PUBLICATIONS
Impulse Dynamics has successfully conducted numerous clinical studies, including several randomized controlled trials to evaluate the safety and efficacy of CCM® therapy as delivered by Optimizer® devices. The results have been published in over 80 articles appearing in (several) leading medical journals. The publications listed here represent much of the evidence amassed in these clinical trials.
Optimizer devices are currently available in the United States, Europe, China, Brazil, India and more than 40 other countries around the world. To date, more than 10,000 patients have received the benefits of CCM® therapy worldwide. Meanwhile, ongoing investigations are planned, and the results will be published here when available.
Clinical Trials
April 2020 – Weign et al: “Safety, Performance, and Efficacy of Cardiac Contractility Modulation Delivered by the 2-Lead Optimizer Smart System - The FIX-HF-5C2 Study, Circulation Heart Failure
Background:
Prior studies of cardiac contractility modulation (CCM) employed a 3-lead Optimizer system. A new 2-lead system eliminated the need for an atrial lead. This study tested the safety and effectiveness of this 2-lead system compared with the 3-lead system.
Methods:
Patients with New York Heart Association III/IVa symptoms despite medical therapy, left ventricular ejection fraction 25% to 45%, and not eligible for cardiac resynchronization therapy could participate. All subjects received an Optimizer 2-lead implant. The primary end point was the estimated difference in the change of peak VO2 from baseline to 24 weeks between FIX-HF-5C2 (2-lead system) subjects relative to control subjects from the prior FIX-HF-5C (3-lead system) study. Changes in New York Heart Association were a secondary end point. The primary safety end point was a comparison of device-related adverse events between FIX-HF-5C2 and FIX-HF-5C subjects.
Results:
Sixty subjects, 88% male, 66±9 years old with left ventricular ejection fraction 34±6% were included. Baseline characteristics were similar between FIX-HF-5C and FIX-HF-5C2 subjects except that 15% of FIX-HF-5C2 subjects had permanent atrial fibrillation versus 0% in FIX-HF-5C. CCM delivery did not differ significantly between 2- and 3-lead systems (19 892±3472 versus 19 583±4998 CCM signals/day, CI of difference [−1228 to 1847]). The change of peak VO2 from baseline to 24 weeks was 1.72 (95% Bayesian credible interval, 1.02–2.42) mL/kg per minute greater in the 2-lead device group versus controls. 83.1% of 2-lead subjects compared with 42.7% of controls experienced ≥1 class New York Heart Association improvement (P<0.001). There were decreased Optimizer-related adverse events with the 2-lead system compared with the 3-lead system (0% versus 8%; P=0.03).
Conclusions:
The 2-lead system effectively delivers comparable amount of CCM signals (including in subjects with atrial fibrillation) as the 3-lead system, is equally safe and improves peak VO2 and New York Heart Association. Device-related adverse effects are less with the 2-lead system.
January 2019 – Anker et al: "Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction" European Journal of Heart Failure
ABSTRACT
Aims: Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS <130 ms and 25%≤left ventricular ejection fraction (LVEF)≤45% (FIX-HF-5C study). The current prospective registry study (CCM-REG) aimed to assess the longer-term impact of CCM on hospitalizations and mortality in real-world experience in this same population.
Methods and Results: A total of 140 patients with 25%≤LVEF≤45% receiving CCM therapy (CCM-REG25-45) for clinical indications were included. Cardiovascular and HF hospitalizations, Minnesota Living with Heart Failure Questionnaire (MLHFQ) and NYHA class were assessed over 2 years. Mortality was tracked through 3 years and compared with predictions by the Seattle Heart Failure Model (SHFM). A separate analysis was performed on patients with 35%≤LVEF≤45% (CCM-REG35-45) and 25%≤LVEF<35% (CCM-REG25-34). Hospitalizations decreased by 75% (from 1.2/patient-year the year before, to 0.35/patient-year during the 2 years following CCM, P <0.0001) in CCM-REG25-45 and by a similar amount in CCM-REG35-45 (P <0.0001) and CCM-REG25-34. MLHFQ and NYHA class improved in all three cohorts, with progressive improvements over time (P <0.002). Three-year survival in CCM-REG25-45 (82.8%) and CCM-REG24-34 (79.4%) were similar to those predicted by SHFM (76.7%, P =0.16; 78.0%, P =0.81, respectively) and was better than predicted in CCM-REG35-45 (88.0% vs. 74.7%, P =0.046).
Conclusion: In real-world experience, CCM produces results similar to those of previous studies in subjects with 25%≤LVEF≤45% and QRS <130 ms; cardiovascular and HF hospitalizations are reduced and MLHFQ and NYHA class are improved. Overall mortality was comparable to that predicted by the SHFM but was lower than predicted in patients with 35%≤LVEF≤45%
May 2018 - Abraham et al, "A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation." JACC HF
ABSTRACT
Objectives: The authors sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects with Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%.
Background: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period.
Methods: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak VO2 (primary endpoint), Minnesota Living With Heart Failure Questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%.
Results: The difference in peak VO2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living with Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048).
Conclusions: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects with Moderate-to-Severe Heart Failure; NCT01381172)
February 2018 – Roger et al: “Long-term results of combined cardiac contractility modulation and subcutaneous defibrillator therapy in patients with heart failure and reduced ejection fraction” Clinical Cardiology
ABSTRACT
Background: Cardiac contractility modulation (CCM) is an electrical-device therapy for patients with heart failure with reduced ejection fraction (HFrEF). Patients with left ventricular ejection fraction (LVEF) ≤35% also have indication for an implantable cardioverter-defibrillator (ICD), and in some cases subcutaneous ICD (S-ICD) is selected.
Hypothesis: CCM and S-ICD can be combined to work efficaciously and safely. Methods: We report on 20 patients with HFrEF and LVEF ≤35% who received CCM and SICD. To exclude device interference, patients received intraoperative crosstalk testing, S-ICD testing, and bicycle exercise testing while CCM was activated. Clinical and QOL measures before CCM activation and at last follow-up were analyzed. S-ICD performance was evaluated while both CCM and S-ICD were active.
Results: Mean follow-up was 34.3 months. NYHA class improved from 2.9 ±0.4 to 2.1 ± 0.7 (P < 0.0001), Minnesota Living With Heart Failure Questionnaire score improved from 50.2 ± 23.7 to 29.6 ± 22.8 points (P < 0.0001), and LVEF improved from 24.4% ± 8.1% to 30.9% ± 9.6% (P = 0.002). Mean follow-up time with both devices active was 22 months. Three patients experienced a total of 6 episodes of sustained ventricular tachycardia, all successfully treated with first ICD shock. One case received an inappropriate shock unrelated to the concomitant CCM. One patient received an LVAD, so CCM and S-ICD were discontinued.
Conclusions: CCM and S-ICD can be successfully combined in patients with HFrEF. S-ICD and CCM remain efficacious when used together, with no interference affecting their function.
June 2011 – Abraham, et al: “Subgroup Analysis of a Randomized Controlled Trial Evaluating the Safety and Efficacy of Cardiac Contractility Modulation in Advanced Heart Failure,” Journal of Cardiac Failure
Background: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n=215) versus OMT alone (n=213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study’s primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM.
Methods and Results: The protocol specified that multiregression analysis would be used to determine if baseline EF, NYHA functional class, pVO2, or etiology of heart failure influenced the impact of CCM on AT. Etiology and baseline pVO2 did not affect efficacy. However, baseline NYHA functional class III and EF ≥25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMT and 109 CCM patients, ≈ 48% of the entire population) VAT increased by 0.10 ± 2.36 in CCM versus -0.54 ± 1.83 mL kg-1 min-1 in OMT (P = .03) and pVO2 increased by 0.34 ± 3.11 in CCM versus -0.97 ± 2.31 (P = .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of ≥1 class in NYHA functional class (P= .002), and 59% of CCM versus 42% of OMT subjects showed a ≥10-point reduction in Minnesota Living with Heart Failure Questionnaire (P = .01). All of these findings were similar to those seen at 50 weeks.
Conclusions: The results of this retrospective hypothesis-generating analysis indicate that CCM significantly improves objective parameters of exercise tolerance in a subgroup of patients characterized by normal QRS duration, NYHA functional class III symptoms, and EF >25%.
February 2011 – Kadish, et al: “A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure," American Heart Journal
Background: Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction.
Methods: We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak VO2 (pVO2), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta).
Results: The groups were comparable for age (58 ± 13 vs 59 ± 12 years), EF (26% ± 7% vs 26% ± 7%), pVO2 (14.7 ± 2.9 vs 14.8 ± 3.2 mL kg−1 min−1), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pVO2 and MLWHFQ (by 0.65 mL kg−1 min−1 [P = .024] and −9.7 points [P b .0001], respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion (P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF ≥25% and New York Heart
Association class III symptoms) in which all parameters were improved by CCM.
Conclusions: In the overall target population, CCM did not improve VAT (the primary end point) but did improve pVO2 and MLWHFQ. Cardiac contractility modulation did not have an adverse effect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure. (Am Heart J 2011;161:329-337.e2.)
May 2008 – Butter C. “Cardiac Contractility Modulation Electrical Signals Improve Myocardial Gene Expression in Patients with heart failure”. Journal of the American College of Cardiology
ABSTRACT
Objectives: The objective of this study was to test whether cardiac contractility modulation (CCM) electric signals induce reverse molecular remodeling in myocardium of patients with heart failure.
Background Heart failure is associated with up-regulation of myocardial fetal and stretch response genes and down regulation of Ca2 cycling genes. Treatment with CCM signals has been associated with improved symptoms and exercise tolerance in heart failure patients. We tested the impact of CCM signals on myocardial gene expression in 11 patients.
Methods: Endomyocardial biopsies were obtained at baseline and 3 and 6 months thereafter. The CCM signals were delivered in random order of ON for 3 months and OFF for 3 months. Messenger ribonucleic acid expression was analyzed in the core lab by investigators blinded to treatment sequence. Expression of A- and B-type natriuretic peptides and -myosin heavy chain (MHC), the sarcoplasmic reticulum genes SERCA-2a, phospholamban and ryanodine receptors, and the stretch response genes p38 mitogen activated protein kinase and p21 Ras were measured using reverse transcription-polymerase chain reaction and bands quantified in densitometric units.
Results: The 3-month therapy OFF phase was associated with increased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase, and p21 Ras and decreased expression of -MHC, SERCA-2a, phospholamban, and ryanodine receptors. In contrast, the 3-month ON therapy phase resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase and p21 Ras and increased expression of -MHC, SERCA-2a, phospholamban, and ryanodine receptors.
Conclusions: The CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca2 cycling and stretch response genes. These changes may contribute to the clinical effects of CCM.
January 2008 – Borggrefe M.M. et al. “Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure”. European Heart Journal.
ABSTRACT
Aims: We performed a randomized, double blind, crossover study of cardiac contractility modulation (CCM) signals in heart failure patients.
Methods and Results: One hundred and sixty-four subjects with ejection fraction (EF), 35% and NYHA Class II (24%) or III (76%) symptoms received a CCM pulse generator. Patients were randomly assigned to Group 1 (n = 80, CCM treatment 3 months, sham treatment second 3 months) or Group 2 (n = 84, sham treatment 3 months, CCM treatment second 3 months). The co-primary endpoints were changes in peak oxygen consumption (VO2, peak) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Baseline EF (29.3±6.7% vs. 29.8±7.8%), VO2, peak (14.1±3.0 vs. 13.6±2.7 mL/kg/min), and MLWHFQ (38.9 ± 27.4 vs. 36.5 ± 27.1) were similar between the groups. VO2, peak increased similarly in both groups during the first 3 months (0.40±3.0 vs. 0.37±3.3 mL/kg/min, placebo effect). During the next 3 months, VO2, peak decreased in the group switched to sham (-0.86+3.06 mL/kg/min) and increased in patients switched to active treatment (0.16±2.50 mL/kg/min). MLWHFQ trended better with treatment (-12.06±15.33 vs. -9.70±16.71) during the first 3 months, increased during the second 3 months in the group switched to sham (+4.70±16.57), and decreased further in patients switched to active treatment (-0.70±15.13). A comparison of values at the end of active treatment periods vs. end of sham treatment periods indicates statistically significantly improved VO2, peak and MLWHFQ (P = 0.03 for each parameter).
Conclusion: In patients with heart failure and left ventricular dysfunction, CCM signals appear safe; exercise tolerance and quality of life (MLWHFQ) were significantly better while patients were receiving active treatment with CCM for a 3-month period.
Reviews
December 2020 – Rao, et al: Cardiac contractility modulation for the treatment of moderate to severe HF
December 2019 – Campbell et al: "Optimizer Smart in the treatment of moderate-to-severe chronic heart failure" Future Cardiology
ABSTRACT
Cardiac contractility modulation, also referred to as CCM™, by the Optimizer Smart device is an innovative intracardiac device-based therapy that has been recently US FDA-approved for the treatment of patients with chronic heart failure, left ventricular ejection fraction (LVEF) between 25 and 45%, QRS <130 ms who remain symptomatic despite optimal medical therapy. Clinical trials demonstrate that CCM therapy is safe and effective in reducing heart failure hospitalization and improving heart failure symptoms, quality of life and functional performance. This novel device-based therapeutic offers benefits to patients who do not otherwise qualify for cardiac resynchronization therapy. CCM expands the indication beyond the traditional LVEF cutoff of 35% to a newer group including patients who fall in midrange LVEF group, up to 45%.
Health Economics
October 2020 – Brooks: “Impulse Dynamics: Using Breakthrough Status to Help Increase Reimbursement" MedTech Strategist – Market Pathways
Enabling reimbursement to keep pace with technology innovation has been a longstanding challenge for the medtech industry. Payors in the US, sometimes including CMS, have typically lagged well behind the introduction of newly FDA-approved/cleared products, resulting in hospitals being reluctant to purchase these devices, clinicians’ being slow to adopt them, and patients—particularly those relying on Medicare—often being denied the benefits of these advanced technologies. To help address this situation, 20 years ago Congress enabled CMS to provide additional incremental reimbursement for new technologies by creating the New Technology Add-on Payment (NTAP) program.
Nonetheless, despite CMS’ efforts over the ensuing two decades to work around the edges to improve NTAP, industry remained concerned that the program was failing in its goal to deliver new technologies to patients in a timely manner. More recently, however, the agency has adopted what could be the most significant shift in administering NTAP by effectively linking the program with FDA’s Breakthrough
device designation. Essentially, this enables companies that have achieved Breakthrough status to automatically meet certain NTAP requirements, thereby making it easier for them to qualify for the added reimbursement program.
January 2020 – Witte, et al: “Cost-effectiveness of a cardiac contractility modulation device in heart failure with normal QRS duration," ESC Heart Failure
Aims: The objective of this paper is to assess whether cardiac contractility modulation (via the Optimizer System) plus standard of care (SoC) is a cost-effective treatment for people with heart failure [New York Heart Association (NYHA) III, left ventricular ejection fraction of 25–45%, and narrow QRS] compared against SoC alone from the perspective of the English National Health Service.
Methods and Results: We developed a regression equation-based cost-effectiveness model, using individual patient data from three randomized control trials (FIX-HF-5 Phases 1 and 2, and FIX-HF-5C) to populate the majority of parameters. A series of regression equations predicted NYHA class over time, mortality, all-cause hospitalization rates, and health-related quality of life. We conducted the analysis in line with the National Institute for Health and Care Excellence reference case, modelling costs from an English National Health Service perspective, and considering outcomes in quality-adjusted life years (QALYs) over a patient lifetime perspective. Our base case analysis produced an incremental cost per additional QALY of GBP22 988 (€25 750) when comparing Optimizer + SoC to SoC alone. This result was not sensitive to parameter uncertainty but was sensitive to the time horizon over which costs and QALYs were captured and the duration over which a survival benefit with Optimizer + SoC can be assumed to apply.
Conclusions: Cardiac contractility modulation is likely to be cost-effective in people with heart failure with reduced ejection fraction, NYHA III, and narrow QRS, provided that the treatment benefit can be maintained beyond the duration of the existing clinical trial follow-up. This analysis supports the current recommendations of the European Society of Cardiology that this therapy may be considered for such patients.
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