Neuromodulation of the Failing Heart

Q: What is the clinical evidence from this study?

Study design: Review. Population: Heart failure with reduced ejection fraction (HFrEF). Intervention: Device-based autonomic neuromodulation (vagus nerve stimulation [VNS], spinal cord stimulation [SCS], and baroreceptor activation therapy [BAT]) vs. Optimal medical therapy / guideline-directed medical therapy or sham control.

Q: What does this research mean for the field?

Device-based neuromodulation using vagus nerve stimulation and spinal cord stimulation fails to improve primary clinical or remodeling endpoints in larger heart failure with reduced ejection fraction trials, despite encouraging preclinical data and preliminary baroreceptor activation therapy studies. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Mirnela Byku; Douglas L. Mann

doi:10.1016/j.jacbts.2016.03.004

April 1, 2016JACC Basic to Translational ScienceOpen Access

Neuromodulation of the Failing Heart

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Key result

Device-based neuromodulation with VNS and SCS failed to improve primary clinical or remodeling endpoints in larger HFrEF trials (INOVATE-HF HR 1.14, p=0.37; DEFEAT-HF p=0.30), while phase II BAT studies remain encouraging.

Why the study?

Does device-based neuromodulation (vagus nerve stimulation, spinal cord stimulation, or baroreceptor activation therapy) improve ventricular remodeling and clinical outcomes in patients with heart failure with reduced ejection fraction?

Key Points

To review the pre-clinical rationale, clinical trial evidence, and translational challenges of device-based autonomic neuromodulation in heart failure with reduced ejection fraction.
Critical review of pre-clinical models and phase II/III clinical trials evaluating autonomic nervous system modulation in heart failure.
Evaluated device-based modalities including spinal cord stimulation (SCS), vagus nerve stimulation (VNS), and baroreceptor activation therapy (BAT).
Phase II clinical trials evaluating baroreceptor activation therapy (BAT) demonstrated encouraging preliminary signals in patients with heart failure with reduced ejection fraction.
Larger clinical trials assessing spinal cord stimulation (SCS) and vagus nerve stimulation (VNS) failed to demonstrate superiority and were neutral with respect to primary clinical endpoints despite robust pre-clinical evidence.

Structured PICO

Does device-based neuromodulation (vagus nerve stimulation, spinal cord stimulation, or baroreceptor activation therapy) improve ventricular remodeling and clinical outcomes in patients with heart failure with reduced ejection fraction?

P

Population

Patients with heart failure with reduced ejection fraction (HFrEF) evaluated across pre-clinical models and phase II/III clinical trials of device-based autonomic neuromodulation.

I

Intervention

Device-based autonomic nervous system neuromodulation, including vagus nerve stimulation (VNS), spinal cord stimulation (SCS), and baroreceptor activation therapy (BAT).

C

Comparator

Guideline-directed optimal medical therapy (OMT) alone or sham stimulation.

This review highlights that despite strong pre-clinical rationale and early pilot data, phase II/III trials of vagus nerve and spinal cord stimulation in HFrEF failed to meet primary endpoints, underscoring the need for better dosing protocols and physiological biomarkers before neuromodulation can become a standard heart failure therapy.

Limitations

Difficulty establishing the correct excitation parameters, stimulation strength, and duty cycles for autonomic modulation devices
Stimulus current amplitude in clinical trials is often limited by patient symptoms (e.g., cough, dysphonia, hoarseness) or hemodynamic effects
Uncertainty regarding whether afferent, efferent, or combined nerve fiber stimulation is optimal in heart failure
Lack of direct physiological measurements or validated biomarkers in trials to confirm restoration of normal sympathovagal balance
Challenges in replicating results of small open-label pilot studies in larger randomized controlled trials due to regression to the mean and lack of proper blinding
Lack of clear methods for establishing proper device stimulation parameters, site of stimulation, and duty cycles
Stimulation intensity limited by patient side effects (e.g., hoarseness, cough, jaw pain) leading to variable nerve fiber recruitment
Uncertainty whether stimulating afferent versus efferent vagus nerve fibers is more beneficial
Absence of direct physiological biomarkers used during trials to verify normalization of autonomic tone
Early positive findings came from small, unblinded, non-randomized pilot studies subject to regression to the mean

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Negative VNS/SCS results warrant HFrEF caution; leaves open refined BAT evaluation in phase III.

Abstract

Sympathovagal imbalance contributes to progressive worsening of HF (HF) and is associated with untoward clinical outcomes. Based on compelling pre-clinical studies which supported the role of autonomic modulation in HF models, a series of clinical studies were initiated using spinal cord stimulation (SCS), vagus nerve stimulation (VNS) and baroreceptor activation therapy (BAT) in patients with HF with a reduced ejection fraction (HFrEF). While the phase II studies with BAT remain encouraging, the larger clinical studies with SCS and VNS have yielded disappointing results. Here we will focus on the pre-clinical studies that supported the role of neuromodulation in the failing heart, as well provide a critical review of the recent clinical trials that have sought to modulate autonomic tone in HF patients. This review will conclude with an analysis of some of the difficulties in translating device-based modulation of the autonomic nervous from pre-clinical models into successful clinical trials, as well as provide suggestions for how to move the field of neuromodulation forward.

Discussion

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Cite This Study

Byku et al. (2016) conducted a review in Heart failure with reduced ejection fraction (HFrEF). Device-based autonomic neuromodulation (vagus nerve stimulation [VNS], spinal cord stimulation [SCS], and baroreceptor activation therapy [BAT]) vs. Optimal medical therapy / guideline-directed medical therapy or sham control was evaluated. Device-based neuromodulation with VNS and SCS failed to improve primary clinical or remodeling endpoints in larger HFrEF trials (INOVATE-HF HR 1.14, p=0.37; DEFEAT-HF p=0.30), while phase II BAT studies remain encouraging.

synapsesocial.com/papers/6a74668751ce19f076093886 https://doi.org/10.1016/j.jacbts.2016.03.004

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Neuromodulation of the Failing Heart

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Neuromodulation of the Failing Heart

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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