HeartWare HVAD: Risk Factors for Adverse Outcomes

Mark S. Slaughter, MDProfessor and Chair

Department Cardiovascular and Thoracic SurgeryUniversity of Louisville

Disclosures

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

HVAD ADVANCE Bridge to HVAD ADVANCE Bridge to Transplantation Study DesignTransplantation 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):3191-200Slaughter, et al. J Heart Lung Transpl. 2013; 32: 675-683

Patient Demographics Patient Demographics

Baseline CharacteristicBTT 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)Patient Demographics (continued)

Baseline CharacteristicBTT and CAP

(N = 382)

BTT

(N = 140)

CAP

(N = 242)

Pulmonary artery pressure (mmHg)

SystolicDiastolic

48.8 ± 14.524.1 + 8.4

51.0 ± 15.1

25.6 + 8.9

48.1 ± 14.323.6 ± 8.2

Arterial blood pressure (mmHg)

SystolicDiastolicMean

103.2 ± 15.363.5 ± 10.677.5 ± 11.0

103.3 ± 15.663.7 ± 11.276.2 ± 12.1

103.7 ± 15.263.4 ± 10.378.1 ± 10.4

Cardiac index (liters/min/m2)

2.2 ± 0.6 2.1 ± 0.6 2.2 ± 0.6

NYHA Class (%)IIIIIIV

0.53.495.8

0.73.695.0

0.43.396.3

INTERMACS (%)

123

4-7

5.534.840.619.1

5.027.942.924.3

5.838.839.316.1

Kaplan Meier Survival in HVAD Kaplan Meier Survival in HVAD BTT+CAP Clinical TrialBTT+CAP Clinical Trial

90%

84%

Days

Ev

ent

Fre

e R

ate

Month 0 2 4 6 8 10 12 18 24Patient 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)Success Outcomes (N=382)

Endpoint Outcome at 6 months

SuccessTransplanted 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)Adverse Events in BTT+CAP (N=382)

N=382 with 406.6 Patient-Years of Support

ComplicationPatients 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 EventsFreedom 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 Multivariate Risk Factors for VAD ThrombusThrombus

Najjar, et al. J Heart Lung Transpl. 2014; 33: 23-34 (e-pub ahead of print 13 Dec 2013)

Freedom from CVAFreedom 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 ICVAMultivariate Risk Factors for ICVA

Manuscript in preparation (Teuteberg, et al.)

Multivariate Risk Factors for HCVAMultivariate 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-procedural Post-procedural

% Patients 1.8% 5.2%

EPPY 0.017 0.06

HCVA  SubduralSub-

arachnoidIntra-

parenchymalIatrogenic*

% Patients 1.8% 1.8% 4.2% 0.8%

EPPY 0.017 0.017 0.039 0.007

ICVA

HCVA

Total patient years – 406.6

50% of ICVAs resulted in full recovery (modified Rankin score = 0)

* Post thrombolysis

p=0.51

p<0.0001

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)

ICVApatients (%)

events (EPPY)20 (5.2%)24 (0.06)

3 (2.7%)4 (0.05)

HCVApatients (%)

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+CAPInfections 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+CAPGastrointestinal 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