PARTNER 3 Low-Risk Computed Tomography (CT) Sub-study ... · PARTNER 3 Low-Risk Computed Tomography (CT) Sub-study: Subclinical Leaflet Thrombosis in Transcatheter and Surgical Bioprosthetic

PARTNER 3 Low-Risk Computed Tomography (CT) Sub-study: Subclinical Leaflet Thrombosis in Transcatheter and

Surgical Bioprosthetic Valves

Raj R. Makkar, MDon behalf of the PARTNER 3 Trial Investigators

Disclosures – Raj Makkar, MDTCT 2019; San Francisco, CA; September 25-29, 2019

Within the past 36 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

• Consultant and research grant from Edwards LifeSciences, Abbott, Medtronic, Boston Scientific

Subclinical Leaflet Thrombosis characterized by hypo-attenuated leaflet thickening (HALT) and reduced leaflet

motion has been frequently observed in transcatheter and surgical aortic bioprosthetic valves.

Background

Reduced leaflet motion

Makkar R. et al. NEJM 2015

Hypoattenuating leaflet thickening (HALT)

Thickened leaflets

Hypoattenuating opacities

Thrombus on bioprosthetic valves can present as a spectrum:• HALT with relatively normal

leaflet motion• HALT with reduced leaflet

motion, but normal gradients• Clinical valve thrombosis with

elevated gradients

Background

• Randomized trial data on prevalence of Subclinical Leaflet Thrombosis between transcatheter and surgical bioprosthetic aortic valves, its natural history, and impact of this finding on valve hemodynamics and clinical outcomes are lacking.

• PARTNER 3 CT substudy was mandated by the FDA to study this finding in low-risk patients undergoing TAVR with SAPIEN 3 or surgery

Background

Study Objectives

The primary objective of the study was to evaluate HALT and reduced leaflet motion (RLM) in terms of:

• Differences in transcatheter and surgical bioprosthetic aortic valves in a randomized cohort

• Natural history of HALT and reduced leaflet motion in the absence of anticoagulation

• Impact on valve hemodynamics and clinical outcomes

Inclusion Criteria• Eligible for the PARTNER 3 Low-Risk Study• Ability to have a high quality multi-phasic, ECG-Gated CT

scans (i.e., 4D) with contrast

Exclusion Criteria• Condition requiring or planned use of anticoagulants

following index procedure• GFR < 50

Key Entry Criteria

Study Methodology

• Serial CTs at 30 days and 1 year post TAVR or SAVR• All CTs analyzed by a CT corelab blinded to patient

information or time of CTs (Jonathon Leipsic, MD, Philipp Blanke, MD University of British Columbia, Vancouver)

• Treating investigators blinded to the results of 30-day and 1-year CT scans

• Key clinical events were adjudicated by clinical events committee

Study Methodology: CT Analysis

• The extent of HALT graded as <25%, 25-50%, >50-75% and >75%

• 4D CT used to assess leaflet motion. Reduced leaflet motion (RLM) graded as no restriction, partially restricted or immobile

Blanke P. et al. Journal of Cardiovascular Computed Tomography 2019

• This was a hypothesis-generating, observational study with no pre-specified statistical analysis plan

• Event rates are binary and p-values (when included) are based on Fisher’s Exact test

• P-values for continuous variables (when included) are based on t-test

Statistical Methods

Evaluable CTs at 30 days and 1 yearAs Treated Population

N = 408

TAVR Initiated (AT) N = 213

Surgery Initiated (AT) N = 195

30 D

ay

30 D

ay

1 Ye

ar

1 Ye

ar

Evaluable CTsN = 184

Evaluable CTs*N = 168

Evaluable CTsN = 162

Evaluable CTs*N = 144

Total evaluable CTs at 30 days

N=346

Total evaluable CTs at 1 year

N=312

*Not all patients who had a 1-year CT had a 30 day CT

Anticoagulation (AC) Usage

No AC Post Index Procedure

N = 297

Valve-Related AC*

N = 7

*Reasons for anticoagulation include elevated gradients, symptoms, and stroke/TIA**Reasons for non-valve related anticoagulation included pre-existing indication for anticoagulation; new onset Afib/A flutter, pulmonary embolism, peripheral vascular disease, heparin induced thrombocytopenia, and untreated pre-existing Afib that worsened; unblinding of CT findings with anticoagulation initiated for imaging finding, DVT prophylaxis, and bioprosthetic valve

AC Post Index Procedure for

Non-Valve Related

ReasonsN = 68**

Patients with Evaluable CTs at 30 days and/or 1 year

N = 372

• Per Protocol Population used for the determination of incidence and natural history of HALT and reduced leaflet motion

No AC Post Index Procedure

N = 297

Valve-Related AC*

N = 7

*Reasons for anticoagulation include elevated gradients, symptoms, and stroke/TIA**Reasons for non-valve related anticoagulation included pre-existing indication for anticoagulation; new onset Afib/A flutter, pulmonary embolism, peripheral vascular disease, heparin induced thrombocytopenia, and untreated pre-existing Afib that worsened; unblinding of CT findings with anticoagulation initiated for imaging finding, DVT prophylaxis, and bioprosthetic valve

AC Post Index Procedure for

Non-Valve Related

ReasonsN = 68**

Patients with Evaluable CTs at 30 days and/or 1 year

N = 372

• All evaluable CTs used for determining the impact of HALT and reduced leaflet motion on valve hemodynamics and clinical outcomes

Anticoagulation (AC) Usage

Incidence of HALT at 30 Days and 1 Year

Outcomes (%)30 Days 1 Year

TAVR (N=165)

Surgery (N=119) P-value

TAVR (N=153)

Surgery (N=109) P-value

HALT 13.3 5.0 0.03 27.5 20.2 0.191 Leaflet 81.8 66.7 64.3 68.22 Leaflets 9.1 33.3 23.8 31.83 Leaflets 9.1 0 11.9 0

Event rates are binary and p-value is based on Fisher’s Exact test

TAVR vs SAVRPer Protocol Population

HALT from 30D to 1YPer Protocol Population

All Patients30 Day 1 Year

No HALTN = 217

HALTN = 25

HALTN = 11 (44%)

No HALTN = 14 (56%)

HALTN = 46 (21%)

No HALTN = 171 (79%)

0/14 received

anticoagulation

HALT from 30D to 1Y (TAVR vs SAVR)

*Of the 10 TAVR patients and 4 SAVR patients with HALT at 30 days and no HALT at 1 year, none received anticoagulation

Per Protocol PopulationTAVR

30 Day 1 Year

No HALTN = 119

HALTN = 20

HALTN = 10 (50%)

No HALT*N = 10 (50%)

HALTN = 27 (23%)

No HALTN = 92 (77%)

SAVR30 Day 1 Year

No HALTN = 98

HALTN = 5

HALTN = 1 (20%)

No HALT*N = 4 (80%)

HALTN = 19 (19%)

No HALTN = 79 (81%)

30-D HALT and Reduced Leaflet MotionAll Patients with Evaluable CTS

HALT Extent30 Day CT

Unrestricted Leaflets

Partially Restricted

Largely Immobile

None 288 0 0<25% 0 11 025-50% 0 8 0>50-75% 0 12 1>75% 0 1 1

Reduced leaflet motion was noted in 100% of patients with HALT*

*Not all CTs evaluable for HALT were evaluable for leaflet mobility

1-Y HALT and Reduced Leaflet MotionAll Patients with Evaluable CTs

HALT Extent1 Year CT

Unrestricted Leaflets

Partially Restricted

Largely Immobile

None 228 0 0<25% 0 31 025-50% 0 17 0>50-75% 0 13 0>75% 0 3 6

Reduced leaflet motion was noted in 100% of patients with HALT*

*Not all CTs evaluable for HALT were evaluable for leaflet mobility

Mean Gradient by 30-day and 1-Year HALT and Leaflet Motion

30 Days 1 Year

HALT (N=35)

No HALT (N=310)

P-Value HALT (N=72)

No HALT (N=232)

P-Value

Mean Gradient 13.2 ± 0.81 11.7 ± 0.24 0.08 13.7 ± 0.82 12.6 ± 0.28 0.24

mean ± SE All Patients with Evaluable CTs

LeafletMotion

30 Days 1 Year

Reduced (N=34)

Normal (N=288)

P-Value Reduced (N=69)

Normal (N=222)

P-Value

Mean Gradient 13.3 ± 0.83 11.4 ± 0.23 0.04 13.6 ± 0.85 12.5 ± 0.28 0.23

mean ± SE

P-values are based on t-test

Mean Aortic Valve Gradient and Severity of HALT at 1 year

All Patients with Evaluable CTs – TAVR & SAVR

13.7 15.1 16.412.6 12.6 12.6

0

25

50

HALT > 25%HALT ≤ 25%


HALT > 25%

HALT ≤ 25%

P=0.07 P=0.08

HALT > 0

No HALT

HALT > 0%No HALT

P=0.24

HALT > 50%

HALT ≤ 50%

Mea

n G

radi

ent (

mm

Hg)


Clinical Events(n)

Day 7-30 Day 31-365

HALT at 30 Days (N=35)

No HALT at 30 Days (N=311)



Death 0 0 0 4Heart Failure 0 1 1 6Angina 0 0 0 9Myocardial Infarction 0 0 0 3Clinical Valve Thrombosis* 0 0 3 1Stroke 1 0 0 1TIA 0 1 1 2Retinal Artery Embolism 0 0 1 1

30-day HALT and Clinical EventsAll Patients with Evaluable CTs – TAVR & SAVR

*Defined according to VARC2 definition

Death / Stroke / TIA / Thromboembolic Events and 30-day HALT

TAVR & SAVR

8.6

2.95.7

2.90.3

2.6

0

25

50

Perc

ent o

f Pat

ient

s (%

) HALTNo HALT

Day 31-365Day 7-30HALTNo HALT

n

HALT1

No HALT1

HALT2

No HALT8

N 35 311 35 311

P=0.19 P=0.27

HALT3

No HALT9

35 311

HALTNo HALT

Day 7-365

P=0.11


0

25

50

75

100

No HALTHALT

307 307 29235 35 32

KCC

Q-O

S

No HALTHALT

No. of ObservationsBaseline 30D 1 Year

69.3

85.0

87.470.880.6

89.1

KCCQ by 30-day HALT Patients with Evaluable CTs (TAVR & SAVR)

Baseline Patient Characteristics

Demographics & Vascular Disease

HALT at 30 Days(N=28)

No HALT at 30 Days

(N=256)

Other Co-Morbidities

HALT at 30 Days(N=28)

No HALT at 30 Days

(N=256)Age (years) 73.2 ± 4.4 72.3 ± 6.1 Diabetes 14.3% 32.9%

Male 71.4% 68.4% COPD (any) 7.1% 4.7%

BMI – kg/m2 28.8 ± 4.1 30.1 ± 4.7 Pulmonary Hypertension 3.6% 4.7%

STS Score 1.8 ± 0.7 1.8 ± 0.7 Creatinine > 2mg/dL 0% 0%

NYHA Class III or IV* 64.3% 40.6% Frailty (overall; > 2/4+) 0% 0%

Coronary Disease 39.3% 29.7% Atrial Fibrillation 0% 5.1%

Prior CABG 7.1% 2.8% Permanent Pacemaker 3.6% 2.0%

Prior Stroke or CVA 3.6% 2.3% Left Bundle Branch Block 3.6% 2.7%

Peripheral Vascular Disease

0% 4.3% Right Bundle Branch Block 7.1% 8.2%

% or mean ± SD

*p = 0.03 based on Fisher’s Exact test

Per Protocol Population

The PARTNER 3 CT Sub-StudyStudy Limitations

• Results reflect only 1-year outcomes. • Any potential impact of HALT on durability will be assessed in

the 10-year follow up of these low-risk patients• Study is not powered to draw conclusions regarding HALT,

leaflet mobility, and clinical events; results are hypothesis generating

Observations from CT sub-study with blinded assessment of serial CTs in randomized low risk patients undergoing TAVR with SAPIEN 3 or surgery:

• Incidence HALT and reduced leaflet motion are frequently present in the bioprosthetic valves. The incidence in the entire cohort was 10% at 30 days and increased to 24% at 1 year.

• TAVR vs. SAVR The prevalence of HALT and reduced leaflet motion was significantly higher in TAVR than SAVR at 30 days, but not at 1 year.

• Natural History HALT was dynamic and spontaneously resolved (50%) in the absence of anticoagulation; new HALT appeared in 20% of patients at 1 year.

The PARTNER 3 CT Sub-StudyConclusions 1

Observations from CT sub-study with blinded assessment of serial CTs in randomized low risk patients undergoing TAVR with SAPIEN 3 or surgery:

• Valve Hemodynamics HALT and reduced leaflet motion resulted in minimal increase in valve gradients, which can be considered clinically insignificant.

• Clinical Outcomes There were no deaths or MIs in patients with HALT. The pooled rates of death/stroke/TIA/thromboembolic events were numerically higher in patients with HALT; however, given the low total number of events, the data are inconclusive and only hypothesis generating. Longer term follow-up and larger data set will further clarify the impact on clinical outcomes.

The PARTNER 3 CT Sub-StudyConclusions 2

Based upon these findings in surgical & transcatheter bioprosthetic valves:

• Despite the high incidence of HALT and reduced leaflet motion, lack of a clear association with serious clinical events such as death, MI and stroke does not justify the routine prophylactic use of anticoagulation in all patients.

• Routine post TAVR/SAVR CT scans, outside of research protocols are not indicated; CTs should be prompted by increased gradients or thromboembolic events.

• The effect of HALT and reduced leaflet motion on valve durability will be known during long-term follow-up.

The PARTNER 3 CT Sub-StudyClinical Implications

National Principal Investigators• Martin B. Leon, MD, Columbia University Medical Center, New York, NY• Michael J. Mack, MD, The Heart Hospital Baylor Plano, Plano, TX

Steering Committee• Howard Herrmann, Samir Kapadia, Susheel Kodali, Martin B. Leon, Michael J. Mack,

Raj Makkar, Craig R. Smith (chair), Wilson Szeto, Vinod Thourani, John WebbData & Safety Monitoring Board

• Cardiovascular Research Foundation, New York, NY; Joseph Carrozza, Jr., MD, chairClinical Events Committee

• Cardiovascular Research Foundation, New York, NY; Steven O. Marx, MD, chairCT Core Laboratory

• The University of British Columbia; Jonathon Leipsic, MD, chair; Philipp Blanke, MD, chair

Echocardiographic Core Laboratory• Quebec Heart & Lung Institute (Laval University); Philippe Pibarot, DVM PhD, chair• Cardiovascular Research Foundation, New York, NY; Rebecca Hahn, MD, chair

Sponsor• Edwards Lifesciences, Irvine, CA

Study Leadership

Thank you to the Partner 3 investigators

Back-Up Slides

Details of 7 patients requiring valve related anticoagulation

Event that triggered

anticoagulation

Timing of Event Type of AC TAVR/SAVR 30-days 1 year Case details

Retinal artery embolism and

elevated gradient

1-year visit Eliquis TAVR HALT –ve

15.8mmHgHALT > 75%35.5mmHg

Retinal artery embolism at day 358 (adjudicated as a stroke)

Elevated Gradient 30-day visit Coumadin TAVR HALT>50%

32mmHgHALT > 50%34.8mmHg

Elevated gradient on 30-day echo; rehospitalized for bleeding on day 56 – subdural hematoma and supratherapeutic INR

Symptomatic 30-day visit Coumadin TAVR HALT –ve

13.7mmHgHALT –ve10.1mmHg

Leaflet thickening on TEE at 30 days + symptomatic (dizziness); CT did not show HALT or leaflet restriction

Stroke Post-op day 10 Coumadin TAVR HALT 50-75%

13.3mmHgHALT > 75%13.3mmHg

Prescribed ASA post procedure and subject non-compliant. Readmitted with ischemic CVA on POD 10; Prescribed ASA and Plavix.

Stroke Post-op day 3

Coumadin (treated for 3

days)TAVR HALT-ve

9.3mmHgHALT-ve5.7mmHg

On post-op day 3, patient had an embolic stroke and was heparinized. Underwent an embolectomy on day 4, started on anticoagulation as a result; patient had a hemorrhagic stroke on post-op day 8, likely related to embolectomy

TIA Post-op day 15 Coumadin SAVR HALT-ve

15.6mmHgHALT-ve

13.2mmHgPatient had visual impairment post-op day 15 – was adjudicated as a TIA

Stroke 3 days post-op Coumadin SAVR HALT –ve

11.8mmHgHALT –ve18.9mmHg

Patient had a stroke on post-op day 3 and started on anticoagulation at that time

Anticoagulation at the Time of CT and HALT/Reduced Leaflet Motion (RLM)

4.4

15.211.0

24.4

0

25

50

Perc

ent o

f Pat

ient

s w

ith H

ALT

(%)

AC

Patients with HALT at 30 days

n 2 33 5 68N 45 301 33 279

P=0.29

P=0.28

4.7

16.1

11.4

24.3

0

25

50

Perc

ent o

f Pat

ient

s w

ith R

LM (%

)

n 2 32 5 65N 43 280 31 267

P=0.28 P=0.38

Patients with HALT at 1 year

No AC AC No AC AC

Patients with RLM at 30 days

Patients with RLM at 1 year

No AC AC No AC


Treatment Arm

Timing of Event

HALT at 30 Days (CT)

HALT at 1 Year (CT)

Mean Gradient Comments / AC

TAVR 30 25-50% HALT, unrestricted

leaflets

No HALT/HAM

Baseline: 59.2 mmHg30-Day: 21.0 mmHG1-Year: 10.2 mmHg

Patient received Coumadin at 30-days for elevated gradient

TAVR 40 50-75% HALT, partially

restricted leaflets

>75% HALT, partially

restricted leaflets

Baseline: 69.1 mmHg30-Day: 32.0 mmHg1-Year: 34.8 mmHg

Elevated gradient at 30 days triggered unblinding of CT; Patient put on Coumadin; rehospitalized for bleeding on day 56; patient had subdural hematoma and supratherapeutic INR

TAVR 30 50-75% HALT, partially

restricted leaflets

NM Baseline: 50.7 mmHg30-Day: 11.6 mmHg1-Year: 7.4 mmHg

Patient had SOB walking uphill at 30 days & HALT with leaflet restriction per CT; Coumadin started at day 190

TAVR 182 No HALT/HAM NM Baseline: 41.6 mmHg30-Day: 13.7 mmHg1-Year: 10.1 mmHg

Leaflet thickening was seen on 30-day echo + patient was symptomatic (dizziness) but CT did not show HALT or leaflet restriction.

Clinical Valve Thrombosis4 events

Treatment Arm

Timing of Event


HALT at 1 Year (CT)


TAVR 10 50-75% HALT, largely

immobile leaflets

>75% HALT, largely

immobile leaflets


Prescribed ASA post procedure and subject non-compliant. Readmitted with ischemic CVA on POD 10; Prescribed ASA and Plavix; At 30d CT, unblinded by site and had 50-75% HALT and largely immobile leaflets. Anticoagulated

TAVR 358 No HALT/HAM

>75% HALT, largely

immobile leaflets


Patient had visual changes; Seen by optho – retinal artery branch occlusion in right eye; Adjudicated by CEC as CVA. Seen at 1 yr f/u on POD 373. TEE – AV moving well w/ no evidence of vegetation or thrombus but elevated gradients; Patient was AC’d w/ Eliquis as a result

Stroke2 events

Treatment Arm

Timing of Event


HALT at 1 Year (CT)


TAVR 57 No HALT/HAM

<25% HALT,

partially restricted leaflets


At enrollment, subject on Eliquis for DVT prophylaxis; Held for procedure and restarted post-procedure; Subject had a transient episode of diplopia; MRI revealed infarct but not in region that would cause vision abnlty. Maintained on Eliquis until ~ 1 year post index procedure


No HALT/HAM


Seen in ER and dx’d w/ TIA. Echo and carotid US were negative; 4DCT performed that showed no clot and good leaflet motion

TAVR 357 25-50% HALT,


<25% HALT,



Episode of left arm numbness lasting 10-15 minutes; neuro exam negative at time of 1 year visit but no f/u by neuro as recommended; Adjudicated as worst case scenario

SAVR 17 No HALT/HAM

No HALT, HAM NM


Patient had visual impairment shortly after index procedure– was adjudicated as a TIA; Also had incidental finding of chronic L frontal infarct; As a result, subject was started on AC.

TIA4 events

Treatment Arm

Timing of Event


HALT at 1 Year (CT)


TAVR 118 25-50% HALT,


25-50% HALT,

HAM NM


TIA early – POD 0; post-op had intermittent visual changes, developed mild ansiscora; MRI revealed multiple small punctate lacunar infarcts, unrelated to symptoms; adjudicated as TIA; on POD 118, developed visual changes in L eye and diagnosed with transient retinal artery occlusion; Carotid US and TTE were negative


No HALT/HAM


Symptom of veil lowering over L eye 2/2 possible emboli; Not AC’d

Retinal artery embolism2 events

Mean Aortic Valve Gradient and Severity of HALT at 30 days

All Patients with Evaluable CTs

13.2 13.8 14.611.7 11.7 11.7

0

25

50M

ean

Gra

dien

t (m

mH

g)HALT > 25%HALT ≤ 25%


HALT > 25%

HALT ≤ 25%

P=0.08 P=0.08

HALT > 0

No HALT

HALT > 0%No HALT

P=0.08

HALT > 50%

HALT ≤ 50%


Clinical Eventsn/N

TAVR Surgery



HALT at 30 Days

(N=7)

No HALT at 30 Days

(N=155)Death 0 0 0 0Heart Failure 0 0 0 1/155Angina 0 0 0 0Stroke 1/28 0 0 0TIA 0 0 0 1/155Myocardial Infarction 0 0 0 0Clinical Valve Thrombosis* 0 0 0 0Retinal Artery Embolism 0 0 0 0

Potential Valve-Related Clinical Events from Day 7-30 by 30-day HALT

Patients with Evaluable CTs

*Defined according to VARC2 criteria

Clinical Eventsn/N

TAVR Surgery



HALT at 30 Days

(N=7)

No HALT at 30 Days

(N=155)Death 0 2/156 0 2/155Heart Failure 0 1/156 1/7 5/155Angina 0 6/156 0 3/155Stroke 0 1/156 0 0TIA 1/28 2/156 0 0Myocardial Infarction 0 0 0 3/155Clinical Valve Thrombosis* 3/28 1/156 0 0Retinal Artery Embolism 1/28 1/156 0 0

Potential Valve-Related Clinical Events from Day 31-365 by 30-day HALT

*Defined according to VARC2 criteria

Patients with Evaluable CTs

Ordinal Analysis of KCCQ-OS by 30-day HALT

Patients with Evaluable CTsDeadWorseNo changeSlight improvementModerate improvementSubstantial improvement

KCCQ

-OS

Chan

ges (

%)

37.2

24.1

11.7

20.0

5.51.4

40.0

20.0

40.0

No HALT HALT

46.6

12.2

15.5

20.3

4.11.4

44.4

14.8

22.2

11.17.4

No HALT HALT

19.3

19.3

7.3

18.0

36.0

42.9

14.3

14.3

28.6

No HALT HALT

41.2

15.7

7.2

26.1

9.8

42.9

14.3

21.4

14.3

7.1

No HALT HALT0

20

40

60

80

100

30 DaysTAVR Surgery TAVR Surgery

153 28 150 7 148 27 145 5No. of Observations:

1 Year

Documents

PARTNER 3 Low-Risk Computed Tomography (CT) Sub-study ... · PARTNER 3 Low-Risk Computed Tomography (CT) Sub-study: Subclinical Leaflet Thrombosis in Transcatheter and Surgical Bioprosthetic