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):3191-200 Slaughter, et al. J Heart Lung Transpl. 2013; 32: 675-683

Patient Demographics

Baseline Characteristic BTT and CAP

(N = 382) BTT

(N = 140) CAP

(N = 242)

Age (years) 53.2 ± 11.7 53.3 ± 10.3 53.1 ± 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/m2) 28. 2 ± 6.1 28.5 ± 6.0 28.0 ± 6.1

Body surface area (m2) 2.0 ± 0.3 2.1 ± 0.3 2.0 ± 0.3

Ischemic cause of heart failure (%) 38.0% 40.7% 36.4%

Left ventricular ejection fraction (%) 17.3 ± 7.3 18.0 ± 7.1 16.9 ± 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 ± 14.5 24.1 + 8.4

51.0 ± 15.1 25.6 + 8.9

48.1 ± 14.3 23.6 ± 8.2

Arterial blood pressure (mmHg)

Systolic Diastolic Mean

103.2 ± 15.3 63.5 ± 10.6 77.5 ± 11.0

103.3 ± 15.6 63.7 ± 11.2 76.2 ± 12.1

103.7 ± 15.2 63.4 ± 10.3 78.1 ± 10.4

Cardiac index (liters/min/m2)

2.2 ± 0.6 2.1 ± 0.6 2.2 ± 0.6

NYHA Class (%)

II III IV

0.5 3.4

95.8

0.7 3.6

95.0

0.4 3.3

96.3

INTERMACS (%)

1 2 3

4-7

5.5 34.8 40.6 19.1

5.0 27.9 42.9 24.3

5.8 38.8 39.3 16.1

Kaplan Meier Survival in HVAD BTT+CAP Clinical Trial

90% 84%

Days

Even

t Fre

e R

ate

Month 0 2 4 6 8 10 12 18 24 Patient at risk 382 356 305 261 218 191 165 114 74

Survival 100% 97% 94% 90% 89% 86% 84% 79% 71%

71% 79%

Success Outcomes (N=382)

Endpoint Outcome at 6 months

Success Transplanted or Myocardial Recovery or Alive on original device

87.6%

Alive on original device 66.5%

Transplanted 20.8%

Myocardial Recovery 0.3%

Died 8.2%

Exchanged 4.2%

Mean duration of support (incl. post exchange) = 423 days

Adverse Events in BTT+CAP (N=382) N=382 with 406.6 Patient-Years of Support

Complication Patients with event, n (%)

Number of Events

Event Rate

Ventricular Arrhythmia 77 (20.2) 101 0.25

Gastrointestinal Bleeding 59 (15.4) 108 0.27

Right Heart Failure (RHF) 129 (33.8) 149 0.37

RHF Requiring RVAD 15 (3.9) 15 0.04

Ischemic Stroke 26 (6.8) 31 0.08

Hemorrhagic Stroke 32 (8.4) 34 0.08

Device Exchange for Suspected Thrombus

16 (4.2) 17 0.04

Driveline Infection 75 (19.6) 102 0.25

Sepsis 72 (18.8) 92 0.23

Renal Failure 39 (10.2) 46 0.11

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: 23-34 (e-pub ahead of print 13 Dec 2013)

Multivariate Risk Factors for VAD Thrombus

Najjar, et al. J Heart Lung Transpl. 2014; 33: 23-34 (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.)

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 1 - 4 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