What have we learned? What is next?

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Research Topics in INTERMACS

• What have we learned? What is next?
• Panel A Adverse Events
• A. Bleeding
• B. Device Function and Malfunction
• Neurological Dysfunction
• Impact of INTERMACS Profiles
• Right Heart Failure
• Discussion

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Adverse Events
INTERMACS Annual Meeting March 2012
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At this point in the meeting are you beginning to
feel like this?
INTERMACS Annual Meeting March 2012
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Research Topics in INTERMACS
Adverse Event Major Bleeding R Kormos


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Coordinator Training Session, March 11, 2012

• BLEEDING

MAJOR BLEEDING AN EPISODE OF SUSPECTED INTERNAL
OR EXTERNAL BLEEDING THAT RESULTS IN ONE OR MORE
OF THE FOLLOWING 1. Death, 2.
Re-operation, 3. Hospitalization, 4.
Transfusion of red blood cells If
TRANSFUSION IS SELECTED, then apply the following
rules During first 7 days post implant ?
Adults ( 50 kg) 4U packed red blood cells
(PRBC) within any
24 hour period during first 7 days post
implant. After 7 days post implant ?
Any transfusion of packed red blood cells (PRBC)
after 7 days
following implant with the investigator
recording the number of
units given. Note
Hemorrhagic stroke is considered a neurological
event and not as a separate bleeding
event.
 
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Coordinator Training Session, March 11, 2012

• BLEEDING

• Major Bleeding
• episode
• Page 64

An episode may span several days.
 
Transfusions for ANEMIA...
It is not the transfusion that determines
bleeding, but the recognized bleeding
event.---Dr. Kormos
Hemolysis Hemorrhagic Stroke have their own AE
Form
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Jun 2006 Sept 2010 Risk for Early
Bleeding Adult Primary LVADs, Bi-VADs, TAH
n3140
LVAD Continuous /Intracorporeal n2130, events780
LVAD Pulsatile/Intracorporeal n521, events212
Freedom from Bleeding
LVAD Pulsatile/Extracorporeal, n93, events45
TAH, n85, events38
Bi-VAD, n311, events184
p lt .0001
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Event First Bleeding Episode
Months after Implant
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Jun 2006 Sept 2010 Risk for Early
Bleeding Adult Primary LVADs, Bi-VADs, TAH
n3140
LVAD Continuous /Intracorporeal n2130, events780
LVAD Pulsatile/Intracorporeal n521, events212
Freedom from Bleeding
LVAD Pulsatile/Extracorporeal, n93, events45
TAH, n85, events38
Bi-VAD, n311, events184
p lt .0001
INTERMACS Annual Meeting March 2012
Event First Bleeding Episode
Months after Implant
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Jun 2006 Sept 2010 Risk for Early
Bleeding Adult Primary Pulsatile Intracorporeal
LVADs n521
INTERMACS Patient Profile Levels
3) Stable but Inotrope Dependent n54, events19
4) Levels 4 7 n77, events25
Freedom from Bleeding
2) Progressive Decline n218, events90
1) Cardiogenic Shock n172, events78
p .06
Event First Bleeding Episode
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Months after Implant
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Jun 2006 Sept 2010 Risk for Early
Bleeding Adult Primary Continuous Intracorporeal
LVADs n2130
Age
Age lt 60 years n1349, events426
Freedom from Bleeding
Age 60 years n781, events354
p lt .0001
Event First Bleeding Episode
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Months after Implant
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Jun 2006 Sept 2010 Risk for Early
Bleeding Adult Primary Pulsatile Intracorporeal
LVADs, n 521
Concommitant Surgery at time of implant
No Concommitant Surgery n343, events123
Freedom from Bleeding
Concommitant Surgery n178, events89
p .0006
Event First Bleeding Episode
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Months after Implant
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Mar 5 2009 Sept 2010 Risk for Early Bleeding
Location of 1st Bleeding Pulsatile
Continuous Episode n n
Mediastinal 34 49 221 39 Chest wall 6
9 39 7 Thoracic plural space 7 10
59 10 Pump pocket 0 0 33 6 Device
anastomosis 1 1 9 2 Outflow or
inflow conduit 3 4 16 3 Aortic or
venous cann site 2 3 4 1 Intra
abdominal 1 1 4 1 Respiratory
1 1 5 1 Urinary tract 0 0 4
1 Upper GI 3 4 54 9 Lower GI
9 13 72 13 Other 13 19 184 32 Total
70 100 569 100
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Pre-Implant Risk Factors for 1st Bleeding
Episode
Jun 2006 Sept 2010 Risk for Early Bleeding

• Risk Factor Hazard Ratio
  P-value Age (older)1
  1.26 lt .0001
• NYHA Class IV 1.40 .004
• Bilirubin (higher)2 1.05 .02
• Dialysis 1.66 .006
• Previous CABG 1.35 .002
• INTERMACS Level 1 1.53 .0001
• INTERMACS Level 2 1.33 .002
• Concommitant Surgery 1.44 lt .0001
• (Pulsatile Pump 1.15 .14)

INTERMACS Annual Meeting March 2012
1The hazard ratio is calculated for a 10 year
increase in age 2The hazard ratio is calculated
for a 1 unit increase
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Research Topics in INTERMACS

• Adverse Event Major Bleeding
• What are the Next Steps?
• Device Evaluation and Development
• Improving Patient Outcomes
• Is GI bleeding an issue

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Research Topics in INTERMACS
Adverse Event Device Function and
Malfunction R Kormos

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Coordinator Training Session, March 11, 2012

• DEVICE MALFUNCTION

• Device Malfunction
• Device malfunction denotes a failure of one or
  more of the components of the MCSD system which
  either directly causes or could potentially
  induce a state of inadequate circulatory support
  (low cardiac output state) or death. The
  manufacturer must confirm device failure. A
  failure that was iatrogenic or recipient-induced
  will be classified as an Iatrogenic/Recipient-Indu
  ced Failure.
• Device failure should be classified according to
  which components fails as follows
• ) Pump failure (blood contacting components of
  pump and any motor or other pump actuating
  mechanism that is housed with the blood
  contacting components). In the special situation
  of pump thrombosis, thrombus is documented to be
  present within the device or its conduits that
  result in or could potentially induce
  circulatory failure.
• 2) Non-pump failure (e.g., external pneumatic
  drive unit, electric power supply unit,
  batteries, controller, interconnect cable,
  compliance chamber)

 
The Adverse Event Device Malfunction Form is to
be collected at time of event. FDA has set forth
regulations regarding these events. For the
purposes of submitting adverse event device
malfunction information to the FDA, you must
enter any device malfunction event that occurs
within 72 hours of the event.
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Service provided by INTERMACS
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Coordinator Training Session, March 11, 2012

• DEVICE MALFUNCTION

 
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Coordinator Training Session, March 11, 2012

• DEVICE MALFUNCTION

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INTERMACS June 2006 March 2010 Device
Exchange Adult Prospective Primary Intracorporeal
LVADs, n1930
LVAD Continuous /Intracorporeal n1446, events30
Freedom from Device Exchange
LVAD Pulsatile/Intracorporeal n469, events55
p lt .0001
Event First Device Exchange
INTERMACS Annual Meeting March 2012
Months after Implant
Note 15 patients have missing intervals
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Research Topics in INTERMACS

• Adverse Event Device Malfunction
• What are the Next Steps?
• Improving Data Acquisition
• Analysis based upon patient factors
• Demographics including social issues
• Perceived compliance
• Analysis based upon component

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Research Topics in INTERMACS
Adverse Event Neurological
Dysfunction F Pagani

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Research Topics in INTERMACS
Adverse Event Neurological Dysfunction
NEUROLOGICAL DYSFUNCTION

• Neurological Dysfunction
• Any new, temporary or permanent, focal or global
  neurological deficit ascertained by a standard
  neurological examination (administered by a
  neurologist or other qualified physician and
  documented with appropriate diagnostic tests and
  consultation note). The examining physician will
  distinguish between a transient ischemic attack
  (TIA), which is fully reversible within 24 hours
  (and without evidence of infarction), and a
  stroke, which lasts longer than 24 hours (or less
  than 24 hours if there is evidence of
  infarction). The NIH Stroke Scale (for patients
  gt 5 years old) must be re-administered at 30 and
  60 days following the event to document the
  presence and severity of neurological deficits.
  Each neurological event must be subcategorized
  as
• Transient Ischemic Attack (acute event that
  resolves completely within 24 hours with no
  evidence of infarction)
• Ischemic or Hemorrhagic Cardiovascular
  Accident/CVA (event that persists beyond 24 hours
  or less
• than 24 hours associated with infarction on an
  imaging study.)

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Research Topics in INTERMACS
Magnitude of the Problem Adverse Event
Neurological Dysfunction

• The most significant complication of MCS therapy
  impacting survival, functional status, and QOL.
• significant impact on caretaker burden and
  family.
• The most significant concern in the consideration
  of MCS therapy for treatment of advanced HF in a
  less ill population of patients.
• Improvements in functional status and QOL likely
  to outweigh survival benefit
• Occurrence of stroke not outweighed by large
  survival benefit
• Adds significant costs to care.

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INTERMACS June 2006 September 2009
Neurological Dysfunction

• What have we learned from INTEMACS
• Importance of device technology

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INTERMACS June 2006 September 2009
Neurological Dysfunction

• What have we learned from INTEMACS
• Age alone, does not appear to be an independent
  risk factor for neurological event

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INTERMACS June 2006 September 2009
Neurological Dysfunction

• What have we learned from INTEMACS
• Severity of illness correlates with risk of
  neurological event

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INTERMACS June 2006 September 2009
Neurological Dysfunction

Early Constant Risk
Factor Hazard ratio p-value
Hazard ratio p-value Female 2.16
0.002 --- --- Ascites 2.33
0.007 --- --- Cardiogenic Shock
2.45 0.0002 ---
--- Destination Therapy 3.05
0.0002 ---
---- Cholesterol (higher) 1.11 0.0003 RA
Pressure (higher) 1.78 0.0006
--- --- Ventilator 2.20
0.01 Concomitant Surgery 1.88
0.008 Pulsatile pump
2.11 0.007
1 Hazard ratio denotes the increased risk with a
20 year increase in age 2 Hazard ratio denotes
the increased risk with a 1.0 increase in INR 3
Hazard ratio denotes the increased risk of a
10-unit increase in RA pressure
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Research Topics in INTERMACS
Neurological Dysfunction Next Steps

• Patient Selection / Patient Management
• Relationship of stroke risk to occurrence of
  other AEs, e.g., infection, hemolysis, pump
  thrombosis.
• Preliminary data supporting increase risk of
  stroke in patients with infectious complications
• Timing of the stroke risk in relationship to the
  infection?
• Specific types of infectious complications that
  increase stroke risk? e.g., bacteremia vs.
  device-related vs. non-device-related
• Alteration in management of anticoagulation /
  antiplatelet therapy
• Preliminary data supporting increase risk of
  stroke in patients experiencing hemolysis
• What is the natural history of patients
  experiencing hemolysis?
• Pre-emptive pump replacement vs medical therapy
  e.g., lytic therapies
• GI Bleeding
• Frequently withholding or reducing optimal target
  INR goal

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Research Topics in INTERMACS
Neurological Dysfunction Next Steps

• Patient Selection / Patient Management
• Perioperative risk factors for strokes
• Atrial fibrillation
• Management of the atrial appendage at the time of
  operation
• Mechanical valve prosthesis in the mitral
  position
• Replacement with a biological prosthesis at the
  time of LVAD implant
• Evaluation of New Technology
• Continuous flow pumps with centrifugal design
• Comparison to CF pumps with axial design

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Research Topics in INTERMACS
Impact of INTERMACS Profiles L Stevenson


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Research Topics in INTERMACS
INTERMACS Patient Profile at time of implant
Select one. These profiles will provide a general
clinical description of the patients receiving
implants. If there is significant clinical
change between the initial decision to implant
and the initial decision to implant and the
actual implant procedure, then the profile
closest to the time of implant should be
recorded. Patients admitted electively for
implant should be described by the profile just
prior to admission.   INTERMACS 1 Critical
cardiogenic shock describes a patient who is
crashing and burning,in which a patient has
life-threatening hypotension and rapidly
escalating inotropic pressor support, with
critical organ hypoperfusion often confirmed by
worsening acidosis and lactate levels. This
patient can have modifier A or TCS (see
Modifiers below) INTERMACS 2 Progressive
decline describes a patient who has been
demonstrated dependent on inotropic support but
nonetheless shows signs of continuing
deterioration in nutrition, renal function, fluid
retention, or other major status indicator.
Patient profile 2 can also describe a patient
with refractory volume overload, perhaps with
evidence of impaired perfusion, in whom inotropic
infusions cannot be maintained due to
tachyarrhythmias, clinical ischemia, or other
intolerance. This patient can have modifiers A
or TCS.   INTERMACS 3 Stable but inotrope
dependent describes a patient who is clinically
stable on mild-moderate doses of intravenous
inotropes (or has a temporary circulatory support
device) after repeated documentation of failure
to wean without symptomatic hypotension,
worsening symptoms, or progressive organ
dysfunction (usually renal). It is critical to
monitor nutrition, renal function, fluid balance,
and overall status carefully in order to
distinguish between a patient who is truly stable
at Patient Profile 3 and a patient who has
unappreciated decline rendering them Patient
Profile 2. This patient may be either at home or
in the hospital. Patient Profile 3 can have
modifier A, and if in the hospital with
circulatory support can have modifier TCS. If
patient is at home most of the time on
outpatient inotropic infusion, this patient can
have a modifier FF if he or she frequently
returns to the hospital.   INTERMACS 4 Resting
symptoms describes a patient who is at home on
oral therapy but frequently has symptoms of
congestion at rest or with ADL. He or she may
have orthopnea, shortness of breath during
ADLsuch as dressing or bathing, gastrointestinal
symptoms (abdominal discomfort, nausea, poor
appetite), disabling ascites or severe lower
extremity edema. This patient should be
carefully considered for more intensive
management and surveillance programs, by which
some may be recognized to have poor compliance
that would compromise outcomes with any therapy.
This patient can have modifiers A and/or FF.  

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Research Topics in INTERMACS
INTERMACS 5 Exertion Intolerant describes a
patient who is comfortable at rest but unable to
engage in any activity, living predominantly
within the house or housebound. This patient has
no congestive symptoms, but may have chronically
elevated volume status, frequently with renal
dysfunction, and may be characterized as exercise
intolerant. This patient can have modifiers A
and/or FF.   INTERMACS 6 Exertion Limited also
describes a patient who is comfortable at rest
without evidence of fluid overload, but who is
able to do some mild activity. Activities of
daily living are comfortable and minor activities
outside the home such as visiting friends or
going to a restaurant can be performed, but
fatigue results within a few minutes or any
meaningful physical exertion. This patient has
occasional episodes of worsening symptoms and is
likely to have had a hospitalization for heart
failure within the past year. This patient can
have modifiers A and/or FF.   INTERMACS 7
Advanced NYHA Class 3 describes a patient who is
clinically stable with a reasonable level of
comfortable activity, despite history of previous
decompensation that is not recent. This patient
is usually able to walk more than a block. Any
decompensation requiring intravenous diuretics or
hospitalization within the previous month should
make this person a Patient Profile 6 or lower.
This patient may have a modifier A only.
  MODIFIERS of the INTERMACS Patient
Profiles  A - Arrhythmia. This modifier can
modify any profile. Recurrent ventricular
tachyarrhythmias that have recently contributed
substantially to the overall clinical course.
This includes frequent shocks from ICD or
requirement for external defibrillator, usually
more than twice weekly. TCS Temporary
Circulatory Support. This modifier can modify
only patients who are confined to the hospital,
Patient Profiles 1, 2, and 3 (a patient who is
listed as Patient Profile 3 stable on inotropes
who has been at home until elective admission for
implantable VAD cannot have a TCS
modifier.) Support includes IABP, ECMO,
TandemHeart, Levitronix, BVS 5000 or AB5000,
Impella.   FF Frequent Flyer. This modifier
is designed for Patient Profiles 4, 5, and 6.
This modifier can modify Patient Profile 3 if
usually at home (frequent admission would require
escalation from Patient Profile 7 to Patient
Profile 6 or worse). Frequent Flyer is
designated for a patient requiring frequent
emergency visits or hospitalizations for
intravenous diuretics, ultrafiltration, or brief
inotropic therapy. Frequent would generally be
at least two emergency visits/admissions in the
past 3 months or 3 times in the past 6 months.
Note if admissions are triggered by
tachyarrhythmias or ICD shocks then the modifier
to be applied to would be A, not FF

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INTERMACS June 2006 September 2009 Changing
Characteristics
Adult Primary LVADs and Bi-VADs n1646
Patients with Critical Cardiogenic
Shock (INTERMACS Patient Profile Level 1)
plt0.0001
of Patients with Pt Profile Level 1
40
46
28
21
INTERMACS Annual Meeting March 2012
Jan 09 Sep 09
Apr 08 Dec 08
Jul 07 Mar 08
Jul 06 Jun 07
Implant Era
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INTERMACS June 2006 September 2009 Pt Profile
Study Adult Primary LVADs BTC, DT and Levels 1-4
- n718
Level 3 (Stable but Inotrope Dependent), n110,
deaths18
Level 4 (Resting symptoms), n83, deaths16
Level 1 (Critical Cardiogenic Shock), n221,
deaths62
Survival
Level 2 (Progressive Decline), n304, deaths79
p (overall) .01
INTERMACS Annual Meeting March 2012
Event Death (censored at transplant or explant
recovery)
Months after Device Implant
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Jun 2006 Sept 2010 Risk for Early
Bleeding Adult Primary Pulsatile Intracorporeal
LVADs n521
INTERMACS Patient Profile Levels
3) Stable but Inotrope Dependent n54, events19
4) Levels 4 7 n77, events25
Freedom from Bleeding
2) Progressive Decline n218, events90
1) Cardiogenic Shock n172, events78
p .06
Event First Bleeding Episode
INTERMACS Annual Meeting March 2012
Months after Implant
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Research Topics in INTERMACS

• Impact of INTERMACS Profiles
• What are the Next Steps?
• Improving Patient Selection and Outcomes
• Device Evaluation and Development

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Research Topics in INTERMACS
Adverse Event Right Heart Failure F Pagani, R
Kormos
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Coordinator Training Session, March 11, 2012

• RIGHT HEART FAILURE

•  Right Heart Failure
• Symptoms and signs of persistent right
  ventricular dysfunction central venous pressure
  (CVP) gt 18 mmHg with a cardiac index lt 2.3
  L/min/m2 in the absence of elevated left
  atrial/pulmonary capillary wedge pressure
  (greater than 18 mmhg), tamponade, ventricular
  arrhythmias or pneumothorax requiring RVAD
  implantation or requiring inhaled nitric oxide
  or inotropic therapy for a duration of more than
  1 week at any time after LVAD implantation.
•  
• LEVEL OF RIGHT HEART FAILURE
• Severe RHF RVAD
• Moderate RHF Inotrope or intravenous or
  inhaled pulmonary
• vasodilator (e.g. prostaglandin E or
  inhaled nitric oxide)
• Mild RHF Meets 2 of the 4 clinical
  criteria listed below
• CVP gt 18 mmHg or mean RA pressure gt 18 mmHg
• CI lt 2.3 L/min/MW2 (by Swan)
• Ascites or evidence of moderate to worse
  peripheral edema
• Evidence of elevated CVP by echo (dilated VC,
  IVS with collapse), physical exam
• (signs of increased jugular venous pressure)

 
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Research Topics in INTERMACS
Magnitude of the Problem Adverse Event Right
Heart Failure

• Significant perioperative adverse event
• Reduces overall MCS survival
• Survival to transplant adversely influenced
• Increases cost, length of stay and hospital
  resource utilization

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INTERMACS June 2006 September 2009 Bi-VAD
Study
Adult Primary Implants, n1706
Pre-Implant Patient Profile LVAD
(n1440) Bi-VAD (n206) 1 Critical Cardiogenic
Shock 380 (26) 112 (54) 2
Progressive Decline 612 (43) 78
(38) 3 Stable but Inotrope dependent
226 (16) 9 (4) 4 Recurrent Advanced
HF 150 (10) 4 (2) 5 Exertion
Intolerant 27 (2) 1 (1) 6
Exertion Limited 22 (1) 2
(1) 7 Advanced NYHA Class III 23 (2)
0 (0) Total 1440 (100) 216
(100) p lt .0001 Total Artificial Heart
devices (TAH) are excluded from this table

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INTERMACS June 2006 September 2009 Bi-VAD
Study
Adult Primary Bi-VAD Implants, n206
Bi-VAD Categories (LVAD/RVAD)
n () Durable/Durable 160 (78) Continuous
Flow Device/Durable 4 (2) Pulsatile Flow
Device/Durable 156 (75) Durable/Temporary
46 (22) Continuous Flow Device/Temporary
26 (13) Pulsatile Flow Device/Temporary 20
(10) Total 206 (100)

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Implant Dates June 2006 September 2009
Bi-VAD Study

• What have we learned from INTEMACS
• Survival significantly worse with the need for
  BiVAD

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Implant Dates June 23, 2006 September 30, 2009

• What have we learned from INTEMACS
• Survival favorably influenced by younger age

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Implant Dates June 2006 September 2009
Bi-VAD Study
Adverse Event Rates within the 1st 12 months post
implant Primary LVADS v BiVADs n1646
71.6
Episodes per 100 pt months
33.2
15.5
14.3
Bi-VAD
7.9
LVAD
4.9
2.6
2.0
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Implant Dates June 2006 September 2009 Bi-VAD
Study All Adult Primary BIVADs n206
Risk Factor Relative Risk p-value Age
(older) 1.56 lt 0.0001 BSA (higher) 4.85
0.0008 Ascites 2.28 0.004 Creatinine
(higher) 1.05 0.0001 Bilirubin
(higher) 2.64 0.001 INR (higher) 1.51
0.004 History of valve surgery 6.01 lt
0.0001 Failure to wean from bypass 7.52 lt
0.0001
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Research Topics in INTERMACS
Right Heart Failure Next Steps

• Patient Management
• Need to identify improved methodology for
  assessment of the RV
• Need to define perioperative risk factors for RV
  Failure
• Severe
• Moderate
• Mild
• Need to accurately define / identify reversible
  and irreversible forms of right heart failure
• Identify patients with the ability to recover
• Impact on patient management Durable vs.
  Temporary forms of RV support
• Perioperative factors identifying likelihood of
  RV recovery
• Failure to thrive syndromes and its
  relationship to right heart failure
• Evaluation of New Technology
• Smaller CF devices provide the option of
  long-term BiVAD support

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Research Topics in INTERMACS

• What have we learned? What is next?
• Panel A Adverse Events
• A. Bleeding
• B. Device Function and Malfunction
• Neurological Dysfunction
• Impact of INTERMACS Profiles
• Right Heart Failure
• Panel Discussion Kormos

INTERMACS Annual Meeting March 2012