Transcript Title Here - Clinical Trial Results

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
Acknowledgments
Steering Committee
W. T. Abraham, J-C. Daubert (study initiator), C. Linde (coordinating clinical Investigator), M. Gold
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.
Presenter Disclosure Information
Cecilia Linde, MD, PhD
The following relationships exist related to this presentation:
• Consulting Fees, Medtronic and St. Jude, moderate level
• Research Grants, Medtronic and the Sweden Heart and Lung Foundation,
significant level
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
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
Study Schematic
Baseline Assessment
Successful
CRT Implant
CRT OFF
1
(OMT ± ICD)
12 Months
Randomized 1:2
2
CRT ON
(OMT ± ICD)
U.S., Canada: at 12 Months, all patients recommended CRT ON
Europe:
at 24 Months, all patients recommended CRT ON
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)
Enrollment and Randomization
684 Enrolled (2004-2006)
-42 ineligible or withdrew
642 Implant Attempts
-21 unsuccessful implant
621 Successful CRT Implants
(97%)
-11 exits after successful implant
610 Patients Randomized
U.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
Baseline Characteristics of
Randomized Cohort (n=610)
CRT OFF
N=191
CRT ON
N=419
P-value
61.8 ± 11.6
62.9 ± 10.6
0.26
NYHA II
ICD
83%
82%
0.82
85%
82%
0.41
Beta-blockers
94%
96%
0.32
ACE-i/ ARB
97%
96%
0.63
Diuretics
77%
81%
0.33
26.4 ± 7.0
26.8 ± 7.0
0.50
70 ± 9
69 ± 9
0.34
QRS (ms)
154.4 ± 24.1
152.8 ± 21.0
0.41
Ischemic
51%
56%
0.22
Age (mean) yrs
EF
LVEDD (mm)
Primary End Point:
Clinical Composite Response
Pre-Specified Analysis
Conventional Analysis
Proportion Worsened
Distribution Worsened/Unchanged
/Improved
100%
100%
21%
Worsened
16%
80%
21%
Worsened
16%
Unchanged
30%
80%
60%
60%
39%
P=0.004
P=0.10
40%
20%
84%
79%
Improved /
Unchanged
0%
40%
20%
40%
Improved
54%
0%
CRT OFF
CRT ON
CRT OFF
CRT ON
Powered Secondary End Point: LVESVi
P<0.0001
115
110
LVESVi (ml/m2)
105
100
CRT OFF
D = -1.3
95
90
85
CRT ON
D = -18.4
80
75
70
Baseline
12 Months
n=487
(ml/m2)
Other Remodeling Parameters
LVEDVi (ml/m2)
P<0.0001
150
140
LVEF (%)
P<0.0001
34
CRT OFF
∆ = -1.4
32
CRT ON
∆ = 3.8
30
130
28
120
CRT ON
∆ = -20.5
26
110
CRT OFF
∆ = 0.6
24
100
22
90
20
Baseline
12 Months
Baseline
n=487
12 Months
Other Secondary Endpoints
35
MN LWHF
P=0.26
NYHA
P=0.06
6-Min Walk Test
P=0.26
440
100%
13%
33
Worse
11%
Same
57%
430
31
29
80%
CRT OFF
D=-6.7
420
410
27
400
23
19
60%
65%
25
21
CRT ON
D=12.7
40%
390
CRT ON
D =-8.4
380
20%
17
370
15
360
Baseline
CRT OFF
D =18.7
12 Mo
Improved 32%
22%
0%
Baseline
12 Mo
CRT OFF
CRT ON
% of Patients Hospitalized for HF
Time to First HF Hospitalization
15%
P=0.03
Hazard Ratio=0.47
10%
CRT OFF
5%
CRT ON
0%
0
3
6
9
12
Months Since Randomization
Number at Risk
CRT OFF
CRT ON
191
419
187
415
181
411
176
409
119
251
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.
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.