Transcript Multicenter Randomized Controlled Trial of Cardiac

Multicenter Randomized Controlled Trial
of Cardiac Contractility Modulation in
Patients with Advanced Heart Failure
William T. Abraham MD, Koonlawee Nademanee MD,
Kent Volosin MD, Steve Krueger MD, Suresh Neelagaru MD,
Nirav Raval MD, Owen Obel MD, Stanley Weiner MD, Mark Wish MD,
Peter Carson MD, Kenneth Ellenbogen MD, Robert Bourge MD,
Mike Parides MD, Richard P Chiacchierini PhD, Rochelle Goldsmith PhD,
Sidney Goldstein MD and Alan Kadish MD on Behalf of the FIX-HF-5
Investigators and Coordinators*
*Dr. Abraham and other members of this group have received consulting fees
and/or research grants from Impulse Dynamics
Cardiac Contractility Modulation (CCM)
Background
• Preclinical and prior clinical studies have
demonstrated that CCM:
•
•
•
•
Increases cardiac contractility
Reduces myocardial work
Produces LV reverse remodeling
Induces molecular changes (in genes,
proteins and phosphorylation) indicative of
improved calcium handling and contractile
function
The Concept Behind Cardiac Contractility
Modulation (CCM)
CCM
Amplitude
Muscle
Force
Apply electric signal
during absolute refractory
period
Detect local
activation
Optimizer III™ System
FIX-HF-5 Trial
• Multi-center, unblinded, randomized, parallelcontrolled clinical trial
• 50 participating centers (all US)
• 6-month efficacy endpoint
• 1-year safety endpoint
• First US randomization occurred on April 8,
2005 and the last on June 12, 2007
• Last follow-up completed June 2008
FIX-HF-5: Study Schematic
Informed Consent
Baseline Testing
Eligibility Determination
Group 1
Group 2
Device Implantation
2 week Run-In
12 Months
Medical
Control
12 Months
CCM 5 hr/day
Study visits at: Baseline, 12Wk, 24Wk and 50Wk
FIX-HF-5: Study Endpoints
• Primary Safety Endpoint: Composite of all-cause
mortality and all-cause hospitalization assessed by noninferiority analysis (active versus control group with
12.5% allowable delta)
• Primary Efficacy Endpoint: Anaerobic Threshold (AT)
assessed by responders analysis (≥20% increase in AT
= responder)
• Secondary Efficacy Endpoints:
• Peak VO2
• Minnesota Living with Heart Failure Questionnaire
• Other Efficacy Endpoints
• NYHA Functional Class Ranking
• 6-Minute Hall Walk Distance
• Subgroup Analyses
• Ischemic vs nonischemic
• EF above or below the median
• NYHA Class III vs IV
Metabolic Exercise Testing and Core Lab
• Single core laboratory where a detailed procedure was
followed for objective determination of AT (using the Vslope method) by two independent readers blinded to
treatment group
• On-site training on standardized procedures for
conducting metabolic exercise tests and electronic data
transfer to the core laboratory
• Site revalidation every 6 months
• Rapid feedback on test quality from the core laboratory
(on the day the tests were performed)
• Despite these efforts, it was anticipated that substantial
number of tests would be classified as indeterminate,
either because of poor test quality, inability of subjects to
reach AT, or because of poor subject compliance
Informed Consent
n=774
345 Withdrew or
Ineligible
1 Death
Death Prior to
Implant
n=3
Randomized
n=428
Treatment
n=215
Control
n=213
Not
Implanted
n=7
8 W/D
1 Death
Successful
Implant
n=203
5 W/D
12Wk
n=204
12Wk
n=2
Primary
Efficacy
3 W/D
24Wk
n=201
50Wk
n=189
2 W/D
4 Deaths
12Wk
n=199
50Wk
n=2
12Wk
n=2
1 W/D
3 Deaths
24Wk
n=2
Primary
Safety
6 W/D
6 Deaths
Failed
Implant
n=2
24Wk
n=195
24Wk
n=2
50Wk
n=189
50Wk
n=2
3 W/D
3 Deaths
FIX-HF-5: Baseline Characteristics
Variable
Control (n=213)
Mean (SD) or n (%)
Treatment (n=215)
Mean (SD) or n (%)
P-value
Age (yrs)
58.55 (12.23)
58.09 (12.79)
0.51091
Male
151 (70.9%)
158 (73.5%)
0.59012
White
142 (66.7%)
154 (71.6%)
0.50263
Black
45 (21.1%)
36 (16.7%)
Other
26 (12.2%)
25 (11.7%)
Weight (kg)
93.30 (22.16)
91.17 (23.27)
0.16321
BMI (kg/m2)
30.95 (6.53)
30.44 (7.04)
0.21791
Resting HR (bpm)
73.74 (12.19)
73.98 (13.13)
0.96811
SBP (mmHg)
115.61 (17.61)
116.65 (19.48)
0.86951
Ischemic
142 (66.7%)
139 (64.7%)
0.64653
Idiopathic
48 (22.5%)
58 (27.0%)
Other
23 (10.8%)
18 (8.3%)
Class I
0 (0%)
0 (0%)
Class II
1 (0.47%)
0 (0%)
Class III
183 (85.92%)
196 (91.16%)
Class IV
29 (13.62%)
19 (8.84%)
Ethnicity
CHF Etiology
NYHA
0.17203
FIX-HF-5: Baseline Characteristics
Continued
Control (n=213)
Mean (SD) or n (%)
Treatment (n=215)
Mean (SD) or n (%)
P-value
QRS Duration (ms)
101.51 (12.81)
101.63 (15.30)
0.59684
PVCs/24hr (Holter)
1365.1 (2000.9)
1323.3 (1930.6)
0.51131
LVEF (%)
26.09 (6.54)
25.74 (6.60)
0.56411
LVEDD (mm)
63.01 (8.56)
62.41 (9.22)
0.77151
MLWHFQ
57.38 (22.62)
60.49 (23.00)
0.11091
6MW (meters)
323.99 (92.44)
326.38 (82.10)
0.59711
Duration (minutes)
11.50 (3.46)
11.34 (3.20)
0.48141
Peak SBP (mmHg)
138.8 (24.6)
139.7 (27.1)
0.97141
Peak HR (bpm)
121.2 (20.5)
122.1 (20.2)
0.52231
Peak RER
1.13 (0.09)
1.14 (0.10)
0.51891
Peak VO2 (ml/kg/min)
14.71 (2.92)
14.74 (3.06)
0.85751
AT (ml/kg/min)
10.97 (2.18)
10.95 (2.24)
0.97194
Variable
CPX (core lab)
FIX-HF-5: Baseline Medications*
Medication
ACE inhibitor (ACEi)
Angiotensin receptor blocker (ARB)
ACEi or ARB
Beta Blocker
Loop Diuretic
Second Diuretic
Aldosterone Inhibitor
Hydralazine
Nitrates
Calcium Channel Blocker
Anti -arrhythmic
Control
n/N (%)
Optimizer
n/N (%)
P-Value
148/213 (69.48)
51/213 (23.94)
195/213 (91.55)
198/213 (92.96)
194/213 (91.08)
12/210 (5.71)
102/213 (47.89)
15/213 (7.04)
75/213 (35.21)
9/213 (4.23)
28/213 (13.15)
153/215 (71.16)
52/215 (24.19)
195/215 (90.70)
202/215 (93.95)
198/215 (92.09)
19/212 (8.96)
95/215 (44.19)
12/215 (5.58)
73/215 (33.95)
18/215 (8.37)
37/215 (17.21)
0.7512
1.0000
0.8654
0.7005
0.7307
0.2629
0.4973
0.5574
0.8391
0.1103
0.2816
*95% of all subjects also had an implantable cardioverter defibrillator
Primary Safety Endpoint
All-Cause Mortality Plus All-Cause Hospitalizations
• Control Group:
• 103 events in 213 subjects = 48%
• CCM Group:
• 112 events in 215 subjects = 52%
• Statistical tests confirm that the safety
endpoint was met:
• Blackwelder: p=0.034 (p<0.05=noninferior)
• Log-Rank test: p=0.22 (p>0.05=noninferior)
Primary Efficacy Endpoint
Anaerobic Threshold Responder Analysis
• Completors analysis:
• Control: 18/154 (11.7%)
• Treatment: 28/159 (17.6%)
• Difference: 5.9% (P = 0.093)
• Intention-to-Treat analysis*:
• Control: 28/213 (13.2%)
• Treatment: 38/215 (17.7%)
• Difference: 4.5% (P = 0.314)
*27% missing data requiring imputation per analysis plan
Primary Efficacy Endpoint
Anaerobic Threshold Comparison of Mean Change
D Anaerobic Threshold
(ml/kg/min)
0.1
0.0
-0.1
-0.2
-0.3
Control
Treatment Difference
p=ns
Secondary Efficacy Endpoint
Peak VO2 Comparison of Mean Change
p=0.024
0.75
D Peak VO 2
(ml/kg/min)
0.50
0.25
0.00
-0.25
-0.50
-0.75
Control
Treatment Difference
Secondary Efficacy Endpoint
Quality of Life Comparison of Mean Change
D MLWHFQ
0
Control
Treatment Difference
-5
-10
-15
-20
p<0.0001
Other Efficacy Endpoint
Change in NYHA Functional Class
NYHA
(% Patients with ≥ 1
Point Reduction)
50
40
30
20
p=0.0026
10
0
Control Treatment Difference
Other Efficacy Endpoint
Six Minute Walk (m)
6-Minute Hall Walk Distance Comparison of
Mean Change
30
20
p=0.108
10
0
Control
Treatment Difference
SUBGROUP ANALYSES*
EF<25
EF≥25
NYHA III
NYHA IV
NYHA III + EF≥25
NYHA IV + EF<25
*Hypothesis Generating
N
205
223
380
48
200
25
∆VAT
(ml/kg/min)
-0.59
0.53
0.13
-1.21
0.69
-1.17
p
0.09
0.15
0.55
0.10
0.04
0.19
Subgroup Analysis:
Baseline EF ≥ 25 and NYHA III
Responders Analysis
Control
Parameter
(n=84)
VAT (ml/kg/min)
4/69(5.8%)
VAT (ml/kg/min) (ITT)
9/97 (9.4%)
Peak VO2 (ml/kg/min)
3/76(3.95%)
MLWHFQ
35/84(41.7%)
NYHA Class
19/82(23.2%)
6MW (meters)
20/79 (25.3)
ITT, intention to treat population
*P values by one-sided Fisher's exact test
Treatment
(n=101)
17/83(20.5%)
23/109 (21.5%)
18/94(19.15%)
60/101(59.4%)
43/97(44.3%)
36/97 (37.1)
TreatmentControl
14.7%
12.1
15.2%
17.7%
21.1%
11.8%
P*
0.0073
0.023
0.002
0.0119
0.0023
0.065
Subgroup Analysis:
Baseline EF ≥ 25 and NYHA III
Comparison of Changes in Mean Values
Parameter
VAT ml/kg/min)
Peak VO2
MLWHFQ
NYHA Class
6MW
Control
(n=84)
-0.54±1.83
-0.97±2.31
-6.0±21.9
-0.17±0.64
0.8 (82.6)
Treatment
(n=101)
0.10±2.36
0.34±3.11
-16.8±20.2
-0.46±0.61
21.5 (77.5)
*P values by one-sided equal varance Student's t-test
TreatmentControl
0.64
1.31
-10.8
-0.29
20.7
P*
0.024
0.001
0.0003
0.0011
0.0445
Potential Study Limitations
• Choice of anaerobic threshold as a
primary endpoint
• Missing VAT data despite rigorous
approach to metabolic exercise
testing
• Use of responders analyses
• Un-implanted control group (no
blinding)
FIX-HF-5: Summary
• CCM failed to improve the anaerobic
threshold, pre-specified as the primary
endpoint of the trial
• In the overall population, CCM significantly
improved
• Peak VO2
• Quality of Life (MLWHFQ score)
• NYHA
• In a subgroup comprising ~50% of study
population (EF≥25, NYHA III), CCM
significantly improved
•
•
•
•
Peak VO2
AT
MLWHFQ
NYHA
Study Oversight Committees
• Executive Steering Committee
• William Abraham, Alan Kadish, Kenneth Ellenbogen,
Robert Bourge, Koonlawee Nademanee, Michael
Parides
• Data Safety Monitoring Board
• Sidney Goldstein, Steven Gottlieb, Andrea Natale,
David Callans, David Naftel
• Events Adjudication Committee
• Peter Carson, Inder Anand, Christopher O’Conner
Study Principal Investigators
Suresh Neelagaru, Amarillo, TX
Andrew Merliss, Lincoln, NE
Stanislav Weiner, Tyler, TX
Jose Joglar, Dallas, TX
Nirav Raval, Atlanta, GA
Koonlawee Nadamanee, Inglewood, CA
Masood Akhtar, Milwaukee, WI
Kent Volosin, Philadelphia, PA
Freddy Abi-Samra, New Orleans, LA
Marc Wish, Fairfax, VA
Imran Niazi, Milwaukee, WI
Gervasio Lamas, Miami, FL
Javier Sanchez, Austin, TX
Eli Gang, Beverly Hills, CA
Davis Baran, Newark, NJ
Randy Lieberman, Detroit, MI
Alan Bank, St. Paul, MN
Jeffrey Goldberger, Chicago, IL
Allan Murphy, Newport, VA
Jonathan Langberg, Atlanta, GA
Charles Love, Columbus, OH
Frank McGrew III, Germantown, TN
Hue-The Shih, Houston, TX
Seth Worley, Lancaster, PA
Roy John, Burlington, MA
David Smull, Winston-Salem, NC
Raffaele Corbisiero, Trenton, NJ
Steven Greenberg, Roslyn, NY
Mari Rosa Costanzo, Naperville, IL
Thomas Mattioni, Scottsdale, AZ
Steven Hao, Larkspur, CA
Mark Wathen, Nashville, TN
David Hayes, Rochester, MN
Andrew Cohen, Aurora, CO
Bengt Herweg, Tampa, FL
Harold Goldberg, Spokane, WA
Jill Kalman, New York, NY
Gregory Jones, Kingsport, TN
Nancy Sweitzer, Madison, WI
Mark Wood, Richmond, VA
Jonathan Steinberg, New York, NY
Jose Tallaj, Birmingham, AL
Alan Heywood, Bellevue, WA
Barbara Czerska, Detroit, MI
Gregory Buser, Larkspur, CA
Steven Klein, Greensboro, NC