HeartWare HVAD: Risk Factors for Adverse Outcomes Mark S. Slaughter, MD Professor and Chair Department Cardiovascular and Thoracic Surgery University of Louisville

Disclosures HeartWare, Inc: research grant support Cormatrix: research grant support Carmat: scientific advisory board APK: research grant support

HVAD ADVANCE Bridge to Transplantation Study Design Objective: To evaluate safety & efficacy of the HeartWare HVAD ® in patients listed for cardiac transplantation Multi-center, prospective, non-randomized, two arm study – HVAD (N=140) vs. Control (INTERMACS™, N=499) Primary endpoint: Non-inferiority to control First BTT using contemporaneous VAD patients as control arm (INTERMACS™ registry) Primary Endpoint: – Success at 180 days – alive on original device, transplanted, or explanted for recovery (alive 60 days post removal) – Kaplan-Meier Survival at 180 days 4 CAP Installments included (Total N=242) Aaronson, et al. Circulation. 2012;125(25): Slaughter, et al. J Heart Lung Transpl. 2013; 32:

Patient Demographics Baseline Characteristic BTT and CAP (N = 382) BTT (N = 140) CAP (N = 242) Age (years)53.2 ± ± ± 12.5 Male sex (%)71.2%72.1%70.7% Race (%) White Black/African American Hispanic/Other 68.1% 26.4% 5.5% 72.1% 22.9% 5.0% 65.7% 28.5% 5.8% Body-mass index (kg/m 2 )28. 2 ± ± ± 6.1 Body surface area (m 2 )2.0 ± ± ± 0.3 Ischemic cause of heart failure (%)38.0%40.7%36.4% Left ventricular ejection fraction (%)17.3 ± ± ± 7.3

Patient Demographics (continued) Baseline Characteristic BTT and CAP (N = 382) BTT (N = 140) CAP (N = 242) Pulmonary artery pressure (mmHg) Systolic Diastolic 48.8 ± ± ± ± 8.2 Arterial blood pressure (mmHg) Systolic Diastolic Mean ± ± ± ± ± ± ± ± ± 10.4 Cardiac index (liters/min/m 2 ) 2.2 ± ± ± 0.6 NYHA Class (%) II III IV INTERMACS (%)

Kaplan Meier Survival in HVAD BTT+CAP Clinical Trial 90% 84% Days Event Free Rate Month Patient at risk Survival100%97%94%90%89%86%84%79%71% 79%

Success Outcomes (N=382) EndpointOutcome at 6 months Success Transplanted or Myocardial Recovery or Alive on original device 87.6% Alive on original device66.5% Transplanted20.8% Myocardial Recovery0.3% Died8.2% Exchanged4.2% Mean duration of support (incl. post exchange) = 423 days

Adverse Events in BTT+CAP (N=382) N=382 with Patient-Years of Support Complication Patients with event, n (%) Number of Events Event Rate Ventricular Arrhythmia77 (20.2) Gastrointestinal Bleeding59 (15.4) Right Heart Failure (RHF)129 (33.8) RHF Requiring RVAD15 (3.9) Ischemic Stroke26 (6.8) Hemorrhagic Stroke32 (8.4) Device Exchange for Suspected Thrombus 16 (4.2) Driveline Infection75 (19.6) Sepsis72 (18.8) Renal Failure39 (10.2)460.11

Freedom from Thrombus Events Freedom from any thrombus event: 6 months = 96%; 1 year = 92% Freedom from exchange for thrombus: 6 months = 98%; 1 year = 95.4% Time to any thrombus event Time to exchange for thrombus Najjar, et al. J Heart Lung Transpl. 2014; 33: (e-pub ahead of print 13 Dec 2013)

Multivariate Risk Factors for VAD Thrombus Najjar, et al. J Heart Lung Transpl. 2014; 33: (e-pub ahead of print 13 Dec 2013)

Freedom from CVA ICVA HCVA Freedom from any ICVA: 6 months = 96%; 1 year = 93%; 2 years = 88% Freedom from HCVA: 6 months = 95%; 1 year = 90%; 2 years = 86% Manuscript in preparation (Teuteberg, et al.)

Multivariate Risk Factors for ICVA Manuscript in preparation (Teuteberg, et al.)

Multivariate Risk Factors for HCVA Manuscript in preparation (Teuteberg, et al.)

Summary of ICVAs and HCVAs 26.5% of HCVAs were non-disabling (modified Rankin score < 2) ICVA Peri-proceduralPost-procedural % Patients 1.8%5.2% EPPY HCVA Subdural Sub- arachnoid Intra- parenchymal Iatrogenic* % Patients 1.8% 4.2%0.8% EPPY ICVA HCVA Total patient years – % of ICVAs resulted in full recovery (modified Rankin score = 0) * Post thrombolysis

p=0.51 p< No Stroke (n=333) ICVA (n=20) HCVA (n=32) Impact of CVA Periprocedural ICVAs are excluded

All HVAD (n=382) Sintered HVAD (n=110) ICVA patients (%) events (EPPY) 20 (5.2%) 24 (0.06) 3 (2.7%) 4 (0.05) HCVA patients (%) events (EPPY) 27 (7.1%) 28 (0.07) 7 (6.4%) 7 (0.09) Note: Procedural-related ICVAs (n=7; within 48 hours of implant), Iatrogenic HCVAs (n=3), and those HCVAs related to a fall (n=3) were excluded. Effect of design changes

BP control – effect on HCVA

Infections in BTT+CAP 84% driveline infections were successfully managed with antibiotics Driveline infections had no adverse impact on survival 3.5% of patients with sepsis had a device exchange for VAD thrombus within days of a sepsis diagnosis. 16% of sepsis events were either concurrent with or were preceded (within 10 days) by a urinary tract infection (UTI) with positive urine cultures. 17.5% of patients with sepsis died due to sepsis-related events such as neurological events and multisystem organ failure. 14% of all sepsis events were associated with a stroke event (stroke within -1 to 6 days of sepsis). Of patients with a stroke and sepsis, 70% subsequently died due to sepsis-related neurological events and associated multisystem organ failure. Manuscript recently accepted by JHLT in April 2014 (John, et al.)

Gastrointestinal Bleeding in BTT+CAP 15.9% (59/382) patients experienced a GI bleed. Overall, the 59 patients had 108 bleeding events that resulted in 0.27 EPPY (range 1-7 events) with 2/3 experiencing a recurrent GIB. Most GI bleeds (>86%) occurred >30 days post implant. Despite interruptions in anticoagulation in 2/3 of patients with GI bleeds, only 8.5% had any subsequent thrombotic events. The most common etiology of GI bleeding was arteriovenous malformations There were no deaths directly related to GI bleeding, and no difference in overall survival between patients with and without GI bleeding events. Manuscript in preparation (Goldstein, et al).

Conclusions ADVANCE/CAP trial met study end points Adverse event profile may vary between axial vs. centrifugal pumps New patient/device management strategies may reduce HVAD related adverse events