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Multicenter Randomized Controlled Trial of Cardiac Contractility Modulation in Patients with Advanced Heart Failure William T. Abraham MD, Koonlawee Nademanee.

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Presentation on theme: "Multicenter Randomized Controlled Trial of Cardiac Contractility Modulation in Patients with Advanced Heart Failure William T. Abraham MD, Koonlawee Nademanee."— Presentation transcript:

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) Detect local activation Apply electric signal during absolute refractory period Delay Duration Amplitude

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 12 Months CCM 5 hr/day 12 Months Medical Control Device Implantation 2 week Run-In 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 VO 2 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 12Wk n=204 Informed Consent n= Withdrew or Ineligible Randomized n=428 1 Death Treatment n=215 Control n=213 24Wk n=201 50Wk n=189 8 W/D 1 Death 3 W/D 6 W/D 6 Deaths Not Implanted n=7 Successful Implant n=203 Failed Implant n=2 12Wk n=2 24Wk n=2 50Wk n=2 5 W/D 12Wk n=199 24Wk n=195 50Wk n=189 2 W/D 4 Deaths 1 W/D 3 Deaths 3 W/D 3 Deaths 12Wk n=2 24Wk n=2 50Wk n=2 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) Male151 (70.9%)158 (73.5%) Ethnicity White142 (66.7%)154 (71.6%) Black45 (21.1%)36 (16.7%) Other26 (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 Ischemic142 (66.7%)139 (64.7%) Idiopathic48 (22.5%)58 (27.0%) Other23 (10.8%)18 (8.3%) NYHA Class I0 (0%) Class II1 (0.47%)0 (0%) Class III183 (85.92%)196 (91.16%) Class IV29 (13.62%)19 (8.84%) VariableP-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) MLWHFQ57.38 (22.62)60.49 (23.00) MW (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 RER1.13 (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* Medication Control n/N (%) Optimizer n/N (%) P-Value ACE inhibitor(ACEi) 148/213 (69.48) 153/215 (71.16) Angiotensin receptor blocker (ARB)51/213 (23.94) 52/215 (24.19) ACEi or ARB 195/213 (91.55) 195/215 (90.70) Beta Blocker 198/213 (92.96) 202/215 (93.95) Loop Diuretic 194/213 (91.08) 198/215 (92.09) Second Diuretic12/210 (5.71) 19/212 (8.96) Aldosterone Inhibitor 102/213 (47.89) 95/215 (44.19) Hydralazine 15/213 (7.04) 12/215 (5.58) Nitrates 75/213 (35.21) 73/215 (33.95) Calcium Channel Blocker 9/213 (4.23) 18/215 (8.37) Anti-arrhythmic 28/213 (13.15) 37/215 (17.21) *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 ControlTreatmentDifference Anaerobic Threshold (ml/kg/min)

16 Secondary Efficacy Endpoint Peak VO 2 Comparison of Mean Change TreatmentDifference Peak VO 2 (ml/kg/min) Control p=0.024

17 Secondary Efficacy Endpoint Quality of Life Comparison of Mean Change ControlTreatmentDifference MLWHFQ p<0.0001

18 Other Efficacy Endpoint Change in NYHA Functional Class ControlTreatmentDifference NYHA ( % Patients with 1 Point Reduction ) p=0.0026

19 Other Efficacy Endpoint 6-Minute Hall Walk Distance Comparison of Mean Change ControlTreatmentDifference Six Minute Walk (m) p=0.108

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 (EF25, 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 OConner

26 Study Principal Investigators Suresh Neelagaru, Amarillo, TXSeth Worley, Lancaster, PA Andrew Merliss, Lincoln, NERoy John, Burlington, MA Stanislav Weiner, Tyler, TXDavid Smull, Winston-Salem, NC Jose Joglar, Dallas, TXRaffaele Corbisiero, Trenton, NJ Nirav Raval, Atlanta, GASteven Greenberg, Roslyn, NY Koonlawee Nadamanee, Inglewood, CAMari Rosa Costanzo, Naperville, IL Masood Akhtar, Milwaukee, WIThomas Mattioni, Scottsdale, AZ Kent Volosin, Philadelphia, PASteven Hao, Larkspur, CA Freddy Abi-Samra, New Orleans, LAMark Wathen, Nashville, TN Marc Wish, Fairfax, VADavid Hayes, Rochester, MN Imran Niazi, Milwaukee, WIAndrew Cohen, Aurora, CO Gervasio Lamas, Miami, FLBengt Herweg, Tampa, FL Javier Sanchez, Austin, TXHarold Goldberg, Spokane, WA Eli Gang, Beverly Hills, CAJill Kalman, New York, NY Davis Baran, Newark, NJGregory Jones, Kingsport, TN Randy Lieberman, Detroit, MINancy Sweitzer, Madison, WI Alan Bank, St. Paul, MNMark Wood, Richmond, VA Jeffrey Goldberger, Chicago, ILJonathan Steinberg, New York, NY Allan Murphy, Newport, VAJose Tallaj, Birmingham, AL Jonathan Langberg, Atlanta, GAAlan Heywood, Bellevue, WA Charles Love, Columbus, OHBarbara Czerska, Detroit, MI Frank McGrew III, Germantown, TNGregory Buser, Larkspur, CA Hue-The Shih, Houston, TXSteven Klein, Greensboro, NC

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