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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 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: day stroke rates

4 Affect % of patients Multiple infarcts (≤36, x̅ = 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 % of Subjects with New Lesions

5 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

6 DEFLECT III Study Overview 5 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) Unprotected TAVR (Control) Subjects with AS undergoing TAVR 1:1 Randomization

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 40 mm)  Contraindication to cerebral MRI (e.g., pacemaker)

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

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

11 Principal Investigators Principal Investigators DEFLECT III Trial Organization MRI Core Lab Angiographic Core Lab Biostatistic Angiographic Core Lab Biostatistic Neurologic & neurocognitive Assessment Neurologic & neurocognitive Assessment Clinical Events Committee Clinical Events Committee Monitoring, Site Mgmt. Data Mgmt Monitoring, Site Mgmt. Data Mgmt

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

13 ITT population TriGuard N=45 Controls N=38 P value Age (y) ± SD82.7 ± ± Male40.9%50.0%0.41 STS Score EuroSCORE II NYHA Class I or II (%)83.3%78.9%0.65 III or IV (%)45.0%37.8%0.85 A Fib on admission22.0%36%0.36 CKD25.0%26.3%0.89 COPD31.8%32.4%0.95 O 2 Dependent6.8%0.0%0.10 Previous stroke/TIA14.0%18.4%0.58 Frailty11.9%18.4%0.42 Porcelain Aorta4.5%0.0%0.18 Baseline Clinical Characteristics

14 ITT population TriGuard N=45 Controls N=38 P value General Anesthesia76.7%76.3%0.96 Valvuloplasty Pre-TAVI61.1%70.4%0.45 TAVI Implantsn=44n=37 CoreValve31.8%26.3%0.59 Edwards Sapien/3/XT63.6%65.8%0.84 Other*2.3% * 5.3% ** 0.47 Total Fluoro time (min) <0.001 Total Contrast (ml) Adjunct Pharmacology ASA + clopidogrel69%67.6%0.89 ASA only16.7%16.2%0.96 Clopidogrel only11.9%8.1%0.58 Warfarin11.9%18.9%0.39 Procedure Details *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 deployment93.5 (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 retrieval100 (46/46)[88.5, 99.9] Device interference (with TAVI system)0 (0/46)[0.0, 7.7] Device Failure0 (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

16 In-hospital Safety Outcomes (ITT) ITT population TriGuard % (n/N) Controls % (n/N) Relative Risk [95% CI] Hierarchical Composite In-hospital MACCE 22.2 (10/45)31.6 (12/38)0.70 [0.34, 1.45] Death2.2 (1/45)5.3 (2/38)0.42 [0.04, 4.48] All stroke2.2 (1/45)5.3 (2/38)0.42 [0.04, 4.48] Life-threatening bleed2.2 (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 Death2.2 (1/45)5.3 (2/38)0.42 [0.04, 4.48] All stroke4.4 (2/45)5.3 (2/38)0.84 [0.12, 5.71] Life-threatening bleed2.2 (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]

17 DW-MRI Results – Single and Max Lesion Volume Intention to Treat Per Treatment Median Lesion Volume (mm 3 ) 45% 41% 19% Protection has lower SLV and MLV Average # of new lesions/pt: 4.5 vs 4.0 for TG and Controls Better

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

19 DW-MRI Results – Percent of patients based on Total Lesion Volume (mm 3 ) (PT) 55% 58% 78% >150 mm 3 P=0.06 for trend Percent of patients Better

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

21 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 Worse 2/41 5/35

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) 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

24 Conclusions 1.Use of the TriGuard was safe and provided complete cerebral coverage in 87% of cases 2.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 assessment 5.Protected patients had a 10% absolute lower stroke rate 6.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

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26 Death Events EventArm Time to Event (days) Comment Cardiovascular Death Control0 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 Control0 Following BAV, hemodynamic instability with suspicion of Ao ring rupture. An Edwards valve was implanted prior to pt. death. Cardiovascular Death TriGuard14 Subject with disabling ischemic stroke. Primary cause of death: pneumonia, contributing causes: cerebral multi-infarct syndrome, vascular disease and COPD.

27 Neurological Events EventArm Time to Event (days) Comment Ischemic Stroke, Non-disabling Control1 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 Control2 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. Ischemic Stroke, Non-Disabling TriGuard1 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 TriGuard1 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

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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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