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

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

Nov 11, 2022 389 likes •663 views

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

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SLIDE 1

NECTAR-HF

(NEuroCardiac TherApy foR Heart Failure)

6 month results

Faiez Zannad, M.D., Ph.D. Inserm, University of Lorraine, France

  • n behalf of the NECTAR-HF Investigators
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SLIDE 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

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SLIDE 3

Autonomic Modulation Therapy

Vagal Stimulation Spinal Stimulation Baroreceptor Stimulation Renal Denervation

Add vagal parasympathetic stimulation Reduce sympathetic stimulation

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SLIDE 4

4

Vagal Stimulation in Canine HF

0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 Baseline Pre 1 mo. 2 mo. 3 mo.

End Diastolic Area

Normal HF-ShamVST HF- VST

NT-proBNP (fmols/ml) 100 200 300 400 500

AMT Control

NT-proBNP

Sabbah H, J. Am. Coll. Cardiol. 2010;55;A16.E153

Normal HF-ShamVST HF- VST

SERCA-2a (du) 20 40 60 80 100 120 140

Normal HF-ShamVST HF- VST

TNF-alpha (du) 20 40 60 80

Normal HF-ShamVST HF- VST

Active Caspace-3 (du) 20 40 60 80

Calcium handling Apoptotic signaling Inflammation

Normal HF - Sham HF - VNS

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SLIDE 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)

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SLIDE 6

Enrollment Criteria

Inclusion

  • NYHA II-III
  • Ejection fraction < 35%
  • LVEDD > 5.5cm
  • Optimal treatment for at least 30

days prior to enrollment

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
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SLIDE 7

Implant and Stimulation Protocol

  • 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

VNS Implanted System

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SLIDE 8

NECTAR-HF Study Flowchart

Enrollment: NYHA Class II-III; EF≤ 35%; Optimal Therapy NECTAR-HF System Implant

~2 Weeks Recovery

Follow-up: 9M, 12M, 15M and 18M Baseline Evaluation and Randomization Follow-up: 3M and 6M 3x Therapy Titration Visits (including sham)* Therapy ON for All Patients Post-6M FU

*6 month window begins after last titration

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SLIDE 9

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

96 Eligible Patients, Implanted 95 Randomized

1 Death

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SLIDE 10

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

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SLIDE 11

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

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SLIDE 12

Stimulation Settings

LT: 0.8 ± 0.5 Range: 0.3-2.7mA Current: 1.3 ± 0.7 Range: 0.3-3.5mA

  • 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.

10 20 30 Number of Patients

VNS Current Setting

0,00 0,20 0,40 0,60 0,80 1,00 1,20 1,40 1,60

Baseline T1 T2 T3 3 Months

Current (mA)

Therapy Group Therapy Group Larygneal Threshold Sham Group Laryngeal Threshold

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SLIDE 13

Therapy (N = 63) Control (N = 32)

Events Patients % Events Patients %

Death and/or HF Hospitalization 11 7

11.1%

11 5

15.6%

Death 1 1

1.6%

2 2

6.3%

HF Hospitalization 10 7

11.1%

9 5

15.6%

Cardiovascular - Non-HF 9 7

11.1%

7 5

15.6%

Non-cardiovascular 8 8

12.7%

12 11

34.4%

Pulmonary

0.0%

3 3

9.4%

Genitourinary 1 1

1.6%

2 2

6.3%

Other Non-cardiovascular 7 7

11.1%

7 7

21.9%

Investigational System-Related 9 9

14.3%

4 4

12.5%

6 Month Safety Results

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SLIDE 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
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SLIDE 15

4,9 4,9 5,2 5,1

1 2 3 4 5 6 7

Baseline 6 Months Baseline 6 Months Therapy Control LVESD (cm)

Primary Endpoint—LVESD

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SLIDE 16

Secondary Endpoints

218 207 235 221

50 100 150 200 250 300

Baseline 6 Months Baseline 6 Months Therapy Control

LVEDV (ml) 154 142 164 152

50 100 150 200 250

Baseline 6 Months Baseline 6 Months Therapy Control

LVESV (ml)

30,5 32,7 30,8 32,1

10 20 30 40

Baseline 6 Months Baseline 6 Months Therapy Control LVEF (%)

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SLIDE 17

Secondary Endpoints

15,6 15,8 15,2 14,7

5 10 15 20 25

Baseline 6 Months Baseline 6 Months Therapy Control

Peak VO2 (ml/kg/min) 879 930 882 839

500 1000 1500 2000

Baseline 6 Months Baseline 6 Months Therapy Control

NT-proBNP (pg/ml)

¥ Median

¥

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SLIDE 18

Secondary Endpoints

44,4 35,8 42,8 41,8

10 20 30 40 50 60 70

Baseline 6 Months Baseline 6 Months Therapy Control

MLHFQ

* p<0.05 ∆ compared to control

36,3 41,2 37,7 38,4

10 20 30 40 50 60

Baseline 6 Months Baseline 6 Months Therapy Control

SF-36 (physical) 41,2 43,8 40,7 41,1

10 20 30 40 50 60

Baseline 6 Months Baseline 6 Months Therapy Control

SF-36 (mental)

62,1 0,2 44,8 10,3

10 20 30 40 50 60 70

Improvement Worsened Improvement Worsened Therapy 6 month change Control 6 month change

% of patients that changed NYHA

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SLIDE 19
  • 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

Blinding

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SLIDE 20

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

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SLIDE 21

Conclusions

  • Although robust pre-clinical data showed the benefit
  • f 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
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SLIDE 22

Oversight committees

Steering Committee

  • Faiez Zannad (Chairman)
  • Josep Brugada
  • Christian Butter
  • Gaetano M. De Ferrari
  • Helmut Klein
  • Kenneth M. Stein
  • Anton Tuinenburg
  • David Jay Wright

Clinical Events Committee

  • Daniel Gras
  • Luigi Tavazzi
  • Henk C.E. van Lambalgen

Data Safety Monitoring Committee

  • Henry J. Dargie (Chair)
  • Poul Erik Bloch Thomsen
  • Erland Erdmann
  • 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
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SLIDE 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
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SLIDE 24
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SLIDE 25
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SLIDE 26

Comparison of VNS Therapeutic Approaches

Parameter NECTAR-HF INOVATE-HF ANTHEM-HF Current (mA) Mean: 1.3 ± 0.8 (range 0.3-3.5) Unknown Unknown Frequency (Hz) 20 1-2Hz (inter-pulse interval 4-20Hz) 10 Duty Cycle (%) 17 ~21 17.5 ON / OFF (sec) 10 / 50 ~2-10 / 10-30 14 / 66 Pulses per minute 200 < 100 105 Cardiac Lead NO YES (RV) NO ECG Synch NO YES (timed to ECG at a 70- 325ms delay from R-wave) NO Afferent block NO YES (Quasi-Trapezoidal waveform; requires >4mA) NO Electrode Bipolar helical cuff Bipolar, multipolar "split- cylinder" cuff Bipolar helical cuff