new trends and indications for lvads

New Trends and Indications for LVADs

Mark S. Slaughter, MDProfessor and Chief

Division of Thoracic and Cardiovascular SurgeryUniversity of Louisville

100

75

50

25

0I II III IV

1

10

NYHA CLASS

Annu

al S

urvi

val R

ate

Hos

pita

lizat

ions

/ y

ear

.1

Deceased

Adapted from Bristow, MR Management of Heart Failure, Heart Disease: A Textbook of Cardiovascular Medicine, 6th edition, ed. Braunwald et al.

Class III

25% of HF Patients

Frequent hospitalizations

Worsening symptoms despite drug therapy

Significant opportunity for new therapies

Survival RateHospitalizations

Natural History of Heart Failure

Presenter

Presentation Notes

What are we looking at in terms of our initial target population for therapies such as Acorn CorCap? To look at that I placed them in the context of the spectrum of patients from NYH class I II III,IV. In the early stages the survival rate is pretty good not unlike what you would see in an ?age-match control population? number of hospitalizations are very low. On the other extreme in the NYH class IV patients, where the mortality rate is very high and very low survival rate, hospitalizations are also high. These are the patients that need things like ”rescue therapies” Lvads, and transplants. In between is a very sizable group in the NYH class III. These are patients that are on the same drug therapies they were on in class II but are failing that therapy. They are having continued symptoms or progressive symptoms despite this medicated therapy. They are having frequent hospitalization causing great morbidity as well as a slippery-slope of increased mortality. Where they go from a state of being stable in class II and transition from that stable class to a class where the mortality rate is very high. So all the action is happening right here in class III. This is where the big gap is and where the focus of the attention is in a lot of centers such as your own. We feel this is the most appropriate and perfect spot for a device such as ours. It is not a rescue therapy and may not be something you want to go through surgery for someone who is stable. But the patient who is at risk for that slippery-slope, repeated hospitalizations high morbidity high potential for mortality is where this opportunity for new therapies are best.. We feel we bridge that gap from the medical therapy to the rescue therapy.

Hall & Debakey VAD - 1963

LVAD Bridge to Recovery - 1966

The Evolution of MCS Devices

Paracorporeal

Pneumatic

Pulsatile

Uni- or Biventricular

Implantable

Electric

Pulsatile

Large

Multiple moving parts

Implantable

Electric

Continuous flow

Axial design

Smaller

Single moving part

Implantable

Electric

Continuous flow

Centrifugal design

Smaller

Bearingless

Implantable

Electric

Continuous flow

Axial design

Smaller

Partial support

Improving Survival in LVAD Trials

Months0 6 12 18 24

Perc

ent S

urvi

val

0102030405060708090

100

HM II BTT Miller NEJM 2007

HM II DT Slaughter NEJM 2009

HM II BTT Pagani JACC 2009

HM II BTT Starling HFSA 2009

VE DT LVAD REMATCH Rose NEJM 2001

XVE DT LVAD Slaughter NEJM 2009

OMM REMATCH Rose NEJM 2001OMM INTrEPID Rogers JACC 2007

Novacor DT LVAD INTrEPID Rogers JACC 2007

Destination Therapy Trials

Fang JC NEJM 2009

Two Center Improvement in DT Survival Since First Cohort

Months0 6 12 18 24

Perc

ent S

urvi

val

0102030405060708090

100

Late Experience June 2007 - April 2009 (n=55)Overall Experience March 2005 - April 2009 (n=93)Early experience March 2005 - May 2007 (n=38)(Included in Slaughter, Rogers, Milano et al NEJM 2009)

Remaining at Risk: 55 43 1293 64 30 38 21 18

59 + 8%

85 + 5%

70 + 8%

56 + 8%

Multicenter Improvement in DT SurvivalHeartMate II Clinical Trial

Months0 6 12 18 24

Perc

ent S

urvi

val

0102030405060708090

100DT Implants mid trial (n=311)(5-4-07 thru 3-1-09)

68 + 4%

58 + 4%

74 + 3%

Remaining at Risk: 311 239 200 116 199 137 119 98 87

DT Implants early trial (n=133)(3-16-05 thru 5-4-07)(Slaughter, Rogers, Milano NEJM 2009)

Patient Functionality and QoL on VAD Therapy

J Am Coll Cardiol 2010; 55: 1826-34

6 Minute Walk Distance

NYHA Functional Class

Minnesota Living with Heart Failure

1

2

3

4

Bleeding vs. Thromboembolism

• Which is one is a problem?• Does it matter?

Bleeding vs. Thromboembolism

• Bleeding much more common than thrombotic/thromboembolic events

• Hemorrhagic stroke most common cause of death in HM II DT trial

• Mucosal bleeding significant cause for re-admission after implantation

• “Pump thrombosis” rare usually from clot ingestion or misaligned inflow cannula

Event Rate vs INR ValuesHeartMate II Clinical Study

Patie

nts

With

Eve

nts

Bleeding Requiring >6 UBleeding RequiringSurgeryHemorrhagic Stroke

Pump Thrombosis

Ischemic Stroke

INR Range: <1.5 1.5-1.99 2.0-2.49 2.5-2.99 >3.0

Thrombotic Events

Hemorrhagic Events8

8

0

4

4

Boyle et al AHA 2007

EJCTS 2008, 33; 4: 679-684

Can Axial Flow Pumps Cause Acquired vWF?

Presenter

Presentation Notes

Analysis of VWF multimers of a VAD patient compared to a sample of a normal person. VWF multimers are separated by electrophoresis according to their size on low-resolution SDS-agarose gels. Smaller multimers run faster through the gel and appear, therefore, in the lower part of the gel. Note the missing bands in the upper part of the gel in the VAD patients’ lane. This is reflected by densitometry curves in the right part of the figure (grey line, normal control sample; black line, VAD patient's sample). �

Nr Gender Age Diagnosis IndicationLVAD

supportvWF:AG1

vWF:CB2

vWF:CB/vWF:AG3

Loss oflargest

vWFMM4

Highmolecular

weight MM5

PFAC-EPI6

PFAC-ADP7

(years) (months) (%) (%) (%vs.pool) (sec) (sec)

1* male 44 CHD BTT 5 176 139 0.79 yes > 250 > 250

2* male 35 DCM BTT 3 248 288 1.16 yes > 250 > 250

3 male 32 DCM BTT 24 172 139 0.81 yes > 250 > 250

4* male 30 CHD BTT 4 110 79 0.72 yes 0.4 vs 20.5 > 250 > 250

5** male 23 DCM BTT 1 520 372 0.72 yes > 250 > 250

6* male 45 CHD BTT 8 168 175 1.04 yes 14.6 vs 30.5 > 250 > 250

7* male 42 DCM BTT 13 133 129 0.97 yes > 250 > 250

8* male 16Myocarditi

s BTT 4 99 85 0.86 yes > 250 > 250

9* male 41 DCM BTT 5 133 108 0.81 yes 7.3 vs 30.8 > 250 > 250

10** male 64 CHD DT 4 190 232 1.22 yes 20.9 vs 32.8 > 250 > 250

11** female 52 CHD BTT 5 182 86 0.47 yes 8.1 vs 33.1 > 250 > 250

12** male 53 DCM BTT 2 273 170 0.62 yes 5 vs 22 > 250 > 250

13** male 41 CHD BTT 1 282 267 0.95 yes 15.1 vs 24.7 > 250 > 250

14* male 28 DCM BTT 5 200 125 0.63 yes > 250 > 250

15 male 60 CHD DT 18 102 84 0.82 yes 6.2 vs 14.8 > 250 > 250

16** male 58 DCM BTT 5 238 200 0.84 yes 3.5 vs 24.7 > 250 > 250

17* male 53 CHD BTT 1 213 220 1.03 yes > 250 > 250

18 male 54 CHD DT 2 258 251 0.97 yes > 250 > 250

19** male 57 DCM BTT 4 135 64 0.47 yes 5.1 vs 35.5 > 250 > 250



22* male 64 DCM BTT 19 196 138 0.7 yes > 250 > 250

23* male 40 CHD BTT 2 122 110 0.9 yes > 250 > 250

24* female 46 DCM BTT 4 155 129 0.83 yes 5.4 vs 24.7 > 250 > 250

25** male 50 CHD DT 3 310 208 0.67 yes 1.6 vs 34 > 250 > 250

NrTime after

Ex/Tx vWF:AG1 vWF:CB2vWF:CB/vWF:AG3

Loss oflargest

vWF MM4

Highmolecular

weightMM5

PFAC-EPI6

PFAC-ADP7 Platelet

Hct8 CRP9

(months) (%) (%) (%vs.pool) (sec) (sec)(1,000/u

l) (%) (mg/l)

1 34 185 174 0.94 no 56.5 vs 31.6 68 69 268 45.6 1

2 24 360 268 0.74 no 20.1 vs 23.2 143 83 199 41.1 2

4 3 199 185 0.92 no 24.6 vs 26.1 n.d. n.d. 149 28.9 1

6 4 490 444 0.91 no n.d. 69 n.d. 383 34.5 74

7 5 157 164 1.04 no n.d. 98 94 256 42.7 2

8 2 101 100 0.99 no n.d. 205 129 130 45.3 1

9 2 280 276 0.99 no 30.4 vs 22.1 84 72 330 41.2 89

14 15 304 244 0.8 no 26.5 vs 27.7 109 83 230 40.2 11

17 21 127 134 1.06 no 33.2 vs 33.2 173 76 265 40.1 6

22 11 216 266 1.23 no 30.4 vs 23.2 164 276 253 33.0 123

23 27 115 102 0.89 no 27.8 vs 26.6 109 90 312 45.1 10

24 7 337 284 0.84 no 34.1 vs 32.2 105 81 260 36.6 4

vwF diagnostics after removal of HM II

NrTime afterfirst test vWF:AG1 vWF:CB2

vWF:CB/vWF:AG3

Loss oflargest

vWF MM4

Highmolecular

weightMM5

PFAC-EPI6

PFAC-

ADP7 Platelet Hct8 CRP9

(months) (%) (%) (%vs pool) (sec) (sec)(1,000/u

l) (%) (mg/l)

5 16 80 50 0.63 yes 10.9 vs 29 266 300 121 39.8 1

10 11 100 94 0.94 yes 8.7 vs 23.3 >300 >300 134 36.9 2

11 11 143 84 0.59 yes 9.2 vs 31 >300 >300 175 36.9 7

12 15 118 72 0.61 yes 6.3 vs 21.4 >300 >300 207 40.3 1

13 20 109 66 0.61 yes 16.5 vs 25.1 >300 >300 273 38.7 10

16 7 336 122 0.36 yes 1.2 vs 17.8 >300 >300 361 37.1 12

19 10 105 59 0.56 yes 7.6 vs 27.6 >300 >300 152 46.3 1

20 15 193 96 0.50 yes 7.2 vs 25.2 >300 >300 177 45.9 4

21 21 112 70 0.63 yes 9.5 vs 33.7 >300 >300 188 40.7 1

25 13 159 56 0.35 yes 7.3 vs 23.6 >300 >300 151 37.6 1

26 25 248 95 0.38 yes 9.2 vs 23.6 300 250 172 38.0 5

2nd analysis in ongoing HMII patients

vWf is it the Cause or Contributor to Mucosal/GI Bleeding

Indications?

• BTT• DT• Myocardial Recovery• Advanced heart failure, inotropic dependent

with end-organ dysfunction

Contemporary Outcomes with the HeartMate II® LVAS

CMS National Coverage Meeting for Destination Therapy

May 12, 2010

U.S. HMII DT Primary Cohort

N Engl J Med 2009; 361: 2241-51

HeartMate II Destination Therapy Trial

Design– Prospective, randomized, multicenter clinical trial

Inclusion criteria:– LVEF ≤ 25% – Peak VO2 <14 ml/kg/min (or 50% age- and sex-predicted)– And either

• NYHA class IIIb-IV symptoms for at least 45 of the prior 60 days on maximally tolerated oral heart failure medications, or

• Dependence on IV inotropes for at least 14 days, or• Dependence on an IABP for at least 7 days

– Not a candidate for transplantation• Exclusion criteria:

– Irreversible renal, pulmonary or hepatic dysfunction or active infection

Defining the Patient Cohort Included in the HMII DT Trial

Definitions:

• Class IIIB: Cardiac disease resulting in marked limitations of physical activity. Patients are comfortable at rest. Mild physical activity causes fatigue, palpitation, dyspnea, or anginal pain.

• Class IV: Cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

HeartMate II DT TrialExploring the Differences Between Class IIIB and IV

PatientsClass IIIB(n=160)

Class IV(n=407) p

Mean Age (yrs) 63 ± 11 63 ± 12 0.87

Female (%) 16 25 0.02

Ischemic (%) 59 62 0.63

Treatment (%)DigoxinBeta blockerCRTInotropic TherapyIABP

5563626810

4246618125

0.0060.0003

0.850.002

<0.0001

Serum sodium (mmol/L) 135 135 0.31

Pre-albumin (mg/dl) 20.5 18.0 0.001

Creatinine (mg/dl) 1.5 1.5 0.84

Hct (%) 35.6 34.4 0.02

WBC (x103 /ml) 7.2 8.0 0.001

HeartMate II DT TrialExploring the Differences Between Class IIIB and IV Patients

NYHA Class IIIB (n=160) NYHA Class IV (n=407)

n Mean SD Median n Mean SD Median P*PCWP (mmHg) 138 22.4 9.3 22.0 360 24.9 7.9 25.0 0.0067

Systolic PA (mmHg) 154 52.1 14.8 52.0 399 54.0 13.5 54.0

0.1381

Diastolic PA (mmHg) 154 24.5 8.4 24.0 398 26.2 7.8 26.0

0.0237

Mean PA (mmHg) 153 35.0 10.3 36.0 393 36.7 9.0 37.0 0.0728

CVP (mmHg) 142 11.8 6.1 11.0 383 13.2 6.8 13.0 0.0176

Cardiac Index (l/min/sqm) 148 2.1 0.6 2.0 379 2.1 0.6 2.0

0.2178

Cardiac Output (l/min) 153 4.1 1.3 4.0 394 3.9 1.3 3.8

0.2013

PVR (Wood Units) 147 3.6 1.8 3.3 359 3.6 1.9 3.2 0.7776

Systolic BP (mmHg) 153 104.8 16.9 102.0 397 102.7 14.9 102.0

0.1556

Diastolic BP (mmHg) 153 62.0 11.4 62.0 396 62.3 12.5 61.0

0.8521

LVEF % 159 16.5 5.5 15.0 396 16.9 5.7 15.0 0.4064

*Unpaired t-test

HeartMate II DT TrialExploring the Differences Between Class IIIB and IV Patients

Patients Discharged on Support (%)Class IIIbClass IV

9678

Median days to DischargeClass IIIBClass IV

23.528.0

Median Duration of Support (days)Class IIIBClass IV

650570

What is REVIVE-IT?• Randomized Evaluation of VAD InterVEntion before

Inotropic Therapy• NHLBI RFP

– Joint NHLBI/Industry support– Solicitation July 2009– Submission Dec 2009

• Cleveland Clinic/Duke (sponsor Thoratec)• Michigan/Pittsburgh (sponsor HeartWare)

– Award pending

REVIVE-IT Trial Design

REVIVE-IT Solicitation

• Study Hypothesis– VAD will improve functional status @ 12 mo– All cause mortality VAD will not exceed that of the

OMM


REVIVE-IT Solicitation• Inclusion Criteria (to achieve estimated mortality in

OMM arm of ≈ 30% @ 1 yr)– NYHA Class IV or Advanced III– Not a transplant candidate– LVEF ≤ 35%– Duration of HF ≥ 1 year– Maximal evidence based Rx ≥ 3 months– Hospitalization in past 6 months– No inotropic support within prior 6 months– Peak VO2 45-65% of predicted peak VO2


REVIVE-IT Solicitation• Study Design

– RCT between VAD and OMM arms– 1:1 randomization, 50 patients per group

• Primary composite endpoint• Survival• Functional status

– ≥ 20% improvement, objectively assessed• Primary outcome assessed at 1 year


REVIVE-IT Solicitation• Secondary endpoints

• Safety• Secondary functional and physiological markers• QOL• Neurocognition• Cost and cost-effectiveness

• 2 year follow-up


Key Issues in REVIVE-IT

CCF/Duke

• LVEF ≤ 30%• Peak VO2 ≤ 14 ml/kg/min or

< 50% age- and sex-predicted

• 6 min walk distance < 300 m• Minn. Living with Heart

Failure Score ≥ 60 or KC Cardiomyopathy Score ≤ 40.

UM/Pitt

• LVEF ≤ 35%• Peak VO2 ≤ 14 ml/kg/min

(♂) or ≤ 16 ml/kg/min (♀) AND < 55% age- and sex-predicted

• Seattle Heart Failure Model score ≥ 1.5


Identification of Sample with 30% 1-yr Mortality

Key Issues in REVIVE-IT

CCF/Duke

• Hospitalization within prior 6 months

UM/Pitt

• No requirement for hospitalization SHFM independent of recent

hospitalization (ACCLAIM)


Identification of Sample with 30% 1-yr Mortality

Seattle Heart Failure ModelAge > 60, NYHA ≥ III, creat ≤ 2.5, LVEF ≤ 35%

N=3238N=3238 pts from PRAISE,ValHeFT andACCLAIM

SHFM vs. Peak VO2Superiority of SHFM for Risk Stratification


N=3238

SHFM discriminates further among pts with peak VO2 10-14

SHFM 0-3 for pts with peak VO2 10-14Peak VO strata for pts with SHFM=2

For SHFM =2, peak VO2 provides no additional risk stratification

TAH: Is there a clinical need?

BIVENTRICULAR HEART ASSIST HeartWare LVADModification for Clinical RVAD

Long-Term MCSS at DHZB 2009 -- New Concepts

Banding of the Pulmomary Artery

GraftPressureadaptation

HeartWareRVAD

HeartWareLVAD

Long-Term MCSS at DHZB 2009 -- New ConceptsBIVENRTICULAR HEART ASSIST WITH CENTRIFUGAL

BLOODPUMPS –Study 1 HeartWare HVAD DHZB Pat HW 6

BIVENRTICULAR HEART ASSIST WITH CENTRIFUGAL BLOODPUMPS –Study 1

HeartWare HVAD DHZB Pat HW 6

HeartWare Biventricular Support

Successful Design Miniaturization

Mock Circulation Study

Simulated Test Conditions1. Normal2. BiV Failure3. Hypotension4. Hypertension5. Hypovolemia

Measurements1. AoP, LVP, LAP2. PAP, RAP, RVP3. BiMVAD (Q, rpm, power)4. AoF, PAF5. LVV, RVV

Protocol1. Baseline (no support)2. Low (< 1.5 lpm) 3. Moderate (2-3 lpm)4. Maximal (> 5 lpm)5. Baseline (no support)

[1] Left Ventricle [2] Right Ventricle[3] Aorta[4] Pulmonary Artery [5] Systemic Resistance[6] Pulmonic Resistance [7] Systemic Compliance [8] Pulmonic Compliances

Mock Circulation Study

Acute Animal Study (n=3)

Test Conditions1. Normal2. BiV Failure (Esmolol)3. Hypotension (Nitroprusside)4. Hypertension (Phenylephrine)5. Hypovolemia (volume reduction)6. Fibrillation (electrical)

Measurements1. AoP, LVP, LAP2. PAP, RAP, RVP3. BiMVAD Flows, RPM, power4. AoF, PAF5. LVV, RVV6. CBC, LDH, PfHb

Protocol1. Baseline (no BiMVAD)2. Low support (< 1.5 lpm) 3. Moderate support (2-3 lpm)4. Maximal support (> 5 lpm)5. Baseline (no BiMVAD

New Trends and Indications for LVADs

• VADs have improved outcomes out to 2 yrs and are the treatment of choice for end-stage heart failure

• Improved outcomes resulting in studies to evaluate earlier implantation

• Blood trauma and bleeding needs additional investigation

• CF VADs can be used for chronic biventricular support

new trends and indications for lvads

Documents