Predictors of Pacemaker Implantation With a Self-Expanding Repositionable Transcatheter Aortic Valve Ian T. Meredith AM, MBBS, PhD, FRACP FACC, FCSANZ, FAPSIC MonashHeart and Monash University, Melbourne, Australia

Potential Conflicts of Interest Speaker's name: Ian T. Meredith  I have the following potential conflicts of interest to report: Consultant: Medtronic and Boston Scientific Medtronic is the sponsor of the CoreValve Evolut R CE and US Studies; and performed all statistical analyses and assisted in the graphical display of the data.

Background Reducing the need for permanent pacemaker implantation (PPI) after TAVI is still a clinical goal. New TAVIs with repositionable capability aid in optimal placement. Several factors can affect the need for a PPI such as implant depth, sizing ratio and the burden and distribution of aorto-ventricular calcification. We evaluated these 3 factors in patients treated with the self-expanding Evolut R transcatheter aortic valve. Fujita B, et al. Eur Heart J Cardiovasc Imaging 2016 Jan 12. pii: jev343. [Epub ahead of print] Petronio AS, et al. JACC Cardiovasc Interv 2015;8:837.

Evolut R US FDA Cohort Patients Evolut R CE Study1–3 N=60 Evolut R US Study N=914* *Enrollment ongoing at the time of this analysis. 1Manoharan G, et al. JACC Intv 2015; 8: 1359-67. 2Meredith IT, et al. EuroPCR 2015 19 May, Paris 3Manoharan G, et al. TCT 2015 13 Oct, San Francisco. 4Williams M, et al. ACC 2016, 02 April, Chicago.

Methods Pre Procedure Procedure Post Procedure Multislice CT mandated for all patients Aortic root dimensions measured Percent oversizing calculated (valve perimeter-annulus perimeter/annulus perimeter) x 100 Procedure Recommended implant depth of 3-5 mm below the aortic annulus Post Procedure Actual depth measured on procedure angiogram (NCC and LCC) Calcium volumes measured using 3mensio (Pie Medical Imaging, NL) & analyzed with MATLAB (Mathworks, USA) Cox proportional hazard model for univariable and multivariable analysis (0.10 threshold)  LCC = left coronary cusp; NCC = non-coronary cusp

Setting a Patient-Specific HU Threshold An initial cohort of subjects was studied A Hounsfield Unit (HU) threshold of median blood attenuation + 200HU provided accurate discrimination of calcium from blood Histogram of HU values exported from 3mensio Median attenuation calculated in MATLAB Need to explain how we set +200 -be above contrast but not too far into calcium Concurrently with our project, other groups were doing similar work. Could describe histo region and mean + 4sd method for Haansson paper. Root region (basal plane to top of leaflets) used to calculate histogram Hansson, et al. J Cardiovasc Comput Tomogr. 2015; 9:382-92. 

Histogram-determined Calcium Segmentation Examples Generic threshold Histogram-determined Patient A mid-valve 850HU, 390 mm3 550HU, 1175 mm3 In this slide, I think the focus should be on pointing out how the calcium segmenation is an underestimate in the first and overestimate in the second when using the generic threshold, and looks much better using the patient-specific, objective setting of the threshold. 850HU, 5229 mm3 1100HU, 370 mm3 Patient B mid-valve

Calcium Volume Measurements Set segmentation threshold of median root attenuation + 200HU Set regions of interest Root: aortic valve basal plane to top of leaflets LVOT: Basal plane to 5mm into LVOT Each axial region divided into three cusp areas (left, right and non-coronary) Measured and recorded aortic valve calcium volumes Individual regions, total root, total LVOT, overall total (root+LVOT) range/asymmetry Root Region LVOT Region One Axial Slice Say how calcium is calculated, show table of volumes, summation across slices LVOT = left ventricular outflow tract

Baseline Characteristics Characteristic, mean ± SD, or % (no.) N = 151 Age (years) 83.7 ± 6.6 Women 68.9 (104) Society of Thoracic Surgeons Predicted Risk of Mortality (%) 7.3 ± 3.5 New York Heart Association class III or IV 73.5 (111) Previous CABG 23.2 (35) Any chronic lung disease 47.0 (71) Diabetes 26.5 (40) Peripheral vascular disease 27.8 (42) Atrial fibrillation / atrial flutter 32.5 (49) Frailty 68.2 (103) Pre-existing permanent pacemaker 14.6 (22) 9

Procedural Characteristics Variable, % (no.) N = 151 General anaesthesia 72.8 (110) Access Approach Iliofemoral 94.7 (143) Direct aortic 4.6 (7) Subclavian 0.7 (1) Pre-TAVI balloon aortic valvuloplasty performed 56.3 (85) Valve Size Implanted 23 mm 1.3 (2)* 26 mm 35.8 (54) 29 mm 62.9 (95) ≥2 Valves implanted 1.3 (2) Post-TAVI balloon dilatation performed 24.5 (37) *Only evaluated in the US. 10

Safety Outcomes at 30 Days Event, Kaplan-Meier rates (no.) 30 Days N=151 All-cause mortality 1.3 (2) Cardiovascular mortality Disabling stroke 3.3 (5) Major vascular complications 8.0 (12) Life-threatening or disabling bleeding 6.6 (10) Embolization or migration 0.0 (0) Endocarditis Coronary obstruction Valve thrombosis Coronary artery obstruction New permanent pacemaker 15.6 (20) 11 MDT Confidential

Total Calcification Aortic Root & Left Ventricular Outflow Tract There was no difference in the total volume or distribution of calcium between patients with or without a new pacemaker. Total (Aortic Root & LVOT) Calcification (mm3) Total (Aortic Root & LVOT) Calcification (mm3) Error bars = standard deviations RCC=right coronary cusp

Pacemaker Rates by Percent Oversizing The need for a new PPI was lower, but not significantly different, using a sizing threshold of 20% (13.9% vs 17.6%, p = 0.51, for ≤ 20% sizing vs. < 20%) Annular Sizing Ratio (%) Patients with a new PPI within 30 days Patients in order of annular sizing ratio 13

Pacemaker Implantation By Average Implant Depth Recommended implant depth of 3-5 mm below the annular plane = annular plane 14

Average Implant Depth Average implant depth was greater in patients who required a new PPI Average Implant Depth (mm) Average Implant Depth (mm) P < 0.001 15 Error bars = standard deviation

Predictors of New Pacemaker Including All Patients UNIVARIABLES MULTIVARIABLES Variable Hazard Ratio [95% CI] P Value P Value Average implant depth (>5 mm) 4.67 [1.77, 12.31] 0.002 6.9 [2.4, 19.6] 0.0003 Presence of RBBB 3.42 [1.36, 8.57] 0.009 6.1 [2.3, 15.9] 26 mm valve 0.56 [0.21, 1.55] 0.266 Oversizing > 20% 1.34 [0.56, 3.22] 0.515 Overall root calcification (>480 mm3) 1.33 [0.51, 3.50] 0.561 Overall LVOT calcification (>4 mm3) 1.97 [0.73, 5.34] 0.181 Overall total calcification (>510 mm3) 1.03 [0.40, 2.66] 0.959 CI = confidence interval; RBBB = right bundle branch block. 16

Predictors of New Pacemaker Excluding Baseline RBBB Patients UNIVARIABLES MULTIVARIABLES Variable Hazard Ratio [95% CI] P Value Average implant depth (>5 mm) 9.98 [2.18, 45.59] 0.003 19.2 [2.5,149.9] 0.005 Oversizing > 20% 1.59 [0.54, 4.74] 0.403 Overall LVOT calcification (>4 mm3) 1.59 [0.51, 5.02] 0.426 Overall root calcification (>480 mm3) 0.64 [0.20, 2.01] 0.445 Overall total calcification (>510 mm3) 0.61 [0.19, 1.93] 26 mm valve 0.30 [0.07, 1.36] 0.118 17

Conclusions In the Evolut R US FDA pooled cohort: Neither the volume or distribution of aortic root and LVOT calcium nor size ratio appeared to be associated with the need for a new PPI In both univariable and multivariable analyses, implant depth and the presence of a pre-existing RBBB were strongly associated with the need for a new PPI Implant depth was a stronger predictor of a new PPI in the absence of a pre-existing RBBB The ability to resheath and reposition the Evolut R TAV may allow the operator to achieve optimal implant depth and potentially avoid the need for a new PPI 18