- Email: [email protected]
Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment (SCS HEART study): First-in-man experience
Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment (SCS HEART study): First-in-man experience Hung-Fat Tse, MD, PhD,* Stuart Turner, MD, PhD,† Prashanthan Sanders, MD, PhD, FHRS,‡ Yuji Okuyama, MD, PhD,§ Katsuhito Fujiu, MD, PhD,¶ Chi-Wai Cheung, MD,* Marc Russo, MD, FHRS,║ Matthew D.S. Green, MD,# Kai-Hang Yiu, MD,* Peter Chen, PhD,** Chika Shuto, OMD,** Elizabeth O.Y. Lau, PhD,** Chung-Wah Siu, MD* From the *University of Hong Kong, Queen Mary Hospital, Hong Kong, †John Hunter Hospital, Newcastle, Australia, ‡Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia, §Osaka University Hospital, Osaka, Japan, ¶University of Tokyo Hospital, Tokyo, Japan, ║ Hunter Pain Clinic, Newcastle, NSW, Australia, #Pain Medicine of South Australia, Ashford Private Hospital, Welland, Australia, and **St. Jude Medical, Inc, Irvine, USA. BACKGROUND Preclinical studies suggest that neuromodulation with thoracic spinal cord stimulation (SCS) improves left ventricular (LV) function and remodeling in systolic heart failure (HF). OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of a SCS system for the treatment of systolic HF. METHODS We performed a prospective, multicenter pilot trial in patients with New York Heart Association (NYHA) class III HF, left ventricular ejection fraction (LVEF) 20%–35%, and implanted defibrillator device who were prescribed stable optimal medical therapy. Dual thoracic SCS leads were used at the T1–T3 level. The device was programmed to provide SCS for 24 hours per day (50 Hz at pulse width 200 μs).
Failure Questionnaire (42 ⫾ 26 vs 27 ⫾ 22, P ¼ .026; 12/17 improved); peak maximum oxygen consumption (14.6 ⫾ 3.3 vs 16.5 ⫾ 3.9 mL/kg/min, P ¼ .013; 10/15 improved); LVEF (25% ⫾ 6% vs 37% ⫾ 8%, P o .001; 14/16 improved); and LV end-systolic volume (174 ⫾ 57 vs 137 ⫾ 37 mL, P ¼ .002; 11/16 improved) but not in N-terminal prohormone brain natriuretic peptide. No such improvements were observed in the 4 nontreated patients. CONCLUSION The results of this first-in-human trial suggest that high thoracic SCS is safe and feasible and potentially can improve symptoms, functional status, and LV function and remodeling in patients with severe, symptomatic systolic HF. KEYWORDS Spinal cord stimulation; Heart failure
RESULTS We enrolled 22 patients from 5 centers:17 patients underwent implantation of a SCS device and 4 patients who did not fulfill the study criteria served as nontreated controls. No deaths or device–device interactions were noted during the 6-month period in the 17 SCS-treated patients. Fifteen of 17 completed the efficacy endpoint assessments: composite score improved by 4.2 ⫾ 1.3, and 11 patients (73%) showed improvement in Z4 of 6 efficacy parameters. There was significant improvement in NYHA class (3.0 vs 2.1, P ¼ .002; 13/17 improved); Minnesota Living with Heart
ABBREVIATIONS HF ¼ heart failure; LV ¼ left ventricle; LVEF ¼ left ventricular ejection fraction; LVESV ¼ left ventricular endsystolic volume; MLHFQ ¼ Minnesota Living with Heart Failure Questionnaire; NT-proBNP ¼ N-terminal prohormone brain natriuretic peptide; NYHA ¼ New York Heart Association; SCS ¼ spinal cord stimulation
Introduction
the aging population and an increasing number of patients who survive acute myocardial infarction.1 Progressive left ventricular (LV) dilation, eccentric hypertrophy, and infarct scar thinning postmyocardial infarction ultimately result in altered LV geometry. This adverse LV remodeling contributes to progressive HF that results in a poor clinical outcome for postmyocardial infarction patients.2 In the presence of HF, dysregulation of the autonomic nervous system, characterized by increased sympathetic tone and decreased parasympathetic tone, is associated with progressive HF and increased mortality.3–5 An understanding of the pivotal
Heart failure (HF) is a leading global cause of morbidity and mortality, with an incidence that continues to rise because of
This study was funded by the Center for Innovation and Strategic Collaboration (CISC), St. Jude Medical Inc, USA. Drs. Tse, Sanders, Okuyama, Fujiu, Yiu, and Siu received an honorarium and research grant from the CISC, St. Jude Medical Inc, USA. ClinicalTrials.gov identifier NCT01362725. Address reprint requests and correspondence: Dr. Hung-Fat Tse, Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
(Heart Rhythm 2015;12:588–595) I 2015 Heart Rhythm Society. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2014.12.014
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role of the imbalance of the autonomic nervous system in the progression of HF has prompted the development of different nonpharmacologic therapeutic approaches, including vagal stimulation and spinal cord stimulation (SCS), which can modulate cardiac autonomic tone.6–9 SCS with an implantable device has been used clinically for more than 30 years to relieve angina symptoms in patients with severe coronary artery disease.10,11 In preclinical studies, short-term thoracic SCS reduced the incidence of ischemic ventricular tachyarrhythmias.12 Our recent acute experimental studies in a porcine model of HF have also demonstrated that dual thoracic SCS leads targeted at the midline and left of the midline at the T1–T3 level improve regional and global LV contractile function in HF without increasing myocardial oxygen consumption.13 These findings concur with the results of improving global myocardial contractile function after bilateral stellate ganglia stimulation.14 Long-term SCS has also improved left ventricular ejection fraction (LVEF) in a canine model of HF compared with a control group of animals treated with an angiotensin-converting enzyme inhibitor and beta-blocker.15 These findings suggest that thoracic SCS can improve HF symptoms and protect against ventricular arrhythmias. Nevertheless, human data on the safety and efficacy of SCS as a treatment of HF are limited. We performed a prospective, multicenter pilot clinical study over a 6-month period to evaluate the safety and efficacy of an implantable SCS system in patients with severe symptomatic HF despite optimal medical therapy.
Methods Study design and participants We recruited patients aged 18 years or older with New York Heart Association (NYHA) class III or ambulatory class IV HF, LV dysfunction (LVEF 20%–35%), LV end-diastolic diameter 55–80 mm, and implantable cardiac defibrillator, on stable (490 days) optimal medical (including coronary revascularization) and device therapies (including cardiac resynchronization therapy) for HF. Patients were excluded if they had any of the following: life expectancy o1 year, history of prior spinal cord stimulator implantation, polyneuropathy, NYHA class IV HF on intravenous inotropic therapy, chronic refractory angina or peripheral vascular pain, persistent atrial fibrillation, or significant valvular heart disease. The research protocol (see Supplemental file: Online Appendix Protocol) was approved by the relevant institutional review board of the institutions, and all participants provided written informed consent. The protocol was registered at ClinicalTrials.gov Identifier NCT01362725. Patients who refused to undergo cardiac defibrillator implantation or who were not eligible because of unknown compatibility of an implanted cardiac defibrillator (devices not from St. Jude Medical Inc) with the SCS system used in this study but who otherwise satisfied the inclusion criteria served as controls.
SCS implant procedure Eligible patients underwent SCS lead and pulse generator implantation using a commercially available neurostimulation
589 system (Eon Mini Neurostimulation System, St. Jude Medical, Plano, TX, USA) under local anesthetic, sterile conditions, and fluoroscopic guidance. Two epidural needles, inserted at the required level using the paramedian approach, were advanced into the epidural space. Two Octrode percutaneous leads (8 electrodes each, St. Jude Medical) were introduced into the epidural space via each epidural needle or lead introducer to cover the T1–T3 level: the first Octrode lead targeted the midline and the second Octrode lead to the left of the midline (Figure 1). Leads were tunneled subcutaneously below the left costal arch and connected to the permanent implantable pulse generator placed in a subcutaneous pocket in the lateral abdominal region. After implantation, a stimulation test was performed in all patients to confirm active SCS-induced paresthesia, and the device was programmed to adequately cover the chest area. Chronic SCS was recommended to be performed at 90% to 110% of the paresthesia threshold (range 1–15 mA) for 24 hours per day at 50 Hz and pulse width 200 microseconds, which has been shown by recent animal studies to provide optimal SCS.16 Patients were followed up at week 1 and 1, 3, 6, 12, 18, and 24 months after SCS device implantation. Physicians were advised whenever possible not to alter drug therapy for the first 6 months.
Study endpoints The primary safety endpoints were death due to ventricular tachyarrhythmia or sudden unexpected death, myocardial infarction, or hospitalization for HF during the first 6 months. Secondary safety endpoints included SCS or implantable defibrillator malfunction due to device–device interaction, incidence of ventricular tachyarrhythmia, and long-term safety of the SCS implant at 24 months based on the safety markers stated in the primary safety endpoint. The primary efficacy endpoint at 6 months was based on the composite endpoint score that provides a single efficacy parameter in which concordant changes across multiple parameters typically assessed in HF intervention, including device therapies, are required to demonstrate efficacy and reduce the chance of false positive results.17–22 In this pilot study, the composite score was based on 6 efficacy parameters measured at baseline and at 6 months: changes in NYHA class (Z1 class), Minnesota Living with Heart Failure Questionnaire score (MLHFQ Z10 points), peak maximum oxygen consumption (VO2max Z1 mL/kg/min) assessed by cardiopulmonary exercise, N-terminal prohormone brain natriuretic peptide (NT-proBNP Z300 pg/mL absolute change or 35% relative change), echocardiography-derived LVEF (Z5% absolute change), and left ventricular end-systolic volume (LVESV Z20 mL absolute change or 10% relative change). The concordant changes in these endpoints were also prospectively defined as the primary efficacy endpoint (for details see Online Supplemental Methods). Changes in each individual parameter within the SCStreated group at baseline vs 6 months and changes in the control group also were determined. All exercise data and echocardiographic images were labeled with study
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Figure 1 A: Radiologic image of the 2 octropolar electrodes with 1 targeted at the midline and the other targeted at left of the midline to cover the T1–T3 level. B: Flow diagram of patient recruitment. HF ¼ heart failure; SCS ¼ spinal cord stimulation; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.
identification and sent to the imaging core at the University of Hong Kong for blinded assessment (in terms of timing and treatment group assignment) by a single experienced technician and operator, respectively.
Statistical analysis In this pilot clinical study, the safety and efficacy of the SCS were the key components for an intended population of 15–20 patients. Results are given as mean ⫾ SD. All reported P values are 2-sided and have not been adjusted for multiple comparisons. Paired comparison of changes at 6 months from baseline within the SCS-treated group were performed using a paired t test if normality was established or the nonparametric Wilcoxon signed rank test if normality could not be established. Because of the small sample size in the treated and
nontreated groups, comparison between groups and adjustment for multiple comparisons were not performed. Statistical analyses were performed using SPSS-19.0 and GraphPad Prism 6.0 software packages (GraphPad Software, Inc. USA).
Role of the funding source This study was funded by the Center for Innovation and Strategic Collaboration (CISC), St. Jude Medical, Inc, USA. The funding source was responsible for the execution of the study. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.
Results Between August 2011 and April 2013, 22 patients from 1 center in Hong Kong (n ¼ 13), 2 centers in Australia (n ¼ 6),
Tse et al Table 1
Thoracic Spinal Cord Stimulation for Heart Failure
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Baseline characteristics of patients SCS-treated group (n ¼ 17)
Sex (male) [n (%)] Age (years) Coronary artery disease [n (%)] Hypertension [n (%)] Diabetes [n (%)] Mitral regurgitation [n (%)] Paroxysmal atrial fibrillation [n (%)] Ventricular tachyarrhythmia [n (%)] Heart failure treatment [n (%)] Angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker Aldosterone antagonist Beta-blocker Diuretic Cardiac glycosides Cardiac resynchronization therapy Baseline efficacy parameters NYHA class III [n (%)] MLHFQ total score (mean) VO2max (mL/kg/min) NT-proBNP (pg/mL) LVEF (%) LVESV (mL)
17 (100%) 62.9 (10.1) 11 (65%) 10 (59%) 8 (47%) 8 (47%) 8 (47%) 9 (53%)
SCS nontreated group (n ¼ 4) 4 (100%) 61.7 (5.8) 2 (50%) 2 (50%) 1 (25%) 1 (25%) 2 (50%) 1 (25%)
16 (94%)
4 (100%)
7 (41%) 15 (88%) 10 (59%) 5 (29%) 8 (47%)
2 (50%) 4 (100%) 2 (50%) 1 (25%) 0 (0)
17 (100%) 41.9 (26.2) 14.4 (3.2) 2364 (2303) 24.9 (6.3) 173.6 (56.7)
4 (100%) NA 16.4 (2.6) 1098 (617) 33.5 (1.3) 128.5 (40.4)
Data are given as n (%) or mean (SD). LVEF ¼ left ventricular ejection fraction; LVESV ¼ left ventricular end-systolic volume; MLHFQ ¼ Minnesota Living with Heart Failure Questionnaire; NA ¼ not available; NT-proBNP ¼ N-terminal prohormone brain natriuretic peptide; NYHA ¼ New York Heart Association; SCS ¼ spinal cord stimulation; VO2max ¼ peak maximum oxygen consumption.
and 2 centers in Japan (n ¼ 3) were screened, and 17 eligible patients underwent SCS device implantation (SCS-treated group) (Figure 1B). The remaining 5 patients did not receive SCS because of refusal to undergo cardiac defibrillator implantation (n ¼ 2), presence of an incompatible device (n ¼ 2), or failure to fulfill the inclusion criteria because of low LVEF (n ¼ 1). Of these 5 patients, the 4 who fulfilled the inclusion criteria were designated as nontreated controls. Table 1 lists the demographics, baseline characteristics, and HF treatment regimens of the SCS-treated and control patients. Mean LVEF was 26.6% ⫾ 6.6%, and VO2max was 14.9 ⫾ 3.2 mL/kg/min. Although the inclusion criteria for LVEF based on echocardiographic measurement by the investigators was 20%–35% per protocol, 4 patients had LVEF o20% (range 17%–19%) as determined by the core laboratory. This was a study population with advanced HF. All SCS-treated patients had NYHA class III HF and an implantable cardiac defibrillator at baseline. Eight had not responded to previous cardiac resynchronization therapy. All control group patients also had NYHA class III HF, but only 2 had an implantable cardiac defibrillator.
Safety All SCS-treated patients underwent successful implantation of SCS leads and pulse generator. There were no acute complications, and implantation of the second lead failed in only 1 subject. Three patients who reported neck or back pain after SCS implantation required reprogramming of the device: 1 underwent lead repositioning 13 days after implantation to correct inappropriate motor stimulation.
Failure of the device battery with consequent battery replacement occurred at 6 months in 1 patient, and in another patient the device was reprogrammed to off after 2.4 months at the discretion of the physician because of lack of efficacy. After 6 months, there were no deaths and no cases of device–device interaction to cause SCS device or implantable cardiac defibrillator malfunction. Nonetheless, 2 patients (12%) experienced ventricular tachyarrhythmia that required intervention, and 2 (12%) were hospitalized for HF. After 18 ⫾ 5 months (range 13–24 months) following SCS implantation, 2 patients, including the patient in whom the device was inactivated at 2.4 months, were hospitalized for a total of 6 occasions for HF and subsequently died of progressive HF at 7.5 and 14.5 months. Overall, 4 patients developed 14 episodes of ventricular tachyarrhythmia that required intervention; all had a history of ventricular tachyarrhythmia before SCS device implantation. Nonetheless, there were incidences of ventricular tachyarrhythmia in 5 and 8 SCS-treated group patients with and without a prior history of ventricular tachyarrhythmia, respectively. No device–device interaction to cause device malfunction was noted at mean follow-up of 16 months after SCS. One patient withdrew from the study at 9 months due to intolerance to SCS because of back and neck paresthesia, and he defaulted from further follow-up. The secondary safety endpoint data at 24 months are pending for the remaining 7 SCS-treated patients.
Efficacy The effects of SCS on the prespecified 6 efficacy domains at 6-month follow-up are listed in Table 2. In the 15
592 Table 2
Heart Rhythm, Vol 12, No 3, March 2015 Changes in clinical efficacy endpoints from baseline to 6 months in SCS-treated patients
Efficacy endpoint NYHA class MLHFQ VO2max NT-proBNP LVEF LVESV
Minimum change from baseline at 6 months *
1 class 10 points* 1.0 mL/kg/min* 300 pg/mL* or 35%† 5%* 20 mL* or 10%†
No. of patients with improved, no change, or worsen from baseline to 6 months based on prespecified minimum change Worsen (–1)
No change (0)
Improved (þ1)
P value comparing paired change from baseline to 6 months‡
1/17 (6%) 1/17 (6%) 0/15 (0%) 4/17 (24%) 0/16 (0%) 0/16 (0%)
3/17 (18%) 4/17 (24%) 5/15 (33%) 6/17 (35%) 2/16 (13%) 5/16 (31%)
13/17 (77%) 12/17 (71%) 10/15 (67%) 7/17 (41%) 14/16 (88%) 11/16 (69%)
.002 .026 .013 .52 o.001 .002
LVEF ¼ left ventricular ejection fraction; LVESV ¼ left ventricular end-systolic volume; MLHFQ ¼ Minnesota Living with Heart Failure Questionnaire; NA ¼ not available; NT-proBNP ¼ N-terminal prohormone brain natriuretic peptide; NYHA ¼ New York Heart Association; SCS ¼ spinal cord stimulation; VO2max ¼ peak maximum oxygen consumption. * Absolute change from baseline. † Relative change from baseline. ‡ P value from Wilcoxon signed rank test, comparing paired values from baseline to 6 months.
SCS-treated patients who completed the efficacy endpoint assessment, the composite score improved by 4.2 ⫾ 1.3, and 11 patients (73%) showed improvement in Z4 of 6 efficacy parameters (Figure 2). Because the MLHFQ score was not available for the control patients, their composite score is not reported. As shown in Figure 3A, NYHA class was almost unchanged in nontreated patients but improved (41 class) in 13 of 17 of the SCS-treated patients (76%; with P ¼ .002 corresponding to the paired comparison between baseline and 6 months after SCS implantation). In the SCS-treated patients, the total mean MLHFQ score decreased (improved) from 41.9 ⫾ 26.2 to 27.2 ⫾ 21.9; P ¼ .026). VO2max increased in the SCS-treated patients from baseline to 6 months (P ¼ .013) but not in the nontreated patients (Figure 3B). There was no significant change in the NTproBNP of the SCS-treated patients from baseline to 6 months (Figure 3C; P ¼ .56). For LV function and
remodeling parameters, LVEF increased (Figure 3D; P o .001) and LVESV decreased (Figure 3E; P ¼ .002) from baseline to 6 months in the SCS-treated patients (see Online Supplementary Video).
Discussion To the best of our knowledge, this is the first human trial to investigate the long-term effects of dual-targeted high thoracic continuous SCS at the T1–T3 level on symptoms, functional capacity, and LV function and remodeling in patients with advanced systolic HF. Our results demonstrate that dual thoracic SCS targeted at the midline and left of the midline at the T1–T3 level is safe and can potentially improve symptoms, functional capacity, and cardiac function in patients with advanced HF. Electrical stimulation of the dorsal column of the spinal cord at a low cervical to high thoracic level is safe
Figure 2 Changes in the primary efficacy endpoints: New York Heart Association (NYHA), Minnesota Living with Heart Failure Questionnaire (MLHFQ), peak maximum oxygen consumption (VO2max), N-terminal prohormone brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-systolic volume (LVESV) after 6 months of spinal cord stimulation.
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Figure 3 Changes in New York Heart Association class (A), peak maximum oxygen consumption (VO2max) (B), N-terminal prohormone brain natriuretic peptide (NT-proBNP) (C), left ventricular ejection fraction (D), and left ventricular end-systolic volume (E) in spinal cord stimulation (SCS)–treated group and nontreated group at 6 months vs baseline. Data are given as mean ⫾ SD.
and provides effective pain relieve in 70% of patients who suffer refractory angina due to severe coronary artery disease.10,11,23,24 In addition to modulation of the nociceptive influx associated with myocardial ischemia,25,26 it has been proposed that SCS can restore the balance between myocardial oxygen supply and demand during ischemia.27 In addition, SCS applied at the C7–C8 and/or T1–T6 level can modulate the reflex activation of the parasympathetic and sympathetic nervous system.26,28 Prior studies suggest that thoracic SCS suppresses peripheral sympathetic tone by modulating intrinsic afferent sensory cardiac neurons related to sympathetic excitation.29,30 SCS also enhances parasympathetic tone as evidenced by slowing of the sinus rate
and prolongation of the atrioventricular nodal conduction time and the ventricular refractory period.31 Thus, SCS may offer a novel therapeutic approach that can restore autonomic balance in HF.8,9 We have demonstrated that long-term SCS using an implantable device is largely safe and well tolerated in this cohort of patients with advanced HF, with no adverse device interaction with an implanted cardioverter defibrillator. After mean follow-up of 16 months, 2 patients (12%), including 1 subject with SCS programmed off at the discretion of the physician, required frequent hospitalization for HF and ventricular tachyarrhythmia and subsequently died of progressive HF. Overall, 24% of patients required intervention
594 for ventricular tachyarrhythmia after SCS. Patients enrolled in this study suffered from advanced HF with an estimated 1year mortality risk of 25% based on their risk profile from other trials.32 The observed number of events in this pilot trial are too low to evaluate the long-term impact of SCS on clinical outcome; nonetheless, the mortality and morbidity rate in this study does not exceed that expected for such HF patients. We observed no new onset of ventricular tachyarrhythmia in any SCS-treated patient or in 56% of those with a history of ventricular tachyarrhythmia. This finding may support recent reports of the potential antiarrhythmic effects of SCS in HF patients.33 In this small study, a clinical composite efficacy endpoint was used to investigate the potential therapeutic effects of SCS to eliminate the potential bias of a single outcome. We observed an overall improvement in this composite endpoint score in SCS-treated patients, and 11 patients showed improvement in Z4 of 6 efficacy parameters. Individual parameters, including NYHA class, MLHFQ, VO2max, LVEF, and LVESV, also significantly improved in SCStreated patients at 6 months. These results concur with findings from preclinical studies13,15 and the initial clinical observation34 that SCS at high thoracic levels improves LV function and remodeling in HF. More recently, the primary results of the DEFEAT-HF study (Determining the Feasibility of spinal cord neuromodulation for the treatment of chronic HF, NCT01112579) have been presented.35 This is the first single blinded randomized controlled trial of SCS for HF. In this study, there was no difference in LVESV index, VO2max, or NT-proBNP between the SCS and control groups at 6 months. Nonetheless, there are significant differences between that trial and the present study. In the DEFEAT-HF study, only intermittent SCS was performed for just 12 hours per day using a single electrode at the T2–T4 level. In the present study, we used continuous high thoracic SCS targeted at the midline and left of the midline at the T1–T3 level. This might account for the different therapeutic efficacies. Nevertheless, the DEFECT-HF study also confirmed that SCS was safe with no increase in major adverse effects observed.
Study limitations This study has limitations. All patients recruited in this study were male, and whether there is any gender difference in the response to SCS remains unclear. Although we noted an improvement in symptoms, functional capacity, and LV function, our study was not a randomized controlled study, and the population was small. Measurements of LVEF and LVESV also could have been affected by loading condition, and LVESV index was not determined. Our results at 6 months may also have been influenced by a placebo effect of SCS. The long-term safety and therapeutic efficacy of chronic SCS will need to be assessed in a future long-term randomized controlled trial with a larger patient cohort.
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Conclusion Our findings indicate that dual-targeted high thoracic SCS appears to be a safe and feasible treatment of HF. The absence of any major acute procedural complications or long-term sequelae is encouraging. Thus, the long-term safety and treatment implications of dual-targeted SCS as a novel device-based therapy for advanced HF warrant further investigation in future randomized controlled trials.
Appendix Supplementary data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2014.12.014.
References 1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics—2014 update: a report from the American Heart Association. Circulation 2014;129:399–410. 2. Savoye C, Equine O, Tricot O, Nugue O, Segrestin B, Sautière K, Elkohen M, Pretorian EM, Taghipour K, Philias A, Aumégeat V, Decoulx E, et al. REmodelage VEntriculaire study group. Left ventricular remodelling after anterior wall acute myocardial infarction in modern clinical practice (from the Remodelage Ventriculaire [REVE] study group. Am J Cardiol 2006;98:1144–1149. 3. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008;118:863–871. 4. Floras JS. Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J Am Coll Cardiol 2009;54:375–385. 5. Schwartz PJ, De Ferrari GM. Sympathetic-parasympathetic interaction in health and disease: abnormalities and relevance in heart failure. Heart Fail Rev 2011;16:101–107. 6. Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A. Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail 2008;10:884–891. 7. De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, Gavazzi A, Sanzo A, Dennert R, Kuschyk J, Raspopovic S, Klein H, et al. CardioFit Multicenter Trial Investigators. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011;32:847–855. 8. Lopshire JC, Zipes DP. Device therapy to modulate the autonomic nervous system to treat heart failure. Curr Cardiol Rep 2012;14:593–600. 9. Singh JP, Kandala J, Camm AJ. Non-pharmacological modulation of the autonomic tone to treat heart failure. Eur Heart J 2014;35:77–85. 10. Murphy DF, Giles KE. Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 1987;28:365–368. 11. Brodison A, Chauhan A. Spinal-cord stimulation in management of angina. Lancet 1999;354:1748–1749. 12. Issa ZF, Zhou X, Ujhelyi MR, Rosenberger J, Bhakta D, Groh WJ, Miller JM, Zipes DP. Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a post-infarction heart failure canine model. Circulation 2005;111:3217–3220. 13. Liu Y, Yue WS, Liao SY, Zhang Y, Au KW, Shuto C, Hata C, Park E, Chen P, Siu CW, Tse HF. Thoracic spinal cord stimulation improves cardiac contractile function and myocardial oxygen consumption in a porcine model of ischemic heart failure. J Cardiovasc Electrophysiol 2012;23:534–540. 14. Zhou W, Yamakawa K, Benharash P, Ajijola O, Ennis D, Hadaya J, Vaseghi M, Shivkumar K, Mahajan A. Effect of stellate ganglia stimulation on global and regional left ventricular function as assessed by speckle tracking echocardiography. Am J Physiol Heart Circ Physiol 2013;304:H840–H847. 15. Lopshire JC, Zhou X, Dusa C, Ueyama T, Rosenberger J, Courtney N, Ujhelyi M, Mullen T, Das M, Zipes DP. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model. Circulation 2009;120:286–294. 16. Lopshire JC, Zipes DP. Spinal cord stimulation for heart failure: preclinical studies to determine optimal stimulation parameters for clinical efficacy. J Cardiovasc Transl Res 2014;7:321–329.
Tse et al
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17. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K, Multicenter InSync ICDRandomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685–2694. 18. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, et al. MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 19. Cohn J, Cleland JG, Lubsen J, Borer JS, Steg PG, Perelman M, Zannad F. Unconventional end points in cardiovascular clinical trials: should we be moving away from morbidity and mortality? J Card Fail 2009;15:199–205. 20. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2þ-ATPase in patients with advanced heart failure. Circulation 2011;124:304–313. 21. Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, et al. Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail 2008;14:355–367. 22. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS, Marbán L, Mendizabal A, Johnston PV, Russell SD, Schuleri KH, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379:895–904. 23. Eliasson T, Augustinsson LE, Mannheimer C. Spinal cord stimulation in severe angina pectoris: presentation of current studies, indications and clinical experience. Pain 1996;65:169–179. 24. Lanza GA, Barone L, Di Monaco A. Effect of spinal cord stimulation in patients with refractory angina: evidence from observational studies. Neuromodulation 2012;15:542–549. 25. Chandler MJ, Brennan TJ, Garrison DW, Kim KS, Schwartz PJ, Foreman RD. A mechanism of cardiac pain suppression by spinal cord stimulation: implications for patients with angina pectoris. Eur Heart J 1993;14:96–105.
595 26. Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci 2008;138:9–23. 27. Gersbach PA, Hasdemir MG, Eeckhout E, von Segesser LK. Spinal cord stimulation treatment for angina pectoris: more than a placebo? Ann Thorac Surg 2001;72:S1100–S1104. 28. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res. 2014;114:1004–1021. 29. Mannheimer C, Eliasson T, Andersson B, Bergh CH, Augustinsson LE, Emanuelsson H, Waagstein F. Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action. BMJ 1993;307: 477–480. 30. Foreman RD, Linderoth B, Ardell JL, Barron KW, Chandler MJ, Hull SS Jr, TerHorst GJ, DeJongste MJ, Armour JA. Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for its therapeutic use in angina pectoris. Cardiovasc Res 2000;47:367–375. 31. Olgin JE, Takahashi T, Wilson E, Vereckei A, Steinberg H, Zipes DP. Effects of thoracic spinal cord stimulation on cardiac autonomic regulation of the sinus and AV nodes. J Cardiovasc Electrophysiol 2002;13:475–481. 32. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319–1331. 33. Grimaldi R, de Luca A, Kornet L, Castagno D, Gaita F. Can spinal cord stimulation reduce ventricular arrhythmias? Heart Rhythm 2012;9:1884–1887. 34. Kujacic V, Eliasson T, Mannheimer C, Jablonskiene D, Augustinsson LE, Emanuelsson H. Assessment of the influence of spinal cord stimulation on left ventricular function in patients with severe angina pectoris: an echocardiographic study. Eur Heart J 1993;14:1238–1244. 35. Zipes DP, Neuzil P, Theres H, Caraway D, Mann DL, Mannheimer C, Van Buren P, Linde C, Linderoth B, Kueffer F, Sarazin SA, De Jongste MJ. Ventricular functional response to spinal cord stimulation for advanced heart failure: Primary results of the randomized DEFECT-HF Trial. Available at: http://my.american heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/download able/ucm_469647.pdf. Accessed on November 18, 2014.
CLINICAL PERSPECTIVES It is well known that dysregulation of the autonomic nervous system plays a pivotal role in the pathophysiology of heart failure. Thoracic spinal cord stimulation (SCS) is one of the therapeutic approaches that has been proposed to restore the homeostasis of the autonomic nervous system in heart failure and shown to improve cardiac function in a large animal model of heart failure. In this first-in-man prospective, multicenter pilot trial of chronic SCS, 17 patients with New York Heart Association (NYHA) class III heart failure and left ventricular ejection fraction (LVEF) 20%–35% who had defibrillator implants and were on stable optimal medical therapy were enrolled. Our results demonstrated that chronic dual thoracic SCS leads targeted at the midline and to the left of the midline at the T1–T3 level to provide SCS for 24 hours per day (50 Hz at pulse width 200 μs) is safe and feasible. Assessment of the combined clinical composite endpoints was carried out at 6 months, including NYHA class, Minnesota Living with Heart Failure Questionnaire, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide, and LVEF and left ventricular end-systolic volume: 11 patients (73%) showed improvement in Z4 of 6 of these efficacy parameters. This first human trial indicates that high thoracic SCS is safe and potentially can improve symptoms, functional status, and left ventricular function and remodeling in patients with severe, symptomatic systolic heart failure. These initial encouraging data need to be confirmed by a future randomized placebo controlled trial in a large patient cohort.
Failure Questionnaire (42 ⫾ 26 vs 27 ⫾ 22, P ¼ .026; 12/17 improved); peak maximum oxygen consumption (14.6 ⫾ 3.3 vs 16.5 ⫾ 3.9 mL/kg/min, P ¼ .013; 10/15 improved); LVEF (25% ⫾ 6% vs 37% ⫾ 8%, P o .001; 14/16 improved); and LV end-systolic volume (174 ⫾ 57 vs 137 ⫾ 37 mL, P ¼ .002; 11/16 improved) but not in N-terminal prohormone brain natriuretic peptide. No such improvements were observed in the 4 nontreated patients. CONCLUSION The results of this first-in-human trial suggest that high thoracic SCS is safe and feasible and potentially can improve symptoms, functional status, and LV function and remodeling in patients with severe, symptomatic systolic HF. KEYWORDS Spinal cord stimulation; Heart failure
RESULTS We enrolled 22 patients from 5 centers:17 patients underwent implantation of a SCS device and 4 patients who did not fulfill the study criteria served as nontreated controls. No deaths or device–device interactions were noted during the 6-month period in the 17 SCS-treated patients. Fifteen of 17 completed the efficacy endpoint assessments: composite score improved by 4.2 ⫾ 1.3, and 11 patients (73%) showed improvement in Z4 of 6 efficacy parameters. There was significant improvement in NYHA class (3.0 vs 2.1, P ¼ .002; 13/17 improved); Minnesota Living with Heart
ABBREVIATIONS HF ¼ heart failure; LV ¼ left ventricle; LVEF ¼ left ventricular ejection fraction; LVESV ¼ left ventricular endsystolic volume; MLHFQ ¼ Minnesota Living with Heart Failure Questionnaire; NT-proBNP ¼ N-terminal prohormone brain natriuretic peptide; NYHA ¼ New York Heart Association; SCS ¼ spinal cord stimulation
Introduction
the aging population and an increasing number of patients who survive acute myocardial infarction.1 Progressive left ventricular (LV) dilation, eccentric hypertrophy, and infarct scar thinning postmyocardial infarction ultimately result in altered LV geometry. This adverse LV remodeling contributes to progressive HF that results in a poor clinical outcome for postmyocardial infarction patients.2 In the presence of HF, dysregulation of the autonomic nervous system, characterized by increased sympathetic tone and decreased parasympathetic tone, is associated with progressive HF and increased mortality.3–5 An understanding of the pivotal
Heart failure (HF) is a leading global cause of morbidity and mortality, with an incidence that continues to rise because of
This study was funded by the Center for Innovation and Strategic Collaboration (CISC), St. Jude Medical Inc, USA. Drs. Tse, Sanders, Okuyama, Fujiu, Yiu, and Siu received an honorarium and research grant from the CISC, St. Jude Medical Inc, USA. ClinicalTrials.gov identifier NCT01362725. Address reprint requests and correspondence: Dr. Hung-Fat Tse, Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
(Heart Rhythm 2015;12:588–595) I 2015 Heart Rhythm Society. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2014.12.014
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role of the imbalance of the autonomic nervous system in the progression of HF has prompted the development of different nonpharmacologic therapeutic approaches, including vagal stimulation and spinal cord stimulation (SCS), which can modulate cardiac autonomic tone.6–9 SCS with an implantable device has been used clinically for more than 30 years to relieve angina symptoms in patients with severe coronary artery disease.10,11 In preclinical studies, short-term thoracic SCS reduced the incidence of ischemic ventricular tachyarrhythmias.12 Our recent acute experimental studies in a porcine model of HF have also demonstrated that dual thoracic SCS leads targeted at the midline and left of the midline at the T1–T3 level improve regional and global LV contractile function in HF without increasing myocardial oxygen consumption.13 These findings concur with the results of improving global myocardial contractile function after bilateral stellate ganglia stimulation.14 Long-term SCS has also improved left ventricular ejection fraction (LVEF) in a canine model of HF compared with a control group of animals treated with an angiotensin-converting enzyme inhibitor and beta-blocker.15 These findings suggest that thoracic SCS can improve HF symptoms and protect against ventricular arrhythmias. Nevertheless, human data on the safety and efficacy of SCS as a treatment of HF are limited. We performed a prospective, multicenter pilot clinical study over a 6-month period to evaluate the safety and efficacy of an implantable SCS system in patients with severe symptomatic HF despite optimal medical therapy.
Methods Study design and participants We recruited patients aged 18 years or older with New York Heart Association (NYHA) class III or ambulatory class IV HF, LV dysfunction (LVEF 20%–35%), LV end-diastolic diameter 55–80 mm, and implantable cardiac defibrillator, on stable (490 days) optimal medical (including coronary revascularization) and device therapies (including cardiac resynchronization therapy) for HF. Patients were excluded if they had any of the following: life expectancy o1 year, history of prior spinal cord stimulator implantation, polyneuropathy, NYHA class IV HF on intravenous inotropic therapy, chronic refractory angina or peripheral vascular pain, persistent atrial fibrillation, or significant valvular heart disease. The research protocol (see Supplemental file: Online Appendix Protocol) was approved by the relevant institutional review board of the institutions, and all participants provided written informed consent. The protocol was registered at ClinicalTrials.gov Identifier NCT01362725. Patients who refused to undergo cardiac defibrillator implantation or who were not eligible because of unknown compatibility of an implanted cardiac defibrillator (devices not from St. Jude Medical Inc) with the SCS system used in this study but who otherwise satisfied the inclusion criteria served as controls.
SCS implant procedure Eligible patients underwent SCS lead and pulse generator implantation using a commercially available neurostimulation
589 system (Eon Mini Neurostimulation System, St. Jude Medical, Plano, TX, USA) under local anesthetic, sterile conditions, and fluoroscopic guidance. Two epidural needles, inserted at the required level using the paramedian approach, were advanced into the epidural space. Two Octrode percutaneous leads (8 electrodes each, St. Jude Medical) were introduced into the epidural space via each epidural needle or lead introducer to cover the T1–T3 level: the first Octrode lead targeted the midline and the second Octrode lead to the left of the midline (Figure 1). Leads were tunneled subcutaneously below the left costal arch and connected to the permanent implantable pulse generator placed in a subcutaneous pocket in the lateral abdominal region. After implantation, a stimulation test was performed in all patients to confirm active SCS-induced paresthesia, and the device was programmed to adequately cover the chest area. Chronic SCS was recommended to be performed at 90% to 110% of the paresthesia threshold (range 1–15 mA) for 24 hours per day at 50 Hz and pulse width 200 microseconds, which has been shown by recent animal studies to provide optimal SCS.16 Patients were followed up at week 1 and 1, 3, 6, 12, 18, and 24 months after SCS device implantation. Physicians were advised whenever possible not to alter drug therapy for the first 6 months.
Study endpoints The primary safety endpoints were death due to ventricular tachyarrhythmia or sudden unexpected death, myocardial infarction, or hospitalization for HF during the first 6 months. Secondary safety endpoints included SCS or implantable defibrillator malfunction due to device–device interaction, incidence of ventricular tachyarrhythmia, and long-term safety of the SCS implant at 24 months based on the safety markers stated in the primary safety endpoint. The primary efficacy endpoint at 6 months was based on the composite endpoint score that provides a single efficacy parameter in which concordant changes across multiple parameters typically assessed in HF intervention, including device therapies, are required to demonstrate efficacy and reduce the chance of false positive results.17–22 In this pilot study, the composite score was based on 6 efficacy parameters measured at baseline and at 6 months: changes in NYHA class (Z1 class), Minnesota Living with Heart Failure Questionnaire score (MLHFQ Z10 points), peak maximum oxygen consumption (VO2max Z1 mL/kg/min) assessed by cardiopulmonary exercise, N-terminal prohormone brain natriuretic peptide (NT-proBNP Z300 pg/mL absolute change or 35% relative change), echocardiography-derived LVEF (Z5% absolute change), and left ventricular end-systolic volume (LVESV Z20 mL absolute change or 10% relative change). The concordant changes in these endpoints were also prospectively defined as the primary efficacy endpoint (for details see Online Supplemental Methods). Changes in each individual parameter within the SCStreated group at baseline vs 6 months and changes in the control group also were determined. All exercise data and echocardiographic images were labeled with study
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Figure 1 A: Radiologic image of the 2 octropolar electrodes with 1 targeted at the midline and the other targeted at left of the midline to cover the T1–T3 level. B: Flow diagram of patient recruitment. HF ¼ heart failure; SCS ¼ spinal cord stimulation; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.
identification and sent to the imaging core at the University of Hong Kong for blinded assessment (in terms of timing and treatment group assignment) by a single experienced technician and operator, respectively.
Statistical analysis In this pilot clinical study, the safety and efficacy of the SCS were the key components for an intended population of 15–20 patients. Results are given as mean ⫾ SD. All reported P values are 2-sided and have not been adjusted for multiple comparisons. Paired comparison of changes at 6 months from baseline within the SCS-treated group were performed using a paired t test if normality was established or the nonparametric Wilcoxon signed rank test if normality could not be established. Because of the small sample size in the treated and
nontreated groups, comparison between groups and adjustment for multiple comparisons were not performed. Statistical analyses were performed using SPSS-19.0 and GraphPad Prism 6.0 software packages (GraphPad Software, Inc. USA).
Role of the funding source This study was funded by the Center for Innovation and Strategic Collaboration (CISC), St. Jude Medical, Inc, USA. The funding source was responsible for the execution of the study. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.
Results Between August 2011 and April 2013, 22 patients from 1 center in Hong Kong (n ¼ 13), 2 centers in Australia (n ¼ 6),
Tse et al Table 1
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Baseline characteristics of patients SCS-treated group (n ¼ 17)
Sex (male) [n (%)] Age (years) Coronary artery disease [n (%)] Hypertension [n (%)] Diabetes [n (%)] Mitral regurgitation [n (%)] Paroxysmal atrial fibrillation [n (%)] Ventricular tachyarrhythmia [n (%)] Heart failure treatment [n (%)] Angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker Aldosterone antagonist Beta-blocker Diuretic Cardiac glycosides Cardiac resynchronization therapy Baseline efficacy parameters NYHA class III [n (%)] MLHFQ total score (mean) VO2max (mL/kg/min) NT-proBNP (pg/mL) LVEF (%) LVESV (mL)
17 (100%) 62.9 (10.1) 11 (65%) 10 (59%) 8 (47%) 8 (47%) 8 (47%) 9 (53%)
SCS nontreated group (n ¼ 4) 4 (100%) 61.7 (5.8) 2 (50%) 2 (50%) 1 (25%) 1 (25%) 2 (50%) 1 (25%)
16 (94%)
4 (100%)
7 (41%) 15 (88%) 10 (59%) 5 (29%) 8 (47%)
2 (50%) 4 (100%) 2 (50%) 1 (25%) 0 (0)
17 (100%) 41.9 (26.2) 14.4 (3.2) 2364 (2303) 24.9 (6.3) 173.6 (56.7)
4 (100%) NA 16.4 (2.6) 1098 (617) 33.5 (1.3) 128.5 (40.4)
Data are given as n (%) or mean (SD). LVEF ¼ left ventricular ejection fraction; LVESV ¼ left ventricular end-systolic volume; MLHFQ ¼ Minnesota Living with Heart Failure Questionnaire; NA ¼ not available; NT-proBNP ¼ N-terminal prohormone brain natriuretic peptide; NYHA ¼ New York Heart Association; SCS ¼ spinal cord stimulation; VO2max ¼ peak maximum oxygen consumption.
and 2 centers in Japan (n ¼ 3) were screened, and 17 eligible patients underwent SCS device implantation (SCS-treated group) (Figure 1B). The remaining 5 patients did not receive SCS because of refusal to undergo cardiac defibrillator implantation (n ¼ 2), presence of an incompatible device (n ¼ 2), or failure to fulfill the inclusion criteria because of low LVEF (n ¼ 1). Of these 5 patients, the 4 who fulfilled the inclusion criteria were designated as nontreated controls. Table 1 lists the demographics, baseline characteristics, and HF treatment regimens of the SCS-treated and control patients. Mean LVEF was 26.6% ⫾ 6.6%, and VO2max was 14.9 ⫾ 3.2 mL/kg/min. Although the inclusion criteria for LVEF based on echocardiographic measurement by the investigators was 20%–35% per protocol, 4 patients had LVEF o20% (range 17%–19%) as determined by the core laboratory. This was a study population with advanced HF. All SCS-treated patients had NYHA class III HF and an implantable cardiac defibrillator at baseline. Eight had not responded to previous cardiac resynchronization therapy. All control group patients also had NYHA class III HF, but only 2 had an implantable cardiac defibrillator.
Safety All SCS-treated patients underwent successful implantation of SCS leads and pulse generator. There were no acute complications, and implantation of the second lead failed in only 1 subject. Three patients who reported neck or back pain after SCS implantation required reprogramming of the device: 1 underwent lead repositioning 13 days after implantation to correct inappropriate motor stimulation.
Failure of the device battery with consequent battery replacement occurred at 6 months in 1 patient, and in another patient the device was reprogrammed to off after 2.4 months at the discretion of the physician because of lack of efficacy. After 6 months, there were no deaths and no cases of device–device interaction to cause SCS device or implantable cardiac defibrillator malfunction. Nonetheless, 2 patients (12%) experienced ventricular tachyarrhythmia that required intervention, and 2 (12%) were hospitalized for HF. After 18 ⫾ 5 months (range 13–24 months) following SCS implantation, 2 patients, including the patient in whom the device was inactivated at 2.4 months, were hospitalized for a total of 6 occasions for HF and subsequently died of progressive HF at 7.5 and 14.5 months. Overall, 4 patients developed 14 episodes of ventricular tachyarrhythmia that required intervention; all had a history of ventricular tachyarrhythmia before SCS device implantation. Nonetheless, there were incidences of ventricular tachyarrhythmia in 5 and 8 SCS-treated group patients with and without a prior history of ventricular tachyarrhythmia, respectively. No device–device interaction to cause device malfunction was noted at mean follow-up of 16 months after SCS. One patient withdrew from the study at 9 months due to intolerance to SCS because of back and neck paresthesia, and he defaulted from further follow-up. The secondary safety endpoint data at 24 months are pending for the remaining 7 SCS-treated patients.
Efficacy The effects of SCS on the prespecified 6 efficacy domains at 6-month follow-up are listed in Table 2. In the 15
592 Table 2
Heart Rhythm, Vol 12, No 3, March 2015 Changes in clinical efficacy endpoints from baseline to 6 months in SCS-treated patients
Efficacy endpoint NYHA class MLHFQ VO2max NT-proBNP LVEF LVESV
Minimum change from baseline at 6 months *
1 class 10 points* 1.0 mL/kg/min* 300 pg/mL* or 35%† 5%* 20 mL* or 10%†
No. of patients with improved, no change, or worsen from baseline to 6 months based on prespecified minimum change Worsen (–1)
No change (0)
Improved (þ1)
P value comparing paired change from baseline to 6 months‡
1/17 (6%) 1/17 (6%) 0/15 (0%) 4/17 (24%) 0/16 (0%) 0/16 (0%)
3/17 (18%) 4/17 (24%) 5/15 (33%) 6/17 (35%) 2/16 (13%) 5/16 (31%)
13/17 (77%) 12/17 (71%) 10/15 (67%) 7/17 (41%) 14/16 (88%) 11/16 (69%)
.002 .026 .013 .52 o.001 .002
LVEF ¼ left ventricular ejection fraction; LVESV ¼ left ventricular end-systolic volume; MLHFQ ¼ Minnesota Living with Heart Failure Questionnaire; NA ¼ not available; NT-proBNP ¼ N-terminal prohormone brain natriuretic peptide; NYHA ¼ New York Heart Association; SCS ¼ spinal cord stimulation; VO2max ¼ peak maximum oxygen consumption. * Absolute change from baseline. † Relative change from baseline. ‡ P value from Wilcoxon signed rank test, comparing paired values from baseline to 6 months.
SCS-treated patients who completed the efficacy endpoint assessment, the composite score improved by 4.2 ⫾ 1.3, and 11 patients (73%) showed improvement in Z4 of 6 efficacy parameters (Figure 2). Because the MLHFQ score was not available for the control patients, their composite score is not reported. As shown in Figure 3A, NYHA class was almost unchanged in nontreated patients but improved (41 class) in 13 of 17 of the SCS-treated patients (76%; with P ¼ .002 corresponding to the paired comparison between baseline and 6 months after SCS implantation). In the SCS-treated patients, the total mean MLHFQ score decreased (improved) from 41.9 ⫾ 26.2 to 27.2 ⫾ 21.9; P ¼ .026). VO2max increased in the SCS-treated patients from baseline to 6 months (P ¼ .013) but not in the nontreated patients (Figure 3B). There was no significant change in the NTproBNP of the SCS-treated patients from baseline to 6 months (Figure 3C; P ¼ .56). For LV function and
remodeling parameters, LVEF increased (Figure 3D; P o .001) and LVESV decreased (Figure 3E; P ¼ .002) from baseline to 6 months in the SCS-treated patients (see Online Supplementary Video).
Discussion To the best of our knowledge, this is the first human trial to investigate the long-term effects of dual-targeted high thoracic continuous SCS at the T1–T3 level on symptoms, functional capacity, and LV function and remodeling in patients with advanced systolic HF. Our results demonstrate that dual thoracic SCS targeted at the midline and left of the midline at the T1–T3 level is safe and can potentially improve symptoms, functional capacity, and cardiac function in patients with advanced HF. Electrical stimulation of the dorsal column of the spinal cord at a low cervical to high thoracic level is safe
Figure 2 Changes in the primary efficacy endpoints: New York Heart Association (NYHA), Minnesota Living with Heart Failure Questionnaire (MLHFQ), peak maximum oxygen consumption (VO2max), N-terminal prohormone brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-systolic volume (LVESV) after 6 months of spinal cord stimulation.
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Figure 3 Changes in New York Heart Association class (A), peak maximum oxygen consumption (VO2max) (B), N-terminal prohormone brain natriuretic peptide (NT-proBNP) (C), left ventricular ejection fraction (D), and left ventricular end-systolic volume (E) in spinal cord stimulation (SCS)–treated group and nontreated group at 6 months vs baseline. Data are given as mean ⫾ SD.
and provides effective pain relieve in 70% of patients who suffer refractory angina due to severe coronary artery disease.10,11,23,24 In addition to modulation of the nociceptive influx associated with myocardial ischemia,25,26 it has been proposed that SCS can restore the balance between myocardial oxygen supply and demand during ischemia.27 In addition, SCS applied at the C7–C8 and/or T1–T6 level can modulate the reflex activation of the parasympathetic and sympathetic nervous system.26,28 Prior studies suggest that thoracic SCS suppresses peripheral sympathetic tone by modulating intrinsic afferent sensory cardiac neurons related to sympathetic excitation.29,30 SCS also enhances parasympathetic tone as evidenced by slowing of the sinus rate
and prolongation of the atrioventricular nodal conduction time and the ventricular refractory period.31 Thus, SCS may offer a novel therapeutic approach that can restore autonomic balance in HF.8,9 We have demonstrated that long-term SCS using an implantable device is largely safe and well tolerated in this cohort of patients with advanced HF, with no adverse device interaction with an implanted cardioverter defibrillator. After mean follow-up of 16 months, 2 patients (12%), including 1 subject with SCS programmed off at the discretion of the physician, required frequent hospitalization for HF and ventricular tachyarrhythmia and subsequently died of progressive HF. Overall, 24% of patients required intervention
594 for ventricular tachyarrhythmia after SCS. Patients enrolled in this study suffered from advanced HF with an estimated 1year mortality risk of 25% based on their risk profile from other trials.32 The observed number of events in this pilot trial are too low to evaluate the long-term impact of SCS on clinical outcome; nonetheless, the mortality and morbidity rate in this study does not exceed that expected for such HF patients. We observed no new onset of ventricular tachyarrhythmia in any SCS-treated patient or in 56% of those with a history of ventricular tachyarrhythmia. This finding may support recent reports of the potential antiarrhythmic effects of SCS in HF patients.33 In this small study, a clinical composite efficacy endpoint was used to investigate the potential therapeutic effects of SCS to eliminate the potential bias of a single outcome. We observed an overall improvement in this composite endpoint score in SCS-treated patients, and 11 patients showed improvement in Z4 of 6 efficacy parameters. Individual parameters, including NYHA class, MLHFQ, VO2max, LVEF, and LVESV, also significantly improved in SCStreated patients at 6 months. These results concur with findings from preclinical studies13,15 and the initial clinical observation34 that SCS at high thoracic levels improves LV function and remodeling in HF. More recently, the primary results of the DEFEAT-HF study (Determining the Feasibility of spinal cord neuromodulation for the treatment of chronic HF, NCT01112579) have been presented.35 This is the first single blinded randomized controlled trial of SCS for HF. In this study, there was no difference in LVESV index, VO2max, or NT-proBNP between the SCS and control groups at 6 months. Nonetheless, there are significant differences between that trial and the present study. In the DEFEAT-HF study, only intermittent SCS was performed for just 12 hours per day using a single electrode at the T2–T4 level. In the present study, we used continuous high thoracic SCS targeted at the midline and left of the midline at the T1–T3 level. This might account for the different therapeutic efficacies. Nevertheless, the DEFECT-HF study also confirmed that SCS was safe with no increase in major adverse effects observed.
Study limitations This study has limitations. All patients recruited in this study were male, and whether there is any gender difference in the response to SCS remains unclear. Although we noted an improvement in symptoms, functional capacity, and LV function, our study was not a randomized controlled study, and the population was small. Measurements of LVEF and LVESV also could have been affected by loading condition, and LVESV index was not determined. Our results at 6 months may also have been influenced by a placebo effect of SCS. The long-term safety and therapeutic efficacy of chronic SCS will need to be assessed in a future long-term randomized controlled trial with a larger patient cohort.
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Conclusion Our findings indicate that dual-targeted high thoracic SCS appears to be a safe and feasible treatment of HF. The absence of any major acute procedural complications or long-term sequelae is encouraging. Thus, the long-term safety and treatment implications of dual-targeted SCS as a novel device-based therapy for advanced HF warrant further investigation in future randomized controlled trials.
Appendix Supplementary data Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.hrthm. 2014.12.014.
References 1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics—2014 update: a report from the American Heart Association. Circulation 2014;129:399–410. 2. Savoye C, Equine O, Tricot O, Nugue O, Segrestin B, Sautière K, Elkohen M, Pretorian EM, Taghipour K, Philias A, Aumégeat V, Decoulx E, et al. REmodelage VEntriculaire study group. Left ventricular remodelling after anterior wall acute myocardial infarction in modern clinical practice (from the Remodelage Ventriculaire [REVE] study group. Am J Cardiol 2006;98:1144–1149. 3. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008;118:863–871. 4. Floras JS. Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J Am Coll Cardiol 2009;54:375–385. 5. Schwartz PJ, De Ferrari GM. Sympathetic-parasympathetic interaction in health and disease: abnormalities and relevance in heart failure. Heart Fail Rev 2011;16:101–107. 6. Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A. Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail 2008;10:884–891. 7. De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, Gavazzi A, Sanzo A, Dennert R, Kuschyk J, Raspopovic S, Klein H, et al. CardioFit Multicenter Trial Investigators. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011;32:847–855. 8. Lopshire JC, Zipes DP. Device therapy to modulate the autonomic nervous system to treat heart failure. Curr Cardiol Rep 2012;14:593–600. 9. Singh JP, Kandala J, Camm AJ. Non-pharmacological modulation of the autonomic tone to treat heart failure. Eur Heart J 2014;35:77–85. 10. Murphy DF, Giles KE. Dorsal column stimulation for pain relief from intractable angina pectoris. Pain 1987;28:365–368. 11. Brodison A, Chauhan A. Spinal-cord stimulation in management of angina. Lancet 1999;354:1748–1749. 12. Issa ZF, Zhou X, Ujhelyi MR, Rosenberger J, Bhakta D, Groh WJ, Miller JM, Zipes DP. Thoracic spinal cord stimulation reduces the risk of ischemic ventricular arrhythmias in a post-infarction heart failure canine model. Circulation 2005;111:3217–3220. 13. Liu Y, Yue WS, Liao SY, Zhang Y, Au KW, Shuto C, Hata C, Park E, Chen P, Siu CW, Tse HF. Thoracic spinal cord stimulation improves cardiac contractile function and myocardial oxygen consumption in a porcine model of ischemic heart failure. J Cardiovasc Electrophysiol 2012;23:534–540. 14. Zhou W, Yamakawa K, Benharash P, Ajijola O, Ennis D, Hadaya J, Vaseghi M, Shivkumar K, Mahajan A. Effect of stellate ganglia stimulation on global and regional left ventricular function as assessed by speckle tracking echocardiography. Am J Physiol Heart Circ Physiol 2013;304:H840–H847. 15. Lopshire JC, Zhou X, Dusa C, Ueyama T, Rosenberger J, Courtney N, Ujhelyi M, Mullen T, Das M, Zipes DP. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model. Circulation 2009;120:286–294. 16. Lopshire JC, Zipes DP. Spinal cord stimulation for heart failure: preclinical studies to determine optimal stimulation parameters for clinical efficacy. J Cardiovasc Transl Res 2014;7:321–329.
Tse et al
Thoracic Spinal Cord Stimulation for Heart Failure
17. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K, Multicenter InSync ICDRandomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685–2694. 18. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, et al. MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 19. Cohn J, Cleland JG, Lubsen J, Borer JS, Steg PG, Perelman M, Zannad F. Unconventional end points in cardiovascular clinical trials: should we be moving away from morbidity and mortality? J Card Fail 2009;15:199–205. 20. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, Yaroshinsky A, Zsebo KM, Dittrich H, Hajjar RJ. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2þ-ATPase in patients with advanced heart failure. Circulation 2011;124:304–313. 21. Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, et al. Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail 2008;14:355–367. 22. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS, Marbán L, Mendizabal A, Johnston PV, Russell SD, Schuleri KH, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379:895–904. 23. Eliasson T, Augustinsson LE, Mannheimer C. Spinal cord stimulation in severe angina pectoris: presentation of current studies, indications and clinical experience. Pain 1996;65:169–179. 24. Lanza GA, Barone L, Di Monaco A. Effect of spinal cord stimulation in patients with refractory angina: evidence from observational studies. Neuromodulation 2012;15:542–549. 25. Chandler MJ, Brennan TJ, Garrison DW, Kim KS, Schwartz PJ, Foreman RD. A mechanism of cardiac pain suppression by spinal cord stimulation: implications for patients with angina pectoris. Eur Heart J 1993;14:96–105.
595 26. Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci 2008;138:9–23. 27. Gersbach PA, Hasdemir MG, Eeckhout E, von Segesser LK. Spinal cord stimulation treatment for angina pectoris: more than a placebo? Ann Thorac Surg 2001;72:S1100–S1104. 28. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res. 2014;114:1004–1021. 29. Mannheimer C, Eliasson T, Andersson B, Bergh CH, Augustinsson LE, Emanuelsson H, Waagstein F. Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action. BMJ 1993;307: 477–480. 30. Foreman RD, Linderoth B, Ardell JL, Barron KW, Chandler MJ, Hull SS Jr, TerHorst GJ, DeJongste MJ, Armour JA. Modulation of intrinsic cardiac neurons by spinal cord stimulation: implications for its therapeutic use in angina pectoris. Cardiovasc Res 2000;47:367–375. 31. Olgin JE, Takahashi T, Wilson E, Vereckei A, Steinberg H, Zipes DP. Effects of thoracic spinal cord stimulation on cardiac autonomic regulation of the sinus and AV nodes. J Cardiovasc Electrophysiol 2002;13:475–481. 32. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319–1331. 33. Grimaldi R, de Luca A, Kornet L, Castagno D, Gaita F. Can spinal cord stimulation reduce ventricular arrhythmias? Heart Rhythm 2012;9:1884–1887. 34. Kujacic V, Eliasson T, Mannheimer C, Jablonskiene D, Augustinsson LE, Emanuelsson H. Assessment of the influence of spinal cord stimulation on left ventricular function in patients with severe angina pectoris: an echocardiographic study. Eur Heart J 1993;14:1238–1244. 35. Zipes DP, Neuzil P, Theres H, Caraway D, Mann DL, Mannheimer C, Van Buren P, Linde C, Linderoth B, Kueffer F, Sarazin SA, De Jongste MJ. Ventricular functional response to spinal cord stimulation for advanced heart failure: Primary results of the randomized DEFECT-HF Trial. Available at: http://my.american heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/download able/ucm_469647.pdf. Accessed on November 18, 2014.
CLINICAL PERSPECTIVES It is well known that dysregulation of the autonomic nervous system plays a pivotal role in the pathophysiology of heart failure. Thoracic spinal cord stimulation (SCS) is one of the therapeutic approaches that has been proposed to restore the homeostasis of the autonomic nervous system in heart failure and shown to improve cardiac function in a large animal model of heart failure. In this first-in-man prospective, multicenter pilot trial of chronic SCS, 17 patients with New York Heart Association (NYHA) class III heart failure and left ventricular ejection fraction (LVEF) 20%–35% who had defibrillator implants and were on stable optimal medical therapy were enrolled. Our results demonstrated that chronic dual thoracic SCS leads targeted at the midline and to the left of the midline at the T1–T3 level to provide SCS for 24 hours per day (50 Hz at pulse width 200 μs) is safe and feasible. Assessment of the combined clinical composite endpoints was carried out at 6 months, including NYHA class, Minnesota Living with Heart Failure Questionnaire, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide, and LVEF and left ventricular end-systolic volume: 11 patients (73%) showed improvement in Z4 of 6 of these efficacy parameters. This first human trial indicates that high thoracic SCS is safe and potentially can improve symptoms, functional status, and left ventricular function and remodeling in patients with severe, symptomatic systolic heart failure. These initial encouraging data need to be confirmed by a future randomized placebo controlled trial in a large patient cohort.