AIM: The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy. METHODS: Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers. RESULTS: Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was -0.04 ± 0.25 cm in the therapy group compared with -0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group. CONCLUSION: Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement.

Azienda Ospedaliera dei Colli Monaldi Napoli Italy

Boston Scientific Corporation St Paul MN USA

Cardiovascular Division Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Department of Cardiology and Cardiovascular Clinical Research Center Fondazione IRCCS Policlinico San Matteo Pavia Italy

Department of Cardiology Catharina Hospital Eindhoven The Netherlands

Department of Cardiology Homolka Hospital Prague Czech Republic

Department of Cardiology Liverpool Heart and Chest Liverpool UK

Department of Cardiology University Medical Center Utrecht The Netherlands

Division of Cardiology Otto von Guericke Universität Magdeburg Magdeburg Germany

Guidant Europe Diegem Belgium

Heart Centre Brandenburg Hospital Bernau Germany

Inserm CIC 1433 Centre Hospitalier Universitaire Department of Cardiology Nancy University Université de Lorraine Nancy France

Thorax Institute Hospital Clinic Barcelona Spain

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Nat Rev Cardiol. 2014 Nov;11(11):621. doi: 10.1038/nrcardio.2014.150. PubMed

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Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation. 1997;96:3450–3458. PubMed

Ponikowski P, Anker SD, Chua TP, Szelemej R, Piepoli M, Adamopoulos S, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1997;79:1645–1650. PubMed

Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation. 2004;109:120–124. PubMed

Sabbah HN, Ilsar I, Zaretsky A, Rastogi S, Wang M, Gupta RC. Vagus nerve stimulation in experimental heart failure. Heart Failure Rev. 2011;16:171–178. PubMed PMC

Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, et al. Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Failure. 2008;10:884–891. PubMed

De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011;32:847–855. PubMed

Members ATF, McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Böhm M, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–1847. PubMed

De Ferrari GM, Tuinenburg AE, Ruble S, Brugada J, Klein H, Butter C, et al. Rationale and study design of the NEuroCardiac TherApy foR Heart Failure Study: NECTAR-HF. Eur J Heart Failure. 2014;16:692–699. PubMed PMC

Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials. 2004;25:143–156. PubMed

DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia. 2000;41:1195–1200. PubMed

Zhang Y, Popovic ZB, Bibevski S, Fakhry I, Sica DA, Van Wagoner DR, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Failure. 2009;2:692–699. PubMed

Hamann JJ, Ruble SB, Stolen C, Wang M, Gupta RC, Rastogi S, et al. Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure. Eur J Heart Failure. 2013;15:1319–1326. PubMed PMC

Zannad F, Stough WG, Pina IL, Mehran R, Abraham WT, Anker SD, et al. Current challenges for clinical trials of cardiovascular medical devices. Int J Cardiol. 2014;175:30–37. PubMed

Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. New Engl J Med. 2014;370:1393–1401. PubMed

Schulz KF, Grimes DA, Altman DG, Hayes RJ. Blinding and exclusions after allocation in randomised controlled trials: survey of published parallel group trials in obstetrics and gynaecology. BMJ (Clin Res Ed) 1996;312:742–744. PubMed PMC

De Ferrari GM, Schwartz PJ. Vagus nerve stimulation: from pre-clinical to clinical application: challenges and future directions. Heart Fail Rev. 2011;16:195–203. PubMed

Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. J Neurosurg. 2011;115:1248–1255. PubMed

Castoro MA, Yoo PB, Hincapie JG, Hamann JJ, Ruble SB, Wolf PD, et al. Excitation properties of the right cervical vagus nerve in adult dogs. Exp Neurol. 2011;227:62–68. PubMed

Yoo PB, Lubock NB, Hincapie JG, Ruble SB, Hamann JJ, Grill WM. High-resolution measurement of electrically-evoked vagus nerve activity in the anesthetized dog. J Neural Eng. 2013;10:026003. PubMed

Sabbah HN, Stein PD, Kono T, Gheorghiade M, Levine TB, Jafri S, et al. A canine model of chronic heart failure produced by multiple sequential coronary microembolizations. Am J Physiol. 1991;260:H1379–H1384. PubMed

De Ferrari G, Schwartz P. Vagus nerve stimulation: from pre-clinical to clinical application: challenges and future directions. Heart Failure Rev. 2011;16:195–203. PubMed

Dicarlo L, Libbus I, Amurthur B, Kenknight BH, Anand IS. Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF Study. J Cardiac Failure. 2013;19:655–660. PubMed

Hauptman PJ, Schwartz PJ, Gold MR, Borggrefe M, Van Veldhuisen DJ, Starling RC, et al. Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J. 2012;163:954–962. e1. PubMed

Verhaert D, Grimm RA, Puntawangkoon C, Wolski K, De S, Wilkoff BL, et al. Long-term reverse remodeling with cardiac resynchronization therapy results of extended echocardiographic follow-up. J Am Coll Cardiol. 2010;55:1788–1795. PubMed

Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol. 2012;30:313–335. PubMed PMC

Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. 2002;195:781–788. PubMed PMC

Tracey KJ. The inflammatory reflex. Nature. 2002;420:853–859. PubMed

Tracey KJ. Reflex control of immunity. Nat Rev Immunol. 2009;9:418–428. PubMed PMC

Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–388. PubMed

Martelli D, Yao ST, McKinley MJ, McAllen RM. Reflex control of inflammation by sympathetic nerves, not the vagus. J Physiol. 2014;592:1677–1686. PubMed PMC

Guzzetti S, Rovere MTL, Pinna GD, Maestri R, Borroni E, Porta A, et al. Different spectral components of 24 h heart rate variability are related to different modes of death in chronic heart failure. Eur Heart J. 2005;26:357–362. PubMed

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