58

CI-TVR = Clinically Indicated Target Vessel Revascularisation

9.5 %

8.4 %

RR: 1.13 (0.87– 1.46)

P = 0.37

DES UNMET NEEDS

Continue TLF creep after one year

Side branch jailing

Permanent presence of incomplete opposition

Diffuse disease stenting leading to full metal jacket

Lack of Vulnerable plaque treatment strategy

Permanent absence of vasomotion

Permanent implant

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BRS (Absorb) Revascularization

with Transient Support

Benign

Resorption

Restoration

of Physiological Environment (shear stress, multidirectional motion, morphology)

1

3 2

For Absorb, the goal is to provide temporary vessel support and then resorb, allowing for natural

vessel movement and remodeling.

State of BRS (Absorb) in US

• FDA approved the Absorb GTI in 7/2016

• Calculated roll out to Absorb IV sites

• Absorb III 2 year data presented at ACC on 3/18/2017

• FDA’s Letter to Health Care provider on same day 3/18/2017 – increased MACE 11% vs 7.9%

• Absorb IV stopped enrollment at 2600 instead of 3000 with sufficient power on 3/27/2017

• AIDA in NEJM 3/29/2017

• Current Absorb penetration is << 5% and mainly in 10 cath labs of early adopters/true believers.

• Concern for litigation (risk vs benefits)

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How did we get here ?

Revascularization

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Catania, Italy

D. Capodanno JIM – February 8, 2017 – Slide 57

Comparative Function of BVS and EES

Serruys PW, et al. Lancet. 2016;388:2479-2491

Absorb Xience P value

MLD (mm)

Pre-procedure 1.06 ± 0.33 1.06 ± 0.31 0.81

Post-procedure 2.22 ± 0.33 2.50 ± 0.33 <0.0001

Acute gain 1.16 ± 0.38 1.45 ± 0.37 <0.0001

3-Year follow-up 1.86 ± 0.54 2.25 ± 0.37 <0.0001

Net gain 0.80 ± 0.61 1.20 ± 0.44 <0.0001

Late loss* 0.37 ± 0.45 0.25 ± 0.25 0.0003

Binary restenosis (%) 7.0% 0.7% 0.0031

ABSORB II - 501 patients randomized 2:1 to Absorb or Xience

*Co-primary endpoint. MLD = minimal lumen diameter

Measurement

Absorb

(N=1322)

(L=1385)

Xience

(N=686)

(L=713) p-value

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

N= number of subjects

L= number of lesions

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30

Absorb

(N=1322)

(L=1385)

Xience

(N=686)

(L=713) p-value

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

TLF by 2 Years (25 Months)

0%

5%

10%

15%

20%

25%

30%

Time Post Index Procedure (Months)

0 13 25

0%

5%

10%

15%

20%

25%

30%

Time Post Index Procedure (Months)

0 13 25

No. at Risk:

Absorb

Xience

1322

686

1141

608

1193

634

1074

549

943

496

982

512

Overall

HR [95%CI]=1.42 [1.04, 1.94]

p=0.03

QCA RVD ≥ 2.25 mm

HR [95%CI]=1.35 [0.93, 1.96]

p=0.12

Absorb BVS (N=1322)

Xience CoCr-EES (N=686)

Absorb BVS (N=1074)

Xience CoCr-EES (N=549)

10.9%

7.8%

9.3%

7.0%

Note: The 2-year window allowed follow-up through 25 months

21/07/2017

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Catania, Italy


The Scaffold, the Lesion or the Doctor?

Abbott Vascular

Prepare the vessel to be re-engineered Pre-dilate using a 1:1 balloon-to-artery ratio using a non-compliant

balloon (it can also help accurately size the vessel). Use

plaque-modification devices if needed. Confirm full expansion of balloon

and residual stenosis of 20-40% in 2 orthogonal views.

Size the vessel appropriately Select the scaffold size for the best fit. Consider using intravascular

ultrasound (IVUS), optical coherence tomography (OCT) or

quantitative coronary angiography (QCA) to aid vessel sizing. Note:

Absorb BVS is indicated for vessels with a reference vessel diameter

of ≥ 2.5 mm and ≤ 3.75 mm.

Post-dilate to embed the struts into the vessel wall Dilate to high pressure with a non-compliant balloon up to 0.5 mm

above nominal scaffold diameter. Verify <10% final residual stenosis in

2 orthogonal views, and ensure full strut apposition.

P

S

P

Restoration

21/07/2017

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Catania, Italy


Comparative Vasomotion of BVS and EES



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

-0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1

Cu

mu

lative

fre

qu

en

cy

Absorb n=258 0.047 ± 0.109 mm

Xience n=130 0.056 ± 0.117 mm

Psuperiority = 0.49

Vasomotion at 3 years (mm)


Catania, Italy


Comparative Angina of BVS and EES



0

10

20

30

40

50

60

70

80

90

100

BASELINE MONTH 6 YEAR 1 YEAR 2 YEAR 3 BASELINE MONTH 6 YEAR 1 YEAR 2 YEAR 3 BASELINE MONTH 6 YEAR 1 YEAR 2 YEAR 3

% Angina Free Physical Limitation Treatment Satisfaction

SAQ

Sco

re

Absorb

Xience Seattle Angina Questionnaire

21/07/2017

33

Resorption (Benign ?)


Catania, Italy


Intraluminal Scaffold Dismantling

A BRS-specific Thrombosis Mechanism

Raber L, et al. J Am Coll Cardiol. 2015;66:1901-14

2D

OCT

3D

OCT

Strut discontinuity with marked suppression of neointimal hyperplasia resulting in prolapse of a scaffold

segment into the vessel lumen before absorption is complete

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Catania, Italy


Very Late Scaffold Thrombosis



Absorb Xience P value

Definite 2.5% 0.0% 0.06

Acute 0.3% 0.0% 1.00

Subacute 0.3% 0.0% 1.00

Late 0.0% 0.0% 1.00

Very late 1.8% 0.0% 0.19

Definite or probable 2.8% 0.0% 0.03

Acute 0.3% 0.0% 1.00

Subacute 0.3% 0.0% 1.00

Late 0.3% 0.0% 1.00

Very late 1.8% 0.0% 0.19

Clinical Endpoints by 2 Years

(25 Months)

Overall

Absorb

(N=1322)

XIENCE

(N=686)

TLF 11.0% (143)* 7.9% (53)*

Cardiac Death 1.1% (14) 0.6% (4)

TV-MI 7.3% (95)** 4.9% (33)**

ID-TLR 5.3% (69) 4.3% (29)

ST (Def/Prob) 1.9% (24) 0.8% (5)

QCA RVD ≥ 2.25mm

Absorb

(N=1074)

XIENCE

(N=549)

9.4% (99) 7.0% (38)

0.9% (10) 0.4% (2)

6.5% (68) 4.8% (26)

4.1% (43) 3.0% (16)

1.3% (13) 0.6% (3)

* P-value=0.03. ** P-value=0.04. P-value >0.05 for all other comparisons

Note: The 2-year window allowed follow-up through 25 months

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State of BRS (Absorb) in US

Longer procedure, higher short term risk plus long term uncertainty….no clear benefits in sight!

Mitigate Risk of BRS

• Will PSP fix the early, late ST?

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ABSORB III

Pooled

(N=2008)

ABSORB III

Pooled

(N=2008)1

ABSORB IV

Pooled

(N=2494)2,3

QCA RVD <2.25 mm 19% 19% 4%

Post-dilatation (BVS) 66% 66% 83%

Pooled stent/scaffold thrombosis

30 days 1.0% 0.9% 0.3%

1 year 1.3% 1.1% 0.5%

ABSORB III: 2008 pts randomized 2:1 BVS:EES (1322:686)

ABSORB IV: 3000 pts being randomized 1:1 BVS:EES

1. Assuming the same event rate for each arm in ABSORB III, but with a 1:1 randomization ratio.

2. Based on January 16, 2016 data cut (N=2349 with 30 day FU and N=1297 with 1 year FU).

3. A-IV includes 25% non A-III like subjects (troponin+ NSTEMI/STEMI, 3 lesions treated, and planned staged procedures).

Blinded, Pooled, Interim ABSORB IV

Outcomes: Comparison to ABSORB III

Absorb Beyond 2 Years: Cohort B. vs Xience 5-Year FU (3.0 x 18 mm)

0%

5%

10%

15%

20%

25%

0 6 12 18 24 30 36 42 48 54 60 66

MA

CE

(%

)

Absorb* (B1 + B2)

Xience* (SPIRIT I + II + III)

Months Post Index Procedure

Days: 0 37 194 284 393 573 758 1123 1488 1853

Absorb: 101 99 96 96 94 92 91 88 86 85

Xience: 227 224 219 211 204 202 191 182 174 169

Δ = 3.3%

Hazard Ratio [95% CI]:

0.77 [0.39, 1.54]

p=0.46 14.3%

11.0%

Serruys PW. TCT 2015

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Future of BRS in the US

• Will PSP solve the VLST and TLF issues?

• Is resorption from year 2 to 5 a benign process in human?

• Does resorption result in a larger “golden tube” which impacts protection against neoatherosclerosis/garden variety atherosclerosis?

• Can we provide patient level benefits?

Distal

Pressure (Pd)

Proximal

Pressure (Pa)

FFR = Pd / Pa

during maximal flow

Pd

Pa

Pd / Pa = 60 / 100

FFR = 0.60

Fractional Flow Reserve

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Putative Reasons Not to FFR:

Financial Implications

Don’t Believe the Data

Uncomfortable with the Technique

Don’t Like the Wire

Time Constraints

Need for Adenosine

Resting Indices: iFR, Pd/Pa

Berry, et al. J Am Coll Cardiol 2013;61:1421-7.

iFR

Pd / Pa

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Resting Indices: iFR, Pd/Pa

De Bruyne, et al. Circulation 1994;89:1013-22.

1994: Comparison of various indices to PET

Resting Pd/Pa and iFR versus FFR

Diagnostic Accuracy

of iFR = 80.4%

Jeremias, et al. J Am Coll Cardiol 2014;63:1253-61.

Resting Pd/Pa , iFR and FFR were measured in 1,678 patients

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VERIFY 2 Study FFR, iFR and Pd/Pa measured in 197 patients (257 lesions)

Hennigan, et al. Circ Cardiovasc Interv 2016;9:e004016

1 in 5 Cases Misclassified

VERIFY 2 Study FFR, iFR and Pd/Pa measured in 197 patients (257 lesions)

Hennigan, et al. Circ Cardiovasc Interv 2016;9:e004016

Using a hybrid strategy, adenosine is required in 50% of

cases, and still 1 in 10 cases are misclassified

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Optimal binary cutoff for cFFR ≤ 0.83

cFFR = 86% accuracy

Pd/Pa = 80% accuracy

iFR = 79% accuracy

superior accuracy (p<0.001)

Contrast FFR (cFFR):

Johnson, et al. JACC Cardiovasc Interv 2016;9:757-67.

FFR

95%

Contrast FFR

86%

Resting Measures

(iFR, Pd/Pa)

80%

Coronary Angiography

70%

Diagnosing Ischemia in the Cath Lab

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DEFINE-FLAIR

Multicenter, international, randomized trial

comparing FFR-guided management with

iFR-guided management in 2,492 patients

with CAD

Primary endpoint of death, MI or unplanned

revascularization at one year

Non-inferiority design with a margin of 3.4%

Davies JE, et al. New Engl J Med 2017

DEFINE-FLAIR

Procedural time longer with FFR-guided

approach (40.5 vs 45.0 min, p=0.001)

More revascularization with FFR (47.5 vs 53.4%,

p=0.003)

Mean FFR = 0.83; 23% of FFRs > 0.90

More dyspnea/chest pain with FFR (3.1 vs

30.8%, p<0.001)


Key Procedural Results

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DEFINE-FLAIR


One Year Outcomes

Event iFR FFR p value

Death/MI/

Revascularization 6.8% 7.0% 0.83

Death 1.9% 1.0% 0.11

MI 2.7% 2.4% 0.62


iFR-SWEDEHEART

Multicenter, randomized trial from SCAAR

comparing FFR-guided management with

iFR-guided management in 2,037 patients

with CAD

Primary endpoint of death, MI or unplanned

revascularization at one year

Non-inferiority design with a margin of 3.2%

Gotberg M, et al. New Engl J Med 2017

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iFR-SWEDEHEART


Procedural time tended to be longer with FFR

(50.8 vs. 53.1 min, p=0.09)

More lesions were significant with FFR (29.1

vs. 36.8, p<0.001)

Mean FFR =0.82

More patients had chest discomfort with FFR

(3.0 vs. 68.3%, p<0.001)

Key Procedural Results

iFR-SWEDEHEART


One Year Outcomes

Event iFR FFR p value

Death/MI/


Death 1.5% 1.2% 0.57

MI 2.2% 1.7% 0.42


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DEFINE-FLAIR and SWEDEHEART

Noninferiority design underpowered because

80% of cases will have concordant FFR and

iFR values and therefore patients will be

treated identically and dilute any potential

differences between the two strategies.

Should focus on the 20% of discordant cases

where FFR directs one treatment and iFR the

other and evaluate outcomes.


Noninferiority margins of 3.2% and 3.4% too

wide.

If comparing PCI with CABG or TAVR with

SAVR, clinicians will accept a somewhat inferior

outcome to avoid the more invasive procedure.

When comparing identical procedure with the

same risk of invasive angiography and pressure

wire placement and only avoiding 2 minutes of

adenosine, such wide margins are not

acceptable.

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Meta-analysis of DEFINE-FLAIR and

SWEDEHEART

Death and MI:

HR1.32 (95%CI 0.96-1.81), p=0.09

favoring FFR over iFR

Importance of Lesion Location CONTRAST Substudy comparing accuracy of adenosine free indices based

on stenosis location in the left main/proximal LAD vs other locations

Dia

gn

os

tic

Ac

cu

rac

y

Kobayashi, et al. J Am Coll Cardiol Intv 2016;9:2390-9.

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Simplifying FFR:

Acist.com

ACIST-FFR Trial

Pearson coefficient = 0.901

P<0.001

*Core laboratory values

5 cases (2.9%) where PW

FFR >0.80, microcatheter

FFR <0.75

Sensitivity:

88% (95% CI: 76-96%)

Specificity:

78% (95% CI: 69-85%)

Diagnostic Agreement:

81% (95% CI: 75-87%)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.00.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

FFR from PW

FFR from Microcatheter

N=169*

Price M, et al. EuroPCR 2017

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Relationship between FFR and MACE 1,029 lesions from 607 medically treated patients in FAME 2

Barbato, et al. J Am Coll Cardiol 2016;68:2247-55.

FFR=0.87-1.0

FFR=0.64-0.77

FFR=0.78-0.86

FFR≤0.63

Relationship between FFR and MACE 8,633 lesions from 5,846 patients with FFR measured in ≥ 1 lesion

Ahn JM, et al. Circulation 2017;135:2241-51.

Death, MI, Revascularization

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All Comers with 3 V CAD

(not involving LM)

Heart team identifies lesions for PCI/CABG

and then patient is randomized

FFR-Guided PCI with Resolute DES

Stent all lesions with FFR ≤ 0.80

(n=750)

Perform CABG based on

coronary angiogram

(n=750)

Primary: One Year follow-up for Death, MI, CVA, Revascularization

Key Secondary: Three Year follow-up for Death/MI/CVA

FAME 3:

Non-inferior Design

NCT02100722 Zimmermann, et al. Am Heart J 2015;170:619-26.

Conclusion:

A number of adenosine-free indices have

been proposed for physiologic evaluation

None are as accurate as FFR

None have as robust data, including

numerous multicenter, prospective,

randomized clinical outcomes trials that FFR

has supporting its utility

If you are absolutely opposed to using

adenosine, these indices are likely better

than angiography guidance

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WANT TO BE AN INTERVENTIONAL CARDIOLOGIST?

Ability to do complex PCI, structural and

peripheral?

Ability to follow-up all the Guidelines and AUC?

Comprehensive knowledge of the IC literature?

Best in class O/E outcome of your procedures?

Best clinical trialist there is?

Best mentor for trainees?

Best interventional cardiologist for your patients

and the at risk population?

Fatima Rodriguez, MD, MPH

May 25, 2017

A FELLOW’S PERSPECTIVE

Clinical Research at Stanford:

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7 Steps To Successful Clinical Research as a Fellow

Step 1: Mentorship

• Identify 2-3 potential mentors

-Track record with mentoring

-Can be outside of the division

• Be an active mentee

• Fellowship mentorship events in the

early fall

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108

Peer Mentors

• Equally as valuable as

faculty mentorship

• Become an integral part of

the “mentorship team”

Step 2. Establishing a Research Niche

Fellow Topic

Alex Perino Atrial fibrillation and health services

research

Sheeva

Rajaei

Lactation patterns and CV outcomes

Alex Sandhu Cost-effectiveness of novel CV treatments

Lee Chang Predictors of short-term risk of CV adverse

events

Rushi Parikh Biomarkers in cardiac allograft

vasculopathy

Petra Mamic The microbiome and heart failure

Fatima

Rodriguez

Health disparities in CV prevention and

guideline-adherence

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Step 3. Finding Funding

• Individual Fellowships

-ACC/Merck

-NIH F32

• CV Med T32

- Imaging

-Vascular

-Prevention (SPRC)

Step 4. Coursework and Other Training

• Auditing vs. Masters programs

• SPECTRUM

- KL2/TL1 Clinical Research Training

Program

- Intensive Course in Clinical Research

(ICCR)

• Grant Writing Academy

• ACC “How to Become a Cardiovascular

Investigator”

• AHA 10-Day Seminar on Epidemiology

and Prevention

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Step 5. Diversify your projects

▪ Review Articles/Chapters

▪ Big Data Projects

▪ Primary Data Collection

▪ Setting up cohorts (e.g. Project

Baseline)

▪ Clinical trial participation (e.g.

ISCHEMIA)

Step 6. Write!

There’s no substitute for regular writing

- Original Investigations

- Review Articles

- Invited editorials (usually with your mentor)

- Grants

Peer-Review work

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Step 7. Re-evaluate

Balance research/clinical responsibilities

- Advanced clinical training fellowships

Frequently re-visit career development

goals

Challenges & Opportunities

• Identifying mentorship takes time

• No “formal” clinical research track or training

- Requires more legwork from the fellow to identify opportunities

• Funding for advanced degree programs is limited

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Summary

1. Find mentorship early

2. Establish a research niche

3. Look for funding, write grants

4. Develop clinical research skillsets

5. Seek diverse projects

6. Write manuscripts/editorials

7. Frequently re-evaluate career development plan

Documents

Intervention Cardiology/Research for Cardiology Trainees Weds Presentations/H2 1100... · 2017. 11. 12. · 21/07/2017 1 Alan C. Yeung, M.D. Li Ka Shing Professor of Medicine Chief,