REsynchronization reVErses Remodeling inSystolic left vEntricular dysfunction:

Results of the REVERSE Trial

Cecilia Linde, Stockholm, SwedenWilliam T. Abraham, Columbus, U.S

Michael R. Gold, Charleston, U.S.Jean-Claude Daubert, Rennes, France

On Behalf of the REVERSEInvestigators and Coordinators

AcknowledgmentsAcknowledgmentsSteering CommitteeSteering Committee

W. T. Abraham, J-C. Daubert (study initiator), C. Linde (coordinating clinical Investigator), M. Gold

Echo Core LabsEcho Core LabsGhio, S, St. John Sutton, MG

Adverse Events Advisory CommitteeAdverse Events Advisory CommitteeD. Böcker, J. P. Boehmer, J. G. F. Cleland, M. Gold, J. T. Heywood, A. Miller (chair)

Data Monitoring CommitteeData Monitoring CommitteeJ. Aranda, J. Cohn (chair), P. Grambsch; M. Komajda

InvestigatorsInvestigatorsAustria: H. Mayr, A. Teubl; Belgium: R. Willems; Canada: C. Simpson; Czech Republic: J. Lukl; Denmark: H. Eiskjær, C. Hassager, M. Møller, T. Vesterlund; France: E. Aliot, P. Chevalier, J-C. Daubert, J-M. Davy, P. Djiane, H. Le Marec; Germany: G. Groth, G. Klein, T. Lawo, C. Reithmann; Hungary: T. Forster, T. Szili-Török; Ireland: R. Sheahan; Italy: S. Lombroso, M. Lunati, L. Padeletti, M. Santini; Netherlands: B. Dijkman; Norway: S. Færestrand, F. T. Gjestvang; Spain: I. Fernandez Lozano, R. Muñoz Aguilera, A. Quesada Dorador; Sweden: C. Linde, F. Maru, K. Säfström; United Kingdom: G. Goode; United States: U. Birgersdotter-Green, J. Boehmer, E. Chung, S. Compton, J. Dinerman, D. Feldman, R. Fishel, G. J. Gallinghouse, M. Gold, S. Hankins, J. Herre, M. Hess, E. Horn, S. Hsu, S. Hustead, S. Jennison, E. Johnson, W. B. Johnson, G. Jones, R. Malik, A. Merliss, S. Mester, S. Moore, N. Nasir, F. Pelosi, Jr., D. Renlund, K. Rist, R. Sangrigoli, R. Silverman, D. Smull, K. Stein, L. Stevenson, J. Stone, N. Sweitzer, D. Venesy, L. Zaman.

SponsorSponsorMedtronic Inc.

Cecilia Linde, MD, PhD

The following relationships exist related to this presentation:The following relationships exist related to this presentation:

Presenter Disclosure InformationPresenter Disclosure Information

• Consulting Fees, Medtronic and St. Jude, moderate level• Research Grants, Medtronic and the Sweden Heart and Lung Foundation, significant level

• To determine the effects of CRT with or without an ICD on disease progression over 12 months in patients with asymptomatic and mildly symptomatic heart failure and ventricular dysynchrony

• Randomized, double-blind, parallel-controlled clinical trial

Purpose and DesignPurpose and Design

• NYHA Class II or I (previously symptomatic)

• QRS 120 ms; LVEF 40%; LVEDD 55 mm

• Optimal medical therapy (OMT)

• Without permanent cardiac pacing

• With or without an ICD indication

Inclusion CriteriaInclusion Criteria

Baseline Assessment

Successful CRT Implant

Randomized 1:2

CRT OFF(OMT ± ICD)

CRT ON(OMT ± ICD)

U.S., Canada: at 12 Months, all patients recommended CRT ONEurope: at 24 Months, all patients recommended CRT ON

1

2

12 Months

Study SchematicStudy Schematic

• Primary: HF Clinical Composite Response, comparing the proportion of patients worsened in CRT OFF vs. CRT ON groups

• Composite includes: all-cause mortality, HF hospitalizations, crossover due to worsening HF, NYHA class, and the patient global assessment assessed in double blind manner

• Prospectively Powered Secondary: Left Ventricular End Systolic Volume Index (LVESVi) comparing CRT OFF vs. CRT ON subjects

• LVESVi is assessed by two core labs (1 in Europe, 1 in U.S)

End PointsEnd Points

684 Enrolled (2004-2006)

642 Implant Attempts

610 Patients RandomizedU.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%)

CRT OFF 191 Patients CRT ON 419 Patients

- 594/598 completed 12 month follow-up - 12 deaths (2%) - 0 lost to follow-up, 0 exits

-21 unsuccessful implant

621 Successful CRT Implants(97%)

-42 ineligible or withdrew

-11 exits after successful implant

Enrollment and RandomizationEnrollment and Randomization

CRT OFFN=191

CRT ONN=419 P-value

Age (mean) yrs 61.8 ± 11.6 62.9 ± 10.6 0.26

NYHA II 83% 82% 0.82

ICD 85% 82% 0.41

Beta-blockers 94% 96% 0.32

ACE-i/ ARB 97% 96% 0.63

Diuretics 77% 81% 0.33

EF 26.4 ± 7.0 26.8 ± 7.0 0.50

LVEDD (mm) 70 ± 9 69 ± 9 0.34

QRS (ms) 154.4 ± 24.1 152.8 ± 21.0 0.41

Ischemic 51% 56% 0.22

Baseline Characteristics of Baseline Characteristics of Randomized Cohort (n=610)Randomized Cohort (n=610)

40%54%

39%30%

16%21%

0%

20%

40%

60%

80%

100%

CRT OFF

CRT ON

Improved / Unchanged

Pre-Specified AnalysisProportion Worsened

Conventional AnalysisDistribution Worsened/Unchanged

/Improved

Worsened

Unchanged

Improved

P=0.004

Primary End Point: Primary End Point: Clinical Composite ResponseClinical Composite Response

79% 84%

16%21%

0%

20%

40%

60%

80%

100%

CRT OFF CRT ON

P=0.10

Worsened

70

75

80

85

90

95

100

105

110

115

Baseline 12 Months

LVES

Vi (m

l/m2 )

CRT OFF = -1.3

CRT ON = -18.4

P<0.0001

n=487

Powered Secondary End Point: LVESViPowered Secondary End Point: LVESVi (ml/m(ml/m22))

12 MonthsBaseline

LVEDVi (ml/m(ml/m22))P<0.0001

LVEF (%)P<0.0001

12 MonthsBaseline

CRT OFF ∆ = 0.6

CRT ON ∆ = 3.8

CRT OFF ∆ = -1.4

CRT ON∆ = -20.5

n=487

20

22

24

26

28

30

32

34

90

100

110

120

130

140

150

Other Remodeling ParametersOther Remodeling Parameters

360

370

380

390

400

410

420

430

440

Baseline 12 Mo

CRT OFF=18.7

CRT ON=12.7

15

17

19

21

23

25

27

29

31

33

35

Baseline 12 Mo

CRT OFF=-6.7

CRT ON=-8.4

MN LWHFP=0.26

6-Min Walk TestP=0.26

NYHAP=0.06

Other Secondary EndpointsOther Secondary Endpoints

32%

65%

57%

13% 11%

22%

0%

20%

40%

60%

80%

100%

CRT OFF CRT ON

Improved

Same

Worse

0%

5%

10%

15%

0 3 6 9 12% o

f Pat

ient

s H

ospi

taliz

ed fo

r HF

Number at Risk CRT OFF 191 187 181 176 119 CRT ON 419 415 411 409 251

P=0.03 Hazard Ratio=0.47

CRT OFF

CRT ON

Months Since Randomization

Time to First HF HospitalizationTime to First HF Hospitalization

• 97% implant success rate• 9.5 % LV-lead related complications

• 66 in 59 / 621 successfully implanted patients• LV lead dislodgements, diaphragmatic

stimulation, subclavian vein thrombosis, etc.

SafetySafety

REVERSE is the first large, randomized, double-blind study to show that CRT in asymptomatic and mildly symptomatic heart failure patients on optimal medical therapy:

• Reverses LV remodeling• Reduces the risk of heart failure hospitalization• May improve clinical outcome as assessed by the

clinical composite response measure

Note: FDA has not yet reviewed the clinical data to determine whether or not CRT systems are safe and effective in this patient population.

ConclusionConclusion

Backup Slides

0% 5% 10% 15% 20% 25%

Death

HF Hospitalization

Crossover

Pt. Assessment & NYHA

NYHA Only

Pt. Assessment Only

----------------

Pt. Assessment & NYHA

NYHA Only

Pt. Assessment Only

CRT OFF (n=191) CRT ON (n=419)

*Note: Data in table is listed in hierarchical order (subjects are included only in one sub-category)

Worsened

Improved

Clinical Composite Response DetailsClinical Composite Response Details

Complication Number of Events

LV lead dislodgement 42

RV lead dislodgement 15

Inappropriate device irritation of tissue 14

RA lead dislodgement 10

Failure to capture 6

Implant site hematoma 5

Atrial fibrillation 5

Most Common Procedure Most Common Procedure Related Complications Related Complications

Missing LVESVi CRT OFF(n=191)

CRT ON(n=419)

Total (n=610)

No baseline, full echo not doneNo baseline, full echo not done 1 (1%)1 (1%) 2 (<1%)2 (<1%) 3 (<1%)3 (<1%)

No baseline, LVESV on echo not readableNo baseline, LVESV on echo not readable 11 (6%)11 (6%) 31 (7%)31 (7%) 42 (7%)42 (7%) Died before 12 monthsDied before 12 months 2 (1%)2 (1%) 9 (2%)9 (2%) 11 (2%)11 (2%)

Missed 12-month follow-up visitMissed 12-month follow-up visit 0 (0%)0 (0%) 3 (1%)3 (1%) 3 (<1%)3 (<1%)

No 12-month, full echo not doneNo 12-month, full echo not done 1 (1%)1 (1%) ------ 1 (<1%)1 (<1%)

No 12-month, limited echo not doneNo 12-month, limited echo not done ------ 10 (2%)10 (2%) 10 (2%)10 (2%)

No 12-month, LVESV on echo not readableNo 12-month, LVESV on echo not readable 13 (7%)13 (7%) 40 (10%)40 (10%) 53 (9%)53 (9%)

TotalTotal 28 (15%)28 (15%) 95 (23%)95 (23%) 123 (20%)123 (20%)

Note: Subjects are included in the first sub-category, reading down

Reasons for Missing Paired LVESVi dataReasons for Missing Paired LVESVi data

Causes of Death Causes of Death

GroupDays Post implant Type Cause of Death

ON 6 SCD Medical cause: unknown

ON 24 Other Gastrointestinal bleed

ON 100 HF Progressive heart failure

ON 107 SCD Tachy-arrhythmia (ventricular fibrillation)

ON 110 Other Medical cause: unknown

ON 196SCD & HF Brady-arrhythmic event (asystole)

ON 300 HF Progressive heart failure, alcoholic cardiomyopathy

ON 343 Other Respiratory failure due to pulmonary fibrosis

OFF 254 Other Renal cancer

OFF 287 HF Progressive heart failure

OFF 344 SCD Electromechanical dissociation (preliminary)

LVESViLVESVi (ml/m(ml/m22) ) by NYHA Class by NYHA Class

70

75

80

85

90

95

100

105

110

115

Baseline 12 Months

LVES

Vi (m

l/m2 )

NYHA I, CRT OFF, =-2.1

NYHA II, CRT OFF, =-1.1

NYHA I, CRT ON, =-15.4

NYHA II, CRT ON, =-19.1