Should TAVR be the Standard for Bicuspid

Aortic Stenosis, or Do We Need a Randomized

Clinical Trial?

Raj R. Makkar, MDDirector, Interventional Cardiology & Cardiac Catheterization Laboratories

Associate Director, Cedars-Sinai Heart Institute

Professor of Medicine, University of California, Los Angeles

Stephen Corday Chair in Interventional Cardiology

Disclosures

Consultant and research grant from Edwards LifeSciences,

Medtronic, Abbott, Boston Scientific and Jena Valve

What is the competition for TAVR vs.

SAVR trials?

• Aortic Regurgitation

• Failed surgical bioprosthetic valves

• Mixed valvular heart disease-AS+MS/MR

• Failed TAVR valves

My 5 key arguments for a randomized trial for

Bicuspid AS• Bicuspid AS will be encountered with greater frequency as

TAVR use expands in the younger patients-50% of SAVR

in young are bicuspid

• The available observational data are limited by treatment

bias..perhaps only favorable anatomies were treated

• Surgical outcomes in young Bicuspid AS patients are

excellent; reasonable to expect robust evidence for TAVR to

replace SAVR

• Anatomically heterogeneous group with frequent

aortopathy-unlike what has been treated in previous IDE

studies

• The precedent for label expansion in TAVR in last decade

has been IDE randomized clinical trials

In low risk Bicuspid AS

Is TAVR=SAVR?

• Low risk trials: (Mack et al, NEJM; Popma et al, NEJM)

TAVR equal/better than SAVR

• STS/ACC-TVT registry: (Makkar et al, JAMA 2019)

1 year Death/Stroke

Bicuspid AS =Tricuspid AS

Prevalence of Bicuspid Aortic Valve

20- 30- 40- 50- 60- 70- 80-

Fre

qu

en

cy o

f B

AV

(%

)

Roberts WC et al. Circulation. 2005;111:920-925

33

6064

69

60

42

28

0

10

20

30

40

50

60

70

80

Age (years)

Prevalence of bicuspid valve in patients undergoing

isolated AVR-almost 50%!

Roberts WC. et al. Circulation 2005

Operatively excised, stenotic aortic valves from 932 patients

aged 26 to 91 years

Prevalence of bicuspid aortic valve in TAVR

studies is less than SAVR studies

• Less than 7% of patients

with bicuspid aortic valve

in TAVR registries

• Septugenerians undergoing

SAVR: 41.7%

• Octogenerians undergoing

SAVR: 27.5%

Zhao ZG. et al. Nature Reviews in Cardiology 2015

Pivotal Randomized Trials

Inoperable

High Risk

Intermediate Risk

Low Risk

Key Anatomic Exclusion Criteria

• Aortic annulus diameter < 16mm or 28mm

• Bicuspid valve (CT imaging)

• Severe AR or MR

• Severe LV dysfunction

• Severe calcification of aortic valve complex

• Vascular anatomy not suitable for safe femoral access

• Complex CAD: LM, Syntax score>32

• Low coronary takeoff

Outcomes of TAVR for Bicuspid vs Tricuspid AS

• 546 pairs of patients with bicuspid and tricuspid AS were created with PS-

matching

• Bicuspid had more frequent aortic root injury with Sapien XT and PVL with

CoreValve, but no differences in complications with Sapien 3/Evolut R/Lotus

• No difference in 1-year mortality between bicuspid and tricuspid AS

Yoon et al: J Am Colle Cardiol 2017;69:2579-89

Contemporary TAVR for Bicuspid vs Tricuspid AS

STS/ACC TVT Registry

Makkar et al: JAMA 2019;321:2193-202

22

Characteristic% or mean ± SD

Bicuspid AS(n=2691)

Tricuspid AS(n=2691)

p-value

Device success 96.5 96.6 0.87

Procedure Time, min 100.7 ± 51.80 98.2 ± 52.09 0.08

Fluoroscopy Time, min 18.5 ± 10.96 17.1 ± 10.17 <0.0001

Conversion to open surgery 0.9 0.4 0.03

Annulus Rupture 0.3 0.0 0.02

Cardiopulmonary bypass 1.4 1.0 0.13

Aortic dissection 0.3 0.1 0.34

Coronary Obstruction 0.4 0.3 0.34

Need for a second valve 0.4 0.2 0.16

Procedural Outcomes

23

30-Day Outcomes

KM estimate % Bicuspid Tricuspid AS p-value

All-cause mortality 2.6 2.5 0.82

All stroke 2.4 1.6 0.02

Life-threatening bleeding 0.1 0.1 0.99

Major vascular complication 0.9 1.0 0.68

New pacemaker 9.1 7.5 0.03

Aortic valve reintervention 0.2 0.3 0.79

24

Bicuspid

Tricuspid

1-Year Mortality – Matched

2691 1259 1222 1162 934

2691 1367 1326 1256 977

P= 0.31HR: 0.90 [95% CI: 0.73, 1.10]

10.5%

12.0%

All-C

au

se M

ort

ality

(%

)

0

5

10

15

20

25

30

35

40

Time in Months

0 3 6 9 12

Bicuspid

Tricuspid

Number at risk

25

Bicuspid

Tricuspid

1-Year Stroke – Matched

2691 1234 1196 1135 910

2691 1341 1296 1226 952

P= 0.16HR: 1.28 [95% CI: 0.91, 1.79]

3.1%

3.4%

Str

oke (

%)

Time in Months

0 3 6 9 12

Bicuspid

Tricuspid

Number at risk

0

5

10

15

20

25

30

35

40

26

Paravalvular Leak – Matched

81.5% 83.7%74.4% 77.2% 75.7% 78.8%

17.0% 15.5%23.6% 20.5% 21.1% 18.7%

1.3% 0.7% 2.0% 2.3% 3.0% 2.5%0.1% 0.1% 0.1% 0.1% 0.2% 0.0%

0%

20%

40%

60%

80%

100%

Bicuspid(n=2179)

Tricuspid(n=2233)

Bicuspid(n=1711)

Tricuspid(n=1782)

Biscuspid(n=593)

Tricuspid(n=673)

Severe

Moderate

Mild

None/Trace

Discharge 30-day 1-year

p=0.44p=0.17p=0.08

27

0

15

30

45

60

Mean

Gra

die

nt

(mm

Hg

)

Mean GradientBicuspid Tricuspid

p=0.6

9

Hemodynamics – Matched

p=0.15 p=0.86p=0.51

0

0.5

1

1.5

2

2.5

3

Baseline DischargeA

VA

(cm

2)

Aortic Valve AreaBicuspid Tricuspid

p=0.15 p=0.34

What are the limitations of this

observational studies?

• No central CT core lab to diagnose bicuspid

anatomy

• No central adjudication of events

• No data on aortopathy

• Most importantly.. “Treatment bias-were there

anatomical factors as to why TAVR was

chosen rather than surgey? Only 3% of the

entire cohort were bicuspid.

The “easy case”: Little calcium, No Raphe

60 y/o female undergoing TAVR

Annulus Area 356.2 mm2

Dmin 18.3, Dmax 24.8 mm

Congenital bicuspid aortic valveMinimal calcification

TAVR with 23mm Sapien3 performed

Trace paravalvular AR

87 y/o male referred for TAVRNYHA 3 heart failure, diastolic

Severely calcified aortic

valve

Severe MR

Mean gradient 34mmHg

AVA 0.5cm2

Bicuspid valve with heavily

calcified raphe

29mm Sapien 3 deploymentPredilation with 23mm x 4cm Z-Med II Balloon

Careful predilation, heavily calcified valve

Severely calcified

aortic valve

29mm Sapien 3

Eccentric deployment of Sapien3Well expanded valve, but eccentrically located

Eccentric deployment of Sapien3

Moderate PVL

Persisent PVL despite post-dilation

Post-dilation performed with the

Sapien3 balloon

Persistent PVL despite post-

dilation

PVL closure performed immediately after post-

dilation due to persistent moderate PVLStep 1: Shuttle sheath

across the leak

Leak crossed with Terumo

glidewire with a MPA catheter;

wire exchanged for a Amplatz stiff

wire

Step 2: Amplatz wire

removed from the LV

Step 3: 10mm AVP 2

plug advanced

Step 4: 10mm AVP 2

plug deployed

Final result s/p 10mm AVP 2 plug

deployment

TEE guidance during the procedure

Position of wire through the PVL

confirmed with TEE

Final result s/p TAVR and PVL closure

10mm AVP2

plug

Cardiac CT for aortic valve evaluation

Bicuspid aortic valve

Left main

RCA

Calcified

Raphe

Type 1 bicuspid

aortic valve

Left Right

Valve-in valve with Sapien XT 26 mm

Valve deployment Mild residual PVL

No diastolic flow reversal Improved diastolic gradient

Hemodynamics improvement post TAVR

Pre valve replacement Post valve replacement

Improved LV systolic function immediately post TAVR

Pre-valve replacement Post-valve replacement

Continuous improvement of LV systolic function post TAVR

Pre-TAVR (EF 15%) Day 1 post-TAVR (EF 40%)

Repeat CT 2 years later revealed

pseudoaneurysm of the sinus of ValsalvaNormal leaflet motion

Pseudoaneurysm

Patient underwent surgical repair of the pseudoaneurysm and bioprosthetic aortic valve

replacement

Bicuspid Aortic Valve with Challenging

Anatomy

• Calcified Raphe

• Excess Leaflet Calcification

Multiple Valvuloplasty with 23mm Z-Med

Balloon

Downsizing to 26mm Sapien 3 Ultra Valve

Multiple Post-Dilatation

Post-TAVR TEE

• Calcified Raphe

• Mild Leaflet

Calcification

Bicuspid Aortic Valve with Favorable

Anatomy

Bicuspid Aortic Valve with Favorable

Anatomy

• No Calcified Raphe

• Mild Leaflet

Calcification

Bicuspid Aortic Valve with Favorable

Anatomy

• Very Large Annulus

• No Calcified Raphe

• Mild Leaflet Calcification

Surgical Outcomes for Bicuspid Aortic

Valve

Total No AgeMortality

30 days 1 year 5 years 10 years

Borger at al 1 201 54±11 2.5% NA NA 19%

Girdauskas et al 2153

(aortopathy)54±11

0.7% (hospital death)

NA NA 14%

Itagaki et al 3 2079 55.3±14.9 1.5% NA NA NA

Desai et al 4 1890 50±14 0.4% 1.0% 4.0% NA

Andrei et al 5Total: 628

Men: 478

Women: 150

Men: 56.3±13.6

Women:

60.7±13.8

0.6%Men: 3.2%

Women: 6.0%

Men: 8.3%

Women: 7.8%NA

1 Borger et al: J Thorac Cardiovasc Surg 2004; 128: 677-832 Girdauskas et al: Eur J Cardiothorac Surg 2012; 42:832-83 Itagaki et al: J Am Coll Cardiol 2015; 65: 2363-94 Desai et al: J Thorac Cardiovasc Surg 2016; 151: 1650-95 Andrei et al: Am J Cardiol 2015;116:250-255

TAVR technology is ready and the

procedure is mature..

• In the low risk trials the 1and 2 year death,

stroke,and rehospitalization rates were very

low and lower than surgery

• Imaging has evolved to help better select

suitable anatomical subsets

Non-calcified Raphe Calcified RapheM

ild

Le

afl

et

Ca

lcif

ica

tio

n

Ex

ce

ss

Le

afl

et

Ca

lcif

ica

tio

n

No Raphe

n = 61 (5.5%)

n = 64 (5.7%)

n = 271 (24.3%)

n = 201 (18.0%)

n = 225 (20.2%)

n = 293 (26.3%)

Phenotype Distribution

Yoon S, Makkar R EuroPCR 2019

0 180 360 540 720

0

10

20

30

40A

ll-c

au

se

Mo

rta

lity

(%

)40

0

30

20

10

12.3

10.8

25.5

Overall P < .001 by log-rank test

HR for Calcified raphe plus Excess leaflet calc vs. Calcified raphe or Excess leaflet calc

2.17 (95%CI, 1.46 – 3.25); P < .001

HR for Calcified raphe plus Excess leaflet calcification vs. None

2.97 (95% CI, 1.82 – 4.84); P < .001

0 180 720360 540

Days

Ca-raphe plus excess calc

None

No. at Risk

293

332

156

225

80

108

Ca-raphe or excess calc 490 301 151

Calcified raphe plus

Excess leaflet calc

None

Calcified raphe or

Excess leaflet calc

All-cause Mortality and BAV Phenotype1115 Bicuspid AS patients, Central CT Core Lab, 25 Centers

Yoon S, Makkar R EuroPCR 2019

14.0

4.8

9.2

5.5 6.1

1.2

4.1

1.6 2.8

0.6

4.5

2.1 0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

18.0

20.0

PVL ≥ moderate Aortic Root Injury Major VascularCompication

30-day Mortality

Both Calcified raphe plusExcess leaflet calcification

Either Calcified raphe orExcess leaflet Calcification

None

Inc

ide

nc

e (

%)

p < 0.001

p < 0.001 p = 0.006 p = 0.004

Procedural and 30-day Outcomes According to BAV Phenotype

(n = 293) (n = 490) (n = 332)

0 180 360 540 720

0

10

20

30

40A

ll-c

au

se

Mo

rta

lity

(%

)40

0

30

20

10

0 180 720360 540

Days

18.5

12.5

Aortopathy

No Aortopathy

Aortopathy

No Aortopathy

No. at Risk

509

606

302

380

147

192

HR, 1.61 (95% CI, 1.13–2.32)

P = .009 by log-rank test

All-cause Mortality and AortopathyAortopathy was not associated with All-cause Mortality with Multivariate Analysis

Independent Correlates of All-cause Mortality

Univariate Analysis Multivariate Analysis

HR (95% CI) P Value HR (95% CI) P Value

Age 1.03 (1.01 – 1.05) 0.006 – –

STS score 1.06 (1.03 – 1.09) < 0.001 1.04 (1.01 – 1.08) 0.02

MR ≥ moderate at baseline 1.77 (1.10 – 2.87) 0.02 1.65 (1.02 – 2.68) 0.04

Prior MI 1.64 (1.05 – 2.54) 0.028 –

Atrial Fibrillation 1.61 (1.08 – 2.40) 0.021 – –

Type of Bicuspid AV < 0.001 0.001

No raphe (Sievers’ type 0) Reference – Reference –

Non-calcified raphe (Sievers’ type 1) 1.33 (0.59 – 2.99) 0.49 1.55 (0.69 – 3.50) 0.29

Calcified raphe (Sievers’ type 1) 2.70 (1.25 – 5.86) 0.01 2.80 (1.29 – 6.08) 0.009

Excess leaflet calcification 1.72 (1.19 – 2.49) 0.004 1.53 (1.05 – 2.22) 0.03

Aortopathy 1.61 (1.13 – 2.32) 0.009 – –

Non-transfemoral access 2.05 (1.29 – 3.25) 0.002 1.70 (1.05 – 2.75) 0.03

Early-generation devices 1.89 (1.31 – 2.73) 0.001 1.71 (1.17 – 2.50) 0.005

Independent Correlates of All-cause Mortality

Univariate Analysis Multivariate Analysis

HR (95% CI) P Value HR (95% CI) P Value

Age 1.03 (1.01 – 1.05) 0.006 – –

STS score 1.06 (1.03 – 1.09) < 0.001 1.04 (1.01 – 1.08) 0.02

MR ≥ moderate at baseline 1.77 (1.10 – 2.87) 0.02 1.65 (1.02 – 2.68) 0.04

Prior MI 1.64 (1.05 – 2.54) 0.028 –

Atrial Fibrillation 1.61 (1.08 – 2.40) 0.021 – –

Type of Bicuspid AV < 0.001 0.001

No raphe (Sievers’ type 0) Reference – Reference –

Non-calcified raphe (Sievers’ type 1) 1.33 (0.59 – 2.99) 0.49 1.55 (0.69 – 3.50) 0.29

Calcified raphe (Sievers’ type 1) 2.70 (1.25 – 5.86) 0.01 2.80 (1.29 – 6.08) 0.009

Excess leaflet calcification 1.72 (1.19 – 2.49) 0.004 1.53 (1.05 – 2.22) 0.03

Aortopathy 1.61 (1.13 – 2.32) 0.009 – –

Non-transfemoral access 2.05 (1.29 – 3.25) 0.002 1.70 (1.05 – 2.75) 0.03

Early-generation devices 1.89 (1.31 – 2.73) 0.001 1.71 (1.17 – 2.50) 0.005

• CT assessment of morphology in bicuspid aortic stenosis helps assess anatomical risk of TAVR

• In absence of randomized clinical trial data in treating Bicuspid Aortic Stenosis, CT based anatomical assessment may identify patients favorable for TAVR and in conjunction with surgical risk help triage patients to TAVR vs. SAVR

Clinical Implications

Pivotal Randomized Trials have been the standard

for indication expansion for TAVR

Inoperable

High Risk

Intermediate Risk

Low Risk

Meta-Analysis

Systemic Reviews

Randomized Controlled Trial

Cohort Studies

Case Control Studies

Case Report/ Case Series

Background Information & Expert Opinion

Hierarchy of Evidence and Research Designs

In low risk Bicuspid AS

Is TAVR=SAVR?

• Low risk trials: (Mack et al, NEJM; Popma et al, NEJM)

TAVR equal/better than SAVR

• STS/ACC-TVT registry: (Makkar et al, JAMA 2019)

1 year Death/Stroke

Bicuspid AS =Tricuspid AS

Why infer? Let us do the randomized clinical trial!

Practical considerations..

• Be careful of unfavorable anatomical features on CT: excessive

calcium, raphe type especially calcified raphe

• Some degree of undersizing (compared to tricuspid) is appropriate

• Positioning is harder than the tricuspid valve. Cross check with

echo. TEE guidance is is preferable due to higher rates of AI and

risk of aortic root rupture

• Predilation is generally a good idea; avoids difficult crossing and

stresses on aorta which may be diseased; also can help with sizing.

• Post dilation and rarely valve in vavle may be needed to optimize

the expansion and procedural outcomes.

Conclusions

• Though the mortality may be “similar” to the tricuspid TAVR, the acute

outcomes in the published literature are worse with respect to AI, and

pacemaker implantation with the first generation devices

• The data with Sapien 3 valve are excellent, no comparative studies are

available with other next generation valves (Evolut R, Lotus, Portico)

• While Bicuspid TAVR is justifiable in higher surgical risk patients, high

risk anatomical features (extreme calcium, heavy-calcified raphe),

concomitant aortopathy should prompt consideration for surgical AVR in

low risk patients

• Randomized trials/prospective registries especially in patients with lower

surgical risk are needed.