Autonomic Regulation Therapy for the Improvement of Left Ventricular - - PowerPoint PPT Presentation

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Autonomic Regulation Therapy for the Improvement of Left Ventricular - - PowerPoint PPT Presentation

Apr 15, 2023 287 likes •533 views

Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms: The ANTHEM-HF Study Rajendra K. Premchand, Kamal Sharma, Sanjay Mittal, Rufino Monteiro, Imad Libbus, Lorenzo DiCarlo, Jeffrey L. Ardell,

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SLIDE 1

Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms: The ANTHEM-HF Study

Rajendra K. Premchand, Kamal Sharma, Sanjay Mittal, Rufino Monteiro, Imad Libbus, Lorenzo DiCarlo, Jeffrey L. Ardell, Thomas S. Rector, Badri Amurthur, Bruce H. KenKnight, Inder S. Anand for the ANTHEM-HF Investigators

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SLIDE 2

Disclosures

This study was sponsored by Cyberonics, Houston, USA Inder Anand has consulted for and/or received research support from Amgen, Critical Diagnostics, Cyberonics, Novartis, Zensun

2 ANTHEM-HF Study

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SLIDE 3

Background

  • In HF there is autonomic imbalance, characterized by

increased sympathetic activity and withdrawal of parasympathetic activity

  • Autonomic imbalance is associated with progression of

HF and worse outcomes

  • Pre-clinical & clinical studies suggest electrical stimulation
  • f the right vagus nerve may restore autonomic balance
  • Left-sided VNS, which could be combined with cardiac

devices, has not been evaluated in HF patients, and the effects of left and right VNS have not been directly compared

3 ANTHEM-HF Study

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SLIDE 4

Objectives

Evaluate a new autonomic regulation therapy (ART) with left

  • r right VNS, for the treatment of chronic symptomatic heart

failure with reduced ejection fraction

  • Feasibility, Tolerability and efficacy of the ART system
  • Primary safety endpoint: Incidence of procedure and device-

related adverse events during the 9-month duration of the study

  • Primary efficacy endpoint: Changes in left ventricular ejection

fraction (LVEF) and end-systolic volume (LVESV) at 6 months

4 ANTHEM-HF Study

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SLIDE 5

Secondary Endpoints

Changes at 6 months in:

  • Left ventricular end-systolic diameter (LVESD)
  • 6-minute walk distance
  • Quality of life (Minnesota Living with HF Questionnaire)
  • NYHA Class
  • Heart rate variability (HRV)
  • Blood biomarkers (NT-proBNP and hs-CRP)

5 ANTHEM-HF Study

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SLIDE 6

Independent Clinical Events Committee Lorenzo DiCarlo, MD, FACC (Chair) David Cannom, MD, FACC Echocardiographic Core Laboratory Care Hospital, Hyderabad, India Blood and Biomarker Core Laboratory Metropolis Healthcare, Mumbai, India Sponsor Cyberonics, Inc., Houston, USA

ANTHEM-HF Committees

6

Steering Committee Inder Anand, MD, FACC (Chair) Jeffrey Ardell, PhD Lorenzo DiCarlo, MD, FACC Sanjay Mittal, MD Badri Amurthur, MS Imad Libbus, PhD Bruce KenKnight, PhD Independent Data & Safety Monitoring Board Gary Francis, MD, FACC (Chair) Thomas Rector, PhD Independent Statistical Analysis Thomas Rector, PhD

ANTHEM-HF Study

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SLIDE 7

Clinical Site Principal Investigator Medanta, New Delhi

  • Dr. Naresh Trehan
  • Dr. Sanjay Mittal

Sanjivani, Ahmedabad

  • Dr. Kamal Sharma
  • Dr. Satyajit Dixit

Narayana Hrudayala, Bangalore

  • Dr. Ravi Kishore

Madras Medical Mission, Chennai

  • Dr. Ulhas Pandurangi
  • Dr. Ajit

KIMS, Hyderabad

  • Dr. Rajendra Kumar

Yashoda Hospital, Hyderabad

  • Dr. Rajasekhar

Sengupta Hospital, Nagpur

  • Dr. Sengupta

DMH Hospital, Pune

  • Dr. Sathe

Vintage Hospital, Goa

  • Dr. Rufino Monteiro

CARE Hospital, Hyderabad

  • Dr. B.K Sastry

Clinical Study Sites

7 ANTHEM-HF Study

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SLIDE 8

Inclusion and Exclusion Criteria

  • Key Inclusion Criteria
  • Stable symptomatic heart failure NYHA class II / III
  • Left ventricular ejection fraction (EF) ≤ 40%
  • Left ventricular end diastolic diameter (LVEDD) ≥ 50 mm and < 80 mm
  • QRS width < 150 ms
  • Optimal pharmacologic therapy for at least 3 months
  • Key Exclusion Criteria
  • Prior cardiac transplant
  • 1st, 2nd, or 3rd-degree heart block
  • Primary autonomic dysfunction
  • Refractory symptomatic hypotension
  • Severe obstructive or restrictive lung disease

ANTHEM-HF Study 8

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SLIDE 9

Study Design

9

2 weeks 10 weeks Randomization

Right side Left side

Informed Consent

Cyclic VNS Therapy (6 months) Titration

VNS Device Implant VNS System Activated Titration Complete 3 months Outcome Measures Outcome Measures

Baseline Assessment

Safety and adverse events Assessment (9 months)

6 months

ANTHEM-HF Study

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Autonomic Regulation Therapy

  • VNS Therapy System (Cyberonics, Houston, USA)
  • 100,000+ left-sided implants in epilepsy patients
  • Implanted on L or R vagus nerve by surgeon
  • Without RV sensing lead
  • Chronic intermittent stimulation delivered to vagus
  • 10 Hz (natural frequency), 250 µsec pulse width
  • VNS intensity titrated over 10 wks to max tolerable current;

below the of threshold of side effects or HR change

  • ECG monitored continuously to confirm no acute HR change
  • Over time the threshold for side-effects gradually increased
  • Average stimulation current: 2.0 ± 0.6 mA

10 ANTHEM-HF Study

ON OFF

10 Hz, 250 µsec pulses 14 sec 66 sec

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SLIDE 11

Screening, Enrollment and Follow-up

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Screening n=78 Randomization n=60 Titration n=29 Right-Sided Implantation n=29

Inc / Exc failure (n=12) Withdrawal (n=4) Brady arrest (n=1) Sudden death (n=1)

Titration n=30 Left-Sided Implantation n=31 3-month F/U n=29 3-month F/U n=28 Death 1 n=1 Death 2 n=2 6-month F/U n=29 6-month F/U n=28

ANTHEM-HF Study

  • 1. Embolic stroke (implant-related)
  • 2. HF death (unrelated) and sudden death (unrelated)
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SLIDE 12

Baseline Characteristics

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Left (n=31) Right (n=29) Pooled (n=60) Age (years) 51.2 ± 12.4 51.9 ± 12.4 51.5 ± 12.2 Male (%) 87 86 87 Heart failure Etiology, Ischemic (%) 68 83 75 NYHA Class II/III 18 / 13 16 / 13 34 / 26 Body mass index (kg/m2) 24.0 ± 3.5 24.2 ± 4.7 24.1 ± 4.1 LVEF (%) 32.8 ± 8.0 31.9 ± 6.4 32.4 ± 7.2 LVESV (mL) 109.1 ± 40.8 106.6 ± 40.1 107.9 ± 40.1 LVESD (mm) 51.5 ± 7.4 51.6 ± 8.6 51.6 ± 7.9 LVEDD (mm) 61.7 ± 6.7 62.2 ± 7.1 61.7 ± 6.7 HR (bpm) 78 ± 11 77 ± 10 78 ± 10 Systolic blood pressure (mmHg) 114 ± 14 112 ± 15 113 ± 15 Diastolic blood pressure (mmHg) 73 ± 8 74 ± 10 73 ± 9 ICD implant

ANTHEM-HF Study

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SLIDE 13

Baseline Characteristics

HF Drug Treatment

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Left (n=31) Right (n=29) Pooled (n=60) -blocker (%) 100 100 100 ACE-I or ARB (%) 83 87 85 Aldosterone antagonist (%) 71 79 75 Digoxin (%) 39 24 32 Loop diuretics (%) 97 79 88

ANTHEM-HF Study

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SLIDE 14

Primary Safety Outcomes

* Post-surgical embolic stroke

† Including 1 unrelated HF death and 1 unrelated sudden death

14

Left Right Pooled SAEs

10 11 21 Related 1 1* Unrelated 9 11 20† Most Common Related Non-Serious AEs Voice alternation, hoarseness 11 8 19 Cough 6 7 13 Oropharyngeal pain 4 4 8

Implant-Related Infections System Malfunctions Therapy discontinuation by Pts or PI

ANTHEM-HF Study

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SLIDE 15

10 5

  • 5
  • 10
  • 15

Pooled Left Right Pooled Left Right

LVESV (mL) LVEF (%)

Primary Efficacy Endpoints

15 ANTHEM-HF Study

Mean 95% Confidence Interval Pooled: n=57; Left: n=28; Right: n=29

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Secondary Efficacy Endpoints

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Baseline 6 Months Change p-value LVESD (mm) 52 ± 8 49 ± 8

  • 1.7

<0.0025 NYHA Class (I/II/III/IV) 0 / 33 / 24 / 0 30 / 24 / 3 / 0 <0.0001 6MWD (m) 287 ± 66 346 ± 78 56 <0.0001 MLHFQ score 40 ± 1 21 ± 10

  • 18

<0.0001 HRV (SDNN, ms) 93 ± 43 111 ± 50 17 <0.01 HR (bpm) 78 ± 10 73 ± 11

  • 3.9

<0.005 NT-proBNP, IQR (pg/mL) 864 [322-1788] 888 [376-1729] 24 NS hs-CRP, IQR (mg/L) 1.7 [0.9-6.0] 1.3 [0.6-2.9]

  • 0.4

<0.025

ANTHEM-HF Study

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SLIDE 17

Limitations

  • The study was uncontrolled and open-label; placebo

effects may have contributed to the observed changes

  • Although no significant differences were observed in any
  • utcome between left and right-sided ART, the confidence

intervals of most measurements were wide, some differences cannot be ruled out

  • The study was conducted in India, and results may not

generalize to other populations

17 ANTHEM-HF Study

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Conclusions

  • The ANTHEM-HF approach to ART (chronic, low-

amplitude, natural frequency), on either the left or right side, was feasible and well-tolerated

  • Safety assessment did not raise concerns
  • Both left and right-sided ART were associated with

improvements in cardiac function (LVEF, LVESD, HRV) and heart failure symptoms (NYHA class, 6-minute walk distance, quality of life)

  • Further investigation of ART in a controlled clinical study

is warranted

18 ANTHEM-HF Study

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SLIDE 19
  • n line publication available in Journal of Cardiac Failure at:

DOI: http://dx.doi.org/10.1016/j.cardfail.2014.08.009

19 ANTHEM-HF Study

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SLIDE 20

BACKUP SLIDES

ANTHEM-HF Study

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SLIDE 21

Related and Unrelated SAEs

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Cardiovascular Events Other Events Sudden Death 1 Pneumonia 1 Heart Failure Death 1 Dengue Fever 1 HF Hospitalization 6 Weight Loss 1 Ventricular Tachy 2 Urine Retention 1 CVA (left hemiparesis) 1 Bone Fracture 1 Unstable Angina 2 Hernia 1 Cataract 1 Cardiovascular Events Other Events Death, Embolic Stroke 1 Implant-Related Events Stimulation-Related Events Stimulation-Related Events 1 Related 20 Unrelated 21 SAEs

ANTHEM-HF Study

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SLIDE 22

Echocardiographic Indices of LV Function

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108 103 101 Baseline 3 Months 6 Months 50 65 80 95 110 125

LVESV (mL)

32.4 35.6 37.2 Baseline 3 Months 6 Months 20 25 30 35 40

LVEF (%)

52 50 49 Baseline 3 Months 6 Months 20 30 40 50 60

LVESD (mm)

p < 0.005 p = 0.0001 p = 0.19 p = 0.12 p < 0.05 p < 0.0025

p-values vs. baseline

ANTHEM-HF Study

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SLIDE 23

Secondary Outcomes

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287 331 346 Baseline 3 Months 6 Months 150 225 300 375

6-Minute Walk Distance (m)

40 24 21 Baseline 3 Months 6 Months 10 20 30 40 50

Quality of Life (MNLHF Score)

93 107 111 Baseline 3 Months 6 Months 40 60 80 100 120

HRV (SDNN, ms)

78 75 73 Baseline 3 Months 6 Months 50 55 60 65 70 75 80

Heart Rate (bpm)

ANTHEM-HF Study

p < 0.0001 p < 0.0001 p < 0.025 p < 0.01 p < 0.0001 p < 0.0001 p = 0.16 p < 0.005

p-values vs. baseline

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SLIDE 24

Change in NYHA Class

77% of patients improved by at least 1 class at 6 months

24

IV III II I

n = 0 n = 0 n = 0

Baseline 6 Months

n = 3 n = 24

3 3 2 2 14 14 10 10 1 1

n = 26 n = 30

7 7

n = 34

ANTHEM-HF Study

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