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

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Presentation on theme: "The DEFLECT III Trial: A Prospective Randomized Evaluation of the TriGuard Embolic DEFLECTion Device during Transcatheter Aortic Valve Replacement Alexandra."— Presentation transcript:

1 The DEFLECT III Trial: A Prospective Randomized Evaluation of the TriGuard Embolic DEFLECTion Device during Transcatheter Aortic Valve Replacement Alexandra Lansky, MD Yale 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

2 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

3 Clinical Stroke after TAVR
30-day stroke rates 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 Stroke is the most devastating complication following TAVI. For many patients the fear of stroke is greater than the fear of mortality 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

4 Silent Embolic Events on DW-MRI after TAVR
% of Subjects with New Lesions Affect % of patients Multiple infarcts (≤36, x̅ = 4.6) Associated with: Neurocognitive decline >2 fold risk of dementia >3 fold risk of stroke Stroke is the most devastating complication following TAVI. For many patients the fear of stroke is greater than the fear of mortality 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

5 The TriGuard Device 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

6 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. Subjects with AS undergoing TAVR 1:1 Randomization 31 :07:24 PM 4 MA MA :07:24 PM 4 31 Embolic Protection (TriGuard) Unprotected TAVR (Control) 5

7 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)

8 DEFLECT III Procedures & Assessments
Screening Procedure Post-Procedure 30 days 4±2 days ̴30 days NIHSS mRS Neurocog* TAVR TriGuard DW-MRI NIHSS mRS Neurocog* DW-MRI NIHSS mRS 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.

9 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)

10 DEFLECT III Patient Disposition
Intent To Treat Population N=83 Embolic Protection (TriGuard) n = 45 Unprotected TAVR (Control) n = 38 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 In-hospital FU Safety n = 45 DW-MRI: n = 32 (71%) (ITT) n = 26 (57%)(PT) In-hospital FU Safety n = 38 DW-MRI: n = 25 (65%) (ITT) n = 25 (65%) (PT)

11 DEFLECT III Trial Organization
Principal Investigators Alexandra Lansky, MD Andreas Baumbach, MD Yale 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, MD John Forrest, MD Abeel Mangi, MD Yale University School of Medicine, New Haven, CT, USA Genae International, Inc. Harvard Clinical Research Institute MRI Core Lab Angiographic Core Lab Biostatistic Neurologic & neurocognitive Assessment Clinical Events Committee Monitoring, Site Mgmt. Data Mgmt

12 DEFLECT III Trial – Enrollment Highlights
Feb 26, 2014 March 4, 2015 April 4, 2015 RCT Enrollment Complete Enrollment Start 30 day FU Complete 5 Countries / 13 Centers 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

13 Baseline Clinical Characteristics
ITT population TriGuard N=45 Controls N=38 P value Age (y) ± SD 82.7 ± 6.5 82.5 ± 5.9 0.62 Male 40.9% 50.0% 0.41 STS Score 4.7 7.4 0.48 EuroSCORE II 10.1 0.66 NYHA Class I or II (%) 83.3% 78.9% 0.65 III or IV (%) 45.0% 37.8% 0.85 A Fib on admission 22.0% 36% 0.36 CKD 25.0% 26.3% 0.89 COPD 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% 0.42 Porcelain Aorta 4.5% 0.18

14 *Direct Flow; **Lotus Valve
Procedure Details ITT population TriGuard N=45 Controls N=38 P value General Anesthesia 76.7% 76.3% 0.96 Valvuloplasty Pre-TAVI 61.1% 70.4% 0.45 TAVI Implants n=44 n=37 CoreValve 31.8% 26.3% 0.59 Edwards Sapien/3/XT 63.6% 65.8% 0.84 Other* 2.3%* 5.3%** 0.47 Total Fluoro time (min) 28.2 18.6 <0.001 Total Contrast (ml) 165.8 138.6 0.16 Adjunct Pharmacology ASA + clopidogrel 69% 67.6% 0.89 ASA only 16.7% 16.2% Clopidogrel only 11.9% 8.1% 0.58 Warfarin 18.9% 0.39 *Direct Flow; **Lotus Valve

15 Device Performance ITT population TriGuard % (n/N) N=45 patients N=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 [0.1, 11.5] *One subjects had 2 TriGuard devices used (valve in valve case) *Per Treatment Population: excludes 6 patients with incomplete cerebral coverage

16 In-hospital Safety Outcomes (ITT)
ITT population TriGuard % (n/N) Controls Relative Risk [95% CI] Hierarchical Composite In-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 Life-threatening bleed AKI (Stage 2/3) 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 4.4 (2/45) 0.84 [0.12, 5.71] 7.9 (3/38) 0.28 [0.03, 2.60] 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]

17 DW-MRI Results – Single and Max Lesion Volume
Average # of new lesions/pt: 4.5 vs 4.0 for TG and Controls Protection has lower SLV and MLV 19% Better Median Lesion Volume (mm3) 45% 19% 41% 32 25 32 25 26 25 26 25 Intention to Treat Per Treatment

18 DW-MRI Results – Patients with No Ischemic Brain Lesions
Protection has more freedom from ischemic lesions 55% 42% Better 32 25 26 25

19 DW-MRI Results – Percent of patients based on Total Lesion Volume (mm3) (PT)
P=0.06 for trend Better Percent of patients 55% 58% 78% 1-50 51-150 >150 mm3

20 DW-MRI Results – Frequency of Patients with No Ischemic Brain Lesions
Sapien CoreValve ITT PT ITT PT Better P int.=0.08 Percent of patients N=18 N=14 All Sapien n=37 Sapien 3 N=22 All Sapien n=35 Sapien 3 N=22

21 Clinical Efficacy Outcomes – NIHSS and MoCA
Protection had fewer strokes and better cognitive outcomes Patients with worsening NIHSS and MoCA from baseline to discharge Worse 2/41 5/35 5/35 NIHSS MoCA

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

23 Clinical Efficacy: CogState-Test Results (PT)
Protection is associated with improved short and delayed memory at discharge Short term memory test Delayed memory test p=0.043 p=0.028 Age Adjusted

24 Conclusions Use of the TriGuard was safe and provided complete cerebral coverage in 87% of cases 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% TriGuard appears to prevent cognitive decline and was associated with improved short-term and delayed memory at discharge compared to controls Stroke was under-reported based on systematic NIHSS assessment Protected patients had a 10% absolute lower stroke rate 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


26 Death Events Event Arm Time to Event (days) Comment
Cardiovascular Death Control Following BAV, transfemoral placement of Edwards valve immediately followed by pericardial effusion. Sternotomy and circulatory assist performed, followed by evidence of Ao ring rupture. Following BAV, hemodynamic instability with suspicion of Ao ring rupture. An Edwards valve was implanted prior to pt. death. TriGuard 14 Subject with disabling ischemic stroke. Primary cause of death: pneumonia, contributing causes: cerebral multi-infarct syndrome, vascular disease and COPD.

27 Neurological Events Event Arm Time 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 2 Edwards 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. TriGuard 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. Disabling 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.

28 AKI Event rates in DEFLECT III compared to Literature
1.Takagi H, Int J Cardiol. 2013;168: ; 2. Konigstein M, Am J Cardiol. 2013; 3. Sinning JM, JACC Cardiovasc Interv. 2010;3: ; 4. Gebauer K, International journal of nephrology. 2012;2012:483748; 5. Smith CR, N Engl J Med. 2011;364: ; 6. Leon MB, New England Journal of Medicine. 2010;363: ; 7. Adams DH, N Engl J Med. 2014;370: ; 8. Popma JJ, J Am Coll Cardiol. 2014;63: ; 9. Najjar Expert Rev Cardiovasc Ther. 2015;13: ; 10. Leon MB, J Am Coll Cardiol. 2011;57: ; 11.Kappetein AP, J Am Coll Cardiol (In Press). 2012


30 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%






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