NECTAR-HF (NEuroCardiac TherApy foR Heart Failure)

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

VagalStimulation

SpinalStimulation

BaroreceptorStimulation

RenalDenervation

Add vagalparasympathetic

stimulation

Reduce sympathetic stimulation

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-p

roBN

P (fm

ols/

ml)

0

100

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400

500

AMT

Control

NT-proBNP

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

Normal HF-ShamVST HF- VST

SERC

A-2a

(du)

0

20

40

60

80

100

120

140

Normal HF-ShamVST HF- VST

TNF-

alph

a (d

u)

0

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40

60

80

Normal HF-ShamVST HF- VST

Act

ive

Cas

pace

-3 (d

u)

0

20

40

60

80Calcium handling Apoptotic signaling Inflammation

Normal

HF - Sham

HF - VNS

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• 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

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

NECTAR-HF Study FlowchartEnrollment: NYHA Class II-III; EF≤ 35%; Optimal TherapyEnrollment: NYHA Class II-III; EF≤ 35%; Optimal Therapy

NECTAR-HF System ImplantNECTAR-HF System Implant

~2 Weeks Recovery ~2 Weeks Recovery

Follow-up: 9M, 12M, 15M and 18MFollow-up: 9M, 12M, 15M and 18M

Baseline Evaluation and RandomizationBaseline Evaluation and Randomization

Follow-up: 3M and 6MFollow-up: 3M and 6M

3x Therapy Titration Visits (including sham)*3x Therapy Titration Visits (including sham)*

Therapy ON for All Patients Post-6M FUTherapy ON for All Patients Post-6M FU

*6 month window begins after last titration

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 Randomized1 Death

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

LT: 0.8 ± 0.5 Range: 0.3-2.7mACurrent: 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.

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 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

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

Secondary Endpoints

Secondary Endpoints

¥ Median

¥

Secondary Endpoints

* p<0.05 ∆ compared to control

• 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

Heart Rate and Heart Rate Variability 24-hour Holter

Therapy (N=55) Control (N=28)

Baseline 6 months Baseline 6 months

Heart RateMean 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 committeesSteering 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

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

Comparison of VNS Therapeutic ApproachesParameter 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