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 on behalf of the NECTAR-HF Investigators
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
Autonomic Modulation Therapy Reduce sympathetic stimulation Add vagal parasympathetic stimulation Vagal Spinal Baroreceptor Renal Stimulation Stimulation Stimulation Denervation
Vagal Stimulation in Canine HF NT-proBNP End Diastolic Area 1.30 500 Normal NT-proBNP (fmols/ml) 1.20 1.10 400 Control HF - Sham 1.00 HF - VNS 0.90 300 AMT 0.80 200 0.70 0.60 100 0.50 0 Baseline Pre 1 mo. 2 mo. 3 mo. Normal HF-ShamVST HF- VST Calcium handling Apoptotic signaling Inflammation 80 140 80 Active Caspace-3 (du) 120 TNF-alpha (du) SERCA-2a (du) 60 100 60 80 40 40 60 40 20 20 20 0 0 0 Normal HF-ShamVST HF- VST Normal HF-ShamVST HF- VST Normal HF-ShamVST HF- VST Sabbah H, J. Am. Coll. Cardiol. 2010;55;A16.E153 4
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)
Enrollment Criteria Inclusion Key Exclusion • • CRT for less than 1 year, or QRS NYHA II-III greater than 130ms and no CRT • Ejection fraction < 35% • Permanent/persistent AF • LVEDD > 5.5cm • Type I diabetes • Optimal treatment for at least 30 • Type II diabetes > 5 years days prior to enrollment • 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
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 VNS Cuff • Pulse Width = 300 µs • Duty Cycle = 10s ON / 50s OFF • Current: highest tolerable (up to 4mA)
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
96 Eligible Patients, Implanted 1 Death 95 Randomized 63 ON therapy 32 OFF therapy Lost Paired Data (n=4) Lost Paired Data (n=4) Deceased (n=1) Deceased (n=2) Safety FU Only (n=2) Safety FU Only (n=1) Lost to FU (n=1) No Echo Data (n=1) 59 Therapy 28 Control Patients with Patients with paired data sets paired data sets Modified intention to treat analysis
Baseline Characteristics Therapy (N=63) Control (N=32) Gender Male [N (%)] 56 (89%) 26 (81%) Age 59.8 + 12.2 59.3 + 10.1 Body Mass Index 28.6 + 5.9* 31.2 + 5.1 NYHA II/III 7/51 7/22 ICD/CRT-D/No device 51/5/7 22/4/6 Resting Heart Rate (bpm) 68.2 + 13.2 71.3 + 12.9 Blood pressure (mmHg) Systolic 118 + 17 115 + 16 Diastolic 73 + 10 73 + 13 *p<0.05
Baseline Characteristics Therapy (N=63) Control (N=32) Clinical History Ischemic heart failure [N (%)] 44 (70) 20 (63) Hypertension [N (%)] 29 (46) 21 (66) Renal Disease [N (%)] 12 (19) 9 (28) Heart failure hospitalization past 6 mo. [N (%)] 8 (13) 4 (13) Previous myocardial infarction [N (%)] 42 (67) 19 (59) Non-insulin dependent diabetes [N (%)] 14 (22) 9 (28) Sleep Apnoea [N (%)] 9 (14) 3 (9) Cardiovascular medications B-blockers [N (%)] 59 (94) 30 (94) Angiotensin converting enzyme inhibitor [N (%)] 51 (81) 24 (75) Angiotensin receptor blocker [N (%)] 17 (27) 7 (22) Mineralocorticoid receptor antagonist [N (%)] 43 (68) 23 (72) Loop Diuretics [N (%)] 54 (86)* 32 (100) Statin [N (%)] 50 (79)* 19 (59) *p<0.05 compared to control
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. 1,60 VNS Current Setting 1,40 30 Number of Patients 1,20 Current (mA) 20 1,00 10 0,80 0,60 0 0,40 0,20 0,00 Baseline T1 T2 T3 3 Months Therapy Group LT: 0.8 ± 0.5 Range: 0.3-2.7mA Therapy Group Larygneal Current: 1.3 ± 0.7 Range: 0.3-3.5mA Threshold Sham Group Laryngeal Threshold
6 Month Safety Results Therapy (N = 63) Control (N = 32) Events Patients % Events Patients % Death and/or HF Hospitalization 11 7 11 5 11.1% 15.6% Death 1 1 2 2 1.6% 6.3% HF Hospitalization 10 7 9 5 11.1% 15.6% Cardiovascular - Non-HF 9 7 7 5 11.1% 15.6% Non-cardiovascular 8 8 12.7% 12 11 34.4% Pulmonary 0 0 0.0% 3 3 9.4% Genitourinary 1 1 1.6% 2 2 6.3% Other Non-cardiovascular 7 7 7 7 11.1% 21.9% Investigational System-Related 9 9 4 4 14.3% 12.5%
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
Primary Endpoint — LVESD 7 5,2 5,1 4,9 4,9 6 5 LVESD (cm) 4 3 2 1 0 Baseline 6 Months Baseline 6 Months Therapy Control
Secondary Endpoints 218 207 235 221 154 142 300 250 164 152 250 200 LVEDV (ml) LVESV (ml) 200 150 150 100 100 50 50 0 0 Baseline 6 Months Baseline 6 Months Baseline 6 Months Baseline 6 Months Therapy Control Therapy Control 32,7 30,5 32,1 30,8 40 LVEF (%) 30 20 10 0 Baseline 6 Months Baseline 6 Months Therapy Control
Secondary Endpoints 2000 882 25 930 ¥ 879 15,8 15,6 14,7 839 20 NT-proBNP (pg/ml) 15,2 1500 Peak VO2 (ml/kg/min) 15 1000 10 500 5 0 0 Baseline 6 Months Baseline 6 Months Baseline 6 Months Baseline 6 Months Therapy Control Therapy Control ¥ Median
Secondary Endpoints 62,1 70 41,2 43,8 40,7 41,1 60 % of patients that 60 changed NYHA SF-36 (mental) 50 44,8 50 40 40 30 30 20 20 10,3 10 10 0,2 0 0 Improvement Worsened Improvement Worsened Baseline 6 Months Baseline 6 Months Therapy 6 month change Control 6 month change Therapy Control 60 38,4 44,4 42,8 41,8 70 37,7 41,2 36,3 35,8 50 SF-36 (physical) 60 40 50 MLHFQ 40 30 30 20 20 10 10 0 0 Baseline 6 Months Baseline 6 Months Baseline 6 Months Baseline 6 Months Therapy Control Therapy Control * p<0.05 ∆ compared to control
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
Heart Rate and Heart Rate Variability 24-hour Holter Therapy (N=55) Control (N=28) Baseline 6 months Baseline 6 months Heart Rate Mean HR (bpm + SD) 70.1 + 10.4 70.7 + 10.0 69.2 + 9.7 73.0 + 10.7 Minimum HR (bpm + SD) 54.6 + 9.2 53.2 + 8.0 53.4 + 8.6 54.6 + 10.0 Maximum HR (bpm + SD) 102.4 + 15.7 107.4 + 19.2 101.0 + 15.9 109.0 + 17.9 Heart Rate Variability SDNN (ms + SD) 146 + 48.3 129.7 + 52.1 146.3 + 47.2 132.1 + 41.3 SDANN (ms + SD)* 29.1 + 2.1 29.4 + 2.3 29.6 + 2.5 28.8 + 2.2 RMSSD (ms + SD)* 78.8 + 41.8 97.0 + 40.2 94.5 + 31.5 89.9 + 37.0 * p<0.05 ∆ compared to control
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
Oversight committees Steering Committee Data Safety Monitoring Committee • • Faiez Zannad (Chairman) Henry J. Dargie (Chair) • • Josep Brugada Poul Erik Bloch Thomsen • • Christian Butter Erland Erdmann • • Gaetano M. De Ferrari Ian Ford • • Helmut Klein Andreas Schulze-Bonhage • Kenneth M. Stein • Anton Tuinenburg Core Laboratories • David Jay Wright • Echocardiography: Scott D. Solomon, Boston • Exercise Testing: Peter Prubaker, Clinical Events Committee Wake Forest University • Holter: Rod Salo, Salo Scientific • Daniel Gras • Biomarkers: Fischer Bioservices, UK • Luigi Tavazzi • Henk C.E. van Lambalgen
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