1. 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

2. 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

3. The Concept Behind Cardiac Contractility Modulation (CCM)
Muscle
Force
Duration
Delay
Amplitude
Apply electric signal during absolute refractory period
Detect local
activation

4. Optimizer III™ System

5. 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

6. Eligibility Determination
FIX-HF-5: Study Schematic
Informed Consent
Baseline Testing
Eligibility Determination
Group 1
Group 2
Device Implantation
12 Months
Medical Control
2 week Run-In
12 Months
CCM 5 hr/day
Study visits at: Baseline, 12Wk, 24Wk and 50Wk

7. 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

8. 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

9. Primary Efficacy Primary Safety
12Wk
n=204
Informed Consent
n=774
345 Withdrew or
Ineligible
Randomized
n=428
1 Death
Treatment
n=215
Control
n=213
24Wk
n=201
50Wk
n=189
8 W/D
3 W/D
6 W/D
6 Deaths
Not
Implanted
n=7
Successful
Implant
n=203
Failed
n=2
5 W/D
n=199
n=195
2 W/D
4 Deaths
1 W/D
3 Deaths
Death Prior to Implant
n=3
Primary Efficacy
Primary Safety

10. FIX-HF-5: Baseline Characteristics
Control (n=213)
Treatment (n=215)
Mean (SD) or n (%)
Age (yrs)
58.55 (12.23)
58.09 (12.79)
Male
151 (70.9%)
158 (73.5%)
Ethnicity
White
142 (66.7%)
154 (71.6%)
Black
45 (21.1%)
36 (16.7%)
Other
26 (12.2%)
25 (11.7%)
Weight (kg)
93.30 (22.16)
91.17 (23.27)
BMI (kg/m2)
30.95 (6.53)
30.44 (7.04)
Resting HR (bpm)
73.74 (12.19)
73.98 (13.13)
SBP (mmHg)
(17.61)
(19.48)
CHF Etiology
Ischemic
139 (64.7%)
Idiopathic
48 (22.5%)
58 (27.0%)
23 (10.8%)
18 (8.3%)
NYHA
Class I
0 (0%)
Class II
1 (0.47%)
Class III
183 (85.92%)
196 (91.16%)
Class IV
29 (13.62%)
19 (8.84%)
 Variable
P-value

11. FIX-HF-5: Baseline Characteristics
Continued
Control (n=213)
Treatment (n=215)
Mean (SD) or n (%)
QRS Duration (ms)
(12.81)
(15.30)
PVCs/24hr (Holter)
(2000.9)
(1930.6)
LVEF (%)
26.09 (6.54)
25.74 (6.60)
LVEDD (mm)
63.01 (8.56)
62.41 (9.22)
MLWHFQ
57.38 (22.62)
60.49 (23.00)
6MW (meters)
(92.44)
(82.10)
Duration (minutes)
11.50 (3.46)
11.34 (3.20)
Peak SBP (mmHg)
138.8 (24.6)
139.7 (27.1)
Peak HR (bpm)
121.2 (20.5)
122.1 (20.2)
Peak RER
1.13 (0.09)
1.14 (0.10)
Peak VO2 (ml/kg/min)
14.71 (2.92)
14.74 (3.06)
AT (ml/kg/min)
10.97 (2.18)
10.95 (2.24)
P-value
CPX (core lab)
 Variable

12. FIX-HF-5: Baseline Medications*
Control
Optimizer
Medication
n/N (%)
n/N (%) P -
Value
ACE inhibitor (
ACEi)
148/213 (69. 48 )
153/215 (71. 16 )
0.7512
Angiotensin receptor bl
ocker (ARB) 5 1
/213 (2 3 . 94 )
52/215 (24. 19 )
1.0000
ACEi or ARB 1 9 5
/213 (
91. 55 ) 1 95
/215 (
90.7 ) .
8654
Beta Blocker
198/213 (9 2 . 96 )
202/215 (9 3 . 95 )
0.7005
Loop Diuretic 19 4
/213 (
91. 08 )
198/215 (92. 09 ) 0.
7307
Second Diuretic
12/210 (5.71)
19/212 (8.96)
.2629
Aldosterone Inhibitor
102/213 (47. 8 9)
95/215 (44. 19 )
0.4973
Hydralazine
15/213 (7.04)
12/215 (5.58)
0.5574
Nitrates 7 5
/213 (3 5 . 2 1 )
73/215 (33.95) 0.
8391
Calcium Channel Blocker
9/213 (4.23) 1 8
/215 ( 8 . 37 )
0.1
103
Anti -
arrhythmic
28/213 (13.15)
37/
215 (17.21)
0.2816
*95% of all subjects also had an implantable cardioverter defibrillator

13. 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)

14. 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

15. Primary Efficacy Endpoint Anaerobic Threshold Comparison of Mean Change
p=ns
Control
Treatment
Difference
-0.3
-0.2
-0.1
0.0
0.1 D
Anaerobic Threshold
(ml/kg/min)

16. Secondary Efficacy Endpoint Peak VO2 Comparison of Mean Change
Treatment
Difference
-0.75
-0.50
-0.25
0.00
0.25
0.50
0.75 D
Peak VO 2
(ml/kg/min)
Control
p=0.024

17. Secondary Efficacy Endpoint
Quality of Life Comparison of Mean Change
Control
Treatment
Difference
-20
-15
-10 -5 D
MLWHFQ
p<0.0001

18. Other Efficacy Endpoint
Change in NYHA Functional Class
Control
Treatment
Difference 10 20 30 40 50
NYHA (
% Patients with ≥ 1
Point Reduction )
p=0.0026

19. Other Efficacy Endpoint
6-Minute Hall Walk Distance Comparison of Mean Change
Control
Treatment
Difference 10 20 30
Six Minute Walk (m)
p=0.108

20. *Hypothesis Generating
SUBGROUP ANALYSES*
*Hypothesis Generating

21. Baseline EF ≥ 25 and NYHA III
Subgroup Analysis:
Baseline EF ≥ 25 and NYHA III
Responders Analysis

22. Baseline EF ≥ 25 and NYHA III Comparison of Changes in Mean Values
Subgroup Analysis:
Baseline EF ≥ 25 and NYHA III
Comparison of Changes in Mean Values

23. 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)

24. 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 AT
MLWHFQ

25. 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

26. Study Principal Investigators
Suresh Neelagaru, Amarillo, TX
Seth Worley, Lancaster, PA
Andrew Merliss, Lincoln, NE
Roy John, Burlington, MA
Stanislav Weiner, Tyler, TX
David Smull, Winston-Salem, NC
Jose Joglar, Dallas, TX
Raffaele Corbisiero, Trenton, NJ
Nirav Raval, Atlanta, GA
Steven Greenberg, Roslyn, NY
Koonlawee Nadamanee, Inglewood, CA
Mari Rosa Costanzo, Naperville, IL
Masood Akhtar, Milwaukee, WI
Thomas Mattioni, Scottsdale, AZ
Kent Volosin, Philadelphia, PA
Steven Hao, Larkspur, CA
Freddy Abi-Samra, New Orleans, LA
Mark Wathen, Nashville, TN
Marc Wish, Fairfax, VA
David Hayes, Rochester, MN
Imran Niazi, Milwaukee, WI
Andrew Cohen, Aurora, CO
Gervasio Lamas, Miami, FL
Bengt Herweg, Tampa, FL
Javier Sanchez, Austin, TX
Harold Goldberg, Spokane, WA
Eli Gang, Beverly Hills, CA
Jill Kalman, New York, NY
Davis Baran, Newark, NJ
Gregory Jones, Kingsport, TN
Randy Lieberman, Detroit, MI
Nancy Sweitzer, Madison, WI
Alan Bank, St. Paul, MN
Mark Wood, Richmond, VA
Jeffrey Goldberger, Chicago, IL
Jonathan Steinberg, New York, NY
Allan Murphy, Newport, VA
Jose Tallaj, Birmingham, AL
Jonathan Langberg, Atlanta, GA
Alan Heywood, Bellevue, WA
Charles Love, Columbus, OH
Barbara Czerska, Detroit, MI
Frank McGrew III, Germantown, TN
Gregory Buser, Larkspur, CA
Hue-The Shih, Houston, TX
Steven Klein, Greensboro, NC