ESC: Left or Right Nerve Stimulation Feasible in HF

ESC: Left or Right Nerve Stimulation Feasible in HF

Published: Sep 1, 2014

By Ed Susman , Contributing Writer, MedPage Today

 

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• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

BARCELONA -- Stimulation of either the right or left vagus nerve appeared to improve cardiac function in patients with heart failure, researchers said here.

In the ANTHEM-HF (Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure) trial, left ventricular ejection fraction (LVEF) increased from 32.4% to 37.2% with the stimulation device (VNS Therapy System) after 6 months, a statistically significant and clinically meaningful change (P<0.0001), reported Inder Anand, MD, DPhil, from the University of Minnesota in Minneapolis, and colleagues.

"We pooled the results of the left and right side vagus nerve stimulation because there were no major differences in outcomes based on which nerve is stimulated," Anand said at a press conference at the European Society of Cardiology meeting. The study results will also be published in the Journal of Cardiac Failure.

In addition to the improvement in left ventricular function, about 70% of the patients in the ANTHEM-HF study improved their NYHA heart failure class by at least one class, Anand reported, and those changes were also statistically significant (P<0.0001).

"No patients' conditions worsened," he told MedPage Today.

Anand also reported that the patients significantly bolstered their distance in the 6-Minute Walk Test, improving by 56 m from baseline (P<0.0001) and saw their heart rates slowed by 3.9 beats per minute (P<0.005). Also, patients recorded an 18-point reduction in the Minnesota Living with Heart Failure Questionnaire (P<0.0001).

"We saw both improvements in objective measures of heart failure and in subjective measures," he said.

The results of the ANTHEM-HF trial differed from another trial of vagal stimulation presented at ESC -- NECTAR-HF showed no benefit was observed.

"ANTHEM showed a very significant effect on beneficial remodeling as a result of vagus nerve stimulation," Mariell Jessup, MD, professor of medicine at the University of Pennsylvania in Philadelphia told MedPage Today. "They compared right sided vagus nerve stimulation to left sided stimulation and both were effective. This is in contrast to NECTAR-HF which showed absolutely no signal, but was done primarily on the right side."

"So we are kind of confused," she added. "We will really have to understand, in a better way, what the differences were in the techniques and how they used the stimulation. There is still a possibility that this is going to offer a new avenue of therapy."

The researchers set out to test whether stimulating the right vagus nerve or the left vagus nerve would better improve outcomes, but Anand said that stimulation of either nerve appeared to help patients achieve changes in cardiac function. There were 60 patients -- all with chronic symptomatic heart failure with LVEF ≤40% -- enrolled, and outcomes were studied at 6 months. Patients were on optimal medical therapy including beta-blockers. There was no control group.

The experimental autonomic regulation therapy system delivered chronic intermittent stimulation to the vagus (10 Hz natural frequency, 250-microsecond pulse width). The stimulation intensity titrated over 10 weeks to maximum tolerable current. The average stimulation current was 2.0 mA.

There were three deaths in the study, including one that involved implantation of the device (postsurgical embolic stroke). The other two deaths were adjudicated as due to worsening heart failure and sudden death. Other serious adverse events were equally distributed among patients with either right or left implantation. The most common nonserious adverse events included voice alternation and hoarseness, cough, and oropharyngeal pain.

There were no instances of system malfunction, the authors reported.

"There is attractiveness to using the left side because that is where we put most of our devices," explained Jessup, who is immediate past president of the American Heart Association. "In theory, if you were implanting a device, you could be implanting the vagal nerve stimulator and, I suppose, you could put the generators in one single pocket."

Kenneth Dickstein, MD, professor of medicine at the University of Bergen, Norway, said the use of the right vagus nerve has been targeted because it was believed that method provided more of a baroreceptor impact than the left side vagus nerve. He said that ANTHEM-HF indicated that the left vagus nerve is at least as effective as the right side and may be easier to access.

The study was sponsored by Cyberonics.

Anand disclosed relevant relationships with Amgen, Critical Diagnostics, Cyberonics, Novartis, and Zensun.

Jessup disclosed no relevant relationships with industry.

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Primary source: European Society of Cardiology
Source reference: Premchand R, et al "Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: The ANTHEM-HF Study" ESC 2014.

http://www.medpagetoday.com/MeetingCoverage/ESC/47450

Cyberonics device improves heart function after Boston flop

Cyberonics device improves heart function after Boston flop

Monday, September 01, 2014 2:35 a.m. CDT

By Ben Hirschler

BARCELONA (Reuters) - A nerve stimulation device from Cyberonics improved cardiac function in heart failure patients in a small clinical trial, in contrast to an unsuccessful study backed by Boston Scientific.

However, the Cyberonics trial reported on Monday did not contain a control arm - unlike the one using the Boston device in which some patients received sham treatment - and experts said further research was now needed.

Both companies are trying to improve outcomes for patients with heart failure, in which the heart fails to pump blood efficiently, by stimulating the vagus nerve – a superhighway connecting the brain to the rest of the body.

Vagus nerve stimulation (VNS), which involves delivering mild electrical pulses to the nerve in the neck, is already used successfully to treat severe epilepsy and treatment-resistant depression.

Cyberonics is the leading proponent of such therapy and the six-month heart failure trial, involving 60 patients, used its system to stimulate both the left and right-sided vagus nerve.

Patients, on average, showed a 4.5 percent improvement in left ventricular ejection fraction, a key measure of heart function, the study found, and there was no difference in the results between the left and right sides.

"I think, at six months, that (4.5 percent improvement) is a very impressive achievement," study leader Inder Anand from the University of Minnesota told reporters at the European Society of Cardiology annual meeting.

The fact that the device worked equally well on both sides is important because the system could be combined with cardiac devices such as implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) devices, the vast majority of which are implanted on the left side.

http://wtaq.com/news/articles/2014/sep/01/cyberonics-device-improves-heart-function-after-boston-flop/

NECTAR-HF fails to demonstrate clinical benefit of vagus nerve stimulation in Heart Failure

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NECTAR-HF fails to demonstrate clinical benefit of vagus nerve stimulation in Heart Failure

Saturday, August 30, 2014

 

BARCELONA, Spain – Stimulating the vagus nerve, which regulates the body’s internal organ systems including the heart, does not improve cardiac function in heart failure patients, according to results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial.

NECTAR-HF was presented as a Hot Line today at ESC Congress 2014,  with simultaneous publication in the European Heart Journal.

The trial’s failure to show a cardiac benefit of vagal nerve stimulation (VNS) was unexpected, said study investigator Faiez Zannad, MD, PhD, from l'Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, in Vandoeuvre-lès-Nancy, France.

“There is robust pre-clinical data showing the benefit of VNS, but the NECTAR-HF trial failed to demonstrate a successful clinical translation of this protocol,” he said.

 

The study is the first randomised, controlled trial designed to evaluate the safety and efficacy of right-sided VNS.

It enrolled 96 heart failure patients from 24 centres across Western Europe to assess the impact of six months of VNS on cardiac function, as well as on cardiac biomarkers, exercise capacity, and quality of life.

Patients, who were about 59 years old and receiving optimal medical therapy, had the VNS device implanted in their neck, near the right vagus nerve, and connected to a pulse generator implanted under the skin of the chest.

After baseline testing of the system, patients were then randomized to either a control group in which the devices remained switched off, or an active VNS group in which the mean stimulation amplitude was 1.24 mA at the start of the study, and 1.42 mA at the 3-month follow-up visit.

After six months, the study found no difference in objective endpoints between the groups.
Both groups had comparable changes from baseline in the primary endpoint of left ventricular end-systolic dimension (LVESD),  as well secondary echocardiographic endpoints, exercise capacity, and levels of the heart failure serum biomarker N-terminal prohormone brain natriuretic peptide (NT-proBNP).

However, there were significant differences between the groups for three subjective endpoints related to quality of life.

Analyses of the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Short Form 36 Health Survey (SF-36) demonstrated statistically significant improvement in quality of life with VNS treatment compared to controls (MLHFQ p=0.049; SF-36 Physical and Mental, p=0.02 and 0.24, respectively).

Additionally, 62% of patients in the VNS group had an improvement of at least one point from baseline in their New York Heart Association (NYHA) functional classification compared to only 45% of control patients (p=0.032).

“The safety profile for this application of VNS appeared acceptable, with an overall infection rate of 7.4%, which is comparable to that in patients implanted with a VNS system for the treatment of epilepsy,” noted Professor Zannad.

Given that preliminary studies suggested a benefit of VNS, there are a number of possible explanations for NECTAR-HF’s negative findings.

First, there is still much to learn about the appropriate dosing and technique of VNS. Data from epilepsy VNS studies show that higher-amplitude dosing might be more effective, but it is often not possible because it causes patient discomfort, said Professor Zannad.

Second, patients in the NECTAR-HF trial were relatively well-managed on medical therapy alone, making them perhaps not the best candidates to show a strong benefit of VNS.

Third, the six-month study period may have been too short to detect changes in cardiac function.

Although patients were blinded to their group assignment, meaning they were not told if they were receiving active treatment, it is possible that those in the active treatment group were able to feel the sensation of stimulation. If this was the case, patients could have been vulnerable to a placebo effect, knowing that they were receiving active therapy.
For this reason, the higher quality of life scores among VNS patients compared to controls should be interpreted with caution, he said.

Authors: ESC Press Office
For background information, please contact the ESC Press Office.
For independent comment on site, please contact the ESC Spokesperson coordinator.

Notes to editor
SOURCES OF FUNDING: The study was funded by Boston Scientific Corporation.
DISCLOSURES: Professor 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. Co-author Gaetano De Ferrari receives honoraria from Amgen, Boston Scientific, Menarini and Merck. Co-authors Stephen Ruble, Doug Daum, Scott Meyer, Craig Stolen, Bernd Schubert, Agnes Ramuzat, Nicholas Wold and Kenneth Stein are employees of Boston Scientific Corporation.

About the European Society of Cardiology
The European Society of Cardiology (ESC) represents more than 80 000 cardiology professionals across Europe and the Mediterranean. Its mission is to reduce the burden of cardiovascular disease in Europe.
About ESC Congress 2014

The ESC Congress is currently the world's largest international congress in cardiovascular medicine.  The spotlight of this year's event is “innovation and the heart”.  ESC Congress 2014 takes place from 30 August to 3 September at the Fira Gran Via in Barcelona, Spain. For more information on ESC Congress 2014 contact the ESC Press Office.
To access all the scientific resources from the sessions during the congress, visit ESC Congress 365.

This press release accompanies both a presentation and an ESC press conference at the ESC Congress 2014. Edited by the ESC from material supplied by the investigators themselves, this press release does not necessarily reflect the opinion of the European Society of Cardiology. The content of the press release has been approved by the presenter.

http://www.healthcanal.com/blood-heart-circulation/heart-disease/54662-nectar-hf-fails-to-demonstrate-clinical-benefit-of-vagus-nerve-stimulation-in-heart-failure.html

Electrical stimulation outside the heart

"In the previous paragraphs, we have discussed the application of electrical stimulation on the heart, which has the advantage of avoiding possible adverse side-effects as regularly encountered with pharmacological therapies. The therapies discussed below are applied outside the heart and usually are applied continuously throughout the cardiac cycle (see Fig. 1). Their benefit may be that the stimulation is affecting a much more integrated system. Studies of these therapies clearly show cardiac benefit, but in most cases, the exact mechanism is unknown. This is likely due to multi-organ and central nervous system pathways.

Vagal nerve stimulation

There has been extensive research demonstrating that acute vagus nerve stimulation results in a decrease in various measures of ventricular function including contractility. Lewis et al. showed that in the human and pig heart, stimulation of the left vagus nerve can profoundly decrease contractility of the left ventricular myocardium, independent of its braducardic effect [54]. This decrease in ventricular contractility during vagal stimulation (VNS) appears to be mediated by the parasympathetic ganglia located in the cranial medial ventricular fat pad [55, 56]. However, at low sympathetic tone, the negative inotropic effect of vagal stimulation is attributable primarily to its negative chronotropic effect [57]. This suggests that the effect of VNS on contractility is mediated via an interaction with the sympathetic system.

It may seem counterintuitive that a reduction in contractility by VNS may be beneficial to patients with heart failure. However, several pre-clinical studies have shown benefit in chronic vagus nerve stimulation in models of systolic heart failure [58]. Recently, Zhang et al. evaluated VNS in a canine high-rate pacing-induced model of heart failure. VNS at an intensity that reduced sinus rate by approximately 20 bpm was delivered in the VNS group. After 4 and 8 weeks, both left ventricular end-diastolic and end-systolic volumes were lower, and left ventricular EF was higher in the VNS group than in the control group [59]. Li et al. showed that VNS markedly improved the long-term survival of chronic heart failure rats through the prevention of pumping failure, remodeling, and increasing contractility [60]. Very recently, the same group showed that VNS applied immediately after MI attenuated LV remodeling, which may be related to the decreased acute inflammatory response or to the reduction in infarct size induced by VNS [61], since the remodeling process increases with a larger infarct."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074071/