Equipoise Does Not Equipoise Does Not Exist for REVIVE ITExist for REVIVE IT

Andrew Boyle, MDHeart and Vascular Center Director, Florida

Chairman of CardiologyMedical Director of Heart Failure, Cardiac Transplantation, and Mechanical Circulatory

SupportCleveland Clinic Florida

Weston, FL

Put Another Way:Put Another Way:

Is this the right time, with the right device, with the right

adverse event profile to move forward with REVIVE IT in a less

ill population of patients?

Relevant Financial Relationship Disclosure Statement

Equipoise with REVIVE IT

Andrew Boyle, MDI will not discuss off label use and/or investigational use of

drugs/devices

The following relevant financial relationships exist related to my role in this session:

Thoratec: Medical Advisory Board and Honoraria

Actuarial Survival vs REMATCHActuarial Survival vs REMATCH

Months

0 6 12 18 24

Per

cen

t S

urv

ival

0

10

20

30

40

50

60

70

80

90

100

CF LVAD

68%

58%55%

PF LVAD 24%

OMM REMATCH 8%

LVAD REMATCH: 23%

25%

52%

Rose E et al. NEJM 2001; 345:1435-43

Slaughter M et al. NEJM 2009; 361: 1-11.

WISL INTERMACS CategoriesWISL INTERMACS Categories

WISL INTERMACS CategoriesWISL INTERMACS Categories

Patient DemographicsPatient Demographics

Group 1: INTERMACS 1: crash and burnGroup 2: INTERMACS 2 and 3: hospitalized and inotrope-dependentGroup 3: INTERMACS 4 – 7: poor functional capacity

Survival to D/C Based on INTERMACSSurvival to D/C Based on INTERMACS

Group 3 vs Group 1: p = 0.02 Group 3 vs Group 2: p = 0.59

Group 2 vs Group 1: p < 0.009

Boyle A, et al. JHLT 2011; 30:402-407.

Lengths of Stay Based on INTERMACSLengths of Stay Based on INTERMACS

Group 1: INTERMACS 1: crash and burnGroup 2: INTERMACS 2 and 3: hospitalized and inotrope-dependentGroup 3: INTERMACS 4 – 7: poor functional capacity

Group 3 vs Group 1: p < 0.001

Group 3 vs Group 2: p < 0.001

Group 2 vs Group 1: p = 0.62

Boyle A, et al. JHLT 2011; 30:402-407.

0

20

40

60

80

100S

urv

iva

l (%

)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Months post-LVAD

Group 1 Group 2 Group 3

Overall SurvivalActuarial Survival on MCSActuarial Survival on MCS

Group 3 vs 1: p = 0.011Group 3 vs 2: p = 0.065Group 2 vs 1: p = 0.18

Boyle A, et al. JHLT 2011; 30:402-407.

60

70

80

90

100

0 60 120 180 240 300 360

Days Post Implant

% S

urv

ival

Event: Death (censored at transplant or recovery)

ITT Population

Heartware BTT Secondary Outcome: SurvivalHeartware BTT Secondary Outcome: Survival

Days Post Implant

Treatment Control

30 98.6% 96.6%

90 95.6% 93.6%

180 93.9% 90.2%

360 90.6% 85.7%

p = .39

HVAD

Control

Presented at AHA 2010 by K. Aaronson et al.

Have We Truly Shifted to a Have We Truly Shifted to a Less Sick Population?Less Sick Population?

The “LVAD Triad” for Successful The “LVAD Triad” for Successful Widespread AdoptionWidespread Adoption

Adverse Events with Adverse Events with Continuous Flow VADsContinuous Flow VADs

Kirklin J et al. J Heart Lung Transpl 2013; 32: 141 – 156.

Heartware Adverse Event ProfileHeartware Adverse Event Profile

Presented by Maltais S et al at ISHLT 2014.

Starling RC et al. N Engl J Med 2014;370:33-40.

Overall Occurrence of Confirmed Pump Thrombosis Overall Occurrence of Confirmed Pump Thrombosis at 3 Months after HM II Implantationat 3 Months after HM II Implantation

Occurrence and Incidence of Confirmed Pump Thrombosis Occurrence and Incidence of Confirmed Pump Thrombosis Stratified According to Implantation Date.Stratified According to Implantation Date.

Starling RC et al. N Engl J Med 2014;370:33-40.

LVAD Pump ThrombosisLVAD Pump Thrombosis

ROADMAP: Thoratec Initiated Post-marketing StudyROADMAP: Thoratec Initiated Post-marketing StudyREVIVE-IT: Thoratec Supported NHLBI Trial REVIVE-IT: Thoratec Supported NHLBI Trial

Title Acronym Objective Status

Risk Assessment and Comparative Effectiveness Of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients

ROADMAP Compare the effectiveness of HM II versus optimal medical management (OMM) in ambulatory non-inotrope dependent NYHA Class IIIB / IV patients

Enrolled 200/200 pts (@ 37 sites)

Randomized Evaluation of LVAD Intervention Before Inotropic Therapy

REVIVE-IT Compare the effectiveness of HeartMate II versus OMM in NYHA Class III patients with illness not severe enough to qualify for transplant or permanent LVAD therapy based on current guidelines

Enrolled 0/100 pts (randomized study)0/2500 pts (screening registry)

0/14 sites

1 1 2 2 3 3

ROADMAP and REVIVE-ITROADMAP and REVIVE-ITComplementary Studies Exploring HeartMate II in Earlier-Stage HFComplementary Studies Exploring HeartMate II in Earlier-Stage HF

4 4 5 5 6 6 7 7INTERMACS

Profiles

CMS Coverage: Class IVCMS Coverage: Class IV

FDA Approval: Class IIIB / IVFDA Approval: Class IIIB / IV

NYHA Class III

Class IIIB

Class IV (Ambulatory

)

Class IV(On

Inotropes)

Currently Not Approved Limited Adoption Growing Acceptance

And How Representative are And How Representative are These Patients Anyways?These Patients Anyways?

• Anticipating 2500 screening failures in the registry to find 100 eligible patients for the study

• How meaningful is that to my clinical practice?

Who Are the Patients Who Would Who Are the Patients Who Would Consent to Such a Study?Consent to Such a Study?

• Have to agree to be randomized to a VAD

• Therefore will be a selected population of patients who are already interested in a VAD

• Being randomized to OMM arm is not a benign event for these patients: remember patients assigned to the XVE arm of the HM II DT trial?

ConclusionsConclusions• We should be moving to a less sick population

which is the ambulatory Class IV patient• Data will be needed to convince MD’s to refer for

MCS in IM 4 and 5 patients let alone IM 6 and 7• The devices currently commercially available do

not have a favorable adverse event profile that would justify moving to a Class III population

• We will not get a DO OVER. If this is done poorly MCS will forever be banished to the inotrope dependent patient. We better do it right the first time.