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Electrical Stimulation of the Vagus Nerve for Chronic Heart Failure: Is It Time to Pull the Plug?
Journal of Cardiac Failure Vol. 22 No. 8 2016
Editorial
Electrical Stimulation of the Vagus Nerve for Chronic Heart Failure: Is It Time to Pull the Plug? BRIAN OLSHANSKY, MD Iowa City, Iowa
However, in the past year, several carefully designed, prospective, clinical trials reported data evaluating VNS in patients with CHF and showed no benefit. The Increase of Vagal Tone in Chronic Heart Failure (INOVATE-HF) Trial involved delivering stimulation to the right vagal nerve with an implanted device and leads in 707 CHF patients who were then followed for a mean of 16 months.5 The largest trial of its kind, INOVATE-HF showed no benefit in the primary efficacy outcome (time to first CHF hospitalization or death), mortality or LV volumes versus a non-blinded control group. Although the system used in INOVATE may have maximized attempts at VNS and minimized the adverse effects, it was not certain that the correct vagus fibers were stimulated or even that the vagus was stimulated long-term at all. Neural Cardiac Therapy fof Heart Failure (NECTARHF), a prospective, double-blinded, randomized, controlled clinical trial of right VNS, enrolling 96 patients with CHF, failed to show improvement in the primary endpoint, LV endsystolic diameter at 6 months, even though quality of life improved.6 Placebo effects may have been minimized by study design, but high-output stimulation was hard to mask. It remained uncertain if the proper fibers were being stimulated or even if harm occurred with the stimulation frequency and intensity. The Diagnosis and determining the Etiology, Fluid volume must be assessed to achieve euvolemia, and Ejection frAction must be determine to guide Therapy (DEFEAT HF) trial, a trial of spinal nerve stimulation, also failed to show benefit.7 Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF), a prospective, open-label study of 60 patients randomized to right- or left-sided VNS showed improvement in echocardiographic measures (LV ejection fraction and LV endsystolic diameter) at 6 months with stimulation of either vagus vs baseline.8 In ANTHEM, stimulation was set at a threshold for safety and tolerance. In this issue of the Journal, 12month follow-up data on 49 of the 60 ANTHEM patients showed continued benefit of VNS.9 Although this study stands out as the sole study showing benefit, without a control arm, the results are open to confounding and are not definitive. Furthermore, there may issues regarding analyzing and interpreting
Parasympathetic activation of the heart, via efferent transmission through the right and left vagus nerves, is regulated, in part, by tonic and phasic activity originating in the central nervous system and modulated by somatosensory inputs and sympathetic/parasympathetic interactions, among others.1 Although the predominant cardiac effect is on heart rate, through a complex series of sympathetic/parasympathetic interactions and through parasympathetic fibers of several types, the vagus can affect atrial and ventricular electrophysiology, cardiac function, and remodeling.1 A strong association exists between high tonic vagus nerve activity and excellent longterm outcomes, but interactions inherent in autonomic modulation for the cardiovascular system are complex, potentially selective, dynamic, and difficult to regulate. Nevertheless, it may follow that enhancing vagus nerve activity, when deficient in various cardiac conditions, such as cardiomyopathy, may improve outcomes. In animal models of systolic congestive heart failure (CHF), efferent vagus nerve stimulation (VNS) has demonstrable beneficial effects, including improvement in cardiac function and survival.2 In acutely ischemic animals, VNS reduces the risk of ventricular fibrillation.3 Similarly, for humans with CHF, in whom sympathetic activation predominates and parasympathetic activation is reduced markedly, VNS could improve outcomes. Initial nonrandomized studies of VNS showed promising results.4 Left ventricular (LV) ejection fraction, LV volumes, New York Heart Association functional class, and exercise capability improved remarkably when there was little else available to do to improve outcomes, raising hopes for a new promising therapy for those who suffer from CHF.
From the Cardiac Electrophysiology, University of Iowa Hospitals, 200 Hawkins Drive, 4426a JCP, Iowa City, Iowa 52242. Manuscript received May 23, 2016; revised manuscript accepted May 23, 2016. Reprint requests: Brian Olshanksky, MD, Cardiac Electrophysiology, University of Iowa Hospitals, 200 Hawkins Drive, 4426a JCP, Iowa City, Iowa 52242. Tel: +1 3193562344. E-mail: [email protected] See page 644 for disclosure information. 1071-9164/$ - see front matter © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2016.05.005
643
644 Journal of Cardiac Failure Vol. 22 No. 8 August 2016 the echocardiographic and blood sample data without proper blinding. There were 11 dropouts; it is possible that they refused to participate because they were nonresponders. There may have been other changes in medical therapy from the initial enrollment of the study that could have affected the outcomes. These data remain preliminary especially because of the small size and nonrandomized nature of the followup. It is possible that a placebo effect was present. How can we better understand these discrepant results? In an animal study reported in this issue,10 vagus nerve stimulation intensity was tested below a threshold that evoked symptoms but also below a voltage that decreased heart rate. In this report, 41 rats received VNS; 16 were shams. The stimulation was 20 Hz at 3 different voltages for 4 weeks. Benefits were seen at half-maximal stimulation. Somewhat unexpectedly, the middle, half-maximal stimulation “dose” resulted in significant improvement in LV function. Larger doses resulted in loss of large vagal nerve fibers. These results indicate that a properly titrated dose of VNS at a specific frequency and with a specific methodology can show benefit from VNS; mechanisms responsible remain uncertain. There have not been measures of inflammation or any obvious evidence that the vagus nerve was even activated other than the outcome measure itself. Dosage of vagal nerve stimulation that are high enough to decrease heart rate may damage the nerve and also have other adverse effects. It would be useful to know a bit more about the actual voltages used in the study. “Dose” may not be the proper terminology because stimulation includes current level (amperes), voltage, pulse width, stimulus frequency, and duty cycle. Data from this compelling animal study may help explain inconsistencies in clinical results with use of VNS. VNS is not simply on or off. The vagus nerve modulates the heart in multiple ways, has a tonic and phasic influence, and can have multiple mechanistic effects perhaps by different fibers. Specific and important afferent effects could influence also cardiac function. Patient selection can be critical. In the trials to date, patients had long-standing CHF refractory to all prior therapies. The initial insult that leads to CHF can be associated with an inflammatory phase. If VNS has benefit, it may be through an effect on inflammation.11 Patients with evidence for cardiac inflammation may be the ones who respond the best. The concerns about patient selection are consistent with results from INOVATE-HF showing that specific subgroups seemed to benefit while others did not. Further analyses will be required to understand better whether patients who did not respond are those who have had sicker hearts, have more longstanding CHF, or are refractory to all other therapies but other may indeed respond. Further, care must be taken to assure that electrical damage with high-output/maximal stimulation does not cause short- or long-term loss of myelinated fibers of the vagus and this leads to a weakened response. Regarding the ANTHEM trial, one has to wonder: did Cyberonics “get it right” with proper adjustment of stimulation output of its devices? Is it simply patient selection or is it that there was no adequate control group and that the
effects, in part, were due to placebo? The data were preliminary by any account nevertheless and were not reproduced by other and larger clinical studies. Based on the data reported so far, the question remains: Is it time to “pull the plug” on VNS for CHF? I think not. The basis for thinking that the vagus nerve is important in progressive CHF is reasonably sound; however, going forward will be much more challenging and will require a critical look at delivery of VNS to affect the proper nerve fiber in the proper way to affect the proper target. Voltage (amperage), frequency, duty cycle, and electrode design, among other things, will require careful consideration. Identifying which patient may benefit and then selecting the correct patient may be necessary to target those individuals who could improve and by what mechanism. Heart rate may or may not be an issue, but measurement of inflammatory markers may be critical. Those with recent-onset cardiomyopathy for whom inflammatory or other markers are present may be better candidates. Whatever the case, before autonomic intervention can be contemplated as a viable alternative for CHF patients, properly powered, blinded, controlled, prospective, and randomized studies will be required with carefully considered, important, objective, and measurable endpoints. Disclosures Nothing to declare. References 1. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008;118:863–71. 2. Sabbah HN, Ilsar I, Zaretsky A, Rastogi S, Wang M, Gupta RC. Vagus nerve stimulation in experimental heart failure. Heart Fail Rev 2011;16:171–8. 3. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68:1471–81. 4. De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011;32:847– 55. 5. Gold MR, Van Veldhuisen DJ, Hauptman PJ, Borggrefe M, Kubo SH, Lieberman RA, et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J Am Coll Cardiol 2016. 6. Zannad F, De Ferrari GM, Tuinenburg AE, Wright D, Brugada J, Butter C, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial. Eur Heart J 2015;36:425–33. 7. Zipes DP, Neuzil P, Theres H, Caraway D, Mann DL, Mannheimer C, et al. Determining the feasibility of spinal cord neuromodulation for the treatment of chronic systolic heart failure: the DEFEAT-HF study. JACC Heart Fail 2016;4:129–36. 8. Dicarlo L, Libbus I, Amurthur B, Kenknight BH, Anand IS. Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF study. J Card Fail 2013;19:655–60. 9. Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, et al. Extended follow-up of patients with heart failure receiving autonomic
Electrical Stimulation of the Vagus Nerve for Chronic Heart Failure regulation therapy in the ANTHEM-HF study. J Card Fail 2016;doi:10.1016/j.cardfail.2015.11.002. 10. Nishizaki A, Sakamoto K, Saku K, Hosokawa K, Sakamoto T, Ogo Y, et al. Optimal titration is important to maximize the beneficial effects
•
Olshansky
645
of vagal nerve stimulation in chronic heart failure. J Card Fail 2016;doi:10.1016/j.cardfail.2016.04.021. 11. Olshansky B. Vagus nerve modulation of inflammation: cardiovascular implications. Trends Cardiovasc Med 2016;26:1–11.
Editorial
Electrical Stimulation of the Vagus Nerve for Chronic Heart Failure: Is It Time to Pull the Plug? BRIAN OLSHANSKY, MD Iowa City, Iowa
However, in the past year, several carefully designed, prospective, clinical trials reported data evaluating VNS in patients with CHF and showed no benefit. The Increase of Vagal Tone in Chronic Heart Failure (INOVATE-HF) Trial involved delivering stimulation to the right vagal nerve with an implanted device and leads in 707 CHF patients who were then followed for a mean of 16 months.5 The largest trial of its kind, INOVATE-HF showed no benefit in the primary efficacy outcome (time to first CHF hospitalization or death), mortality or LV volumes versus a non-blinded control group. Although the system used in INOVATE may have maximized attempts at VNS and minimized the adverse effects, it was not certain that the correct vagus fibers were stimulated or even that the vagus was stimulated long-term at all. Neural Cardiac Therapy fof Heart Failure (NECTARHF), a prospective, double-blinded, randomized, controlled clinical trial of right VNS, enrolling 96 patients with CHF, failed to show improvement in the primary endpoint, LV endsystolic diameter at 6 months, even though quality of life improved.6 Placebo effects may have been minimized by study design, but high-output stimulation was hard to mask. It remained uncertain if the proper fibers were being stimulated or even if harm occurred with the stimulation frequency and intensity. The Diagnosis and determining the Etiology, Fluid volume must be assessed to achieve euvolemia, and Ejection frAction must be determine to guide Therapy (DEFEAT HF) trial, a trial of spinal nerve stimulation, also failed to show benefit.7 Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF), a prospective, open-label study of 60 patients randomized to right- or left-sided VNS showed improvement in echocardiographic measures (LV ejection fraction and LV endsystolic diameter) at 6 months with stimulation of either vagus vs baseline.8 In ANTHEM, stimulation was set at a threshold for safety and tolerance. In this issue of the Journal, 12month follow-up data on 49 of the 60 ANTHEM patients showed continued benefit of VNS.9 Although this study stands out as the sole study showing benefit, without a control arm, the results are open to confounding and are not definitive. Furthermore, there may issues regarding analyzing and interpreting
Parasympathetic activation of the heart, via efferent transmission through the right and left vagus nerves, is regulated, in part, by tonic and phasic activity originating in the central nervous system and modulated by somatosensory inputs and sympathetic/parasympathetic interactions, among others.1 Although the predominant cardiac effect is on heart rate, through a complex series of sympathetic/parasympathetic interactions and through parasympathetic fibers of several types, the vagus can affect atrial and ventricular electrophysiology, cardiac function, and remodeling.1 A strong association exists between high tonic vagus nerve activity and excellent longterm outcomes, but interactions inherent in autonomic modulation for the cardiovascular system are complex, potentially selective, dynamic, and difficult to regulate. Nevertheless, it may follow that enhancing vagus nerve activity, when deficient in various cardiac conditions, such as cardiomyopathy, may improve outcomes. In animal models of systolic congestive heart failure (CHF), efferent vagus nerve stimulation (VNS) has demonstrable beneficial effects, including improvement in cardiac function and survival.2 In acutely ischemic animals, VNS reduces the risk of ventricular fibrillation.3 Similarly, for humans with CHF, in whom sympathetic activation predominates and parasympathetic activation is reduced markedly, VNS could improve outcomes. Initial nonrandomized studies of VNS showed promising results.4 Left ventricular (LV) ejection fraction, LV volumes, New York Heart Association functional class, and exercise capability improved remarkably when there was little else available to do to improve outcomes, raising hopes for a new promising therapy for those who suffer from CHF.
From the Cardiac Electrophysiology, University of Iowa Hospitals, 200 Hawkins Drive, 4426a JCP, Iowa City, Iowa 52242. Manuscript received May 23, 2016; revised manuscript accepted May 23, 2016. Reprint requests: Brian Olshanksky, MD, Cardiac Electrophysiology, University of Iowa Hospitals, 200 Hawkins Drive, 4426a JCP, Iowa City, Iowa 52242. Tel: +1 3193562344. E-mail: [email protected] See page 644 for disclosure information. 1071-9164/$ - see front matter © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2016.05.005
643
644 Journal of Cardiac Failure Vol. 22 No. 8 August 2016 the echocardiographic and blood sample data without proper blinding. There were 11 dropouts; it is possible that they refused to participate because they were nonresponders. There may have been other changes in medical therapy from the initial enrollment of the study that could have affected the outcomes. These data remain preliminary especially because of the small size and nonrandomized nature of the followup. It is possible that a placebo effect was present. How can we better understand these discrepant results? In an animal study reported in this issue,10 vagus nerve stimulation intensity was tested below a threshold that evoked symptoms but also below a voltage that decreased heart rate. In this report, 41 rats received VNS; 16 were shams. The stimulation was 20 Hz at 3 different voltages for 4 weeks. Benefits were seen at half-maximal stimulation. Somewhat unexpectedly, the middle, half-maximal stimulation “dose” resulted in significant improvement in LV function. Larger doses resulted in loss of large vagal nerve fibers. These results indicate that a properly titrated dose of VNS at a specific frequency and with a specific methodology can show benefit from VNS; mechanisms responsible remain uncertain. There have not been measures of inflammation or any obvious evidence that the vagus nerve was even activated other than the outcome measure itself. Dosage of vagal nerve stimulation that are high enough to decrease heart rate may damage the nerve and also have other adverse effects. It would be useful to know a bit more about the actual voltages used in the study. “Dose” may not be the proper terminology because stimulation includes current level (amperes), voltage, pulse width, stimulus frequency, and duty cycle. Data from this compelling animal study may help explain inconsistencies in clinical results with use of VNS. VNS is not simply on or off. The vagus nerve modulates the heart in multiple ways, has a tonic and phasic influence, and can have multiple mechanistic effects perhaps by different fibers. Specific and important afferent effects could influence also cardiac function. Patient selection can be critical. In the trials to date, patients had long-standing CHF refractory to all prior therapies. The initial insult that leads to CHF can be associated with an inflammatory phase. If VNS has benefit, it may be through an effect on inflammation.11 Patients with evidence for cardiac inflammation may be the ones who respond the best. The concerns about patient selection are consistent with results from INOVATE-HF showing that specific subgroups seemed to benefit while others did not. Further analyses will be required to understand better whether patients who did not respond are those who have had sicker hearts, have more longstanding CHF, or are refractory to all other therapies but other may indeed respond. Further, care must be taken to assure that electrical damage with high-output/maximal stimulation does not cause short- or long-term loss of myelinated fibers of the vagus and this leads to a weakened response. Regarding the ANTHEM trial, one has to wonder: did Cyberonics “get it right” with proper adjustment of stimulation output of its devices? Is it simply patient selection or is it that there was no adequate control group and that the
effects, in part, were due to placebo? The data were preliminary by any account nevertheless and were not reproduced by other and larger clinical studies. Based on the data reported so far, the question remains: Is it time to “pull the plug” on VNS for CHF? I think not. The basis for thinking that the vagus nerve is important in progressive CHF is reasonably sound; however, going forward will be much more challenging and will require a critical look at delivery of VNS to affect the proper nerve fiber in the proper way to affect the proper target. Voltage (amperage), frequency, duty cycle, and electrode design, among other things, will require careful consideration. Identifying which patient may benefit and then selecting the correct patient may be necessary to target those individuals who could improve and by what mechanism. Heart rate may or may not be an issue, but measurement of inflammatory markers may be critical. Those with recent-onset cardiomyopathy for whom inflammatory or other markers are present may be better candidates. Whatever the case, before autonomic intervention can be contemplated as a viable alternative for CHF patients, properly powered, blinded, controlled, prospective, and randomized studies will be required with carefully considered, important, objective, and measurable endpoints. Disclosures Nothing to declare. References 1. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation 2008;118:863–71. 2. Sabbah HN, Ilsar I, Zaretsky A, Rastogi S, Wang M, Gupta RC. Vagus nerve stimulation in experimental heart failure. Heart Fail Rev 2011;16:171–8. 3. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 1991;68:1471–81. 4. De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011;32:847– 55. 5. Gold MR, Van Veldhuisen DJ, Hauptman PJ, Borggrefe M, Kubo SH, Lieberman RA, et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J Am Coll Cardiol 2016. 6. Zannad F, De Ferrari GM, Tuinenburg AE, Wright D, Brugada J, Butter C, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial. Eur Heart J 2015;36:425–33. 7. Zipes DP, Neuzil P, Theres H, Caraway D, Mann DL, Mannheimer C, et al. Determining the feasibility of spinal cord neuromodulation for the treatment of chronic systolic heart failure: the DEFEAT-HF study. JACC Heart Fail 2016;4:129–36. 8. Dicarlo L, Libbus I, Amurthur B, Kenknight BH, Anand IS. Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF study. J Card Fail 2013;19:655–60. 9. Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, et al. Extended follow-up of patients with heart failure receiving autonomic
Electrical Stimulation of the Vagus Nerve for Chronic Heart Failure regulation therapy in the ANTHEM-HF study. J Card Fail 2016;doi:10.1016/j.cardfail.2015.11.002. 10. Nishizaki A, Sakamoto K, Saku K, Hosokawa K, Sakamoto T, Ogo Y, et al. Optimal titration is important to maximize the beneficial effects
•
Olshansky
645
of vagal nerve stimulation in chronic heart failure. J Card Fail 2016;doi:10.1016/j.cardfail.2016.04.021. 11. Olshansky B. Vagus nerve modulation of inflammation: cardiovascular implications. Trends Cardiovasc Med 2016;26:1–11.