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Cardiac contractility modulation: A new technologically advanced placebo?
EDITORIAL COMMENTARY
Cardiac contractility modulation: A new technologically advanced placebo? Sunil K. Sinha, MD, Hugh G. Calkins, MD From the Division of Cardiology, Johns Hopkins University, Baltimore, Maryland. Increasingly, general cardiologists and heart failure specialists are faced with a growing clinical dilemma. Simply put, can anything beyond pharmacologic therapy be proffered to patients with symptomatic severe left ventricular dysfunction and a normal QRS duration to improve quality of life?1,2 To date, cardiac electrophysiologists and implantologists have had little to offer from their device armamentaria in this regard. In this issue of Heart Rhythm, Neelagaru et al3 present a pilot study addressing this large clinical problem with a fascinating new technology—the implantable OPTIMIZER system (IMPULSE Dynamics, Orangeburg, NY, USA). The physiologic rationale for this proposed therapy is intriguing. Prior experimental animal studies have suggested that extracellular electrical signals can enhance transsarcolemmal calcium influx and thus increase peak intracellular calcium levels, with a resulting enhancement of myocardial contractility,4,5 Hence, the OPTIMIZER system with its prepectoral canister and transvenous leads is designed to deliver high-energy but nonexcitatory electrical signals during the ventricular absolute refractory period to improve global left ventricular performance. Earlier publications of the initial use of this novel technology in small, unblinded, nonrandomized uncontrolled human studies have appeared promising.6,7 In this privately sponsored, prospective, double-blind, randomized controlled trial, 52 patients with severe systolic left ventricular dysfunction (left ventricular ejection fraction ⱕ35%, New York Heart Association (NYHA) class III–IV) and normal QRS duration, who were undergoing appropriate medical therapy, were invasively screened upon device implantation. Of these patients, 50 met criteria for permanent implantation and, subsequently, 49 patients were enrolled for either active electrical therapy for five 1-hour periods per day or no active therapy for a 6-month period. The authors’ stated intention was to fashion their trial after the MIRACLE (Multicenter Randomized Clinical Evaluation ([North America]) study, which established the utility of cardiac resynchronization therapy for symptomatic left ventricular systolic dysfunction with a wide QRS duration leading to amendment of the ACC/AHA/NASPE 2002 imAddress reprint requests and correspondence: Dr. Sunil K. Sinha, Division of Cardiology, The Johns Hopkins Hospital, 600 North Wolfe Street, Carnegie 530, Baltimore, Maryland 21287-0409. E-mail address: [email protected].
plantation guidelines and garnering of approval from the Food and Drug Administration.8 –10 However, instead of focusing upon the same primary outcomes as the MIRACLE study (6-minute walk, NYHA class, and Minnesota Living with Heart Failure Questionnaire score), they instead chose “any hospitalization” as their primary outcome. Although a trend toward a significant relative risk reduction in any hospitalization was noted in the treatment arm, a remarkable 50% (12/24) of all hospital admissions during the study period were actually due to noncardiac causes. Of note, no difference in admission for heart failure (two patients in each arm) was observed. In fact, all pertinent study endpoints (6-minute walk, anaerobic threshold, NYHA class, Minnesota Living with Heart Failure Questionnaire score, left ventricular ejection fraction) were both clinically and statistically negative. Remarkably, a majority of both treatment and control patients described a similar degree of improvement in NYHA class and Minnesota Living with Heart Failure Questionnaire score—no doubt a testament to the strength of the “placebo effect.” Despite participation by several experienced high-volume implantation centers, there appeared to be a complication rate of 16% (8/50). This disconcertingly high complication rate may have been attributable to the extended length of the procedure and large canister size (two pocket infections), the requirement for three transvenous leads (three lead dislodgments, one pericardial effusion), and problematic cardiac contractility modulation programming (one chest sensation, one inappropriate implantable cardioverter-defibrillator shock). Interestingly, as the authors report, a larger multicenter, open-label, randomized controlled trial (FIX-HF-5) of this unique device is under way and due for completion in 2007. However, given the neutral results of this pilot study, we remain skeptical that the OPTIMIZER system will definitively prove to be of significant clinical benefit. A more rewarding approach might be application of cardiac resynchronization therapy/defibrillator therapy for such patients. In this regard, a phase III, multicenter, double-blind, randomized controlled trial (RETHINQ), sponsored by St. Jude Medical Inc., of cardiac resynchronization therapy/defibrillator therapy in more than 200 patients with left ventricular ejection fraction ⱕ35%, NYHA III, normal QRS duration, and echocardiographic evidence of left ventricular mechanical dyssynchrony is currently ongoing.
1547-5271/$ -see front matter © 2006 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2006.07.012
Sinha and Calkins
Editorial Commentary
References 1. Sandhu R, Bahler RC. Prevalence of QRS prolongation in a community hospital cohort of patients with heart failure and its relation to left ventricular systolic dysfunction. Am J Cardiol 2004;93:244 –246. 2. Shenkman HJ, Pampati V, Khandelwal AK, McKinnon J, Nori D, Kaatz S, Sandberg KR, McCullough PA. Congestive heart failure and QRS duration: establishing prognosis study. Chest 2002;122:528 –534. 3. Neelagaru SB, Sanchez JE, Lau SK, Greeberg SM, Raval NY, Worley S, Kalman J, Merliss AD, Krueger S, Wood M, Wish M, Burkhoff D, Nadamanee K. Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration. Heart Rhythm 2006;3:1140 –1147. 4. Mohri S, Shimizu J, Mika Y, Shemer I, Wang J, Ben-Haim S, Burkhoff D. Electric currents applied during the refractory period enhance contractility and systolic calcium in the ferret heart. Am J Physiol Heart Circ Physiol 2003;284: H1119 –H11123. 5. Morita H, Suzuki G, Haddad W, Mika Y, Tanhehco EJ, Sharov VG, Goldstein S, Ben-Haim S, Sabbah HN. Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure. J Card Fail 2003;9:69 –75.
1149 6. Pappone C, Augello G, Rosanio S, Vicedomini G, Santinelli V, Romano M, Agricola E, Maggi F, Buchmayr G, Morreti G, Mika Y, Ben-Haim SA, Wolzt M, Stix G, Schmidinger H. First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study. J Cardiovasc Electrophysiol 2004;15:418 – 427. 7. Stix G, Borggrefe M, Wolpert C, Hindricks G, Kottkamp H, Bocker D, Wichter T, Mika Y, Ben-Haim S, Burkhoff D, Wolzt M, Schmidinger H. Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J 2004;25:626 – 628. 8. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 9. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, Winters SL. ACC/AHA/ NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices—summary article. J Am Coll Cardiol 2002;40:1703– 1719. 10. Laskey WK, Maisel WH. Cardiac resynchronization therapy: a regulatory perspective. Am Heart J 2006;151:757–761.
Cardiac contractility modulation: A new technologically advanced placebo? Sunil K. Sinha, MD, Hugh G. Calkins, MD From the Division of Cardiology, Johns Hopkins University, Baltimore, Maryland. Increasingly, general cardiologists and heart failure specialists are faced with a growing clinical dilemma. Simply put, can anything beyond pharmacologic therapy be proffered to patients with symptomatic severe left ventricular dysfunction and a normal QRS duration to improve quality of life?1,2 To date, cardiac electrophysiologists and implantologists have had little to offer from their device armamentaria in this regard. In this issue of Heart Rhythm, Neelagaru et al3 present a pilot study addressing this large clinical problem with a fascinating new technology—the implantable OPTIMIZER system (IMPULSE Dynamics, Orangeburg, NY, USA). The physiologic rationale for this proposed therapy is intriguing. Prior experimental animal studies have suggested that extracellular electrical signals can enhance transsarcolemmal calcium influx and thus increase peak intracellular calcium levels, with a resulting enhancement of myocardial contractility,4,5 Hence, the OPTIMIZER system with its prepectoral canister and transvenous leads is designed to deliver high-energy but nonexcitatory electrical signals during the ventricular absolute refractory period to improve global left ventricular performance. Earlier publications of the initial use of this novel technology in small, unblinded, nonrandomized uncontrolled human studies have appeared promising.6,7 In this privately sponsored, prospective, double-blind, randomized controlled trial, 52 patients with severe systolic left ventricular dysfunction (left ventricular ejection fraction ⱕ35%, New York Heart Association (NYHA) class III–IV) and normal QRS duration, who were undergoing appropriate medical therapy, were invasively screened upon device implantation. Of these patients, 50 met criteria for permanent implantation and, subsequently, 49 patients were enrolled for either active electrical therapy for five 1-hour periods per day or no active therapy for a 6-month period. The authors’ stated intention was to fashion their trial after the MIRACLE (Multicenter Randomized Clinical Evaluation ([North America]) study, which established the utility of cardiac resynchronization therapy for symptomatic left ventricular systolic dysfunction with a wide QRS duration leading to amendment of the ACC/AHA/NASPE 2002 imAddress reprint requests and correspondence: Dr. Sunil K. Sinha, Division of Cardiology, The Johns Hopkins Hospital, 600 North Wolfe Street, Carnegie 530, Baltimore, Maryland 21287-0409. E-mail address: [email protected].
plantation guidelines and garnering of approval from the Food and Drug Administration.8 –10 However, instead of focusing upon the same primary outcomes as the MIRACLE study (6-minute walk, NYHA class, and Minnesota Living with Heart Failure Questionnaire score), they instead chose “any hospitalization” as their primary outcome. Although a trend toward a significant relative risk reduction in any hospitalization was noted in the treatment arm, a remarkable 50% (12/24) of all hospital admissions during the study period were actually due to noncardiac causes. Of note, no difference in admission for heart failure (two patients in each arm) was observed. In fact, all pertinent study endpoints (6-minute walk, anaerobic threshold, NYHA class, Minnesota Living with Heart Failure Questionnaire score, left ventricular ejection fraction) were both clinically and statistically negative. Remarkably, a majority of both treatment and control patients described a similar degree of improvement in NYHA class and Minnesota Living with Heart Failure Questionnaire score—no doubt a testament to the strength of the “placebo effect.” Despite participation by several experienced high-volume implantation centers, there appeared to be a complication rate of 16% (8/50). This disconcertingly high complication rate may have been attributable to the extended length of the procedure and large canister size (two pocket infections), the requirement for three transvenous leads (three lead dislodgments, one pericardial effusion), and problematic cardiac contractility modulation programming (one chest sensation, one inappropriate implantable cardioverter-defibrillator shock). Interestingly, as the authors report, a larger multicenter, open-label, randomized controlled trial (FIX-HF-5) of this unique device is under way and due for completion in 2007. However, given the neutral results of this pilot study, we remain skeptical that the OPTIMIZER system will definitively prove to be of significant clinical benefit. A more rewarding approach might be application of cardiac resynchronization therapy/defibrillator therapy for such patients. In this regard, a phase III, multicenter, double-blind, randomized controlled trial (RETHINQ), sponsored by St. Jude Medical Inc., of cardiac resynchronization therapy/defibrillator therapy in more than 200 patients with left ventricular ejection fraction ⱕ35%, NYHA III, normal QRS duration, and echocardiographic evidence of left ventricular mechanical dyssynchrony is currently ongoing.
1547-5271/$ -see front matter © 2006 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2006.07.012
Sinha and Calkins
Editorial Commentary
References 1. Sandhu R, Bahler RC. Prevalence of QRS prolongation in a community hospital cohort of patients with heart failure and its relation to left ventricular systolic dysfunction. Am J Cardiol 2004;93:244 –246. 2. Shenkman HJ, Pampati V, Khandelwal AK, McKinnon J, Nori D, Kaatz S, Sandberg KR, McCullough PA. Congestive heart failure and QRS duration: establishing prognosis study. Chest 2002;122:528 –534. 3. Neelagaru SB, Sanchez JE, Lau SK, Greeberg SM, Raval NY, Worley S, Kalman J, Merliss AD, Krueger S, Wood M, Wish M, Burkhoff D, Nadamanee K. Nonexcitatory, cardiac contractility modulation electrical impulses: feasibility study for advanced heart failure in patients with normal QRS duration. Heart Rhythm 2006;3:1140 –1147. 4. Mohri S, Shimizu J, Mika Y, Shemer I, Wang J, Ben-Haim S, Burkhoff D. Electric currents applied during the refractory period enhance contractility and systolic calcium in the ferret heart. Am J Physiol Heart Circ Physiol 2003;284: H1119 –H11123. 5. Morita H, Suzuki G, Haddad W, Mika Y, Tanhehco EJ, Sharov VG, Goldstein S, Ben-Haim S, Sabbah HN. Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure. J Card Fail 2003;9:69 –75.
1149 6. Pappone C, Augello G, Rosanio S, Vicedomini G, Santinelli V, Romano M, Agricola E, Maggi F, Buchmayr G, Morreti G, Mika Y, Ben-Haim SA, Wolzt M, Stix G, Schmidinger H. First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study. J Cardiovasc Electrophysiol 2004;15:418 – 427. 7. Stix G, Borggrefe M, Wolpert C, Hindricks G, Kottkamp H, Bocker D, Wichter T, Mika Y, Ben-Haim S, Burkhoff D, Wolzt M, Schmidinger H. Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure. Eur Heart J 2004;25:626 – 628. 8. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 9. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccarelli GV, Schoenfeld MH, Silka MJ, Winters SL. ACC/AHA/ NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices—summary article. J Am Coll Cardiol 2002;40:1703– 1719. 10. Laskey WK, Maisel WH. Cardiac resynchronization therapy: a regulatory perspective. Am Heart J 2006;151:757–761.