Transcript Zannad - NECTAR-HF - Clinical Trial Results

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
Reduce
sympathetic
stimulation
Add vagal
parasympathetic
stimulation
Vagal
Stimulation
Spinal
Stimulation
Baroreceptor
Stimulation
Renal
Denervation
Vagal Stimulation in Canine HF
NT-proBNP
End Diastolic Area
Normal
1.20
1.10
1.00
0.90
Control
HF - Sham
AMT
HF - VNS
0.80
0.70
0.60
0.50
1 mo.
100
80
60
40
20
Normal HF-ShamVST HF- VST
400
300
200
100
3 mo.
0
Normal HF-ShamVST HF- VST
Calcium handling
0
4
2 mo.
Active Caspace-3 (du)
SERCA-2a (du)
140
120
Pre
500
80
Apoptotic signaling
80
TNF-alpha (du)
Baseline
NT-proBNP (fmols/ml)
1.30
60
40
20
Inflammation
60
40
20
0
0
Normal HF-ShamVST HF- VST
Normal HF-ShamVST HF- VST
Sabbah H, J. Am. Coll. Cardiol. 2010;55;A16.E153
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
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• 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
Implant and Stimulation Protocol
VNS Implanted System
VNS Cuff
• 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)
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)
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
28 Control
Patients with
paired data sets
Patients with
paired data sets
Modified intention to treat analysis
Baseline Characteristics
Therapy (N=63)
Control (N=32)
56 (89%)
26 (81%)
Age
59.8 + 12.2
59.3 + 10.1
Body Mass Index
28.6 + 5.9*
31.2 + 5.1
7/51
7/22
51/5/7
22/4/6
68.2 + 13.2
71.3 + 12.9
Systolic
118 + 17
115 + 16
Diastolic
73 + 10
73 + 13
Gender Male [N (%)]
NYHA II/III
ICD/CRT-D/No device
Resting Heart Rate (bpm)
Blood pressure (mmHg)
*p<0.05
Baseline Characteristics
Clinical History
Ischemic heart failure [N (%)]
Hypertension [N (%)]
Renal Disease [N (%)]
Heart failure hospitalization past 6 mo. [N (%)]
Previous myocardial infarction [N (%)]
Non-insulin dependent diabetes [N (%)]
Sleep Apnoea [N (%)]
Cardiovascular medications
B-blockers [N (%)]
Angiotensin converting enzyme inhibitor [N (%)]
Angiotensin receptor blocker [N (%)]
Mineralocorticoid receptor antagonist [N (%)]
Loop Diuretics [N (%)]
Statin [N (%)]
Therapy (N=63)
Control (N=32)
44 (70)
29 (46)
12 (19)
8 (13)
42 (67)
14 (22)
9 (14)
20 (63)
21 (66)
9 (28)
4 (13)
19 (59)
9 (28)
3 (9)
59 (94)
51 (81)
17 (27)
43 (68)
54 (86)*
50 (79)*
30 (94)
24 (75)
7 (22)
23 (72)
32 (100)
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
Current (mA)
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
Baseline
LT:
0.8 ± 0.5 Range: 0.3-2.7mA
Current: 1.3 ± 0.7 Range: 0.3-3.5mA
T1
T2
T3
Therapy Group
Therapy Group Larygneal
Threshold
Sham Group Laryngeal Threshold
3
Months
6 Month Safety Results
Therapy
Control (N = 32)
(N = 63)
Events
Patients
Events
Patients
7
%
11.1%
11
5
%
15.6%
11
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%
9
9
14.3%
4
4
12.5%
Death and/or HF Hospitalization
Investigational System-Related
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
6
4.9
4.9
5.2
5.1
Baseline
6 Months
Baseline
6 Months
LVESD (cm)
5
4
3
2
1
0
Therapy
Control
Secondary Endpoints
218
207
235
221
LVESV (ml)
200
150
100
152
100
0
0
Baseline 6 Months Baseline 6 Months
Control
30.5
164
150
50
Baseline 6 Months Baseline 6 Months
142
200
50
Therapy
154
250
250
Therapy
32.7
40
LVEF (%)
LVEDV (ml)
300
30.8
32.1
30
20
10
0
Baseline 6 Months Baseline 6 Months
Therapy
Control
Control
Secondary Endpoints
2000
25
15.8
20
Peak VO2 (ml/kg/min)
879
15.2
14.7
15
10
NT-proBNP (pg/ml)
15.6
882
¥
930
839
1500
1000
500
5
0
0
Baseline
6 Months
Therapy
Baseline
6 Months
Control
Baseline 6 Months Baseline 6 Months
Therapy
Control
¥ Median
70
62.1
60
60
44.8
50
40
30
20
10.3
10
0.2
0
Worsened
Therapy 6 month change
35.8
Improvement
43.8
40.7
41.1
Baseline
6 Months
Baseline
6 Months
50
40
30
20
10
Worsened
Control 6 month change
42.8
Therapy
41.8
50
40
30
20
10
Control
60
SF-36 (physical)
44.4
60
MLHFQ
41.2
0
Improvement
70
SF-36 (mental)
% of patients that
changed NYHA
Secondary Endpoints
50
36.3
41.2
37.7
38.4
Baseline
6 Months
Baseline
6 Months
40
30
20
10
0
0
Baseline
6 Months
Therapy
Baseline
6 Months
Control
Therapy
* p<0.05 ∆ compared to control
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)
Baseline
Control (N=28)
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
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Faiez Zannad (Chairman)
Josep Brugada
Christian Butter
Gaetano M. De Ferrari
Helmut Klein
Kenneth M. Stein
Anton Tuinenburg
David Jay Wright
Core Laboratories
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Clinical Events Committee
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Daniel Gras
Luigi Tavazzi
Henk C.E. van Lambalgen
Henry J. Dargie (Chair)
Poul Erik Bloch Thomsen
Erland Erdmann
Ian Ford
Andreas Schulze-Bonhage
Echocardiography: Scott D. Solomon,
Boston
Exercise Testing: Peter Prubaker,
Wake Forest University
Holter: Rod Salo, Salo Scientific
Biomarkers: Fischer Bioservices, UK
Investigators
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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
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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 Approaches
Parameter
Current (mA)
NECTAR-HF
Mean: 1.3 ± 0.8
(range 0.3-3.5)
INOVATE-HF
ANTHEM-HF
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 70325ms delay from R-wave)
NO
Afferent block
NO
YES (Quasi-Trapezoidal
waveform; requires >4mA)
NO
Electrode
Bipolar helical cuff
Bipolar, multipolar "splitcylinder" cuff
Bipolar helical cuff