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)
Detect localactivation
Apply electric signal during absolute refractory period
Delay
Duratio
n
Amplitude
CCM
MuscleForce
Optimizer III™ System
FIX-HF-5 Trial
• Multi-center, unblinded, randomized, parallel- controlled 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
12 MonthsCCM 5 hr/day
12 MonthsMedical Control
Device Implantation
2 week Run-In
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 non-inferiority 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 V-slope 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
12Wkn=204
Informed Consentn=774
345 Withdrew orIneligible
Randomizedn=428
1 Death
Treatmentn=215
Controln=213
24Wkn=201
50Wkn=189
8 W/D1 Death
3 W/D
6 W/D6 Deaths
NotImplanted
n=7 SuccessfulImplantn=203
FailedImplant
n=2
12Wkn=2
24Wkn=2
50Wkn=2
5 W/D
12Wkn=199
24Wkn=195
50Wkn=189
2 W/D4 Deaths
1 W/D3 Deaths
3 W/D3 Deaths
12Wkn=2
24Wkn=2
50Wkn=2
Death Prior to Implant
n=3
Primary Efficacy
Primary Safety
FIX-HF-5: Baseline CharacteristicsControl (n=213) Treatment (n=215)
Mean (SD) or n (%) Mean (SD) or n (%)Age (yrs) 58.55 (12.23) 58.09 (12.79) 0.51091Male 151 (70.9%) 158 (73.5%) 0.59012Ethnicity 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) 0.16321BMI (kg/m2) 30.95 (6.53) 30.44 (7.04) 0.21791Resting HR (bpm) 73.74 (12.19) 73.98 (13.13) 0.96811SBP (mmHg) 115.61 (17.61) 116.65 (19.48) 0.86951CHF Etiology Ischemic 142 (66.7%) 139 (64.7%) 0.64653 Idiopathic 48 (22.5%) 58 (27.0%) Other 23 (10.8%) 18 (8.3%)NYHA Class I 0 (0%) 0 (0%) 0.17203 Class II 1 (0.47%) 0 (0%) Class III 183 (85.92%) 196 (91.16%) Class IV 29 (13.62%) 19 (8.84%)
Variable P-value
FIX-HF-5: Baseline CharacteristicsContinued
Control (n=213) Treatment (n=215)Mean (SD) or n (%) Mean (SD) or n (%)
QRS Duration (ms) 101.51 (12.81) 101.63 (15.30) 0.59684PVCs/24hr (Holter) 1365.1 (2000.9) 1323.3 (1930.6) 0.51131LVEF (%) 26.09 (6.54) 25.74 (6.60) 0.56411LVEDD (mm) 63.01 (8.56) 62.41 (9.22) 0.77151MLWHFQ 57.38 (22.62) 60.49 (23.00) 0.110916MW (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
P-value
CPX (core lab)
Variable
FIX-HF-5: Baseline Medications*
Medication
Control n/N (%)
Optimizer n/N (%) P-Value
ACE inhibitor (ACEi) 148/213 (69.48) 153/215 (71.16) 0.7512 Angiotensin receptor blocker (ARB) 51/213 (23.94) 52/215 (24.19) 1.0000 ACEi or ARB 195/213 (91.55) 195/215 (90.70) 0.8654 Beta Blocker 198/213 (92.96) 202/215 (93.95) 0.7005 Loop Diuretic 194/213 (91.08) 198/215 (92.09) 0.7307 Second Diuretic 12/210 (5.71) 19/212 (8.96) 0.2629 Aldosterone Inhibitor 102/213 (47.89) 95/215 (44.19) 0.4973 Hydralazine 15/213 (7.04) 12/215 (5.58) 0.5574 Nitrates 75/213 (35.21) 73/215 (33.95) 0.8391 Calcium Channel Blocker 9/213 (4.23) 18/215 (8.37) 0.1103 Anti -arrhythmic 28/213 (13.15) 37/215 (17.21) 0.2816
*95% of all subjects also had an implantable cardioverter defibrillator
Primary Safety EndpointAll-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 EndpointAnaerobic 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 EndpointAnaerobic Threshold Comparison of Mean Change
p=ns
Control Treatment Difference
-0.3
-0.2
-0.1
0.0
0.1
Ana
erob
ic T
hres
hold
(ml/k
g/m
in)
Secondary Efficacy EndpointPeak VO2 Comparison of Mean Change
Treatment Difference
-0.75
-0.50
-0.25
0.00
0.25
0.50
0.75
Pe
ak V
O2
(ml/k
g/m
in)
Control
p=0.024
Secondary Efficacy EndpointQuality of Life Comparison of Mean Change
Control Treatment Difference
-20
-15
-10
-5
0
M
LWH
FQ
p<0.0001
Other Efficacy EndpointChange in NYHA Functional Class
Control Treatment Difference0
10
20
30
40
50
NYH
A
( % P
atie
nts
with
≥ 1
Po
int R
educ
tion )
p=0.0026
Other Efficacy Endpoint6-Minute Hall Walk Distance Comparison of
Mean Change
Control Treatment Difference0
10
20
30Si
x M
inut
e W
alk
(m)
p=0.108
SUBGROUP ANALYSES*
N∆VAT
(ml/kg/min) pEF<25 205 -0.59 0.09EF≥25 223 0.53 0.15NYHA III 380 0.13 0.55NYHA IV 48 -1.21 0.10NYHA III + EF≥25 200 0.69 0.04NYHA IV + EF<25 25 -1.17 0.19
*Hypothesis Generating
Subgroup Analysis: Baseline EF ≥ 25 and NYHA III
Responders AnalysisParameter
Control(n=84)
Treatment(n=101)
Treatment-Control P*
VAT (ml/kg/min) 4/69(5.8%) 17/83(20.5%) 14.7% 0.0073VAT (ml/kg/min) (ITT) 9/97 (9.4%) 23/109 (21.5%) 12.1 0.023Peak VO2 (ml/kg/min) 3/76(3.95%) 18/94(19.15%) 15.2% 0.002MLWHFQ 35/84(41.7%) 60/101(59.4%) 17.7% 0.0119NYHA Class 19/82(23.2%) 43/97(44.3%) 21.1% 0.00236MW (meters) 20/79 (25.3) 36/97 (37.1) 11.8% 0.065ITT, intention to treat population*P values by one-sided Fisher's exact test
Subgroup Analysis: Baseline EF ≥ 25 and NYHA III
Comparison of Changes in Mean Values
ParameterControl(n=84)
Treatment(n=101)
Treatment-Control P*
VAT ml/kg/min) -0.54±1.83 0.10±2.36 0.64 0.024Peak VO2 -0.97±2.31 0.34±3.11 1.31 0.001MLWHFQ -6.0±21.9 -16.8±20.2 -10.8 0.0003NYHA Class -0.17±0.64 -0.46±0.61 -0.29 0.00116MW 0.8 (82.6) 21.5 (77.5) 20.7 0.0445
*P values by one-sided equal varance Student's t-test
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 InvestigatorsSuresh Neelagaru, Amarillo, TX Seth Worley, Lancaster, PAAndrew Merliss, Lincoln, NE Roy John, Burlington, MAStanislav Weiner, Tyler, TX David Smull, Winston-Salem, NCJose Joglar, Dallas, TX Raffaele Corbisiero, Trenton, NJNirav Raval, Atlanta, GA Steven Greenberg, Roslyn, NYKoonlawee Nadamanee, Inglewood, CA Mari Rosa Costanzo, Naperville, ILMasood Akhtar, Milwaukee, WI Thomas Mattioni, Scottsdale, AZKent Volosin, Philadelphia, PA Steven Hao, Larkspur, CAFreddy Abi-Samra, New Orleans, LA Mark Wathen, Nashville, TNMarc Wish, Fairfax, VA David Hayes, Rochester, MNImran Niazi, Milwaukee, WI Andrew Cohen, Aurora, COGervasio Lamas, Miami, FL Bengt Herweg, Tampa, FLJavier Sanchez, Austin, TX Harold Goldberg, Spokane, WAEli Gang, Beverly Hills, CA Jill Kalman, New York, NYDavis Baran, Newark, NJ Gregory Jones, Kingsport, TNRandy Lieberman, Detroit, MI Nancy Sweitzer, Madison, WIAlan Bank, St. Paul, MN Mark Wood, Richmond, VAJeffrey Goldberger, Chicago, IL Jonathan Steinberg, New York, NYAllan Murphy, Newport, VA Jose Tallaj, Birmingham, ALJonathan Langberg, Atlanta, GA Alan Heywood, Bellevue, WACharles Love, Columbus, OH Barbara Czerska, Detroit, MIFrank McGrew III, Germantown, TN Gregory Buser, Larkspur, CAHue-The Shih, Houston, TX Steven Klein, Greensboro, NC