COMMENTARY

Vagal Nerve Stimulation in HF: Mixed Findings at ESC

Gerhard Hindricks, MD

Disclosures

October 15, 2014

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Hello, and welcome to the annual Congress of the European Society of Cardiology (ESC) in Barcelona, Spain.

My name is Gerhard Hindricks. I am an interventional electrophysiologist working at the University of Leipzig, Heart Center Leipzig. I would like to share with you today the results of the ANTHEM-HF study,[1,2] which has been presented as part of the ESC hotline sessions.

ANTHEM-HF was a prospective, multicenter study evaluating the effects of vagal nerve stimulation on various outcome parameters in patients with advanced heart failure.

The study included 60 patients; most had coronary artery disease and a significantly reduced left ventricle ejection fraction (LVEF), below 40%; enlarged left ventricular dimensions; and New York Heart Association (NYHA) class II or III heart failure. All of the patients underwent implantation of a pacemaker-like device stimulator capable of stimulating the right or left vagal nerve. Stimulation sites were assigned randomly.

After the implantation of the device, the patients had to be on stable heart failure medication and they underwent a so-called titration phase. In the titration phase, the maximal stimulation output (not resulting in intolerable side effects) was assessed and the patient was then put on the maximal stimulation output.

The therapy phase was six months. The primary efficacy endpoint of the ANTHEM-HF trial was any change in LVEF and any change in left ventricular and systolic dimension at six months. The primary safety outcome was any procedure or therapy-related adverse event during the nine-month period (including the titration phase).

Secondary outcome parameters included Living With Heart Failure quality-of-life score, six-minute walk distance, heart rate, and other parameters.

What are the results of ANTHEM-HF? There was a significant increase in LVEF, while left ventricular and diastolic dimension did not significantly change with the therapy. So one primary efficacy endpoint was met while the other was not.

In terms of safety outcomes, there were three deaths in the left vagal nerve stimulation group: One was clearly attributed to the implantation procedure—a stroke directly after implantation; and one heart failure death and one sudden cardiac death, which were not considered procedure-related. However, I consider this at least questionable. There were 18 additional serious adverse events and more than 40 nonserious adverse events observed in the nine-month follow-up period.

The secondary outcome parameters included subjective outcome parameters such as Living With Heart Failure score; NYHA heart failure class; and in some ways, six-minute walk test, which was significantly increased, while heart rate decreased from 75 beats/min to 71 beats/min. ProBNP did not significantly change at six months.

In summary, how should we judge these results of the ANTHEM-HF study? I think that the results of the study are not fully convincing. The fact that the subjective secondary outcome parameters were met raises the question of expectation bias and placebo effects that are often observed in nonrandomized, noncontrolled, and non-sham-controlled studies of this type. We have to keep that in mind when we look to these results.

To me, the study was underpowered and did not convincingly answer the question of whether there are safety issues with vagal nerve stimulation. Putting things into perspective, we also heard the results of the NECTAR-HF trial[3] in Barcelona. This was another study assessing the feasibility of vagal nerve stimulation in patients with heart failure. NECTAR-HF had a stronger design; it was a randomized, sham-controlled trial and the results were negative. The investigators could not show any significant improvement for the primary outcome parameter. With that in mind, I would call the results of ANTHEM-HF mixed. I think it is reasonable not to expect significant advancement in heart failure therapy by application of vagal nerve stimulation in the immediate future.

We need to wait for the next big study, which is being conducted by Peter Schwartz, who is one of the inventors of vagal nerve stimulation. The INOVATE-HF study will have approximately 650 patients. I talked to Peter this morning and he said, "Wait another year, maybe two years, for more news from the field of vagal nerve stimulation."

Thank you for your attention.

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