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NECTAR-HF ( NE uro C ardiac T her A py fo R H eart F ailure) 6 month results

NECTAR-HF ( NE uro C ardiac T her A py fo R H eart F ailure) 6 month results. Faiez Zannad , M.D., Ph.D. Inserm , University of Lorraine, France o n behalf of the NECTAR-HF Investigators. Disclosures.

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NECTAR-HF ( NE uro C ardiac T her A py fo R H eart F ailure) 6 month results

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  1. NECTAR-HF (NEuroCardiac TherApy foRHeart Failure) 6 month results FaiezZannad, M.D., Ph.D. Inserm, University of Lorraine, France on behalf of the NECTAR-HF Investigators

  2. Disclosures Faiez Zannad receives honoraria from Air Liquide, Bayer, Biomérieux, Biotronik, Boston Scientific, CVCRx, Janssen, Novartis, Pfizer, Resmed, Roche Diagnostics, Sanofi, Servier, St Jude, Takeda, speaker fees from Mitsubishi and owns stocks at CVCT and CardioRenal diagnostics

  3. Autonomic Modulation Therapy Reduce sympathetic stimulation Vagal Stimulation Spinal Stimulation Baroreceptor Stimulation Renal Denervation Add vagal parasympathetic stimulation

  4. Vagal Stimulation in Canine HF NT-proBNP End Diastolic Area Normal Control HF - Sham HF - VNS AMT Calcium handling Inflammation Apoptotic signaling Sabbah H, J. Am. Coll. Cardiol. 2010;55;A16.E153

  5. Objective • To evaluate whether right Vagus Nerve Stimulation (VNS) is safe and might attenuate cardiac remodelling in patients with systolic heart failure using a randomised sham controlled trial design (NCT01385176)

  6. Enrollment Criteria Inclusion Key Exclusion CRT for less than 1 year, or QRS greater than 130ms and no CRT Permanent/persistent AF Type I diabetes Type II diabetes > 5 years Heart failure hospitalization in the previous 30 days Initiation of sleep apnea treatment in the previous 180 days MI in the previous 90 days Renal Failure • NYHA II-III • Ejection fraction < 35% • LVEDD > 5.5cm • Optimal treatment for at least 30 days prior to enrollment

  7. Implant and Stimulation Protocol VNS Implanted System • Implant duration • Mean: 85 min • Min: 36 min • Max: 225 min • Implants by surgical specialty • 34 by neurosurgeons • 62 by cardiac or vascular surgeons • Anesthesia • General: 89 • Local/Sedation: 7 • Stimulation protocol • Frequency = 20 Hz • Pulse Width = 300 µs • Duty Cycle = 10s ON / 50s OFF • Current: highest tolerable (up to 4mA) VNS Cuff

  8. NECTAR-HF Study Flowchart Enrollment: NYHA Class II-III; EF≤ 35%; Optimal Therapy NECTAR-HF System Implant ~2 Weeks Recovery Baseline Evaluation and Randomization 3x Therapy Titration Visits (including sham)* Follow-up: 3M and 6M Therapy ON for All Patients Post-6M FU Follow-up: 9M, 12M, 15M and 18M *6 month window begins after last titration

  9. 96 Eligible Patients, Implanted 1 Death 95 Randomized 63 ON therapy 32 OFF therapy Lost Paired Data (n=4) Deceased (n=1) Safety FU Only (n=2) Lost to FU (n=1) Lost Paired Data (n=4) Deceased (n=2) Safety FU Only (n=1) No Echo Data (n=1) 59 Therapy Patients with paired data sets 28 Control Patients with paired data sets Modified intention to treat analysis

  10. Baseline Characteristics *p<0.05

  11. Baseline Characteristics *p<0.05 compared to control

  12. Stimulation Settings • Laryngeal threshold (LT) is the first evidence of vagus nerve capture and was reported subjective by each patient. Usually felt as a tickling sensation in the throat. • Settings above LT are dependent on tolerability; high output can cause pain or coughing, and thus can limit the current settings in some patients. LT: 0.8 ± 0.5 Range: 0.3-2.7mA Current: 1.3 ± 0.7 Range: 0.3-3.5mA

  13. 6 Month Safety Results

  14. 6 Month Safety Results • Infection rate: 7.4% (7 infections) • 3 explant of the VNS system • 4 managed with antibiotics. • One patient needed a pulse generator pocket revision (problems recharging the device) • One lead revision due to inappropriate lead movement. • No interference of the device wih ICDs

  15. Primary Endpoint—LVESD

  16. Secondary Endpoints

  17. Secondary Endpoints ¥ ¥ Median

  18. Secondary Endpoints p = <0.032 p <0.05 p <0.05 * p<0.05 ∆ compared to control

  19. Blinding • Primary echo endpoint was blinded • However, many patients felt the stimulation (slight tickling/vibration in the neck) • At the 6-month follow-up visit, patients were asked to which group they believed they were randomized • Blinding index 0 means blinding was perfect • Blinding index 1 would be completely un-blinded

  20. Heart Rate and Heart Rate Variability 24-hour Holter * p<0.05 ∆ compared to control

  21. Conclusions • Although robust pre-clinical data showed the benefit of VNS, NECTAR-HF, the first VNS randomized sham controlled trial, failed to demonstrate a successful clinical translation of VNS therapy to the primary endpoint of cardiac remodelling. • There were statistically significant improvements seen in the quality of life measures. • There were no significant safety concerns through 6 months (primary safety will be assessed at 18 months). • Additional clinical research may provide additional insights into the effectiveness of VNS for heart failure. • Sham control and checking for blinding are critical

  22. Oversight committees Steering Committee • Faiez Zannad (Chairman) • JosepBrugada • Christian Butter • Gaetano M. De Ferrari • Helmut Klein • Kenneth M. Stein • Anton Tuinenburg • David Jay Wright Clinical Events Committee • Daniel Gras • Luigi Tavazzi • HenkC.E. van Lambalgen Data Safety Monitoring Committee • Henry J. Dargie (Chair) • Poul Erik Bloch Thomsen • ErlandErdmann • Ian Ford • Andreas Schulze-Bonhage Core Laboratories • Echocardiography: Scott D. Solomon, Boston • Exercise Testing: Peter Prubaker, Wake Forest University • Holter: Rod Salo, Salo Scientific • Biomarkers: Fischer Bioservices, UK

  23. Investigators • Jean-Benoit le Polain de Waroux , Brussels, Belgium • Petr Neuzil, Prague, Czech Republic • Salem Kacet, Lille, France • Faiez Zannad, Nancy, France • Christian Butter, Bernau, Germany • Markus Zabel, Goettingen, Germany • Ali Aydin, Hamburg, Germany • Christian Kühne, Leipzig, Germany • Christian Meyer, Düsseldorf, Germany • Antonio D’Onofrio, Napoli, Italy • Gaetano M. De Ferrari, Pavia, Italy • Maurizio Lunati, Milan, Italy • Maria Ángeles Castel, Barcelona, Spain • Ignacio Fernandez Lozano, Madrid, Spain • Juan José Gavira Gómez, Pamplona, Spain • María López Gil, Madrid Spain • Luis Almenar Bonet, Valencia, Spain • Cornelis Botman, Eindhoven, Netherlands • Anton Tuinenburg, Utrech, Netherlands • Angus Nightingale, Bristol , England • Pier Lambiase, London, England • David Wright, Liverpool, England • Prapa Kanagaratnam, London, England • Francis Murgatroy, London, England

  24. Comparison of VNS Therapeutic Approaches

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