Disclosures. Consultant Thoratec, HeartWare Research Support Thoratec (2012) No off label use/indications will be discussed.

Asking a Question? Question (Respondent) What movie would you like to see?( Spouse) Is it cancer?(Radiologist) Would you agree that the standard was not met? (Lawyer) What is the best treatment?(Clinician) What should a surgeon do with AI at the time of a VAD?(INTERMACS) Response Tread lightly- consider previous choices and whose choice was last made. Cannot rule out…. Please restate. It depends. Let’s look at the data.

Aortic Insufficiency Clinician Aspects Mechanical Valve Carries Perceived Risk Of Stroke Aortic Insufficiency Impaisr MCS By Short Circuit Aortic Insufficiency Will Worsen With Time How durable are any of the options? Considerations The addition of ischemic time ( cross clamp) to sick hearts (RV) Cross clamp time varies by technique Don’t Valves and repairs just fuse eventually anyway?

DAAP Suggestions 1) What are the outcomes of patients with important AI who do not undergo an AV procedure compared to those that do have an AV procedure performed; and, Compare important outcomes of patients stratified to the following groups by pre-implant assessment of the degree of AI and subsequent intervention: Group 1: AI – None; Group 2: AI – Mild with NO AV procedure performed; Group 3: AI – Mild with AV procedure performed; Group 4: AI – Moderate or more with NO AV procedure performed; and Group 5: AI – Moderate or more with AV procedure performed. The outcome measures that the DAAP Committee would recommend/suggest to assess would be: 1) survival; 2) duration of inotrope support; 3) freedom from RV failure; 4) renal function (both early and late); 5) duration of ICU stay; 6) total LOS for index hospitalization; 7) freedom from readmission; and 8) freedom from AI – Moderate or more. 2) What are the outcomes of patients that undergo an AV procedure with respect to the type of procedure performed? For those patients that did receive an AV procedure, the patients should be stratified by type of procedure; Group I – AV replacement; Group II – AV repair; Group III – Other AV procedure. The outcome measures that the DAAP Committee would recommend/suggest to follow would be 1: Survival; 2) Freedom from stroke; 3) Freedom from AI – Moderate or More; and 4) Freedom from RV failure. These outcomes measures would importantly assess the stroke risk from each of the procedures and durability of preventing recurrence of AI.

Why INTERMACS? Size of Data Prospective data Data Capture LONGITUDINAL DATA- ALIVE/DEAD/ECHO DATA Nice People.

Adults: n=7808 All Primary Pts implanted As of 12/31/2012 N=7887 Pediatric Patients: n=79 (patients < 19 yrs of age at time of implant) Pulsatile Flow: * N=1087 Continuous Flow: n=6721 Bi VAD: 179LVAD: 6542 BiVAD: 301TAH: 158LVAD: 628 * The left ventricular device indicates the type of pump implanted (continuous flow or pulsatile flow). Patient Pool INTERMACS: June 2006 – December 2012: Aortic Insufficiency 7

A visit to INTERMACS

Problems? Data not complete Apparent Inconsistencies in responses – Severe AI with no procedure???? – Replacement with mechanical valve Previous version did not capture the same fields/data Massive Variation in Clinical practice and terminology.

"The aorta was clamped and infused with cold blood cardioplegia antegrade for a total of 1L. A Transverse aortotomy was made. Mildly to moderately thickened aortic valve lesions were noted. Using three stripes of Teflon and running 4-0 Prolene suture, the aortic valve was closed shut to deal with the aortic insufficiency. The aortomoy was then closed with 4-0 Prolene suture in two layers." "The previously placed Bjork-Shiley valve was visualized. A sandwich felt technique was used to patch the valve from the ventricular and the aortic aspect in order to prevent any exposure of the valave to circulation to reduced the development of thrombosis and passive mobilization. This was done with 2 circular patches sutured together through the aortic valve prosthesis. An additional portion of felt patch had to be used to completely cover the aotic valve on the aortic aspect. The patch was then sewn to the side of the graft to fully exclude the valve. The aortotomy was then closed with 2 running layers of 4-0 Prolene." 3 pledgeted sutures 4 pledgeted matress sutures 4-0 prolene pursestring suture on each leaflet; additional pledgeted 4-0 prolene between rt & lt commissures. A piece of bovine pericardial patch was fashioned to the size of the aortic valve. It was sewn into place to cover the aortic valve using a series of 4 pledgeted 4-0 Prolene sutures. All had notes that stated AV was repaired, but in details in the notes all were found to have been oversewn with leaflets closed. Aortic VALVE OVERSEWN-pericardial patch AV oversewn closed w/ pledgetted suture and prolene N/A Oversewing of aortic valve Pre-exisiting MECHANICAL AV SURGERY--Aortic VALVE OVERSEWN-percardial patch Replacement of aortic valve with Hemashield patch These were the good ones!

INTERMACS: June 2006 – December 2012: Aortic Insufficiency Additional Data Collection Summary Question 1: Patients with Moderate/Severe Aortic Insufficiency at time of implant but no concomitant AV surgery recorded: patients=131, hospitals=59 Question 2: Patients with Documented Concomitant Aortic Repair at time of implant – verification of AV closure and/or AV repair: patients=213, hospitals=62 Total Patients = 326 Total Hospitals = 88 11

INTERMACS: June 2006 – December 2012: Aortic Insufficiency Groups nLVADBiVAD 1)Aortic Closure )Aortic Repair )Aortic Replacement – Bio/Mech )All Others Total Group distribution AFTER finalization of additional data collection 13 Final Groups nLVADBiVAD 1)Aortic Closure )Aortic Repair )Aortic Replacement – Bio/Mech )All Others Total Original Groups prior to additional data collection

INTERMACS: June 2006 – December 2012: Aortic Insufficiency Aortic Regurg – Pre-implant Groups nNoneMildModSev Unknown 1)Aortic Closure (14.0%) 58 (42.6%)34 (25.0%) 8 (5.9%) 17 (12.5%) 2)Aortic Repair (12.1%) 69 (41.8%)47 (28.5%) 1 (0.7%) 28 (16.9%) 3)Aortic Replacement (Bio/Mech) (11.7%) 33 (32.0%)28 (27.2%) 7 (6.8%) 23 (22.3%) 4)All Others (56.7%)1348 (21.3%)83 (1.3%)14 (0.2%) 1288 (20.4%) Total (54.1%)1508 (22.4%)192 (2.9%)30 (0.4%) 1356 (20.2%) Group Summary AFTER finalization of additional data collection 14 Aortic Regurg – Pre-implant Groups nNoneMildModSev 1)Aortic Closure (16.0%) 58 (48.7%)34 (28.6%) 8 (6.7%) 2)Aortic Repair (14.6%) 69 (50.4%)47 (34.3%) 1 (0.7%) 3)Aortic Replacement (Bio/Mech) (15.0%) 33 (41.3%)28 (35.0%) 7 (8.7%) 4)All Others (71.3%)1348 (26.8%)83 (1.6%)14 (0.3%) Total (67.8%)1508 (28.1%)192 (3.5%)30 (0.6%)

INTERMACS: June 2006 – December 2012: Aortic Insufficiency COD Summary AFTER finalization of additional data collection 15 Group 1 = Aortic Closure Primary Cause of Deathn % Circulatory: Arterial Non-CNS Thromboembolism Circulatory: Myocardial Infarction Circulatory: Other, Specify Device Malfunction Major Infection Respiratory: Respiratory Failure Respiratory: Pulmonary: Other, specify Circulatory: Sudden Unexplained Death Other: Trauma/accident, specify Circulatory: Major Bleeding Digestive: Hepatic Dysfunction Nervous System: Neurological Dysfunction Multisystem Organ Failure Withdrawal of Support, specify Circulatory: Cardiac Arrhythmia Other/Unknown Totals Group 2 = Aortic Repair Primary Cause of Deathn % Other: Cancer Circulatory: Myocardial Infarction Circulatory: Other, Specify Major Infection Respiratory: Pulmonary: Other, specify Digestive: Renal Dysfunction Circulatory: Sudden Unexplained Death Other: Trauma/accident, specify Circulatory: Right Heart Failure Circulatory: Major Bleeding Circulatory: CHF Circulatory: End Stage Cardiomyopathy Digestive: Hepatic Dysfunction Nervous System: Neurological Dysfunction Multisystem Organ Failure Circulatory: Cardiac Arrhythmia Other/Unknown Total

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Concomitant Aortic Valve Procedures in Patients Undergoing Implantation of Continuous-Flow LVADs: An INTERMACS Database Analysis Jason Robertson, M.D., M.S.; David C. Naftel, Ph.D., Sunil Prasad, M.D.; Akinobu Itoh, M.D.; Susan Myers; Gail Mertz, B.S., R.N., CCRC; James Kirklin, M.D.; and Scott Silvestry, M.D. April 11, 2014 Disclosures: Robertson – none; Naftel – none; Prasad - none; Itoh – none; Myers – none; Mertz – none; Kirklin – none; Silvestry – Consultant for Thoratec and HeartWare This project has been funded in whole or in part with federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN C

Outcomes Following Aortic Valve Procedures Previous studies have disagreed on whether mortality after concomitant aortic valve procedures is increased, with some studies demonstrating equivalent or improved survival. The largest of these used data from the HeartMate II BTT and DT Trials (n=1,106), including: 30 AVRs 32 AV closures 18 AV repairs Long term survival was significantly reduced compared to HMII implant alone: 1-year Survival: 57% vs. 75%, p= year Survival: 43% vs. 64%, p=0.001 Dranishnikov N, et al. Int J Artif Organs. 2012; 35 (7): John R, et al. JTCVS. 2014; 147: Pal JD, et al. Circulation. 2009; 120: S Adamson RM, et al. JHLT. 2011; 30: Goda A, et al. Ann Thorac Surg. 2011; 91: Morgan JA, et al. JHLT. 2013; 32:

INTERMACS Database Additional Data Collection Summary Question 1: Audit of patients with documented moderate/severe AI without a documented AVP to determine if an AVP was in fact performed: Queried: patients=113 hospitals=59 Responded: patients=86 (76%) hospitals=47 (80%) Question 2: Clarification of whether patients with documented AV repairs underwent a closure or a repair: Queried: patients=213 hospitals=62 Responded:patients=143(67%) hospitals=40 (65%) Unconfirmed:patients=70 (33%)hospitals=19 (31%) Total Patients queried = 326 Total Hospitals queried = 88 Total Patients with response = 229 (70%) Total Hospitals responded = 63 (72%)

Adults: N=7,808 All patients implanted as of 12/31/2012 N=7,887 All patients implanted as of 12/31/2012 N=7,887 Pediatric Patients: N=79 (patients < 19 yrs of age at time of implant) Pediatric Patients: N=79 (patients < 19 yrs of age at time of implant) Pulsatile Flow: N=1,087 N=1,087 Continuous Flow: N=6,721 Bi VAD: N=179 LVAD: N=6,542 BiVAD N=301 TAHN=158TAHN=158LVADN=628LVADN=628 INTERMACS Patient Population: June 2006 – December 2012 Bi VAD: N=140 LVAD: N=5,204 Total Cohort: N=5,344 Database Audit Reduced Cohort: Mean Follow-up = 12.3 months

Aortic Valve Closure Total=125Total=125 LVAD=121LVAD=121 BiVAD=4BiVAD=4 Aortic Valve Repair Total=95Total=95 LVAD=93LVAD=93 BiVAD=2BiVAD=2 Aortic Valve Replacement Total=85Total=85 LVAD=83LVAD=83 BiVAD=2BiVAD=2 All Others Total=5,039Total=5,039 LVAD=4,907LVAD=4,907 BiVAD=132BiVAD=132 INTERMACS Patient Population: June 2006 – December 2012

Event = Death with a device in place (censored at transplant or recovery) Months Post Implant % Survival AV Repair n=95, deaths=22 AV Closure, n=125, deaths=46 AV Replacement n=85, deaths=24 Overall p = No AV Procedure n=5039, deaths=1078 Survival by Type of Aortic Valve Procedure Performed

Months Post Implant % Survival % Survival post implant Groups n events 6 months 1 year AV Closure % 56% AV Repair % 76% AV Replacement % 67% No AVP % 79% Survival for INTERMACS Level 1-2 Patients by Type of AVP Overall p=0.003

Months Post Implant % Survival Overall p = 0.04 % Survival post implant Groups n events 6 months 1 year AV Closure % 73% AV Repair % 82% AV Replacement % 75% No AVP % 84% Survival for INTERMACS Level 3-7 Patients by Type of AVP

Multivariate Model for Death After Implant Risk FactorHazard RatioConfidence Interval P-value Aortic Regurgitation AV Repair AVR Closure < INTERMACS Level Dialysis BiVAD < Risk FactorHazard RatioConfidence Interval P-value Aortic Regurgitation AV Repair AVR Closure < INTERMACS Level Dialysis BiVAD < Risk FactorHazard RatioConfidence Interval P-value Aortic Regurgitation AV Repair AVR Closure < INTERMACS Level Preop Dialysis BiVAD <0.0001

Aortic Closure, n=112 Aortic Repair, n=85 Aortic Replacement, n=67 No AV Procedure, n=4,061 % of Patients with Moderate/Severe Aortic Regurgitation Note: If the total n for the group is < 20 then it is not plotted in this figure. p (6 months) < Recurrence of Aortic Insufficiency Postoperatively by Group

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Question Answered? Elements of Spouse, Radiologist, Lawyer, clinician answers rolled up into one. Our study highlights some of the strengths and weakness of the data in INTERMACS Clinical Question answered but questions remain. –Role of CPB/Cross Clamp –Clinician Bias? –Non Responsive centers- some want in. 28

Thank You to INTERMACS 29