TAVI intermediate risk:

Reality or passion?

Prof. Flavio Ribichini

Università di Verona

Italy

TAVI vs Surgical AVR for Moderate to Low

Risk Patients

Reality

Prof. Flavio Ribichini

Università di Verona

Italy

TAVI vs Surgical AVR for Moderate to Low

Risk Patients

Thyregod HG et al JACC 2015

- RCT involving 280 pts in 3 Nordic Centers, 1:1 TAVI vs SAVR

- Esclusion Criteria: severe valve (other than aortic) disease, CAD requiring intervention, previous cardiac surgery, MI, stroke (within 30 days), severe renal failure requiring dialysis, pulmonary failure.

- Primary Endpoint: composite rate of all-cause death, stroke or MI at 1 year FU.

- Only self-explandable (CoreValve) and valve sizing by means of EchoTOE

NOTION Trial

NOTION Trial Intention-to-treat analysis: the composite rate of death from any cause, stroke, orMI at 1 year (the primary outcome) was similar in the 2 groups: 13.1% vs. 16.3% for TAVR and SAVR (-3.2% absolute difference; p = 0.43 for superiority)

NOTION Trial

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

Randomized Patients

n = 2032

Symptomatic Severe Aortic Stenosis

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

Key Exclusion Criteria

• Aortic annulus diameter < 18 mm or > 27 mm (echo or CT)

• Bicuspid AV or predominant AR (> 3+)

• Severe LV dysfunction (LVEF < 20%)

• Untreated CAD requiring revascularization with either unprotected LM coronary disease or Syntax score > 32

• Pre-existing surgical valve in any position

Anatomic:

• Serum Cr > 3.0 mg/dL or dialysis dependent

• Acute MI within 1 month

• CVA or TIA within 6 months

• Hemodynamic instability

• Life expectancy < 24 months

Clinical:

Characteristic TAVR

(n = 1011)

Surgery

(n = 1021) p-value

Age - yrs 81.5 ± 6.7 81.7 ± 6.7 0.63

Male - % 54.2 54.8 0.79

STS Score - % 5.8 ± 2.1 5.8 ± 1.9 0.29

NYHA Class III or IV - % 77.3 76.1 0.53

CAD - % 69.2 66.5 0.20

Prior CABG - % 23.6 25.6 0.33

Cerebrovascular Disease - % 32.1 31.0 0.60

PVD - % 27.9 32.9 0.02

Baseline Patient Characteristics Demographics and Vascular Disease

Characteristic (%) TAVR

(n = 1011)

Surgery

(n = 1021) p-value

Diabetes 37.7 34.2 0.11

COPD - Any 31.8 30.0 0.48

O2 dependent 3.4 3.1 0.64

Creatinine > 2 mg/dL 5.0 5.2 0.92

Atrial Fibrillation 31.0 35.2 0.05

Permanent Pacemaker 11.7 12.0 0.84

Frailty (15 ft walk > 7 s) 44.4 46.4 0.43

Liver Disease 1.9 2.5 0.37

Baseline Patient Characteristics Other Co-morbidities

1

1011 918 901 870 842 825 811 801 774

1021 838 812 783 770 747 735 717 695

Number at risk:

TAVR

Surgery

p (log rank) = 0.253

HR [95% CI] = 0.89 [0.73, 1.09]

TAVR

Surgery

0

10

20

30

40

50

19.3%

21.1%

14.5%

16.4%

0 3 6 9 12 15 18 21 24

6.1%

8.0%

Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke

Months from Procedure

All

-Cau

se M

ort

ality

or

Dis

ab

lin

g S

tro

ke (

%)

1

775 718 709 685 663 652 644 634 612

775 643 628 604 595 577 569 557 538

TF TAVR

TF Surgery

p (log rank) = 0.05

HR: 0.79 [95% CI: 0.62, 1.00]

16.8%

20.4%

0 3 6 9 12 15 18 21 24

0

10

20

30

40

50

15.9%

7.7%

12.3%

4.9%

TF Primary Endpoint (ITT) All-cause Mortality or Disabling Stroke

TF TAVR

TF Surgery

Months from Procedure Number at risk:

All

-Cau

se M

ort

ality

or

Dis

ab

lin

g S

tro

ke (

%)

The PARTNER 2A Trial Conclusions

In intermediate-risk patients with symptomatic severe

aortic stenosis, results from the PARTNER 2A trial

demonstrated that...

• TAVR using SAPIEN XT and surgery were similar

(non-inferior) for the primary endpoint (all-cause mortality

or disabling stroke) at 2 years.

• In the transfemoral subgroup (76% of patients), TAVR

using SAPIEN XT significantly reduced all-cause

mortality or disabling stroke vs. surgery (ITT: p = 0.05,

AT: p = 0.04).

Intermediate Surgical Risk Predicted risk of operative mortality ≥3% and <15%

Heart Team Evaluation Assess inclusion/exclusion

Risk classification

Randomization Stratified by need for revascularization

TAVR SAVR

TAVR + PCI SAVR + CABG TAVR only SAVR only

Baseline neurological assessments

Screening Committee Confirmed eligibility

SURTAVI Trial Design

First patient enrolled June 19, 2012

Primary endpoint assessment

Dec 2016

CoreValve (n=724) Evolut R (n=139)

2012 2013 2014 2015 2016

Enrollment completed June 30, 2016

Evolut R (US)

CoreValve: 23, 26 and 29 mm (CAN, EU)

CoreValve: 31 mm (US, CAN, EU)

94% TF 4% DA 2% SCA

CoreValve: 23, 26 and 29 mm (US)

April

Study Timeline

• Contraindication for placement of a bioprosthetic valve • A known hypersensitivity or contraindication to all anticoagulation/

antiplatelet regimens • Any PCI or peripheral intervention within 30 days of randomization • Symptomatic carotid or vertebral artery disease or successful treatment of

carotid stenosis within six weeks of randomization • Recent cerebrovascular accident or transient ischemic attack • Acute MI within 30 days • Multivessel CAD with Syntax score >22 • Severe liver, lung or renal disease • Unsuitable anatomy including native aortic annulus <18 mm or >29 mm • Severe mitral or tricuspid regurgitation • Congenital bicuspid or unicuspid valve verified by echo

Key Exclusion Criteria

n (%) or mean ± SD TAVR (N=864) SAVR (N=796)

Age, years 79.9 ± 6.2 79.7 ± 6.1

Male sex 498 (57.6) 438 (55.0)

Body surface area, m2 1.9 ± 0.2 1.9 ± 0.2

STS PROM, % 4.4 ± 1.5 4.5 ± 1.6

Logistic EuroSCORE, % 11.9 ± 7.6 11.6 ± 8.0

Diabetes mellitus 295 (34.1) 277 (34.8)

Serum creatinine >2 mg/dl 14 (1.6) 17 (2.1)

Prior stroke 57 (6.6) 57 (7.2)

Prior TIA 58 (6.7) 46 (5.8)

Peripheral vascular disease 266 (30.8) 238 (29.9)

Permanent pacemaker 84 (9.7) 72 (9.0)

Baseline Characteristics*

*mITT population; no significant difference in any baseline characteristics

n (%) TAVR (N=864) SAVR (N=796)

Coronary artery disease 541 (62.6) 511 (64.2)

Prior CABG 138 (16.0) 137 (17.2)

Prior PCI 184 (21.3) 169 (21.2)

Prior myocardial infarction 125 (14.5) 111 (13.9)

Congestive heart failure 824 (95.4) 769 (96.6)

History of arrhythmia 275 (31.8) 250 (31.4)

Atrial fibrillation 243 (28.1) 211 (26.5)

NYHA Class III/IV 520 (60.2) 463 (58.2)

Baseline Cardiac Risk Factors*

*mITT population; no significant difference in any baseline characteristics

0%

5%

10%

15%

20%

25%

30%

0 6 12 18 24

All-

Cau

se M

ort

alit

y o

r D

isab

ling

Stro

ke

Months Post-Procedure No. at Risk

796 674 555 407 241

864 755 612 456 272 TAVR

SAVR

All-Cause Mortality or Disabling Stroke

24 Months

TAVR SAVR

12.6% 14.0%

0%

5%

10%

15%

20%

25%

30%

0 6 12 18 24

All-

Cau

se M

ort

alit

y

Months Post-Procedure No. at Risk

796 690 569 414 249

864 762 621 465 280 TAVR

SAVR

All-Cause Mortality

30 Day SAVR 1.7% O:E 0.38 TAVR 2.2% O:E 0.50

TAVR

SAVR

0%

5%

10%

15%

20%

25%

30%

0 6 12 18 24

24 Months

TAVR

SAVR 95% CI for Difference

11.4% 11.6% -3.8, 3.3

0%

5%

10%

15%

20%

25%

30%

0 6 12 18 24

All-

Cau

se M

ort

alit

y

Months Post-Procedure

TAVR

SAVR

No. at Risk 796 690 569 414 249

864 762 621 465 280 TAVR

SAVR

All-Cause Mortality

30 Day SAVR 1.7% O:E 0.38 TAVR 2.2% O:E 0.50

0%

2%

4%

6%

8%

10%

0 6 12 18 24

Dis

ablin

g St

roke

Months Post-Procedure No. at Risk

796 674 555 407 241

864 755 612 456 272 TAVR

SAVR

Disabling Stroke

24 Months

TAVR SAVR 95% CI for Difference

2.6% 4.5% -4.0, 0.1

• TAVR had significantly less 30 day stroke, AKI, atrial fibrillation and transfusion use and a superior quality of life at 30 days.

• SAVR had less residual aortic regurgitation, major vascular complications and fewer new pacemakers.

• Need for a new pacemaker after TAVR was not associated with increased mortality.

Summary

• SURTAVI met its primary endpoint demonstrating that TAVR with a self-expanding CoreValve or Evolut R bioprosthesis is noninferior to SAVR for all-cause mortality or disabling stroke at 24 months.

Guidelines AHA/ACC Update 2017

1. The research of the optimal anti-thrombotic therapy 2. Valve performance at long-term 3. Indications: low surgical risk? 4. What remains for surgical AVR and conservative management

TAVI intermediate risk:

Reality or passion?

1. TAVI, valve thrombosis and the ideal therapy

- Study investigating the use of CT scan to reveal «subclinical leaflet thrombosis» by finding a reduced leaflet motion in patients who underwent TAVI.

- Data obtained from the Portico IDE Trial and Resolve and Savory registries.

- Reduced leaf let motion was noted on CT in 22 of 55 patients (40%) in the clinical trial and in 17 of 132 patients (13%) in the two registries.

- Therapeutic anticoagulation with warfarin, as compared with dual antiplatelet therapy, was associated with a decreased incidence of reduced leaf let motion (0% and 55%, respectively, P=0.01 in the clinical trial; and 0% and 29%, respectively, P=0.04 in the pooled registries.

Makkar RR et al NEJM 2015

Volume rendered CT images of bioprosthetic valves

Normal leaflets Thickened leaflets with thrombus

Systole Systole

Diastole Diastole

Makkar R. et al. NEJM 2015

Study Objectives

To study subclinical leaflet thrombosis of

bioprosthetic aortic valves in terms of

• Prevalence in a large heterogenous cohort of patients

• Differences in TAVR and SAVR

• Impact of novel-oral anticoagulants (NOACs)

• Impact on valve hemodynamics

• Impact on clinical outcomes

Study design

890 patients with interpretable CTs were included in the

analysis

RESOLVE registry:

626patients

SAVORY registry:

264 patients

931 patients undergoing CTs

657 patients underwent CTs in

the RESOLVE registry Cedars-Sinai Medical Center, Los Angeles

274 patients underwent CTs in

the SAVORY registry Rigshospitalet, Copenhagen

Valve types and timing of CT Time from TAVR to CT vs. SAVR to CT: p<0.0001

890 patients with interpretable CTs

Median time from AVR to CT 83 days (IQR 32-281 days)

752 transcatheter valves

Median time from TAVR to

CT 58 days (IQR 32–236

days)

138 surgical valves

Median time from SAVR to

CT 162 days (IQR 79–417

days)

Reduced leaflet motion of at least 50% in

multiple valve types

Sapien Evolut R Lotus Portico Centera Symetis Perimount Magna

Prevalence of reduced leaflet motion

Transcatheter vs. surgical bioprosthetic aortic valves: p=0.001

Reduced leaflet motion was present in 106

(11.9%) patients

Transcatheter valves

13.4% (101 out of 752)

Surgical valves

3.6% (5 out of 138)

Anticoagulation and reduced leaflet

motion Anticoagulation vs. no anticoagulation

0.

0

2.

0

4.

0

6.

0

10.

0

8.0

12.

0

14.

0

16.

0

Pre

va

len

ce

of

red

uc

ed

leafl

et

mo

tio

n

Anticoagulation NOACs Warfarin No

anticoagulation

8/224

(3.6%) 3/107

(2.8%)

5/117

(4.3%)

98/666

(14.7%) Anticoagulation vs. no anticoagulation: p<0.0001

NOACs vs. no anticoagulation: p=0.0002

Warfarin vs. no anticoagulation: p=0.001 NOACs

vs. warfarin: p=0.72

Anticoagulation and reduced leaflet motion Anticoagulation vs. antiplatelet therapy

4.

0

10.

0

8.0

6.0

12.

0

14.

0

16.

0

18.

0

Pre

va

len

ce

of

red

uc

ed

leafl

et

mo

tio

n

2.0

0.0

Anticoagulation NOACs Warfarin DAPT

8/224

(3.6%) 3/10

7 (2.8%)

5/117

(4.3%)

31/208

(14.9%) Anticoagulation vs. DAPT: p<0.0001

Anticoagulation vs. monoantiplatelet

therapy: p<0.0001

63/405

(15.6%)

Monoantiplatelet

therapy

Impact of initiation of anticoagulation on reduced leaflet motion

0.0

20.0

40.0

60.0

80.0

100.0

120.

0

Pre

va

len

ce

of

red

uce

d le

afl

et

mo

tio

n

Resolution

36/36

(100%

)

• Resolution in 36

out of 36 patients

treated with

anticoagulation

(NOACs, n=12;

warfarin, n=24)

• Persistence/progres

sion in 20 out of 22

patients not treated

with anticoagulation

P<0.0001

No change or

progression Resolution No change or

progression

0/36

(0%)

2/22

(9.1%)

20/22

(89.1%)

Anticoagulation initiated No anticoagulation initiated

Anticoagulation vs. DAPT

Index CT Follow-up CT

DAPT

continued after

index CT

Warfarin

initiated after

index CT

Rivaroxaban

initiated after

index CT

Apixaban

initiated after

index CT

Progression of reduced leaflet motion

Resolution of reduced leaflet motion

Resolution of reduced leaflet motion

Resolution of reduced leaflet motion

Impact of reduced leaflet motion on clinical outcomes

All clinical events post-TAVR/SAVR included

TIA=Transient ischemic attack

* All strokes include hemorrhagic and ischemic

strokes

No significant difference in strokes; but increased risk of TIAs and

strokes/TIAs

All events

Normal leaflet motion (N=784)

n/N (%) Rate per

100

person-

years

Reduced leaflet motion (N=106)

n/N (%) Rate per

100 person-

years

Hazard

ratio

(95% CI)

p-value

Death 34/784 (4·3%) 2· 91 4/106 (3·8%) 2· 66 0· 96 (0· 34-2· 72) 0· 94

Myocardial infarction 4/784 (0· 5%) 0· 34 1/106 (0· 9%) 0· 67 1· 91 (0· 21-17·08) 0· 56

Strokes/TIAs 27/784 (3·4%) 2· 36 11/106 (10·4%) 7· 85 3· 27 (1· 62-6· 59) 0· 001

All strokes* 22/784 (2·8%)

1· 92 6/106 (5·7%) 4· 12 2· 13 (0· 86-5· 25)

0· 10

Ischemic strokes 21/784 (2·7%) 1· 83 6/106 (5·7%) 4· 12 2· 23 (0· 90-5· 53) 0· 08

TIAs 7/784 (0·9%) 0· 60 6/106 (5·7%) 4· 18 7· 02 (2· 35-20· 91) 0· 0005

2. TCVT performance at long-term

PARTNER 1 - Echocardiographic data

Valve Area

PARTNER 1 - Echocardiographic data

Valve Gradient

Four-year experience with the CoreValve

transcatheter heart valve

Four-year experience with the CoreValve

transcatheter heart valve

First look at long-term durability of

transcatheter heart valves: Assessment of valve function up to

10-years after implantation

Danny Dvir, St. Paul’s Hospital, Vancouver, Canada.

On behalf of coauthors: Helene Eltchaninoff, Jian Ye, Arohumam Kan, Eric Durand, Anna Bizios, Anson Cheung, Mina Aziz, Matheus Simonato, Christophe Tron, Yaron Arbel, Robert Moss, Jonathon Leipsic, Hadas Ofek, Gidon Perlman, Marco Barbanti, Michael A. Seidman, Philippe Blanke, Robert Yao, Robert Boone, Sandra Lauck, Sam Lichtenstein, David Wood, Alain Cribier, John Webb

• Time to degeneration: median of 61months (IQR 36-79months).

• Degenerated valves:

Cribier Edwards (n=3, 8.6%)

Edwards SAPIEN (n=19, 54.3%)

SAPIEN XT (n=13, 37.1%)

Degenerated THV

(n = 35)

Regurgitation

(n = 23)

Stenosis/Mixed

(n = 12)

THV degeneration

Pathological examinations

Severely calcified valve 2.5 years after TAVI

Pathological examinations

Asymmetric degeneration 5 years after TAVI

Pathological examinations

Symmetric degeneration 7 years after TAVI

Freedom from THV degeneration

Patients WITHOUT chronic renal failure

Freedom from THV degeneration

Patients WITHOUT chronic renal failure

Patients WITH chronic renal failure p= 0.004

3. TAVI for patients at LOW RISK ?

We do not have reliable data yet…

Circ Cardiovasc Interv. 2016

- Observational, prospective multicenter study;

- Consecutive pts entolled in 93 centers (between Dec2010 - Jun2012)

- Low risk pts defined as Logistic Euroscore II <4%.

- Primary Endpoint: 3-years survival; Secondary endpoint: 30-day mortality, in-hospital adverse events (stroke, vascular complications, severe bleeding and AKI)

- Both self-explandable (CoreValve) & balloon-expandable (Sapien XT)

Baseline Clinical Characteristics of Propensity Score–Matched Pairs of Patients With EuroSCORE II <4%

OBSERVANT LOW-RISK

OBSERVANT LOW-RISK

Primary Endpoint

SAVR: 83.4%

TAVI: 72%

p<0.001

OBSERVANT LOW-RISK

Three-years freedom from MACCEs

SAVR: 80.9%

TAVI: 67.3%

p<0.001

4. The risk evaluation “gap”

1) Definition of “intermediate risk” patients and understanding the concept of “frailty”

2) Who may rather be a surgical candiadate

3) When TAVI is “futile”

Who is an Intermediate-risk patient?

INTERMEDIATE RISK STS score: between 4% and 8%

Logistic EuroScore I <8% Logistic EuroScore II <4%

Consider SAVR Consider TAVI

Age >80 Previous CABG or Surgical Valve intervention (Re

do)

CAD requiring intervention Bicuspid valve

Age 75-79….? Age <75

Neoplasia (survival >2y)

Low weight-Obesity Moderate-severe CKD

Intellectual Impairment Female Sex/Fraility

Small annulus/miss-match

Syntax Score >23 Syntax Score <23

Frailty not defined

Frailty, disability and comorbidity accoridng to the Deficit Index

Comorbidity

Disability

Frailty

Rockwood K et al, CMAJ 2005

Fraility, disability and comorbidity according to the Phenotype Frailty Index

Dysability (n=67)

Comorbidity (n=2131)

Fraility 26.6% (n=98)

(n=196)

5.7% (n=21)

46.2% (n=170)

21.5% (n=79)

Fried L, et al. J Gerontol 2001

COPD CKD PAD Diabetes CAD Low EF%

Intellectual impairment Arthrosis Orthopedic prosthesis Multiple slerosis Previous stroke

Advanced age Sarcopenia Osteopeoporosis Low body weight Chronic anemia

These are not the same thing…

How to define “fraility” : The Canadian Cardiovascular Health Study

Fried L, et al. J Gerontol 2001

1. Handgrip inferior quintile

2. Gait speed in the inferior quintile

3. Spontaneous weight loos ≥4,5 kg in the last year

4. Easy exhaustibility

5. Physical activity in the inferior quartile

PHENOTYPE FRAILTY INDEX

Frail: ≥3 components

Intermediate (pre-frail): 1 o 2 components

Non frail (robust): 0 component

Short Physical Performance Battery (SPPB)

Test della marcia

Tempo per percorrere 4 metri

di passo normale: ____sec

(tempo migliore di 2 prove)

<4.8 sec 4 punti

4.8-6.2 sec 3 punti

6.3-8.7 sec 2 punti

>8.7 sec 1 punto

incapace 0 punti

0 1 2 3 4 m

Capace

Alzarsi e sedersi per 5 volte più

velocemente possibile a braccia

incrociate

<11.2 sec 4 punti

11.2-13.7 sec 3 punti

13.8-16.7 sec 2 punti

16.8-60 sec 1 punto

>60 sec o incapace 0 punti

Test della sedia

Punteggio totale:

0-12

Guralnik et al, J Gerontol 1994

Posizione piedi uniti

per 10 sec 1 punto

Posizione

semitandem

per 10 sec 1 punto

Posizione tandem

tempo:____ sec

per 10 sec 2 punti

3-9.9 sec 1 punto

<3 sec 0 punti

tempo:____ sec

<10 secondi 0 punti

tempo:____ sec

<10 secondi 0 punti

Test dell’equilibrio

SI

SI

NO

NO

Prognostic value of the SPPB in the aged population

Mobility disability

Non-disabled

BADL disability

%

SPPB score 4 5 6 7 8 9 10 11 12

100

80

60

40

20

0

N= 1122, FU 4 yrs.

Guralnik J, et al. N Engl J Med 1995

The Italian Ministry of Health suggests the introduction in clinical practice of the Short Physical Performance Battery (SPPB) (2013)

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60

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70

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75

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Poder caminar

No orinarse encima

Tener amigos

Poder conducir

Poder hacer sexo

Ganar dinero

Parabola vital: poque NO hay que tratar a los ancianos de manera diferente a los jòvenes...