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Does Cardiac Resynchronization Therapy Prevent Disease Progression in NYHA

Class I and II Heart Failure Patients?

24 month results from the European cohort

of the REsynchronization reVErses Remodeling in

Systolic left vEntricular dysfunction trial

Jean-Claude Daubert, Rennes, France

On Behalf of the REVERSEREVERSE

Investigators and Coordinators

Purpose and DesignPurpose and Design

To evaluate the long-term benefits of CRT in the European patients included in REVERSEREVERSE and prospectively followed for 24 months

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

Inclusion CriteriaInclusion Criteria

NYHA Class II or I (previously symptomatic)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

End PointsEnd Points

Primary: HF Clinical Composite ResponsePrimary: 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: Prospectively Powered Secondary: LV End Systolic Volume Index LV End Systolic Volume Index (LVESVi(LVESVi)) comparing CRT OFF vs. CRT ON subjects LVESVi assessed by core labs (1 in Europe, 1 in U.S)

Study SchematicStudy Schematic

Baseline Assessment

Successful CRT Implant

Randomized 1:2

CRT OFF(OMT ± ICD)

CRT ON(OMT ± ICD)

1

2

12 Months:North American

randomization complete (CRT

recommended in all pts)

24 Months: European randomization

complete (CRT recommended

in all pts)

684 Enrolled (2004-2006)

642 Implant Attempts

610 Patients Randomized610 Patients RandomizedU.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%)U.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%)

CRT OFF 191 Patients CRT ON 419 Patients

-21 unsuccessful implants

621 Successful CRT Implants(97%)

-42 ineligible or withdrew

-11 exits after successful implant

Enrollment and RandomizationEnrollment and Randomization

C Linde et Al, JACC 2008; 52: 1834-1843

40%

54%

39%

30%

16%21%

0%

CRT OFF

CRT ON

Pre-Specified Analysis Proportion Worsened

Worsened

Unchanged

Improved

P=0.10

Main Study: 12-MonthMain Study: 12-Month

Clinical Composite Response Powered Secondary ObjectiveClinical Composite Response Powered Secondary Objective

40%

60%

100%

80%

20%

C Linde et Al, JACC 2008; 52: 1834-1843

2)

70

75

80

85

90

95

100

105

110

115

Baseline 12 Months

LVE

SV

i (m

l/m2 )

CRT OFF = -1.3

CRT ON = -18.4

12 Month Change in LVESVi

P<0.0001

12 Month Change in LVESVi

70

80

90

100

110

LV

ES

Vi

(ml/

m2)

Baseline 12 Months

CRT OFF=-1.3

CRT ON=-18.4

P<0.0001

684 Enrolled (2004-2006)

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

CRT OFF 191 Patients CRT ON 419 Patients

621 Successful CRT Implants(97%)

- 42 ineligible or withdrew

- 11 exits after successful implant

Enrollment and RandomizationEnrollment and Randomization

262 patients (Europe) followed for 24 months262 patients (Europe) followed for 24 months

CRT OFF 82 Patients CRT ON 180 Patients

US/Can N=348US/Can N=348 Europe N=262Europe N=262 P-valueP-value

Age (mean) yrsAge (mean) yrs 63.4 ± 11.363.4 ± 11.3 61.3 ± 10.461.3 ± 10.4 0.020.02

IschemicIschemic 63% 63% 44%44% <0.0001<0.0001

NYHA IINYHA II 82%82% 83%83% 0.750.75

ICDICD 95%95% 68%68% <0.0001<0.0001

EFEF 26.3 ± 7.226.3 ± 7.2 27.1 ± 6.827.1 ± 6.8 0.160.16

LVEDD (mm)LVEDD (mm) 65.5 ± 8.465.5 ± 8.4 68.8 ± 9.268.8 ± 9.2 <0.0001<0.0001

QRS (ms)QRS (ms) 151 ± 21151 ± 21 156 ± 23156 ± 23 0.0080.008

Beta-blockersBeta-blockers 96%96% 94%94% 0.130.13

ACE-i/ ARBACE-i/ ARB 95%95% >99%>99% 0.00030.0003

6-min. Walk (m)6-min. Walk (m) 363 ± 134363 ± 134 439 ± 103439 ± 103 <0.0001<0.0001

Baseline CharacteristicsBaseline Characteristics

Primary End Point: Primary End Point: Clinical Composite Response at 24-monthClinical Composite Response at 24-month

% worsened% worsened

19%

34%

27%

0%

20%

40%

60%

80%

100%

CRT OFF CRT ON

Worsened

Improved/Unchanged

Per

cent

age

of P

atie

nts

P=0.01

66%

34%

81%

54%/27%

66%

29%/37%

19%

CRT ON

Entire distribution analysis of worsened, unchanged and improved: P=0.0006

CRT OFF

Primary End Point Primary End Point Clinical Composite Response Clinical Composite Response

% worsened over time% worsened over time

34%

29%

22%20%

19%

11%

7%

15%

0%

10%

20%

30%

40%

0 6 12 18 24

Months Randomized

Per

cent

age

of P

atie

nts

Wor

sene

d

P=0.01

CRT ON

CRT OFF

P=0.005

P=0.02

P=0.01

Worsening attributed to death or HF hospitalization in 68% of worsened patients in the CRT OFF group

Powered Secondary End Point: LVESViPowered Secondary End Point: LVESVi

91,688,8

94,5

76,8

73,6

69,2 69,7

92,5

93,9

96,6

60

70

80

90

100

110

0 6 12 18 24

Months Since Randomization

LVE

SV

i (m

l/m2 )CRT OFF

CRT ONP<0.0001

P-value compares 24-month changes.

Other Remodeling ParametersOther Remodeling Parameters

129128

124

132

112

108

103 103

129

133

90

100

110

120

130

140

150

0 6 12 18 24

Months

LVE

DV

i (m

l/m2 )

CRT OFF

CRT ON

P<0.0001

29.0 29.129.5

29.9

32.733.4

34.9 34.8

27.8

28.1

25

30

35

40

0 6 12 18 24

Months

LV

EF

(%

)CRT OFF

CRT ON

P<0.0001

P-values compare 24-month changes.

LVEDVi (ml/m2) LVEF (%)

Other Secondary Endpoints: Functional ParamatersOther Secondary Endpoints: Functional Paramaters

10

15

20

25

30

0 6 12 18 24

Months

CRT OFF

CRT ON

P=0.62

Minnesota Living with HF Score

400

425

450

475

500

0 6 12 18 24

Months

CRT OFF

CRT ON

P=0.57

Six-minute Hall Walk (m)

0%

20%

40%

60%

80%

100%

0 6 12 18 24

Months

NYHA Class

% NYHA Class I

% Class I or II

p=0.17

P-values compares 24-month changes. P-value compares 24-month NYHA.

0%

5%

10%

15%

20%

25%

30%

0 6 12 18 24

Months Since Randomization

Per

cent

age

Hos

pita

lized

for

HF

or

Die

d

CRT ON

CRT OFF

24.0%

11.7%

HR (95%CI): 0.38 (0.20-0.73)P=0.003

Number at Risk CRT OFF 82 79 76 70 39 CRT ON 180 176 173 168 77

Time to First HF Hospitalization or DeathTime to First HF Hospitalization or Death

The 24 month results of the European cohort of REVERSE show that CRT in asymptomatic and mildly symptomatic

HF patients on optimal medical therapy:

• Improves clinical outcome • Improves ventricular structure and function

CRT thus modifies disease progression in NYHA Class I-II HF patients

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

AcknowledgmentsAcknowledgmentsSteering CommitteeSteering Committee

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

Echo Core LabsEcho Core Labs S. Ghio, M.G. St. John Sutton

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.