REsynchronization reVErses Remodeling in

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REsynchronization reVErses Remodeling in Systolic
left vEntricular dysfunction Results of the
REVERSE Trial Cecilia Linde, Stockholm,
Sweden William T. Abraham, Columbus, U.S Michael
R. Gold, Charleston, U.S. Jean-Claude Daubert,
Rennes, France On Behalf of the
REVERSE Investigators and Coordinators
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Acknowledgments

• Steering Committee
• W. T. Abraham, J-C. Daubert (study initiator),
  M. Gold, C. Linde (coordinating clinical
  Investigator)
• Echo Core Labs
• Ghio, S, St. John Sutton, MG
• Adverse Events Advisory Committee
• D. Böcker, J. P. Boehmer, J. G. F. Cleland, M.
  Gold, J. T. Heywood, A. Miller (chair)
• Data Monitoring Committee
• J. Aranda, J. Cohn (chair), P. Grambsch M.
  Komajda
• Investigators
• Austria 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.
• Sponsor
• Medtronic Inc.

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Landscape of CRT Trials in NYHA I, II
2010 MADIT CRT Approx. 33 months, n1820
2010 RAFT Minimum 18 months, n1800
Primary Obj mortality or HF events (i.e. HF hosp
or IV therapy)
2008 REVERSE 12 months, n610
Primary Obj composite (total mortality and HF
hospitalization)
2004 MICD II 6 months, n186
Primary Obj Packers HF Clinical Composite
2003 Contak CD 6 months, n 263
Primary Obj Peak V02
Primary Obj composite (mortality, HF
hospitalization, and VT/VF)
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REVERSE Purpose and Design

• 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

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Inclusion Criteria

• 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

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Study Schematic
Baseline Assessment
Successful CRT Implant
CRT OFF (OMT ICD)
1
12 Months
Randomized 12
CRT ON (OMT ICD)
2
U.S., Canada at 12 Months, all patients
recommended CRT ON Europe remain in
randomization assignment for 24 Months, all
patients recommended CRT ON at 24 months All
Geographies Follow-up 5 years
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End Points

• 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)

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Enrollment and Randomization
684 Enrolled (2004-2006)
-42 ineligible or withdrew
642 Implant Attempts
-21 unsuccessful implants
621 Successful CRT Implants (97)
-11 exits after successful implant
610 Patients Randomized U.S. 343 (56) Europe
262 (43) Canada 5 (lt1)
CRT OFF 191 Patients
CRT ON 419 Patients
- 594/598 completed 12 month follow-up - 12
deaths - 0 lost to follow-up, 0 exits
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Baseline Characteristics (n610)
CRT OFF N191 CRT ON N419 P-value
Age (mean) 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
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Baseline Characteristics (n610)
CRT OFF N191 CRT ON N419 P-value
BMI kg/m2 28.3 29 0.11
Systolic BP mmHg  125 123 0.25
Diastolic BP mmHg 72.2 72.0 0.82
Female 22.0 20.4 0.75
LBBB 76.6 78.0 0.76
1st degree AV block 19.1 20.9 0.59
6-min walk distance (m) 386 403 0.34
MN LWHF QOL score (0-105) 29.1 26.9 0.32
KCCQ QOL score (0-100) 70.8 73.8 0.14
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Primary End Point Clinical Composite Response
Pre-Specified Analysis Proportion Worsened

100
16
21
Worsened
80
60
P0.10
84
40
79
Improved / Unchanged
20
0
CRT OFF
CRT ON
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Primary End Point Clinical Composite Response
Pre-Specified Analysis Proportion Worsened
Conventional Analysis Distribution
Worsened/Unchanged /Improved

100
16
Worsened
21
Worsened
80
Unchanged
60
P0.004
P0.10
84
40
79
Improved / Unchanged
Improved
20
0
CRT OFF
CRT ON
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Clinical Composite Response Details
Clinical Composite Response CRT OFF (n191) CRT ON (n419)
WORSENED 41 (21) 67 (16)
      Death 3 (2) 9 (2)
      Hosp. For worsening HF 14 (7) 12 (3)
      Crossover due to worsening HF 5 (3) 1 (lt1)
      Worsened Patient Global Assessment and NYHA 0 (0) 2 (lt1)
      Worsened NYHA Only 18 (9) 40 (10)
      Worsened Patient Global Assessment Only 1 (1) 3 (1)
IMPROVED 76 (40) 228 (54)
      Improved on Patient Global Assessment and NYHA 11 (6) 69 (16)
      Improved NYHA Only 28 (15) 59 (14)
      Improved Patient Global Assessment Only 37 (19) 100 (24)
UNCHANGED 74 (39) 124 (30)
Note Data in table is listed in hierarchical
order (subjects are included only in one
sub-category)
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Powered Secondary End Point LVESVi (ml/m2)
Plt0.0001
115
110
105
)
100
2
CRT OFF
95
D
-1.3
LVESVi (ml/m
90
85
CRT ON
D
-18.4
80
75
70
Baseline
12 Months
n487
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Other Remodeling Parameters
LVEDVi (ml/m2) Plt0.0001
LVEF () Plt0.0001
150
34
CRT OFF ? -1.4
32
140
CRT ON ? 3.8
30
130
28
120
CRT ON ? -20.5
26
CRT OFF ? 0.6
110
24
100
22
20
90
12 Months
Baseline
12 Months
Baseline
n487
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Time to First HF Hospitalization
of Patients Hospitalized for HF
P0.03
Hazard Ratio0.47
CRT OFF
CRT ON
Months Since Randomization
Number at Risk CRT OFF
191 187 181
176 119 CRT ON
419 415
411 409 251
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Other Secondary End Points QOL, 6MHW
6-Min Walk Test P0.26
MN LWHF P0.26
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Other Secondary End Points NYHA
P0.06
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Safety

• 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.

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Conclusion

• 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.