European Journal of Heart Failure (2014) 16, 788–795 doi:10.1002/ejhf.107
Spinal cord stimulation is safe and feasible in patients with advanced heart failure: early clinical experience Guillermo Torre-Amione1,2*, Kenneth Alo1, Jerry D. Estep1, Miguel Valderrabano1, Nashwa Khalil1, Taraneh G. Farazi3, Stuart P. Rosenberg3, Lanitia Ness3, and John Gill3 1 Catedra
de Cardiologia y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, México; 2 Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, USA; and 3 St. Jude Medical, Sylmar, CA, USA
Received 29 December 2013; revised 3 April 2014; accepted 11 April 2014 ; online publish-ahead-of-print 24 June 2014
Aims
Pre-clinical work suggests that upper thoracic spinal cord stimulation (SCS) may have therapeutic effects in the treatment of heart failure (HF). We therefore aim to assess the safety and feasibility of SCS in HF patients. ..................................................................................................................................................................... Methods A prospective, randomized, double-blind, crossover pilot study was conducted in symptomatic HF patients receiving and results optimal medical therapy. Patients were implanted with an SCS system and randomized to an SCS-ACTIVE, delivered at 90% paraesthesia threshold, or an SCS-INACTIVE phase for 3 months, followed by a 1-month washout period and crossover to the alternative phase. The safety of SCS therapy was assessed by death and cardiac events. Implantable cardioverter defibrillator (ICD) function in the presence of SCS was tested by defibrillation testing during SCS system implant and review of real-time and stored electrograms during follow-up. The efficacy of SCS therapy was assessed by changes in patient symptoms, LV function, and BNP level. Nine patients were investigated. In all cases, ICD sensing, detection, and therapy delivery were unaffected by SCS. During follow-up, one patient died and one was hospitalized for HF while in the SCS-INACTIVE phase, and two patients had HF hospitalizations during the SCS-ACTIVE phase. Symptoms were improved in the majority of patients with SCS, while markers of cardiac structure and function were, in aggregate, unchanged. ..................................................................................................................................................................... Conclusion This study shows that an SCS system can be safely implanted in patients with advanced HF and that the SCS system does not interfere with ICD function.
.......................................................................................................... Neuromodulation •
Neurostimulation •
Introduction Spinal cord stimulation (SCS) is a non-pharmacological strategy comprised of an implantable pulse generator connected to one or more epidural leads. SCS systems are indicated for treating chronic pain by stimulating distinct levels of the spinal cord, thereby creating a response in the dermatome-associated area of interest.1 In the cardiovascular system, SCS has been used to treat pain associated with peripheral vascular disease2,3 and angina.4,5 Preliminary
Neuroradiology •
...........................
Keywords
Heart failure
studies in humans suggest that SCS may be associated with vasodilatory effects and lead to decreased catecholamine production.6,7 Experimental observations suggest that the use of SCS in a canine model of HF may improve LVEF and decrease arrhythmogenicity.8 These data suggest that SCS may be an innovative therapy that improves the underlying neurohormonal imbalances associated with progressive HF. Accordingly; we conducted a pilot study to investigate the safety and feasibility of SCS in patients with advanced systolic dysfunction and symptomatic HF.
*Corresponding author. 6550 Fannin Street, Suite 1901, Houston, TX 77030, USA. Tel: +1 713 441 2762, Fax: +1 713 790 2643, Email: [email protected]
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
789
Methods Patient selection and study design Patients were recruited at the Houston Methodist Hospital between August 2010 and August 2011. Eligible patients had symptomatic HF despite standard optimal medical therapy, NYHA class III HF symptoms, LVEF ≤30%, were hospitalized for HF or received i.v. inotropic support at least once in the previous year, and walked 6 months. SCS pulse generator implant location was in the left (n = 8) or right (n = 1) buttock. Figure 2 shows an exemplary X-ray image of one patient with an SCS system and CRT-D leads. All patients were discharged within two post-operative days. Two patients had minor implant-related events; one patient had a reaction at the incision site of the SCS pulse generator that did not extend the hospitalization stay, and a second patient experienced an infection at the site of SCS pulse generator implant requiring readmission for treatment of this infection. The infection was treated with oral antibiotics and did not result in interruption of SCS therapy. There were no reported implant-related HF exacerbations or hospitalizations.
Spinal cord stimulator–implantable cardioverter defibrillator interaction: intraoperative evaluation The intraoperative PT was 9.0 ± 3.7 mA. During the intraoperative device interaction evaluation at 90% PT (8.1 ± 3.3 mA), SCS
........................................................................................................................................................................
off and subsequently turned on, noting any SCS pulses or SCS-induced myopotentials. Additional data were obtained at baseline and at the 3-, 4-, and 7-month follow-ups. These data included the assessment of NYHA class, as assessed by a blinded observer; quality of life (QOL), as assessed using the Minnesota Living with Heart Failure Questionnaire; LVEF, measured by 2D echocardiography using a blinded echocardiographer; and blood samples were drawn for measurement of BNP.
G. Torre-Amione et al.
Table 1 Baseline characteristics of the study cohort Age, median/range (years) 66/54–80 ................................................................ Gender, male/female HF aetiology, ischaemic/non-ischaemic Implanted CRM device, CRT-D/ICD CRM device average implantation duration/range (months) ICD CRT-D QRS duration, median/range (ms) LVEF, median/range (%) NYHA class, III/IV 6MHW distance, median range (m) QOL score, median/range Patients on beta-blockers Patients on ACE inhibitors/ARBs Patients on antiarrhythmic drugs Patients on digoxin Patients on diuretics Patients on aldactone
8/1 7/2 6/3
7/4–11 39/9–91 168/94–100 25/15–32 9/0 335/46–411 66/23–86 9 7/1 2 7 9 7
CRM, cardiac rhythm management; HF, heart failure; ICD, implantable cadioverter defibrillator; 6MHW, 6 min hall walk; QOL, quality of life.
or SCS-induced myopotentials were not sensed or detected by the ICD in any patient and no reprogramming of ICD sensing parameters was needed to avoid ICD detection of SCS pulses. Table 2 shows the results of the device interaction testing during VF induction and defibrillation testing. In all patients, VF was successfully induced, and the ICD appropriately detected it and successfully defibrillated it with the first prescribed shock, at the previously prescribed defibrillation energy of 26.1 ± 6.3 J. The time from VF onset to VF diagnosis was 2.8 ± 0.5 s. Visual evaluation of the ICD IEGMs recorded during VF induction and defibrillation testing did not reveal any evidence of SCS pulse generator output.
Primary safety events Table 3 shows the results of the primary safety events that occurred during the study. Three patients were hospitalized for worsening HF over the course of the study, one while in the SCS-INACTIVE phase, and the other two in the SCS-ACTIVE phase. Four patients experienced a total of five events under the definition of the primary safety endpoint. Among these, two patients experienced three events while randomized to SCS-ACTIVE, and two patients experienced two events while randomized to SCS-INACTIVE. Of the two patients in the SCS-ACTIVE phase, one was admitted twice within a short period of time. One patient died during the study, ∼2 months after SCS system implant and while in the SCS-INACTIVE phase. The investigator and safety review board determined that the death was not related to the study procedures or therapy. For this patient, baseline and implant data are reported here but not long-term data. As shown in Table 3, there were no symptomatic bradyarrhythmia events, or tachyarrhythmia events requiring high voltage therapy. © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
791
Figure 2 X-ray image from one patient showing the placement of the spinal cord stimulator (SCS) lead, CRT-D, and CRT-D leads. An exemplary X-ray image of one patient with an SCS system and CRT-D leads. The SCS pulse generator is not shown in this figure as it was implanted in the left buttock. CRT, cardiac resynchronization therapy.
Table 2 Spinal cord stimulation (SCS)–implantable cardioverter defibrillator (ICD) interaction data from defibrillation testing Patient no.
Time from Time from VF Was onset of VF diagnosis to defibrillation to VF diagnosis shock successful by the device (s) delivery (s) (yes/no) ................................................................ 1 2 3 4 5 6 7 8 9 Averagea
2 N/A 3 3 3 3 3 3 2 2.8 ± 0.5
9 N/A 5 6 6 4 5 4 7 5.8 ± 1.7
Yes Yes Yes Yes Yes Yes Yes Yes Yes Y
N/A, not available; VF, ventricular fibrillation. a Average values were computed for patients with available data.
Follow-up data THe SCS–ICD system device interaction was evaluated during study follow-ups both through the review of any stored IEGMs recorded between follow-ups and through in-clinic testing. There were 28 stored IEGMs of ambulatory tachyarrhythmias (12 recorded during SCS-ACTIVE and 16 during SCS-INACTIVE)
........................................................................................................................................................................
Spinal cord stimulation in patients with advanced HF
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Table 3 Primary safety endpoint; event characteristics. No. of patients No. of events with events ................... .................. Safety endpoint: Total Active: Total Active: event description inactive inactive ................................................................ Death Hospitalization for HF Symptomatic bradyarrhythmia Tachyarrhythmia requiring cardioversion For all safety events
1 3 0
0:1 2:1 0:0
1 4 0
0:1 3:1 0:0
0
0:0
0
0:0
4
2:2
5
3:2
HF, heart failure; SCS, spinal cord stimulation. Active: SCS active phase; Inactive: SCS inactive phase; Total = active + inactive.
from five patients. Twenty-four of these arrhythmias were device classified as ventricular tachycardia (VT) [nine non-sustained VT (NSVT)] and the other four were atrial tachyarrhythmias. The device withheld antitachycardia pacing (ATP) for NSVT events as these events terminated spontaneously. The remaining 15 VT episodes that were not labelled as NSVT per device’s NSVT criteria came from three patients. Only one of those three patients received ATP for six episodes. The rest of the episodes from three patients did not meet the device’s criteria for ATP delivery and terminated spontaneously. These IEGMs exhibited no evidence of interaction between the SCS pulse generator and ICD sensing. Review of the IEGM during the additional in-clinic testing revealed no evidence of SCS system noise and no inappropriate sensing by the ICD due to SCS system output (Figure 3). In total, 238 VT events in five patients were diagnosed by the ICDs over the course of the study, 137 while in SCS-INACTIVE and 101 while in SCS-ACTIVE. All of these VTs terminated either spontaneously or with a single round of ICD-initiated antitachycardia pacing; no high voltage therapy was required to terminate any of these VT events. Furthermore, review of the subset of 28 of these tachyarrhythmias eliciting stored IEGMs revealed that there were no inappropriate therapies delivered. Over the course of the PT reassessments made during the follow-ups, the average PT was 6.0 ± 1.8 mA, and the average programmed SCS pulse generator output was 5.4 ± 1.6 mA. Programmed amplitude varied over the course of follow-up in each patient by 3.1 ± 1.7 mA. The effects of SCS-ACTIVE and SCS-INACTIVE on the various clinical and cardiovascular markers measured are presented in Figure 4. Over the 3-month SCS-ACTIVE phase, five patients improved by at least one NYHA class and three patients were unchanged, while no patient worsened. Data on QOL were unavailable from one patient, showed an improvement in six patients, and worsened in one patient. Changes in LVEF and BNP were mixed, with minimal overall change from baseline. Over the 3 months of SCS-INACTIVE, two patients improved by at least one NYHA class
792
G. Torre-Amione et al.
and five patients were unchanged, while one patient worsened. QOL was improved in four patients and worsened or unchanged in the other four patients. As in the SCS-ACTIVE phase, changes in LVEF and BNP were mixed. At the end of the 3-month randomization periods, seven of the eight patients in the SCS-ACTIVE phase reported the perception that SCS had been on for the previous months. At the end of the SCS-INACTIVE phase, six of the eight patients had the perception that SCS had been off.
Discussion This study reports, for the first time, the feasibility of the use of SCS for the treatment of HF in patients with LV dysfunction and advanced, symptomatic HF. There are a number of important observations from this experience. First, implantation of the SCS system was accomplished successfully in the cardiac catheterization laboratory with a coordinated multidisciplinary team in a safe manner. Secondly, the delivery of SCS did not affect ICD functionality, including the ability to detect VT and VF appropriately and deliver necessary antitachycardia and defibrillation therapy. Thirdly, these patients were able to tolerate electrical SCS and complete the study protocol, except for the single patient who died while SCS was disabled. Finally, SCS therapy did not cause cardiac events, and in fact a majority of the patients receiving SCS subjectively improved in their HF symptoms, although no objective measures of HF improvement, through LVEF and BNP, were noted.
Spinal cord stimulation for cardiovascular conditions In Europe, Australia, and several other worldwide geographies, SCS use is approved for the treatment of chronic refractory angina pectoris and peripheral vascular disease. SCS relieves anginal pain and reduces anginal frequency, allowing for improved exercise tolerance, decreased use of antianginal drugs, and improved QOL.11 – 13 Notably, such improvements in angina appear not to be driven
............................................................................................................
Figure 3 IEGM recordings with SCS disabled and enabled. The IEGMs with SCS off (left panel) and SCS on (right panel) showing no evidence of interaction. IEGM, implantable cardioverter defibrillator intracardiac electrogram; RV, right ventricular; SCS, spinal cord stimulator.
by increases in coronary flow or perfusion,7,14,15 but rather may be related to redistribution of blood flow from well-perfused to underperfused areas.16 Experimentally, the use of SCS has been tested in a canine model of HF, wherein SCS treatment has been shown to lead to a more rapid and greater reverse remodelling compared with neurohormonal medical therapy alone.10 Application of SCS in canine and porcine models of HF has also demonstrated reduction in ventricular tachyarrhythmias8,17,18 and immediate improvements in LV function.17
Paraesthesia and patient blinding to spinal cord stimulation This study was a prospective, double-blind, randomized, crossover design between SCS-ACTIVE and SCS-INACTIVE. As conventional SCS to treat chronic pain is delivered at amplitudes that elicit paraesthesia, blinding of the patient in SCS studies can be a challenge. In a recent placebo-controlled study in angina patients, Eddicks et al.10 demonstrated that patient blinding was possible, as delivery of SCS at an amplitude below the PT had functional and symptomatic improvements comparable with SCS delivered at the PT. In order to maintain patient blinding, we chose to deliver SCS in this study at an amplitude of 90% of the PT. Our selection of three daily ‘doses’ of SCS for 2 h each was based on data from the angina study by Eddicks et al.,10 and the HF study by Lopshire et al. using SCS in canines.8 Notably, most of the patients in our study were able to identify correctly their SCS-ACTIVE and SCS-INACTIVE randomization periods afterwards. It is unclear whether the patients’ correct assessment of their SCS therapy phase might have been due to their subjective improvement in symptoms or if they might have felt the SCS due to variability in PT over time or with posture while ambulatory. While we cannot be certain that a placebo effect did not influence patient subjective measures, larger studies with additional objective outcome measures may establish SCS benefit beyond any possibility of a placebo © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
793
Spinal cord stimulation in patients with advanced HF
A
B
C
D
Figure 4 Effect of spinal cord stimulation (SCS) on heart failure markers. NYHA class (A), quality of life (B), LVEF (C), and BNP (D) changes
effect. Furthermore, even though efforts were made to see patients at a consistent time of day to maintain consistent SCS delivery timing across the patients, the timing of SCS delivery (three 2-h deliveries per day) was not uniform across the patients. Measures should be put in place in future studies to ensure that the timing of SCS delivery is kept consistent across study subjects to remove any potential confounding effect that variable SCS delivery timings might cause in interpreting the data.
Safety of using spinal cord stimulation in heart failure patients An important consideration in the use of SCS in the treatment of cardiovascular conditions, and in particular in patients with advanced HF, is the team necessary to conduct the intervention safely and the area within the hospital in which the SCS system is implanted. In this protocol, we formed a multidisciplinary team
..................................................
before (baseline or 4- month follow-up) and after (3- or 7-month follow-up) th eSCS-ACTIVE and SCS-INACTIVE phases. The blue dotted line represents the average before and after SCS for each parameter.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
composed of a HF specialist, a cardiac electrophysiologist, and a pain management specialist highly experienced with SCS implantation, and relied on support from field representatives for both the SCS system and the ICD. SCS system implantations in this study were conducted in the cardiac catheterization laboratory, in order to provide a safe environment, with particular attention to haemodynamic and cardiac rhythm monitoring. This strategy resulted in the absence of significant peri- and post-procedural cardiac complications and provided a setting for testing of ICD functionality after SCS system implantation. In this study, only two patients experienced minor procedure-related events, with one patient requiring readmission for treatment of infection. A possible concern of delivering SCS therapy in HF patients is the potential for proarrhythmia. During the course of this study, all spontaneous ventricular tachyarrhythmias either terminated spontaneously or were ably terminated with a single round of antitachycardia pacing, and none required defibrillation therapy.
794
Markers of efficacy in heart failure by spinal cord stimulation We observed some directional results suggesting benefit of SCS for HF in this pilot study. Self-assessed QOL and the physician-assessed NYHA classification showed an improvement in the majority of patients over the SCS-ACTIVE period, slightly more so than over the SCS-INACTIVE period. It is noteworthy that all patients with previously implanted CRT devices were enrolled following at least 9 months of CRT therapy; thus, it is unlikely that any improvements observed in this study were due to CRT. Given that a majority of the patients correctly identified whether SCS was on or off in this study despite setting the SCS amplitude at 90% of the PT, a placebo effect contributing to the symptomatic improvements observed cannot be ruled out. However, this pilot study was not principally designed to test the efficacy of SCS for HF treatment; SCS blinding should be considered to be incorporated into future SCS studies directly testing HF therapy efficacy. Objective measures of LV function and HF status did not exhibit benefit by SCS in this pilot study. LVEF monitoring indicated that there was no deterioration in LV function as a result of SCS, as there were no meaningful differences in LVEF during SCS-ACTIVE and SCS-INACTIVE. It remains to be seen, through larger investigations over longer periods of time, if SCS impacts cardiac function. Similarly, BNP, a marker associated with HF progression, did not show any trend toward improvement or worsening as a result of SCS therapy. It should be noted that the relatively short duration and/or dosage of SCS therapy prescribed in this study may have been insufficient to provide meaningful benefit, either among subjective indices of HF symptoms or among
........................................................................................................................................................................................................................
Furthermore, the number of arrhythmic events during the ACTIVE phase was lower than the number observed during the INACTIVE phase. These data are certainly suggestive that SCS therapy is not proarrhythmic. There is growing evidence that SCS systems can be safely used in the presence of an ICD.19 Neurostimulator product warnings as well as Heart Rhythm Society guidelines recommend proper testing for interactions with an SCS system implanted in patients with ICDs. Importantly, our interaction testing revealed that the previously programmed ICD settings did not require any changes after the introduction of the SCS system. The absence of interaction that we observed between SCS and cardiac sensing, detection, and defibrillation therapy delivery at implant and during the 7 months of follow-up in our cohort reinforces the available evidence of compatibility between the systems. We were particularly aggressive with our device interaction testing, inducing VF with SCS enabled, to ensure that the ICD would appropriately detect and classify the tachyarrhythmia, that therapy would be delivered rapidly, and that the defibrillation shock would successfully terminate the tachyarrhythmia. In our cohort, all induced VF events were successfully detected by the ICD with no evidence of sensing pulses from or myopotentials induced by the SCS system, and all episodes were successfully terminated and sinus rhythm restored without the need to modify any of the programmed ICD settings. The time from VF onset to VF diagnosis was 2.8 ± 0.5 s, well within the range of detection durations reported in previous studies.20,21
G. Torre-Amione et al.
objective measures of remodelling. Optimal SCS duration and dosage for HF treatment remain to be investigated for this therapy.
Limitations This study was a small prospective randomized trial to test the safety and feasibility of a novel approach for patients with advanced symptomatic HF. While this is a first study of this novel approach, there are a number of limitations in this study. First, the number of patients enrolled was small, a limitation defined by the regulatory agency. Secondly, the patients were all in an advanced stage of HF despite aggressive medical and device therapy prior to receiving SCS, and therefore the ability to detect an objective signal of benefit, such as LV reverse remodelling or reduction in BNP, beyond those reported may be limited. Finally, because the active form of therapy produces a pinprick sensation during electrical stimulation, it is difficult to avoid—at least in the present form of delivery of therapy—a true placebo effect.
Conclusions This study is the first published human experience of the use of SCS in patients to treat advanced HF. We demonstrated feasible implantation of a SCS system within the cardiac catheterization laboratory using a multidisciplinary team approach. Importantly, the use of SCS was safe, did not interact with the function of existing ICDs, and was not arrhythmogenic. Finally, we have shown that SCS therapy can be safely utilized in patients with progressive HF and that this therapy may improve symptoms. The precise mechanisms for this effect, as well as the utility and efficacy of SCS for the treatment of HF require further investigation. Conflict of interest: T.F., S.R., L.N., and J.G. are St. Jude Medical employees and own St. Jude Medical stocks.
References 1. Lee AW, Pilitsis JG. Spinal cord stimulation: indications and outcomes. Neurosurg Focus 2006;21:E3. 2. Raso L, Deer T. Spinal cord stimulation in the treatment of acute and chronic vasculitis: clinical discussion and synopsis of the literature. Neuromodulation 2011;14: 225–228; discussion 228. 3. Claeys LG, Berg W, Jonas S. Spinal cord stimulation in the treatment of chronic critical limb ischemia. Acta Neurochir 2007;97:259–265. 4. Fanciullo GJ, Robb JF, Rose RJ, Sanders JH Jr. Spinal cord stimulation for intractable angina pectoris. Anesthes Analg 1999;89:305–306. 5. DeJongste MJ. Spinal cord stimulation for ischemic heart disease. Neurol Res 2000; 22:293–298. 6. Latif OA, Nedeljkovic SS, Stevenson LW. Spinal cord stimulation for chronic intractable angina pectoris: a unified theory on its mechanism. Clin Cardiol 2001;24: 533–541. 7. Diedrichs H, Zobel C, Theissen P, Weber M, Koulousakis A, Schicha H, Schwinger RH. Symptomatic relief precedes improvement of myocardial blood flow in patients under spinal cord stimulation. Curr Controll Trials Cardiovasc Med 2005;6:7. 8. 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. 9. Falowski S, Celii A, Sharan A. Spinal cord stimulation: an update. Neurotherapeutics 2008;5:86–99. 10. Eddicks S, Maier-Hauff K, Schenk M, Muller A, Baumann G, Theres H. Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study. Heart 2007;93:585–590.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
795
11. Sanderson JE, Ibrahim B, Waterhouse D, Palmer RB. Spinal electrical stimulation for intractable angina—long-term clinical outcome and safety. Eur Heart J 1994; 15:810–814. 12. Mannheimer C, Eliasson T, Augustinsson LE, Blomstrand C, Emanuelsson H, Larsson S, Norrsell H, Hjalmarsson A. Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 1998;97: 1157–1163. 13. Greco S, Auriti A, Fiume D, Gazzeri G, Gentilucci G, Antonini L, Santini M. Spinal cord stimulation for the treatment of refractory angina pectoris: a two-year follow-up. Pacing Clin Electrophysiol 1999;22:26–32. 14. Norrsell H, Eliasson T, Albertsson P, Augustinsson LE, Emanuelsson H, Eriksson P, Mannheimer C. Effects of spinal cord stimulation on coronary blood flow velocity. Coron Artery Dis 1998;9:273–278. 15. De Landsheere C, Mannheimer C, Habets A, Guillaume M, Bourgeois I, Augustinsson LE, Eliasson T, Lamotte D, Kulbertus H, Rigo P. Effect of spinal cord stimulation on regional myocardial perfusion assessed by positron emission tomography. Am J Cardiol 1992;69:1143–1149. 16. Hautvast RW, Blanksma PK, DeJongste MJ, Pruim J, van der Wall EE, Vaalburg W, Lie KI. Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am J Cardiol 1996;77:462–467.
...............................................
Spinal cord stimulation in patients with advanced HF
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
17. 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. 18. 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 postinfarction heart failure canine model. Circulation 2005;111: 3217–3220. 19. Ooi YC, Falowski S, Wang D, Jallo J, Ho RT, Sharan A. Simultaneous use of neurostimulators in patients with a preexisting cardiovascular implantable electronic device. Neuromodulation 2011;14:20–25; discussion 25–26. 20. Wilkoff BL, Williamson BD, Stern RS, Moore SL, Lu F, Lee SW, BirgersdotterGreen UM, Wathen MS, Van Gelder IC, Heubner BM, Brown ML, Holloman KK. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol 2008;52:541–550. 21. Wilkoff BL, Ousdigian KT, Sterns LD, Wang ZJ, Wilson RD, Morgan JM. A comparison of empiric to physician-tailored programming of implantable cardioverterdefibrillators: results from the prospective randomized multicenter EMPIRIC trial. J Am Coll Cardiol 2006;48:330–339.
Spinal cord stimulation is safe and feasible in patients with advanced heart failure: early clinical experience Guillermo Torre-Amione1,2*, Kenneth Alo1, Jerry D. Estep1, Miguel Valderrabano1, Nashwa Khalil1, Taraneh G. Farazi3, Stuart P. Rosenberg3, Lanitia Ness3, and John Gill3 1 Catedra
de Cardiologia y Medicina Vascular, Escuela de Medicina, Tecnológico de Monterrey, México; 2 Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, USA; and 3 St. Jude Medical, Sylmar, CA, USA
Received 29 December 2013; revised 3 April 2014; accepted 11 April 2014 ; online publish-ahead-of-print 24 June 2014
Aims
Pre-clinical work suggests that upper thoracic spinal cord stimulation (SCS) may have therapeutic effects in the treatment of heart failure (HF). We therefore aim to assess the safety and feasibility of SCS in HF patients. ..................................................................................................................................................................... Methods A prospective, randomized, double-blind, crossover pilot study was conducted in symptomatic HF patients receiving and results optimal medical therapy. Patients were implanted with an SCS system and randomized to an SCS-ACTIVE, delivered at 90% paraesthesia threshold, or an SCS-INACTIVE phase for 3 months, followed by a 1-month washout period and crossover to the alternative phase. The safety of SCS therapy was assessed by death and cardiac events. Implantable cardioverter defibrillator (ICD) function in the presence of SCS was tested by defibrillation testing during SCS system implant and review of real-time and stored electrograms during follow-up. The efficacy of SCS therapy was assessed by changes in patient symptoms, LV function, and BNP level. Nine patients were investigated. In all cases, ICD sensing, detection, and therapy delivery were unaffected by SCS. During follow-up, one patient died and one was hospitalized for HF while in the SCS-INACTIVE phase, and two patients had HF hospitalizations during the SCS-ACTIVE phase. Symptoms were improved in the majority of patients with SCS, while markers of cardiac structure and function were, in aggregate, unchanged. ..................................................................................................................................................................... Conclusion This study shows that an SCS system can be safely implanted in patients with advanced HF and that the SCS system does not interfere with ICD function.
.......................................................................................................... Neuromodulation •
Neurostimulation •
Introduction Spinal cord stimulation (SCS) is a non-pharmacological strategy comprised of an implantable pulse generator connected to one or more epidural leads. SCS systems are indicated for treating chronic pain by stimulating distinct levels of the spinal cord, thereby creating a response in the dermatome-associated area of interest.1 In the cardiovascular system, SCS has been used to treat pain associated with peripheral vascular disease2,3 and angina.4,5 Preliminary
Neuroradiology •
...........................
Keywords
Heart failure
studies in humans suggest that SCS may be associated with vasodilatory effects and lead to decreased catecholamine production.6,7 Experimental observations suggest that the use of SCS in a canine model of HF may improve LVEF and decrease arrhythmogenicity.8 These data suggest that SCS may be an innovative therapy that improves the underlying neurohormonal imbalances associated with progressive HF. Accordingly; we conducted a pilot study to investigate the safety and feasibility of SCS in patients with advanced systolic dysfunction and symptomatic HF.
*Corresponding author. 6550 Fannin Street, Suite 1901, Houston, TX 77030, USA. Tel: +1 713 441 2762, Fax: +1 713 790 2643, Email: [email protected]
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
789
Methods Patient selection and study design Patients were recruited at the Houston Methodist Hospital between August 2010 and August 2011. Eligible patients had symptomatic HF despite standard optimal medical therapy, NYHA class III HF symptoms, LVEF ≤30%, were hospitalized for HF or received i.v. inotropic support at least once in the previous year, and walked 6 months. SCS pulse generator implant location was in the left (n = 8) or right (n = 1) buttock. Figure 2 shows an exemplary X-ray image of one patient with an SCS system and CRT-D leads. All patients were discharged within two post-operative days. Two patients had minor implant-related events; one patient had a reaction at the incision site of the SCS pulse generator that did not extend the hospitalization stay, and a second patient experienced an infection at the site of SCS pulse generator implant requiring readmission for treatment of this infection. The infection was treated with oral antibiotics and did not result in interruption of SCS therapy. There were no reported implant-related HF exacerbations or hospitalizations.
Spinal cord stimulator–implantable cardioverter defibrillator interaction: intraoperative evaluation The intraoperative PT was 9.0 ± 3.7 mA. During the intraoperative device interaction evaluation at 90% PT (8.1 ± 3.3 mA), SCS
........................................................................................................................................................................
off and subsequently turned on, noting any SCS pulses or SCS-induced myopotentials. Additional data were obtained at baseline and at the 3-, 4-, and 7-month follow-ups. These data included the assessment of NYHA class, as assessed by a blinded observer; quality of life (QOL), as assessed using the Minnesota Living with Heart Failure Questionnaire; LVEF, measured by 2D echocardiography using a blinded echocardiographer; and blood samples were drawn for measurement of BNP.
G. Torre-Amione et al.
Table 1 Baseline characteristics of the study cohort Age, median/range (years) 66/54–80 ................................................................ Gender, male/female HF aetiology, ischaemic/non-ischaemic Implanted CRM device, CRT-D/ICD CRM device average implantation duration/range (months) ICD CRT-D QRS duration, median/range (ms) LVEF, median/range (%) NYHA class, III/IV 6MHW distance, median range (m) QOL score, median/range Patients on beta-blockers Patients on ACE inhibitors/ARBs Patients on antiarrhythmic drugs Patients on digoxin Patients on diuretics Patients on aldactone
8/1 7/2 6/3
7/4–11 39/9–91 168/94–100 25/15–32 9/0 335/46–411 66/23–86 9 7/1 2 7 9 7
CRM, cardiac rhythm management; HF, heart failure; ICD, implantable cadioverter defibrillator; 6MHW, 6 min hall walk; QOL, quality of life.
or SCS-induced myopotentials were not sensed or detected by the ICD in any patient and no reprogramming of ICD sensing parameters was needed to avoid ICD detection of SCS pulses. Table 2 shows the results of the device interaction testing during VF induction and defibrillation testing. In all patients, VF was successfully induced, and the ICD appropriately detected it and successfully defibrillated it with the first prescribed shock, at the previously prescribed defibrillation energy of 26.1 ± 6.3 J. The time from VF onset to VF diagnosis was 2.8 ± 0.5 s. Visual evaluation of the ICD IEGMs recorded during VF induction and defibrillation testing did not reveal any evidence of SCS pulse generator output.
Primary safety events Table 3 shows the results of the primary safety events that occurred during the study. Three patients were hospitalized for worsening HF over the course of the study, one while in the SCS-INACTIVE phase, and the other two in the SCS-ACTIVE phase. Four patients experienced a total of five events under the definition of the primary safety endpoint. Among these, two patients experienced three events while randomized to SCS-ACTIVE, and two patients experienced two events while randomized to SCS-INACTIVE. Of the two patients in the SCS-ACTIVE phase, one was admitted twice within a short period of time. One patient died during the study, ∼2 months after SCS system implant and while in the SCS-INACTIVE phase. The investigator and safety review board determined that the death was not related to the study procedures or therapy. For this patient, baseline and implant data are reported here but not long-term data. As shown in Table 3, there were no symptomatic bradyarrhythmia events, or tachyarrhythmia events requiring high voltage therapy. © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
791
Figure 2 X-ray image from one patient showing the placement of the spinal cord stimulator (SCS) lead, CRT-D, and CRT-D leads. An exemplary X-ray image of one patient with an SCS system and CRT-D leads. The SCS pulse generator is not shown in this figure as it was implanted in the left buttock. CRT, cardiac resynchronization therapy.
Table 2 Spinal cord stimulation (SCS)–implantable cardioverter defibrillator (ICD) interaction data from defibrillation testing Patient no.
Time from Time from VF Was onset of VF diagnosis to defibrillation to VF diagnosis shock successful by the device (s) delivery (s) (yes/no) ................................................................ 1 2 3 4 5 6 7 8 9 Averagea
2 N/A 3 3 3 3 3 3 2 2.8 ± 0.5
9 N/A 5 6 6 4 5 4 7 5.8 ± 1.7
Yes Yes Yes Yes Yes Yes Yes Yes Yes Y
N/A, not available; VF, ventricular fibrillation. a Average values were computed for patients with available data.
Follow-up data THe SCS–ICD system device interaction was evaluated during study follow-ups both through the review of any stored IEGMs recorded between follow-ups and through in-clinic testing. There were 28 stored IEGMs of ambulatory tachyarrhythmias (12 recorded during SCS-ACTIVE and 16 during SCS-INACTIVE)
........................................................................................................................................................................
Spinal cord stimulation in patients with advanced HF
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
Table 3 Primary safety endpoint; event characteristics. No. of patients No. of events with events ................... .................. Safety endpoint: Total Active: Total Active: event description inactive inactive ................................................................ Death Hospitalization for HF Symptomatic bradyarrhythmia Tachyarrhythmia requiring cardioversion For all safety events
1 3 0
0:1 2:1 0:0
1 4 0
0:1 3:1 0:0
0
0:0
0
0:0
4
2:2
5
3:2
HF, heart failure; SCS, spinal cord stimulation. Active: SCS active phase; Inactive: SCS inactive phase; Total = active + inactive.
from five patients. Twenty-four of these arrhythmias were device classified as ventricular tachycardia (VT) [nine non-sustained VT (NSVT)] and the other four were atrial tachyarrhythmias. The device withheld antitachycardia pacing (ATP) for NSVT events as these events terminated spontaneously. The remaining 15 VT episodes that were not labelled as NSVT per device’s NSVT criteria came from three patients. Only one of those three patients received ATP for six episodes. The rest of the episodes from three patients did not meet the device’s criteria for ATP delivery and terminated spontaneously. These IEGMs exhibited no evidence of interaction between the SCS pulse generator and ICD sensing. Review of the IEGM during the additional in-clinic testing revealed no evidence of SCS system noise and no inappropriate sensing by the ICD due to SCS system output (Figure 3). In total, 238 VT events in five patients were diagnosed by the ICDs over the course of the study, 137 while in SCS-INACTIVE and 101 while in SCS-ACTIVE. All of these VTs terminated either spontaneously or with a single round of ICD-initiated antitachycardia pacing; no high voltage therapy was required to terminate any of these VT events. Furthermore, review of the subset of 28 of these tachyarrhythmias eliciting stored IEGMs revealed that there were no inappropriate therapies delivered. Over the course of the PT reassessments made during the follow-ups, the average PT was 6.0 ± 1.8 mA, and the average programmed SCS pulse generator output was 5.4 ± 1.6 mA. Programmed amplitude varied over the course of follow-up in each patient by 3.1 ± 1.7 mA. The effects of SCS-ACTIVE and SCS-INACTIVE on the various clinical and cardiovascular markers measured are presented in Figure 4. Over the 3-month SCS-ACTIVE phase, five patients improved by at least one NYHA class and three patients were unchanged, while no patient worsened. Data on QOL were unavailable from one patient, showed an improvement in six patients, and worsened in one patient. Changes in LVEF and BNP were mixed, with minimal overall change from baseline. Over the 3 months of SCS-INACTIVE, two patients improved by at least one NYHA class
792
G. Torre-Amione et al.
and five patients were unchanged, while one patient worsened. QOL was improved in four patients and worsened or unchanged in the other four patients. As in the SCS-ACTIVE phase, changes in LVEF and BNP were mixed. At the end of the 3-month randomization periods, seven of the eight patients in the SCS-ACTIVE phase reported the perception that SCS had been on for the previous months. At the end of the SCS-INACTIVE phase, six of the eight patients had the perception that SCS had been off.
Discussion This study reports, for the first time, the feasibility of the use of SCS for the treatment of HF in patients with LV dysfunction and advanced, symptomatic HF. There are a number of important observations from this experience. First, implantation of the SCS system was accomplished successfully in the cardiac catheterization laboratory with a coordinated multidisciplinary team in a safe manner. Secondly, the delivery of SCS did not affect ICD functionality, including the ability to detect VT and VF appropriately and deliver necessary antitachycardia and defibrillation therapy. Thirdly, these patients were able to tolerate electrical SCS and complete the study protocol, except for the single patient who died while SCS was disabled. Finally, SCS therapy did not cause cardiac events, and in fact a majority of the patients receiving SCS subjectively improved in their HF symptoms, although no objective measures of HF improvement, through LVEF and BNP, were noted.
Spinal cord stimulation for cardiovascular conditions In Europe, Australia, and several other worldwide geographies, SCS use is approved for the treatment of chronic refractory angina pectoris and peripheral vascular disease. SCS relieves anginal pain and reduces anginal frequency, allowing for improved exercise tolerance, decreased use of antianginal drugs, and improved QOL.11 – 13 Notably, such improvements in angina appear not to be driven
............................................................................................................
Figure 3 IEGM recordings with SCS disabled and enabled. The IEGMs with SCS off (left panel) and SCS on (right panel) showing no evidence of interaction. IEGM, implantable cardioverter defibrillator intracardiac electrogram; RV, right ventricular; SCS, spinal cord stimulator.
by increases in coronary flow or perfusion,7,14,15 but rather may be related to redistribution of blood flow from well-perfused to underperfused areas.16 Experimentally, the use of SCS has been tested in a canine model of HF, wherein SCS treatment has been shown to lead to a more rapid and greater reverse remodelling compared with neurohormonal medical therapy alone.10 Application of SCS in canine and porcine models of HF has also demonstrated reduction in ventricular tachyarrhythmias8,17,18 and immediate improvements in LV function.17
Paraesthesia and patient blinding to spinal cord stimulation This study was a prospective, double-blind, randomized, crossover design between SCS-ACTIVE and SCS-INACTIVE. As conventional SCS to treat chronic pain is delivered at amplitudes that elicit paraesthesia, blinding of the patient in SCS studies can be a challenge. In a recent placebo-controlled study in angina patients, Eddicks et al.10 demonstrated that patient blinding was possible, as delivery of SCS at an amplitude below the PT had functional and symptomatic improvements comparable with SCS delivered at the PT. In order to maintain patient blinding, we chose to deliver SCS in this study at an amplitude of 90% of the PT. Our selection of three daily ‘doses’ of SCS for 2 h each was based on data from the angina study by Eddicks et al.,10 and the HF study by Lopshire et al. using SCS in canines.8 Notably, most of the patients in our study were able to identify correctly their SCS-ACTIVE and SCS-INACTIVE randomization periods afterwards. It is unclear whether the patients’ correct assessment of their SCS therapy phase might have been due to their subjective improvement in symptoms or if they might have felt the SCS due to variability in PT over time or with posture while ambulatory. While we cannot be certain that a placebo effect did not influence patient subjective measures, larger studies with additional objective outcome measures may establish SCS benefit beyond any possibility of a placebo © 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
793
Spinal cord stimulation in patients with advanced HF
A
B
C
D
Figure 4 Effect of spinal cord stimulation (SCS) on heart failure markers. NYHA class (A), quality of life (B), LVEF (C), and BNP (D) changes
effect. Furthermore, even though efforts were made to see patients at a consistent time of day to maintain consistent SCS delivery timing across the patients, the timing of SCS delivery (three 2-h deliveries per day) was not uniform across the patients. Measures should be put in place in future studies to ensure that the timing of SCS delivery is kept consistent across study subjects to remove any potential confounding effect that variable SCS delivery timings might cause in interpreting the data.
Safety of using spinal cord stimulation in heart failure patients An important consideration in the use of SCS in the treatment of cardiovascular conditions, and in particular in patients with advanced HF, is the team necessary to conduct the intervention safely and the area within the hospital in which the SCS system is implanted. In this protocol, we formed a multidisciplinary team
..................................................
before (baseline or 4- month follow-up) and after (3- or 7-month follow-up) th eSCS-ACTIVE and SCS-INACTIVE phases. The blue dotted line represents the average before and after SCS for each parameter.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
composed of a HF specialist, a cardiac electrophysiologist, and a pain management specialist highly experienced with SCS implantation, and relied on support from field representatives for both the SCS system and the ICD. SCS system implantations in this study were conducted in the cardiac catheterization laboratory, in order to provide a safe environment, with particular attention to haemodynamic and cardiac rhythm monitoring. This strategy resulted in the absence of significant peri- and post-procedural cardiac complications and provided a setting for testing of ICD functionality after SCS system implantation. In this study, only two patients experienced minor procedure-related events, with one patient requiring readmission for treatment of infection. A possible concern of delivering SCS therapy in HF patients is the potential for proarrhythmia. During the course of this study, all spontaneous ventricular tachyarrhythmias either terminated spontaneously or were ably terminated with a single round of antitachycardia pacing, and none required defibrillation therapy.
794
Markers of efficacy in heart failure by spinal cord stimulation We observed some directional results suggesting benefit of SCS for HF in this pilot study. Self-assessed QOL and the physician-assessed NYHA classification showed an improvement in the majority of patients over the SCS-ACTIVE period, slightly more so than over the SCS-INACTIVE period. It is noteworthy that all patients with previously implanted CRT devices were enrolled following at least 9 months of CRT therapy; thus, it is unlikely that any improvements observed in this study were due to CRT. Given that a majority of the patients correctly identified whether SCS was on or off in this study despite setting the SCS amplitude at 90% of the PT, a placebo effect contributing to the symptomatic improvements observed cannot be ruled out. However, this pilot study was not principally designed to test the efficacy of SCS for HF treatment; SCS blinding should be considered to be incorporated into future SCS studies directly testing HF therapy efficacy. Objective measures of LV function and HF status did not exhibit benefit by SCS in this pilot study. LVEF monitoring indicated that there was no deterioration in LV function as a result of SCS, as there were no meaningful differences in LVEF during SCS-ACTIVE and SCS-INACTIVE. It remains to be seen, through larger investigations over longer periods of time, if SCS impacts cardiac function. Similarly, BNP, a marker associated with HF progression, did not show any trend toward improvement or worsening as a result of SCS therapy. It should be noted that the relatively short duration and/or dosage of SCS therapy prescribed in this study may have been insufficient to provide meaningful benefit, either among subjective indices of HF symptoms or among
........................................................................................................................................................................................................................
Furthermore, the number of arrhythmic events during the ACTIVE phase was lower than the number observed during the INACTIVE phase. These data are certainly suggestive that SCS therapy is not proarrhythmic. There is growing evidence that SCS systems can be safely used in the presence of an ICD.19 Neurostimulator product warnings as well as Heart Rhythm Society guidelines recommend proper testing for interactions with an SCS system implanted in patients with ICDs. Importantly, our interaction testing revealed that the previously programmed ICD settings did not require any changes after the introduction of the SCS system. The absence of interaction that we observed between SCS and cardiac sensing, detection, and defibrillation therapy delivery at implant and during the 7 months of follow-up in our cohort reinforces the available evidence of compatibility between the systems. We were particularly aggressive with our device interaction testing, inducing VF with SCS enabled, to ensure that the ICD would appropriately detect and classify the tachyarrhythmia, that therapy would be delivered rapidly, and that the defibrillation shock would successfully terminate the tachyarrhythmia. In our cohort, all induced VF events were successfully detected by the ICD with no evidence of sensing pulses from or myopotentials induced by the SCS system, and all episodes were successfully terminated and sinus rhythm restored without the need to modify any of the programmed ICD settings. The time from VF onset to VF diagnosis was 2.8 ± 0.5 s, well within the range of detection durations reported in previous studies.20,21
G. Torre-Amione et al.
objective measures of remodelling. Optimal SCS duration and dosage for HF treatment remain to be investigated for this therapy.
Limitations This study was a small prospective randomized trial to test the safety and feasibility of a novel approach for patients with advanced symptomatic HF. While this is a first study of this novel approach, there are a number of limitations in this study. First, the number of patients enrolled was small, a limitation defined by the regulatory agency. Secondly, the patients were all in an advanced stage of HF despite aggressive medical and device therapy prior to receiving SCS, and therefore the ability to detect an objective signal of benefit, such as LV reverse remodelling or reduction in BNP, beyond those reported may be limited. Finally, because the active form of therapy produces a pinprick sensation during electrical stimulation, it is difficult to avoid—at least in the present form of delivery of therapy—a true placebo effect.
Conclusions This study is the first published human experience of the use of SCS in patients to treat advanced HF. We demonstrated feasible implantation of a SCS system within the cardiac catheterization laboratory using a multidisciplinary team approach. Importantly, the use of SCS was safe, did not interact with the function of existing ICDs, and was not arrhythmogenic. Finally, we have shown that SCS therapy can be safely utilized in patients with progressive HF and that this therapy may improve symptoms. The precise mechanisms for this effect, as well as the utility and efficacy of SCS for the treatment of HF require further investigation. Conflict of interest: T.F., S.R., L.N., and J.G. are St. Jude Medical employees and own St. Jude Medical stocks.
References 1. Lee AW, Pilitsis JG. Spinal cord stimulation: indications and outcomes. Neurosurg Focus 2006;21:E3. 2. Raso L, Deer T. Spinal cord stimulation in the treatment of acute and chronic vasculitis: clinical discussion and synopsis of the literature. Neuromodulation 2011;14: 225–228; discussion 228. 3. Claeys LG, Berg W, Jonas S. Spinal cord stimulation in the treatment of chronic critical limb ischemia. Acta Neurochir 2007;97:259–265. 4. Fanciullo GJ, Robb JF, Rose RJ, Sanders JH Jr. Spinal cord stimulation for intractable angina pectoris. Anesthes Analg 1999;89:305–306. 5. DeJongste MJ. Spinal cord stimulation for ischemic heart disease. Neurol Res 2000; 22:293–298. 6. Latif OA, Nedeljkovic SS, Stevenson LW. Spinal cord stimulation for chronic intractable angina pectoris: a unified theory on its mechanism. Clin Cardiol 2001;24: 533–541. 7. Diedrichs H, Zobel C, Theissen P, Weber M, Koulousakis A, Schicha H, Schwinger RH. Symptomatic relief precedes improvement of myocardial blood flow in patients under spinal cord stimulation. Curr Controll Trials Cardiovasc Med 2005;6:7. 8. 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. 9. Falowski S, Celii A, Sharan A. Spinal cord stimulation: an update. Neurotherapeutics 2008;5:86–99. 10. Eddicks S, Maier-Hauff K, Schenk M, Muller A, Baumann G, Theres H. Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study. Heart 2007;93:585–590.
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
795
11. Sanderson JE, Ibrahim B, Waterhouse D, Palmer RB. Spinal electrical stimulation for intractable angina—long-term clinical outcome and safety. Eur Heart J 1994; 15:810–814. 12. Mannheimer C, Eliasson T, Augustinsson LE, Blomstrand C, Emanuelsson H, Larsson S, Norrsell H, Hjalmarsson A. Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study. Circulation 1998;97: 1157–1163. 13. Greco S, Auriti A, Fiume D, Gazzeri G, Gentilucci G, Antonini L, Santini M. Spinal cord stimulation for the treatment of refractory angina pectoris: a two-year follow-up. Pacing Clin Electrophysiol 1999;22:26–32. 14. Norrsell H, Eliasson T, Albertsson P, Augustinsson LE, Emanuelsson H, Eriksson P, Mannheimer C. Effects of spinal cord stimulation on coronary blood flow velocity. Coron Artery Dis 1998;9:273–278. 15. De Landsheere C, Mannheimer C, Habets A, Guillaume M, Bourgeois I, Augustinsson LE, Eliasson T, Lamotte D, Kulbertus H, Rigo P. Effect of spinal cord stimulation on regional myocardial perfusion assessed by positron emission tomography. Am J Cardiol 1992;69:1143–1149. 16. Hautvast RW, Blanksma PK, DeJongste MJ, Pruim J, van der Wall EE, Vaalburg W, Lie KI. Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am J Cardiol 1996;77:462–467.
...............................................
Spinal cord stimulation in patients with advanced HF
© 2014 The Authors European Journal of Heart Failure © 2014 European Society of Cardiology
17. 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. 18. 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 postinfarction heart failure canine model. Circulation 2005;111: 3217–3220. 19. Ooi YC, Falowski S, Wang D, Jallo J, Ho RT, Sharan A. Simultaneous use of neurostimulators in patients with a preexisting cardiovascular implantable electronic device. Neuromodulation 2011;14:20–25; discussion 25–26. 20. Wilkoff BL, Williamson BD, Stern RS, Moore SL, Lu F, Lee SW, BirgersdotterGreen UM, Wathen MS, Van Gelder IC, Heubner BM, Brown ML, Holloman KK. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol 2008;52:541–550. 21. Wilkoff BL, Ousdigian KT, Sterns LD, Wang ZJ, Wilson RD, Morgan JM. A comparison of empiric to physician-tailored programming of implantable cardioverterdefibrillators: results from the prospective randomized multicenter EMPIRIC trial. J Am Coll Cardiol 2006;48:330–339.
