Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated for therapy in patients with resistant hypertension. However, patients with significant impairment of renal function have been largely excluded from clinical trials. Thus, there is little information on blood pressure and renal responses to baroreflex activation in subjects with advanced chronic kidney disease, which is common in resistant hypertension. Changes in arterial pressure and glomerular filtration rate were determined in 5 dogs after combined unilateral nephrectomy and surgical excision of the poles of the remaining kidney to produce ≈70% reduction in renal mass. After control measurements, sodium intake was increased from ≈45 to 450 mol/d. While maintained on high salt, animals experienced increases in mean arterial pressure from 102±4 to 121±6 mm Hg and glomerular filtration rate from 40±2 to 45±2 mL/min. During 7 days of baroreflex activation, the hypertension induced by high salt was abolished (103±6 mm Hg) along with striking suppression of plasma norepinephrine concentration from 139±21 to 81±9 pg/mL, but despite pronounced blood pressure lowering, there were no significant changes in glomerular filtration rate (43±2 mL/min). All variables returned to prestimulation values during a recovery period. These findings indicate that after appreciable nephron loss, chronic suppression of central sympathetic outflow by baroreflex activation abolishes hypertension induced by high salt intake. The sustained antihypertensive effects of baroreflex activation occur without significantly compromising glomerular filtration rate in remnant nephrons.

HomeHypertensionVol. 65, No. 1Design Considerations for Clinical Trials of Autonomic Modulation Therapies Targeting Hypertension and Heart Failure Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBDesign Considerations for Clinical Trials of Autonomic Modulation Therapies Targeting Hypertension and Heart Failure Faiez Zannad, Wendy Gattis Stough, Felix Mahfoud, George L. Bakris, Sverre E. Kjeldsen, Robert S. Kieval, Hermann Haller, Nadim Yared, Gaetano M. De Ferrari, Ileana L. Piña, Kenneth Stein and Michel Azizi Faiez ZannadFaiez Zannad From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Wendy Gattis StoughWendy Gattis Stough From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Felix MahfoudFelix Mahfoud From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , George L. BakrisGeorge L. Bakris From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Sverre E. KjeldsenSverre E. Kjeldsen From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Robert S. KievalRobert S. Kieval From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Hermann HallerHermann Haller From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Nadim YaredNadim Yared From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Gaetano M. De FerrariGaetano M. De Ferrari From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Ileana L. PiñaIleana L. Piña From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). , Kenneth SteinKenneth Stein From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). and Michel AziziMichel Azizi From the Department of Cardiology, INSERM, Center d'Investigation Clinique 9501 and Unité 961, Center Hospitalier Universitaire, Nancy University, Université de Lorraine, Nancy, France (F.Z.); Departments of Pharmacy Practice and Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC (W.G.S.); Klinik für Innere Medizin III, Universtitätsklinikum des Saarlandes, Homburg/Saar, Germany (F.M.); Harvard-MIT Biomedical Engineering, Institute of Medical Engineering and Science, Cambridge, MA (F.M.); ASH Comprehensive Hypertension Center, The University of Chicago Medicine, IL (G.L.B.); Oslo University Hospital, Ullevaal, Institute for Clinical Medicine, University of Oslo, Oslo, Norway (S.E.K.); CVRx, Inc, Minneapolis, MN (R.S.K., N.Y.); Department of Nephrology, Medizinische Hochschule Hannover, Hannover, Germany (H.H.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (G.M.D.F.); Department of Medicine, Division of Cardiology, Montefiore-Einstein Medical Center, Bronx, NY (I.L.P.); Boston Scientific Corporation, St. Paul, MN (K.S.); Université Paris Descartes, Paris, France (M.A.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Hypertension Unit, Paris, France (M.A.); and Inserm CIC 9201, Paris, France (M.A.). Originally published27 Oct 2014https://doi.org/10.1161/HYPERTENSIONAHA.114.04057Hypertension. 2015;65:5–15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 Several device-based approaches to autonomic nervous system modulation are under investigation for the treatment of resistant hypertension and heart failure (Table 1).1 This line of research has evolved from the recognition that these diseases originate or are worsened by excess sympathetic activity and loss of parasympathetic tone.9–13 Drug therapies, including β-blockers, α-blockers, and centrally acting antihypertensive drugs, can modulate these neurohormonal systems, but they are often insufficient to control blood pressure (BP) or are limited by side effects or nonadherence. Technological innovations have produced devices that modulate the autonomic nervous system, including renal denervation, carotid baroreceptor stimulation, vagal nerve stimulation, and spinal cord stimulation.Table 1. Select Completed and Ongoing Clinical Trials of Autonomic Modulation Therapies in Hypertension and Heart FailureTrialNo. and PopulationBlindingControl GroupPrimary End PointLength of Follow-UpResultsRenal denervation SWAN HTNCT01417221200Resistant hypertensionOpen-labelMedical managementComposite of MI, stroke, HF, and sudden death3 yOngoing EnligHTN-INCT0143822947Resistant hypertensionOpen-labelSingle armSafety and office BP6 moOngoing SYMPLICITY HTN-321,65NCT01418261535Resistant hypertensionSingle-blind (masked-procedure, randomization occurs at time of renal angiogram, patients and research staff assessing BP blinded)Medical management plus sham procedure (renal angiogram only)Change in office-based BP6 moMean change in SBP renal denervation: −14.13±23.93 mm Hg vs sham control −11.74±25.94 mm Hg (both P<0.001 compared with baseline)Difference −2.39 mm Hg; 95% CI, −6.89 to 2.12; P=0.26 ReSET-2NCT0176248870Resistant hypertensionDouble-blind (except for operator)Medical management plus sham procedure (renal angiogram only)Change from baseline in daytime SBP (24 h ABPM)6 moOngoing DENER-HTNNCT01570777120Resistant hypertensionOpen-labelOptimal medical therapyMean diurnal SBP assessed by ABPMCost-effectiveness6 moOngoing EnligHTNment25000 Patients with SBP >160 mm HgOpen-labelOptimal medical therapyMI, stroke, hospitalization for heart failure, and death72 moOngoing INSPIRED62240Resistant hypertension (≥140/90 office and ≥130/80 24 ABPM on ≥3 antihypertensive drugs; aldosterone antagonist or β-blocker should be attempted unless contraindicated)Open-labelOptimal medical therapyBaseline adjusted between group difference in 24 h SBP and in eGFR36 moOngoing REACHNCT01639378100Chronic heart failure, NYHA class II–IV, LVEF <40%Double-blindSham procedure+optimal medical therapySymptoms assessed by KCCQ12 moOngoing DIASTOLENCT0158388160Heart failure with normal LVEF (≥50%)Controlled HTN (<140/90 mm Hg by 24 h ABPM on ≥2 antihypertensive drugs)Open-labelNo details on clinicaltrials.govChange from baseline in E/E′12 moOngoing SWAN HFNCT01402726200NYHA class II–IV, LVEF ≤40% or ≥45%Open-labelMedical managementComposite of MI, HF, sudden death, and cardiogenic death3 yOngoing RE-ADAPT-HFNCT02085668100NYHA class II–III, LVEF ≤40%, SBP >90 mm HgRandomizedMedical managementSafety3 yOngoing SYMPLICITY HFFeasibilityNCT0139219640NYHA class II–III, LVEF <40%, GFR 30–75 mL/min per 1.73 m2Open-labelSingle armSafety6 moOngoingBaroreceptor activation therapy DEBuT-HT3FeasibilityNCT0071019045Resistant hypertensionOpen-labelSingle arm (nonrandomized cohort of 10 subjects who were eligible but declined participation used to compare BP efficacy and SAEs)Safety and efficacy (mean change in office BP) 2 ySBP −33±8 mm Hg (P=0.001)DBP −22±6 mm Hg (P=0.002)SBP −53 mm Hg (P<0.001), DBP 30 mm Hg (P<0.001) at 4 y4 Rheos Feasibility5NCT0107718010Resistant hypertensionOpen-labelSingle armSafety and peri-implantation hemodynamic effectivenessn/aSafe and associated with short-term significant BP reductions Rheos Pivotal29,30NCT00442286265Resistant hypertensionDouble-blindDevice off5 prespecified coprimary end points: acute efficacy, sustained efficacy, procedural safety, BAT safety, and device safety12 moAcute efficacy: 54% responders (device on) vs 46% responders (device off); P=0.9742% (device on) vs 24% (device off) achieved SBP ≤140 mm Hg at 6 mo (P=0.005)Sustained efficacy 88% at 12 mo (P<0.001) XR-1 BAT6NCT0147183440Resistant hypertensionOpen-labelSingle arm (safety data compared with first-generation device)Change from baseline in systolic blood pressure6 moSBP reduced by 26 mm Hg at 6 mo (P<0.001)6 patients postrenal nerve ablation showed statistically equivalent SBP reduction of 22 mm Hg XR-1 HF7NCT01471860150Symptomatic HFOpen-labelMedical management aloneChange from baseline in LVEF6 moOngoing Barostim HOPE4HF8NCT0172016060LVEF ≤35%, NYHA class III HFOpen-labelMedical management aloneHeart failure metric improvements from baseline12 moOngoingVagal nerve stimulation ACES-IINCT014584839HypertensionOpen-labelSingle armChange in SBP during electric stimulationIntraoperativeFeasibility/proof of concept CardioFit94NCT0046101932NYHA class II–IV, LVEFOpen-labelSingle armSafety and tolerability6 moSafe and well tolerated, additional trials warranted INOVATE-HF97NCT01303718650NYHA class III, LVEF <40%, QRS <120 msOpen-labelBlinded CECOptimal medical therapyTime to first all-cause death or unplanned HF hospitalization18 moOngoing NECTAR-HFNCT01385176250NYHA class III, LVEF ≤35%, QRS ≤130 msDouble-blindDevice off for first 6 mo after randomization, and then device onChange in LVESDAll-cause mortality6 mo (LVESD)18 mo (all-cause mortality)Ongoing ANTHEM-HFNCT0182388760NYHA class II/III, reduced LVEF with cardiac dilatationOpen-labelRight vs left-sided cervical vagal nerve stimulationChange in LVESV, LVESD, and LVEF6 moOngoingABPM, ambulatory blood pressure monitoring; ACES II, Acute Carotid Sinus Endovascular Stimulation II Study; ANTHEM-HF, Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure; BAT, baroreflex activation therapy; BP, blood pressure; CEC, clinical events committee; CI, confidence interval; DBP, diastolic blood pressure; DEBuT-HT, Device-Based Therapy in Hypertension Trial; DENER-HTN, Renal Denervation in Hypertension; DIASTOLE, Denervation of the Renal Sympathetic Nerves in Heart Failure With Normal LV Ejection Fraction; eGFR, estimated glomerular filtration rate; EnligHTN-I, Ablation-Induced Renal Sympathetic Denervation Trial; GFR, glomerular filtration rate; HF, heart failure; HOPE4HF, Health Outcomes Prospective Evaluation for Heart Failure; INOVATE-HF, Increase of Vagal Tone in Chronic Heart Failure; INSPIRED, Intravascular Renal Denervation for Management of Drug-Resistant Hypertension; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic diameter; LVESV, left ventricular end systolic volume; MI, myocardial infarction; NECTAR-HF, Neural Cardiac Therapy for Heart Failure; NYHA, New York Heart Association; REACH, Renal Artery Denervation in Chronic Heart Failure; RE-ADAPT-HF, Renal Denervation in Patients With Chronic Heart Failure; ReSET-2, Renal Denervation in Treatment Resistant Hypertension; SAE, serious adverse events; SBP, systolic blood pressure; SWAN HF, Renal Sympathetic Modification in Patients With Heart Failure; SWAN HT, Renal Sympathetic Modification in Patients With Essential Hypertension; and XR-1 BAT, Barostim Neo System in the Treatment of Resistant Hypertension.In Europe, several autonomic modulation therapy devices have received the Conformité Européenne mark.14 US Food and Drug Administration evaluation of these devices is ongoing. The need for adequately powered, randomized, controlled studies with longer follow-up to capture definitive evidence of safety and effectiveness has been noted.14–17The 9th and 10th Global Cardiovascular Clinical Trialists Forum (Paris, France, December 2012 and December 2013) convened a panel of primary investigators of ongoing trials, along with biostatisticians, National Institutes of Health scientists, European, and United States regulators, and medical device and pharmaceutical industry scientists to discuss the strengths and limitations of current clinical trials, optimal designs for future trials, approvability of new devices, and considerations for integrating these technologies into practice. This article summarizes the key discussion points and identifies knowledge gaps in this field that need to be addressed by additional research.Overview of Autonomic Modulation TherapyThe mechanisms of autonomic modulation are complex, and a comprehensive review of these mechanisms is outside the scope of this article. Briefly, all existing strategies aim to decrease central sympathetic outflow. Renal denervation is hypothesized to achieve this objective through ablation of renal afferent and efferent sympathetic nerves, thereby reducing sympathetic efferent signaling to the kidneys and other organ systems.18 Baroreceptor activation therapy stimulates baroreceptors in the carotid sinus via a lead connected to an implantable pulse generator; these baroreceptors play a major role in sympathetic and parasympathetic autonomic regulation.19 Vagal nerve stimulation activates vagal efferent and afferent fibers. These actions also result in reduced central sympathetic drive.12,20Autonomic Modulation Therapy Clinical Trials: Methodologic ChallengesSeveral characteristics of autonomic modulation devices pose challenges for clinical trial design. First, the introduction of bias can be problematic because these trials are difficult, but not impossible, to blind. Second, the mechanism of treatment effect is difficult to establish. Although a reduction in central sympathetic activity is the proposed mechanism of action, generating proof that sympathetic outflow is reduced either acutely post procedure or during long-term follow-up can be difficult, especially in a large-scale clinical study.18 Third, the adequacy of surrogate end points (eg, changes in BP or cardiac dimensions) to reflect clinical benefits in trials of autonomic modulation devices has been debated. Finally, safety assessments are of key importance because these devices require invasive procedures, the interventions may be irreversible (renal denervation), or require a repeat invasive procedure when stimulator replacement is necessary. Cumulative data from the Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3) study21 and from the SYMPLICITY International Registry22 show a low rate of short-term adverse events with renal denervation delivered by the Symplicity (Medtronic, Minneapolis, MN) catheter, but the number of patients with long-term follow-up is currently insufficient to assure a robust level of safety.BlindingBlinding enhances the scientific internal validity of trial results by minimizing the influence of potential biases.23 However, blinding trials of devices that deliver autonomic modulation therapy is complex, requiring either sham procedures (renal denervation) or device implantation in both active and control arms with the device turned off in the control group (baroreflex or vagal nerve stimulation). Even when a trial is blinded by design, the potential for unblinding exists because of stimulation-related adverse effects such as dysphonia that may occur with vagal nerve stimulation or baroreceptor activation therapy.24 The ethics, costs, low acceptability rate by both patients and physicians (especially when therapies have been approved), and operational challenges associated with blinding have led to the use of open-label or single-arm designs for many feasibility trials of autonomic modulation therapies (Table 1).The lack of blinding and potential introduction of bias is problematic in these trials that typically evaluate a physiological measure (eg, BP) or symptoms as the primary end point.23,25 This concern is particularly relevant when BP is measured at the office and not by ambulatory BP monitoring (ABPM). BP can be affected by many factors including regression to the mean, placebo effect, patient anxiety, knowledge of the procedure, anticipation, adherence to lifestyle measures and treatment, or other changes in behavior (eg, lifestyle modification by study subjects, known as Hawthorne effect), or physicians' expectations. Knowledge of treatment allocation may also influence physicians' decisions to use add-on therapies, subject drop-out rates, and adverse event reporting.26 Because bias often results in an overestimation of treatment effects,23 the results of unblinded feasibility studies may lead to erroneous event rate assumptions that negatively affect the design of pivotal trials.When feasible, trials should be

Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease.

Background— Autonomic abnormalities exist in heart failure and contribute to disease progression. Activation of the carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electric activation of the CSB improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic heart failure. Methods and Results— Studies were performed in 14 dogs with coronary microembolization-induced heart failure (LV ejection fraction ≈25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos System (CVRx Inc, Minneapolis, Minn) and 6 were not and served as controls. All dogs were followed for 3 months, and none received other background therapy. During follow-up, treatment with CSB increased LV ejection fraction 4.0±2.4% compared with a reduction in control dogs of −2.8±1.0% ( P <0.05). Similarly, treatment with CSB decreased LV end-systolic volume −2.5±2.7 mL compared with an increase in control dogs of 6.7±2.9 mL ( P <0.05). Compared with control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac β 1 -adrenergic receptors, β-adrenergic receptor kinase, and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy. Conclusions— In dogs with advanced heart failure, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.

Le système Rheos™ est un système implantable d’activation du baroréflexe du sinus carotidien comprenant un générateur d’impulsion et des électrodes implantées bilatéralement au niveau du sinus carotidien (ESC) qui est actuellement en cours d’évaluation dans des études prospectives pour le traitement de l’hypertension artérielle résistante au traitement médical. Nous avons évalué l’intégrité structurale de la carotide après implantation d’ESC.

Background: The Rheos (TM) System is a chronically implanted carotid sinus baroreflex activating system with a pulse generator and bilateral perivascular carotid sinus leads (CSLs) that is being evaluated in prospective clinical trials for the treatment of drug-resistant hypertension. We evaluated carotid artery structural integrity after implantation of the CSLs.Methods: To assess the effect of chronic CSL attachment, 29 CSLs were implanted on the common carotid arteries of eight sheep. The studies were terminated at 3 and 6 months postimplantation to assess anatomic and histologic changes. Additionally, 10 patients with resistant hypertension were enrolled in the Rheos Multicenter Feasibility Trial. Duplex ultrasound (DUS) was performed before device implantation and at 1 and 4 months postimplantation in this patient cohort. An independent core laboratory assessed all DUSs.Results: Ovine carotid angiography revealed no significant stenoses, while anatomic and histologic evaluations demonstrated electrode encapsulation in a thin layer of connective tissue with no evidence of stenosis, erosion, or inflammation. DUS evaluation revealed no significant increase in peak systolic velocities of the common and internal carotid arteries 1 and 4 months after initial implantation, indicating a lack of injury, remodeling, or stenosis.Conclusion: The current data suggest that the CSLs used with the Rheos System are not associated with the development of carotid stenosis or injury. These short-term data support the concept of CSL placement and merit long-term investigation in a larger multicenter prospective trial.