The DEFLECT III Trial:A Prospective Randomized Evaluation of the TriGuard Embolic DEFLECTion Device during Transcatheter Aortic Valve Replacement

Alexandra Lansky, MDYale University School of Medicine

New Haven, CT

Joachim Schofer, Szilard Voros, Adam Brickman, Didier Tchetche, Pieter Stella, Jochen Reinöhl Thomas Cuisset, Daniel Blackman, Michael Cleman, John Forrest, Gil

Bolotin, Med Spitzer, Martine Gilard, Thomas Modie, David Hildick-Smith, Kevin Abrams, Michael Haude, and Andreas Baumbach

Disclosure Statement of Financial Interest

Affiliation Financial Relationship

• Research grants:

• Consultant/Speaker Honoraria:

• Minor Ownership interest:

Company

• Keystone Heart, Bard, Biotronik, Boston Scientific, CardioKinetix, Direct Flow, Gilead Sciences, Gore, Intact Vascular, Micell, Recor Medical, Shockwave Medical, SilkRoad Medical, St Jude Medical, TriReme Medical, Ventrix Medical, Veryan Medical

• AstraZeneca Pharmaceuticals, Eli Lilly and Company, Daichi Sankyo, CardioDX, Merk & Co.

• Keystone Heart

Clinical Stroke after TAVR• 4-7% at 30 days in RCTs• Generally under-reported (17% after

SAVR when evaluated by neurologist)• Confer 3- to 9-fold increased risk of

mortality• 50% are peri-procedural

Leon et al. NEJM. 2010;363:1597, Smith et al. NEJM. 2011;364:2187, Adams et al. NEJM 2014;370:1790, Leon MB ACC 2013, Popma et al. JACC 2014;63:1872, Eggebrecht et al. EuroIntervention. 2012;8:129, Messe et al. Circulation 2014;129:2253, Tchetche et al. JACC Cardiovasc Interv 2014;7:1138, Miller et al. J Thorac Cardiovasc Surg 2012;143:832

PARTNER 1A

PARTNER 1B

PARTNER 2B

CoreValve High

Risk

CoreValve Extr

eme0.0%1.0%2.0%3.0%4.0%5.0%6.0%7.0%8.0%

MajorMajor/minor

30-day stroke rates

• Affect 58-100% of patients • Multiple infarcts (≤36, x� = 4.6) • Associated with:

Neurocognitive decline >2 fold risk of dementia >3 fold risk of stroke

Restrepo et al. Stroke 2002;33:2909, Lund et al. Eur Heart J. 2005;26:1269, Schwarz et al. Am Heart J 2011;162:756, Knipp et al. Ann Thorac Surg 2008;85:872, Vermeer et al. NEJM 2003;

348:1215, Vermeer et al. Stroke 2003; 34:1126, Arnold et al. JACC Cardiovasc Interv. 2010;3:1126, Astarci et al. J Heart Valve Dis. 2013;22:79, Fairbairn et al. Heart 2012;98:18,

Ghanem et al. EuroIntervention. 2013;8:1296, Kahlert et al. Circ. 2010;121:870, Knipp et al. Interact Cardiovasc Thorac Surg. 2013;16:116, Linke et al. TCT 2014,

Rodes-Cabau et al. JACC Cardiovasc Interv 2014;7:1146

Silent Embolic Events on DW-MRI after TAVR

Arnold

Astarci

Fairb

airn

Ghanem

Kahlert

Knipp

Rodes-Cab

auUddin

CLEAN TAVI

PROTAVI C0%

50%

100%

68%

93%

77%72%

84%

58%

68%

82%

98% 100%

% of Subjects with New Lesions

• Single-wire nitinol frame and mesh filter with pore size of 130μm designed to deflect cerebral emboli during TAVR while allowing maximal blood flow

• Device is positioned across all 3 cerebral vessels and maintained by a stabilizer in the innominate

• Delivered via 9 Fr sheath from femoral artery

The TriGuard Device

DEFLECT III Study Overview

Design: Multicenter prospective single-blind randomized controlled trial at 13 sites (EU/IL)Objective: To evaluate the safety, efficacy and performance of TriGuard protection compared with unprotected TAVR. Sample Size: Exploratory study with no formal hypothesis testing. 86 patients selected to benchmark events for the design of a pivotal RCT.

Embolic Protection (TriGuard)

Unprotected TAVR

(Control)

Subjects with AS undergoing TAVR

1:1 Randomization

DEFLECT III Eligibility Criteria

• Key Inclusion Criteria Patients undergoing TAVR via the transfemoral approach

Exclusion Criteria Stroke or TIA within prior 6 months Any other cardiac intervention within prior 2 weeks Aortic arch or innominate anatomy deemed to prevent

positioning and stability of the device (ostium diameter <11 mm, transverse aortic diameter >40 mm)

Contraindication to cerebral MRI (e.g., pacemaker)

Screening Procedure Post-Procedure 30 days

DEFLECT III Procedures & Assessments

NIHSSmRS

Neurocog*

4±2 days

TAVR±

TriGuard

DW-MRI

NIHSSmRS

Neurocog*

*Neurocognitive test battery includes the Montreal Cognitive Assessment (MoCA) and computerized CogState Research Test. Baseline and 30-day evaluations include supplemental Digit Symbol Substitution, Trailmaking, and Word Fluency Tests.

DW-MRI

NIHSSmRS

Neurocog*

30 days

DEFLECT III Endpoints• Primary Safety Endpoint (ITT population)

In-hospital MACCE defined as the composite of death, stroke, life-threatening or disabling bleeding, AKI (2/3), and major vascular complications (VARC-2)

• Secondary Performance (ITT population) Technical success: successful positioning (complete 3-vessel coverage

verified by angiography) and retrieval without TAVR interference

• Secondary Efficacy (ITT and Per Treatment* populations) DW-MRI: Frequency, number, and average single, maximal, and total

lesion volumes by DW-MRI at 4+2 days (range 2-6 days) Neurocognitive: Postoperative and change from baseline to

postprocedure and 30 days

*Per treatment (PT) population: subjects with complete TriGuard cerebral vessel coverage throughout the procedure (core lab adjudicated)

Embolic Protection (TriGuard)

n = 45

Unprotected TAVR(Control)

n = 38

Intent To Treat PopulationN=83

DEFLECT III Patient Disposition

In-hospital FUSafety n = 45

DW-MRI: n = 32 (71%) (ITT) n = 26 (57%)(PT)

In-hospital FUSafety n = 38

DW-MRI: n = 25 (65%) (ITT) n = 25 (65%) (PT)

MRI Loss to FU n=13 (29%)• Stroke n=1• Refused n = 3• PPM n=9

MRI Loss to FU n=13 (34%)• Death n = 2• Stroke/PPM n=1• Refused n = 4• PPM n=6

PrincipalInvestigators

Alexandra Lansky, MD Andreas Baumbach, MDYale University School of Medicine,USA Bristol Heart Institute, UK

Szilard Voros, MD (Director)Global Institute for Research, Richmond, VA, USA

Ecaterina Cristea, MD (Director) Helen Parise, PhD Yale University School of Medicine, New Haven, CT, USA (Statistics)

Adam Brickman, MD (Director) Kevin Abrams, MD (chief)Columbia University, New York, USA Baptist Hospital, Miami, Fl

Michael Cleman, MD (Chair) Joseph Brennan, MDJohn Forrest, MD Abeel Mangi, MDYale University School of Medicine, New Haven, CT, USA

Genae International, Inc.Harvard Clinical Research Institute

DEFLECT III Trial Organization

MRI Core Lab

AngiographicCore LabBiostatisticNeurologic & neurocognitiveAssessment

Clinical EventsCommittee

Monitoring,Site Mgmt.Data Mgmt

Joachim Schofer (17)Hamburg, Germany

Andreas Baumbach (8)Bristol, United Kingdom

Martine Gilard (2)Brest, France

Didier Tchetche (13)Toulouse, France

Daniel Blackman (6)Leeds, United Kingdom

Thomas Modine (1)Lille, France

Pieter Stella (11)Utrecht, Netherlands

Gil Bolotin (4)Haifa, Israel

Michael Haude (1)Neuss, Germany

Thomas Cuisset (10)Marseille, France

Med Spitzer (2)Dresden, Germany David Hildick-Smith (1)

Brighton, United Kingdom

Jochen Reinöhl (10)Freiburg, Germany

Feb 26, 2014 March 4, 2015

Enrollment Start

RCT Enrollment Complete

5 Countries / 13 Centers

DEFLECT III Trial – Enrollment HighlightsApril 4, 2015

30 day FUComplete

ITT population TriGuardN=45

ControlsN=38 P value

Age (y) ± SD 82.7 ± 6.5 82.5 ± 5.9 0.62Male 40.9% 50.0% 0.41STS Score 4.7 7.4 0.48EuroSCORE II 10.1 7.4 0.66NYHA Class I or II (%) 83.3% 78.9% 0.65 III or IV (%) 45.0% 37.8% 0.85A Fib on admission 22.0% 36% 0.36CKD 25.0% 26.3% 0.89COPD 31.8% 32.4% 0.95 O2 Dependent 6.8% 0.0% 0.10

Previous stroke/TIA 14.0% 18.4% 0.58

Frailty 11.9% 18.4% 0.42Porcelain Aorta 4.5% 0.0% 0.18

Baseline Clinical Characteristics

ITT population TriGuardN=45

ControlsN=38 P value

General Anesthesia 76.7% 76.3% 0.96Valvuloplasty Pre-TAVI 61.1% 70.4% 0.45TAVI Implants n=44 n=37

CoreValve 31.8% 26.3% 0.59Edwards Sapien/3/XT 63.6% 65.8% 0.84Other* 2.3%* 5.3%** 0.47

Total Fluoro time (min) 28.2 18.6 <0.001Total Contrast (ml) 165.8 138.6 0.16Adjunct Pharmacology

ASA + clopidogrel 69% 67.6% 0.89ASA only 16.7% 16.2% 0.96Clopidogrel only 11.9% 8.1% 0.58Warfarin 11.9% 18.9% 0.39

Procedure Details

*Direct Flow; **Lotus Valve

Device Performance

ITT population

TriGuard % (n/N)

N=45 patientsN=46 devices*

95% CI

Technical success (composite): 87 (40/46) [68.6, 92.2]Successful deployment 93.5 (43/46) [82.1, 98.6]*Successful positioning (complete 3-vessel coverage until final valve deployment of first valve, verified by QCA)

87.0 (40/46) [73.7, 95.1]

Successful retrieval 100 (46/46) [88.5, 99.9]Device interference (with TAVI system) 0 (0/46) [0.0, 7.7]

Device Failure 0 (0/46) [0.1, 11.5]

*One subjects had 2 TriGuard devices used (valve in valve case)

*Per Treatment Population: excludes 6 patients with incomplete cerebral coverage

In-hospital Safety Outcomes (ITT) ITT population TriGuard

% (n/N)Controls% (n/N)

Relative Risk[95% CI]

Hierarchical CompositeIn-hospital MACCE 22.2 (10/45) 31.6 (12/38) 0.70 [0.34, 1.45]

Death 2.2 (1/45) 5.3 (2/38) 0.42 [0.04, 4.48]All stroke 2.2 (1/45) 5.3 (2/38) 0.42 [0.04, 4.48]Life-threatening bleed 2.2 (1/45) 5.3 (2/38) 0.42 [0.04, 4.48]AKI (Stage 2/3) 2.2 (1/45) 0 (0/38) 2.54 [0.11, 60.7]Major vascular comp. 15.6 (7/45) 15.8 (6/38) 0.99 [0.36, 2.68]

Non-hierarchical components

Death 2.2 (1/45) 5.3 (2/38) 0.42 [0.04, 4.48]All stroke 4.4 (2/45) 5.3 (2/38) 0.84 [0.12, 5.71]Life-threatening bleed 2.2 (1/45) 7.9 (3/38) 0.28 [0.03, 2.60]AKI (Stage 2/3) 2.2 (1/45) 0 (0/38) 2.54 [0.11, 60.7]Major vascular comp. 17.8 (8/45) 21.1 (8/38) 0.84 [0.35, 2.04]

TAVR Device Success (VARC-2 Composite) 97.8 (44/45) 94.7 (36/38) 1.03 [0.95, 1.13]

SLV MLV SLV MLV0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

28.0

53.8

19.6

35.534.5

66.2

33.2

64.7

TriGuard

Control

DW-MRI Results – Single and Max Lesion Volume

Intention to Treat Per Treatment

Med

ian

Lesi

on V

olum

e (m

m3 )

45%

41%

19%

19%

Protection has lower SLV and MLVAverage # of new lesions/pt: 4.5 vs 4.0 for TG and Controls

32 25 32 25 26 25 26 25

Bett

er

DW-MRI Results – Patients with No Ischemic Brain Lesions

ITT PT0.0

5.0

10.0

15.0

20.0

25.0

30.0

22

27

12.5 12.5

TriGuard

Control

Perc

ent o

f Sub

ject

s

42%

55%

Protection has more freedom from ischemic lesions

32 25 26 25

Bett

er

DW-MRI Results – Percent of patients based on Total Lesion Volume (mm3) (PT)

0

5

10

15

20

25

30

35

40

45

50

27

19

8

46

128

36

46TriGuard Control

55% 58% 78%

0 1-50 51-150 >150mm3

P=0.06 for trend

Perc

ent o

f pati

ents

Better

0

10

20

30

40

50

60

35

50

39

50

0 0

17.5

10

17.5

10

0 0

TriGuard HDH

ITT

All Sapienn=35

Sapien CoreValve

N=18 N=14

P int.=0.08

DW-MRI Results – Frequency of Patients with No Ischemic Brain Lesions

PT

Sapien 3N=22

All Sapienn=37

Sapien 3N=22

Perc

ent o

f pati

ents

ITT PT

Bett

er

ITT (n=76) PT (n=70) ITT (n=67) PT (n=60)0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

4.9

0

27.8 27.5

14.3 14.3

35.5 35.5TriGuard

Control

Perc

ent o

f Sub

ject

s

Clinical Efficacy Outcomes – NIHSS and MoCA

Patients with worsening NIHSS and MoCA from baseline to discharge

NIHSS MoCA

Protection had fewer strokes and better cognitive outcomes

Wor

se

2/41 5/35 5/35

MoCA Score –Change from Baseline to Discharge (ITT)Protection prevents a decline in cognition at discharge

Bett

er

Age Adjusted

Clinical Efficacy: CogState-Test Results (PT)

p=0.043 p=0.028

Short term memory test

Protection is associated with improved short and delayed memory at discharge

Delayed memory test

Age Adjusted

Conclusions1. Use of the TriGuard was safe and provided complete cerebral

coverage in 87% of cases2. TriGuard protection increased the proportion of patients completely

free of ischemic brain lesions by more than 50% and reduced single and maximum lesion volume by about 40%

3. TriGuard appears to prevent cognitive decline and was associated with improved short-term and delayed memory at discharge compared to controls

4. Stroke was under-reported based on systematic NIHSS assessment5. Protected patients had a 10% absolute lower stroke rate6. DEFLECT III provides proof of concept of the benefits of

neuroprotection with the TriGuard device during TAVR and will benchmark event rates for a planned definitive randomized US approval trial

Death Events

Event ArmTime to Event(days)

Comment

Cardiovascular Death Control 0

Following BAV, transfemoral placement of Edwards valve immediately followed by pericardial effusion. Sternotomy and circulatory assist performed, followed by evidence of Ao ring rupture.

Cardiovascular Death Control 0

Following BAV, hemodynamic instability with suspicion of Ao ring rupture. An Edwards valve was implanted prior to pt. death.

Cardiovascular Death TriGuard 14

Subject with disabling ischemic stroke. Primary cause of death: pneumonia, contributing causes: cerebral multi-infarct syndrome, vascular disease and COPD.

Neurological Events

Event ArmTime to Event(days)

Comment

Ischemic Stroke,Non-disabling Control 1

MDT CV implanted too deep → manipulation prior to implantation. Post TAVI blurred vision, slurred speech. Resolved at 30 D F/U.

Stroke, Undetermined,Non-Disabling

Control 2Edwards valve. 2 days following TAVI changes in visual field were reported. Subject was unable to fix gaze at times. Neurological consult performed. MRI not performed.

Ischemic Stroke, Non-Disabling TriGuard 1

TriGuard maintained position, 3/3 vessels covered. Presentation included slurred speech, right sided weakness. At one month was still under neurology team care but residing at home.

Ischemic Stroke,Disabling TriGuard 1

TriGuard lost position during TAVI with 0/3 vessel coverage. Prior existing TAVI device, Edwards implant. Bilateral ischemic stroke (anterior and posterior) confirmed by MRI/CT. NIHSS: 30, MRS: 5. Subject died of pneumonia day 14.

AKI Event rates in DEFLECT III compared to Literature

1.Takagi H, Int J Cardiol. 2013;168:1631-1635; 2. Konigstein M, Am J Cardiol. 2013; 3. Sinning JM, JACC Cardiovasc Interv. 2010;3:1141-1149; 4. Gebauer K, International journal of nephrology. 2012;2012:483748; 5. Smith CR, N Engl J Med. 2011;364:2187-2198; 6. Leon MB, New England Journal of Medicine. 2010;363:1597-1607; 7. Adams DH, N Engl J Med. 2014;370:1790-1798; 8. Popma JJ, J Am Coll Cardiol. 2014;63:1972-1981; 9. Najjar Expert Rev Cardiovasc Ther. 2015;13:301-316; 10. Leon MB, J Am Coll Cardiol. 2011;57:253-269; 11.Kappetein AP, J Am Coll Cardiol (In Press). 2012

Reporting Stroke: What if we ask Neurologists ?

• Prospective evaluation of pts undergoing surgical AVR• Pre and post assessment and DW MRI

• Clinical strokes in hospital: 17% • Moderate/severe: 4%• TIA 2%• Silent infarcts on MRI: 54%