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Multicenter Randomized Controlled Trial of Cardiac Contractility Modulation in Patients with Advanced Heart Failure

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,

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Multicenter Randomized Controlled Trial of Cardiac Contractility Modulation in Patients with Advanced Heart Failure

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  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. CCM Muscle Force The Concept Behind Cardiac Contractility Modulation (CCM) 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. 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. 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 Failed Implant n=2 Successful Implant n=203 8 W/D 1 Death 5 W/D 2 W/D 4 Deaths 12Wk n=204 12Wk n=2 12Wk n=2 12Wk n=199 Primary Efficacy 3 W/D 1 W/D 3 Deaths 24Wk n=201 24Wk n=2 24Wk n=2 24Wk n=195 Primary Safety 6 W/D 6 Deaths 3 W/D 3 Deaths 50Wk n=189 50Wk n=2 50Wk n=189 50Wk n=2

  10. Control (n=213) Treatment (n=215)  Variable Mean (SD) or n (%) 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 Ethnicity 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 CHF 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%) FIX-HF-5: Baseline Characteristics

  11. Control (n=213) Treatment (n=215)  Variable Mean (SD) or n (%) 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 CPX (core lab) 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 FIX-HF-5: Baseline Characteristics Continued

  12. FIX-HF-5: Baseline Medications* Control Optimizer P - Value n/N (%) n/N (%) Medication 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 0 ) 0 . 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) 0 .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 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

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

  16. 0.75 p=0.024 0.50 0.25 2 Control Peak VO (ml/kg/min) 0.00 Treatment Difference -0.25 D -0.50 -0.75 Secondary Efficacy EndpointPeak VO2Comparison of Mean Change

  17. Control Treatment Difference 0 -5 MLWHFQ -10 p<0.0001 D -15 -20 Secondary Efficacy Endpoint Quality of Life Comparison of Mean Change

  18. 50 40 ) 30 % Patients with ≥ 1 Point Reduction NYHA 20 p=0.0026 10 ( 0 Control Treatment Difference Other Efficacy Endpoint Change in NYHA Functional Class

  19. 30 20 Six Minute Walk (m) p=0.108 10 0 Control Treatment Difference Other Efficacy Endpoint 6-Minute Hall Walk Distance Comparison of Mean Change

  20. SUBGROUP ANALYSES* *Hypothesis Generating

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

  22. 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 • Peak VO2 • AT • MLWHFQ • NYHA

  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. 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 Study Principal Investigators

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