Cardiac Contractility Modulation (CCM) Therapy
Number: 0930
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses cardiac contractility modulation (CCM) therapy.
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Experimental, Investigational, or Unproven
Aetna considers cardiac contractility modulation (CCM) therapy, administered by Impulse Dynamics’ Optimizer system, and the OPTIMIZER Integra CCM-D System experimental, investigational, or unproven because the effectiveness of this approach has not been established.
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Related Policies
Background
Impulse Dynamics offers cardiac contractility modulation (CCM) therapy to treat adults with moderate-to-severe “chronic” heart failure that is symptomatic despite optimal medical therapy. CCM delivers non-excitatory electrical signals to the right side of the intraventricular septum during the absolute refractory period of the ventricular contraction, and does not trigger a new action potential. CCM signals are delivered by Impulse Dynamics’ Optimizer system (i.e., Optimizer IVs), which is an implantable pulse generator. This device is implanted in a minimally-invasive procedure under local anesthesia, typically in the right pectoral region. CCM has been evaluated in patients with heart failure with reduced ejection fraction (HFrEF) in New York Heart Association (NYHA) Classes II to IV with normal QRS duration (less than 120 ms). In contrast to a pacemaker or a defibrillator, the system is designed to modulate the strength of contraction of the heart muscle rather than the rhythm. CCM therapy is delivered at regular intervals throughout the day. The "common patient profile" for this therapy is NYHA II to III, normal QRS, EF greater than 20 %, peak VO2 ≥ 10 ml/kg/min, and ventricular ectopies or bigeminies less than 10,000 per day (Impulse Dynamics, 2018).
Some individuals may also require and implantable cardioverter-defibrillator (ICD) device, or already have one implanted. The Optimizer IVs is designed to work in parallel with any ICD device and generally does not cause any interruption of ICD function. The Optimizer IVs is contraindicated for patients with permanent or long-standing persistent atrial fibrillation or flutter, mechanical tricuspid valve, no venous access, and device programmed to 100 % VVI pacing (Impulse Dynamics, 2018).
Kadish et al (2011) conducted a randomized controlled prospective study (FIX-HF-5) to evaluate the safety and efficacy of CCM in advanced HF. A total of 428 adults with NYHA class III or IV, narrow QRS (defined as less than 130 msec duration) and EF less than or equal to 35 % were randomly assigned to receive optimal medical therapy (OMT) plus CCM (n = 215), or OMT alone (n = 213). The primary efficacy endpoint, required by the U.S. Food and Drug Administration (FDA), was the change from baseline in the ventilatory anaerobic threshold (VAT) measured on CPX. Secondary efficacy endpoints were peak Vo2 (pVo2), and quality of life (QOL) assessed by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ) at 6 months. The primary safety endpoint was a test of non-inferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations through 50 weeks. While VAT did not improve at 6 months, CCM significantly improved pVo2 (p = 0.024) and MLWHFQ (p < 0.0001), respectively, over OMT; 48 % of OMT and 52 % of CCM patients experienced a safety endpoint, which satisfied the non-inferiority criterion (p = 0.03). Post-hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline greater than or equal to 25 and NYHA class III symptoms) in which all parameters were improved by CCM. The authors concluded that further study is required to clarify the roll of CCM therapy in refractory HF.
Lyon et al (2013) stated that CCM is the application of non-excitatory electrical signals to the myocardium, during the absolute refractory period of the action potential, to elicit a positive inotropic effect without increasing myocardial oxygen consumption. These effects are independent of QRS duration; consequently, CCM device therapy might benefit symptomatic patients with reduced LVEF; and who are not candidates for CRT. Pre-clinical studies have demonstrated a rapid positive inotropic effect of CCM, which appeared to be mediated by modulation of cardiomyocyte Ca(2+) fluxes and alterations in the phosphorylation of cardiac phospholamban. In-vivo translational and clinical studies that utilized double biphasic voltage pulses to the right ventricular aspect of the inter-ventricular septum have demonstrated positive global effects on cardiac reverse re-modeling and contractility. Long-term application of CCM appeared to improve patients' exercise tolerance (ET) and QOL. These benefits were apparently accomplished with an acceptable safety profile; however, to-date, no data have demonstrated reductions in hospitalizations for HF or mortality. The authors concluded that CCM is currently available in Europe and ongoing studies are attempting to identify the ideal target population and accumulate additional outcome data.
Abraham et al (2015) designed a confirmatory study (the FIX-HF-5C) to prospectively confirm the efficacy of CCM originally identified in the FIX-HF-5 study of patients with EF 25 % to 45 %. This Impulse Dynamics FIX-HF-5C study is an ongoing, prospective, multi-center, randomized, parallel-controlled trial that evaluated the safety and efficacy of CCM signals delivered by the implantable Optimizer System (specifically the Optimizer IVs) in patients with NYHA class III and IV HF and an EF 25 to 45 %. A total of 160 adult subjects were recruited and have been randomly assigned to either the Optimizer IVs plus OMT, or to a control group receiving OMT alone. One of the exclusion criteria included QRS duration greater than or equal to 130 msec duration. Based on difficulties encountered in reliably quantifying VAT, the relatively large number of studies in which VAT could not be quantified, and the statistical inefficiency and arbitrary nature of thresholds employed in a “responders” analysis of a continuous variable in the FIX-HF-5 study, the primary efficacy endpoint was changed to compare changes in peak VO2 between the treatment and control groups. This study was registered in ClinicalTrials.gov with an estimated completion date of March 2019 (NCT01381172).
Muller et al (2017) evaluated clinical effects of long-term CCM in subjects with HF caused by left ventricular systolic dysfunction. Out of 143 subjects from 24 sites, 106 with HFrEF completed the 24 month follow-up which was recorded via a clinical registry. Recordings included NYHA class, MLWHFQ score, 6-min walk test (6MWT) distance, left ventricular ejection fraction (LVEF), and peak VO2 at baseline and 6 month intervals as clinically indicated. Serious adverse events, and all cause as well as cardiovascular mortality were recorded. Data are presented stratified by LVEF (all subjects, LVEF less than 35 %, LVEF greater than or equal to 35 %). The investigators found that baseline parameters were similar among LVEF groups. NYHA and MLWHFQ improved in all 3 groups at each time-point. LVEF in the entire cohort improved 2.5, 2.9, 5.0, and 4.9 % at 6, 12, 18, and 24 months, respectively. Insufficient numbers of subjects had follow-up data for 6MWT or peak VO2 assessment, precluding comparative analysis. Serious adverse events (n = 193) were observed in 91 subjects and similarly distributed between groups with LVEF less than 35 % and LVEF greater than or equal to 35 %, and similar to other device trials for HF; 18 deaths (7 cardiovascular-related) over 2 years. Overall survival at 2 years was 86.4 % (95 % confidence intervals [CI]: 79.3 to 91.2 %). The investigators concluded that in patients with HFrEF and persistent symptoms despite GDMT, CCM provided sustained improvement in both cardiac function and QOL. The benefit was present not only in subjects with baseline LVEF less than 35 %, but also in those with LVEF greater than or equal to 35 %. These data suggested that CCM may be beneficial in select patients with HF, narrow QRS, and symptoms despite OMT. Limitations of the study included: lack of a control group, improvement in NYHA, MLWHFQ, and LVEF could have resulted from the increased use of pharmacological treatment of HF in these patients, and registry follow-up testing was performed based on clinical need, which may have limited the number of patients available with outcomes data related to LVEF and exercise tolerance including 6MWT, and peak VO2.
The Optimizer Smart medical device is indicated to improve 6-minute hall walk distance, QOL, and functional status of NYHA Class III heart failure patients who remain symptomatic despite guideline directed medical therapy, who are in normal sinus rhythm, are not indicated for cardiac resynchronization therapy, and have a LVEF ranging from 25 % to 45 %. Moreover, the FDA requires the performance of a post-approval study. The purpose of the Optimizer System post-approval study is to provide long-term safety and effectiveness data for the Optimizer Smart System. The study is a prospective, multi-center, non-randomized, single-arm, open-label study. As per the protocol dated March 19, 2019, the goal is to enroll approximately 620 patients such that 500 implanted patients reach the 36-month follow-up.
Furthermore, on October 26, 2021, the FDA approved a modification of labeling for the Optimizer Smart medical device, allowing the removal of “normal sinus rhythm” (NSR) from the indications for use statement.
Abraham and colleagues (2018) 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 CCM improved exercise tolerance (ET) and QOL in patients with EFs between 25 % and 45 %. A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration of less than 130 ms, and EF of greater than or equal to 25 % and less than or equal to 45 % were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo2 (primary end-point), 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 end-point analysis with 30 % borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events (AEs) with a pre-specified lower bound of 70 %. The difference in peak Vo2 between groups was 0.84 (95 % Bayesian CI: 0.123 to 1.552) ml O2/kg/min, satisfying the primary end-point. 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 end-point. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8 % to 2.9 % (p = 0.048). The authors concluded that CCM was safe, improved exercise tolerance and QOL in the specified group of HF patients, and led to fewer HF hospitalizations. Moreover, these researchers stated that future research is needed to examine the impact of CCM on mortality in the current target population. Furthermore, because CCM works through a mechanism completely different than cardiac resynchronization therapy (CRT), future research can examine the impact of CCM in patients with prolonged QRS duration in addition to CRT, in particular in CRT non-responders.
The authors stated that short-term follow-up duration (24 weeks) and small sample size (n = 74 in the CCM group) were the 2 main drawbacks of this trial. The short-term follow-up duration limited the ability to evaluate the long-term effects of CCM on mortality and hospitalizations. Although a double-blinded trial design employing an implanted, non-activated control group as used in some device trials (including the prior feasibility study of the OPTIMIZER [5]) was initially considered, this was deemed unfeasible as detailed in the description of the original FIX-HF-5 study. Accordingly, given the unblinded nature of the study, several measures were taken to minimize placebo effect and investigator bias. Cardiopulmonary exercise tests were performed according to rigorous protocols with significant oversight of a core laboratory. Test results were read blinded, with specific criteria applied to exclude tests that were not performed properly and resulted in inadequate tests. Patients were required to perform 2 tests on separate days at each time-point to ensure that maximal efforts were achieved.
Tschope et al (2018) noted that HF is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced EF (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, ET and QOL and reduce the rate of HF hospitalizations in patients with EF between 25 % and 45 %. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. In particular, CCM is beneficial in patients with baseline EF between 35 % and 45 %, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the fetal myocyte gene program associated with HF, and to facilitate reverse re-modeling. The authors highlighted the pre-clinical and clinical literature related to CCM in HFrEF and HFmrEF and outlined the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs. These researchers stated that whether the mechanisms observed in HFrEF also apply to patients with heart failure with preserved ejection fraction (HFpEF) needs to be investigated. Therefore, a prospective, multi-center, single-arm, open‐label 24‐week exploratory study evaluating CCM therapy in patients who are symptomatic despite optimal medical therapy is planned: Cardiac Contractility Modulation (CCM™) Therapy in Subjects with Heart Failure with preserved Ejection Fraction, in brief CCM‐HFpEF.
Kuschyk and colleagues (2019) noted that a significant proportion of patients receiving cardiac resynchronization therapy (CRT) are non-responders. In a multi-center, open-label, treatment-only, feasibility study, these researchers evaluated the efficacy of CCM in subjects with reduced LVEF who, despite CRT, continued to experience clinically significant symptoms. This was a trial of 17 CRT non-responders who received CCM therapy. Changes in NYHA class, EF, MLWHFQ score, and exercise tolerance (6 minute walk test [6MWT] and pVo2) were analyzed over 6 months. Mortality and hospitalization rates were determined. Patients (82 % men) were 69.4 ± 9.6 years of age with baseline EF = 22.8 ± 6.5 %. Among primary end-points, peak VO2 increased 1.1 ± 1.6 ml/kg/min (p = 0.03) and MLWHFQ improved (-16 ± 16 points; p < 0.01). Mean NYHA class improved (-0.33 ± 0.49; p = 0.02), 6MWT increased (52 ± 60 m; p < 0.01), while EF trended up (2.9 ± 5.8 %; p = 0.08) at 6 months. During the 6-month follow-up period, there were 18 hospitalizations in 9 subjects and 2 patients died. The authors concluded that patients with HF and reduced EF who remained moderately to severely symptomatic despite use of CRT, may benefit from CCM therapy with improvement in QOL and exercise tolerance. These researchers stated that a larger prospective study in this population is needed.
Mann and Abraham (2019) stated that despite advances in medical therapy, HFrEF is still a leading cause of mortality, hospitalizations, and healthcare costs. These researchers described 2 novel, implantable devices for the treatment of patients with HFrEF: CCM and baroreflex activation therapy (BAT), and summarized literature regarding these devices from the last 5 years. CCM improved QOL and functional capacity as indexed by the MLWHFQ score, 6MHWT distance, NYHA functional class, pVo2, HF hospitalizations, and mortality. BAT improved MLWHFQ, 6MWT distance, NYHA functional class, and HF hospitalizations. Both devices have been shown to be safe. CCM and BAT have been shown to be safe and effective treatment modalities for HFrEF. The authors concluded that CCM has been approved for use in Europe and has been implanted in thousands of patients; BAT has also been approved in Europe and continues to show promise in treating patients with HFrEF who fail OMT. These investigators noted that at present, both therapies are considered investigational in the United States.
Tint and associates (2019) noted that HF is a major cause of morbidity and mortality throughout the world. Despite substantial progress in its prevention and treatment, mortality rates remain high. Device therapy for HF mainly includes CRT and the use of an ICD. Recently, however, a new device therapy – CCM – became available. These researchers presented a first case-series of patients with different clinical patterns of HFrEF, supported with the newest generation of CCM devices. A total of 5 patients with a LVEF of less than or equal to 35 % and a NYHA class of greater than or equal to III were supported with CCM OPTIMIZER SMART IPGCCMX10 at the authors’ clinic. Subjects had a median age of 67 ± 8.03 years (47 to 80) and were all men (4 with ischemic etiology dilated cardiomyopathy). In 2 cases, CCM was added on top of CRT (non-responders), and, in 1 patient, CCM was delivered during persistent atrial fibrillation (AF). After 6 months of follow-up, the LVEF increased from 25.4 ± 6.8 % to 27 ± 9 %, and the 6MWT distance increased from 310 ± 65.1 m to 466 ± 23.6 m. One patient died 47 days after device implantation. The authors concluded that CCM therapy provided with the new model OPTIMIZER SMART IPG CCMX10 was safe, feasible, and applicable to a wide range of patients with HF. These researchers stated that further trials are needed to determine the magnitude of the effect of CCM provided by the new OPTIMIZER SMART IPG CCMX10 on HF in patients with AF or who fail CRT.
The authors stated that this study had several drawbacks. This was a case-series study involving only a limited number of patients (n = 5), with a relatively short follow-up (6 months), without a randomized control group. It should be noted, however, that, even in previously published trials and studies, the number of patients enrolled was quite small and much lower compared to studies focusing on CRT and/or ICD therapy.
Mando and colleagues (2019) carried out an updated meta-analysis of the randomized clinical trials (RCTs) to examine the safety and efficacy of CCM therapy. These investigators conducted a systematic review and meta-analysis of RCTs between January 2001 and June 2018. Outcomes of interest were peak VO2, 6-Minute Walk Distance (6MWD), Minnesota Living with Heart Failure Questionnaire (MLHFQ), HF hospitalizations, cardiac arrhythmias, pacemaker/ICD malfunctioning, all-cause hospitalizations, and mortality. Data were expressed as standardized mean difference (SMD) or odds ratio (OR). A total of 4 RCTs including 801 patients (CCM; n = 394) were available for analysis. The mean age was 59.63 ± 0.84 years, mean EF was 29.14 ± 1.22 %, and mean QRS duration was 106.23 ± 1.65 msec. Mean follow-up duration was 6 months. CCM was associated with improved MLWHFQ (SMD -0.69, p = 0.0008). There were no differences in HF hospitalizations (OR 0.76, p = 0.12), 6MWD (SMD 0.67, p = 0.10), arrhythmias (OR 1.40, p = 0.14), pacemaker/ICD malfunction/sensing defect (OR 2.23, p = 0.06), all-cause hospitalizations (OR 0.73, p = 0.33), or all-cause mortality (OR 1.04, p = 0.92) between the CCM and non-CCM groups. The authors concluded that short-term treatment with CCM may improve MLFHQ without significant difference in 6MWD, arrhythmic events, HF hospitalizations, all-cause hospitalizations, and all-cause mortality. There is a trend towards increased pacemaker/ICD device malfunction. These researchers stated that larger RCTs might be needed to determine if the CCM therapy will be beneficial with longer follow-up.
Anker et al (2019) stated that CCM improved symptoms and ET and reduced HF hospitalizations over 6-month follow-up in patients with NYHA class III or IV symptoms, QRS of less than 130 ms and 25 % ≤ LVEF ≤ 45 % (FIX-HF-5C study). The current prospective registry study (CCM-REG) aimed to evaluate the longer-term impact of CCM on hospitalizations and mortality in real-world experience in this same population. A total of 140 patients with 25 % ≤ LVEF ≤ 45 % receiving CCM therapy (CCM-REG25-45 ) for clinical indications were included. Cardiovascular and HF hospitalizations, 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 3 cohorts, with progressive improvements over time (p < 0.002); 3-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 % versus 74.7 %, p = 0.046). The authors concluded that in real-world experience, CCM produced results similar to those of previous studies in subjects with 25 % ≤ LVEF ≤ 45 % and QRS < 130 ms; cardiovascular and HF hospitalizations were reduced and MLHFQ and NYHA class were improved. Overall mortality was comparable to that predicted by the SHFM but was lower than predicted in patients with 35 % ≤ LVEF ≤ 45 %.
The authors stated that this study had several drawbacks. First, this was not a randomized study and there was no separate control group. Their choice of the SHFM to provide a basis for interpreting observed survival, while not as ideal as a control group, was chosen over the MAGGIC score since it provided more conservative estimates. These investigators also did not report any measure of functional capacity since this was not a standard clinical test and was required for the present registry study. Furthermore, the fact that this study was a voluntary registry collecting data from routine clinical visits imposed at least 2 limitations. First, study participation was offered to all patients implanted with an Optimizer at each participating center, approximately 30 % of patients did not agree to participate; there is no way to determine the characteristics of those that did not participate compared to those that did participate, and whether this created selection bias in the results. Second, several clinical parameters including hospitalizations, NYHA class and MLHFQ scores were difficult to collect over the past 2 years. Interpretation of the changes in LVEF was limited by lack of an adjudicating echocardiography core (each site calculated this parameter separately) and by the relatively small number of LVEF values at later time-points, which increased the possibility of a type II error and of selection bias. For this reason, these investigators only reported changes for paired observations at 6 months. For similar reasons, the authors did not attempt to collect measures of ET that were not performed in the course of routine clinical care such as 6-minute hall walk or pVo2. In the context of randomized studies, core labs were used for analysis of endpoints such as LVEF, and adjudication committees were used to examine clinical endpoints; these were not utilized in the present study and were typically not used in real-world registry studies. It should also be noted that this registry was supported by Impulse Dynamics, Orangeburg, NY, through a clinical trials agreement with each enrolling site. Conflict of interest: Each of the following authors served as site principal investigators and received support from Impulse Dynamics for the registry study as part of a clinical trial agreement between their institution and Impulse Dynamics: M.B., H.N., M.A.O., S.R., A.G., B.A.R., and K.H.K. S.D.A. is a paid advisor for Impulse Dynamics and a member of a scientific steering committee. K.B.N., D.B., and B.R. are paid consultants to Impulse Dynamics. Impulse Dynamics provided support to the Medical College of Wisconsin for the consulting services of D.G.
Wiegn and associates (2020) noted that prior studies of CCM employed a 3-lead Optimizer system. A new 2-lead system eliminated the need for an atrial lead. These investigators examined the safety and effectiveness of this 2-lead system compared with the 3-lead system. Patients with NYHA III/IVa symptoms despite medical therapy, LVEF 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 NYHA classification were a secondary end-point. The primary safety end-point was a comparison of device-related adverse events (AEs) between FIX-HF-5C2 and FIX-HF-5C subjects. A total of 60 subjects, 88 % men, 66 ± 9 years old with LVEF of 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 AF versus 0 % in FIX-HF-5C. CCM delivery did not differ significantly between 2- and 3-lead systems (19,892 ± 3,472 versus 19,583 ± 4,998 CCM signals/day, CI of difference: -1,228 to 1,847). The change of peak VO2 from baseline to 24 weeks was 1.72 (95 % Bayesian CI: 1.02 to 2.42) ml/kg/min greater in the 2-lead device group versus controls. 83.1 % of 2-lead subjects compared with 42.7 % of controls experienced greater than or equal to 1 class NYHA improvement (p < 0.001). There were decreased Optimizer-related AEs with the 2-lead system compared with the 3-lead system (0 % versus 8 %; p = 0.03). The authors concluded that the 2-lead system effectively delivered comparable amount of CCM signals (including in subjects with AF) as the 3-lead system, was equally safe and improved peak VO2 and NYHA. Device-related adverse effects were less with the 2-lead system.
The authors stated that the major drawback of this study was that it was a non-randomized, unblinded study with a relatively small number of patients (n = 60) that used a historical control group from the prior FIX-HF-5C study. The 2 studies were reasonably contemporaneous, having been completed less than 2 years of each other. The only significant difference in background medical therapy was a slightly greater use of valsartan / sacubitril in the current study (15 % versus 4 %) due to its introduction into clinical practice toward the completion of enrollment into the FIX-HF-5C study. Furthermore, there were some imbalances in baseline characteristics between the prospective treatment and retrospective control groups; however, frequentist mixed modeling of the results by sequential addition of baseline characteristics showing differences between groups showed little impact of these differences on the results. Regarding un-blinding, this aspect was similar to the prior FIX-HF-5C study, so these investigators considered it unlikely that it would have influenced the comparisons made between the 2 studies.
Campbell and co-workers (2020) stated that CCM by the Optimizer Smart device is an innovative intracardiac device-based therapy that has been recently received FDA approval for the treatment of patients with chronic HF (CHF), LVEF between 25 and 45 %, QRS of less than 130 ms who remain symptomatic despite optimal medical therapy. Clinical trials demonstrated that CCM therapy is safe and effective in reducing HF hospitalization and improving HF symptoms, QOL and functional performance. This novel device-based therapeutic offered benefits to patients who do not otherwise qualify for cardiac resynchronization therapy. CCM expands the indication beyond the traditional LVEF cut-off of 35 % to a newer group including patients who fall in midrange LVEF group, up to 45 %. The authors noted that CCM is a novel, innovative, device-based therapy for HF recently approved by the FDA in March 2019. Based on the most recent randomized clinical trials, CCM could benefit patients with symptomatic HF despite optimized medical therapy with normal sinus rhythm and QRS less than 130 s. The significance of CCM is that it provides additional device-based therapeutic benefits to patients who do not otherwise qualify for CRT (narrow QRS). CCM also expands the indication beyond the traditional LVEF cut-off of 35 % to a newer group including patients who fall in mid-range LVEF group, up to 45 %. More importantly, these studies were conducted in era before extensive use of sacubitril/valsartan and ivabradine. These researchers stated that further prospective trials that address mortality in a prospective randomized fashion on background of current medical therapies are needed to confirm survival benefits.
Giallauria and associates (2020) performed a comprehensive individual patient data meta-analysis of all non-confounded prospective RCTs of CCM versus control that have measured functional capacity and/or QOL questionnaires in patients with HF. The Cochrane Central Register of Controlled Trials, Medline, and Embase were searched in January 2020 to identify eligible RCTs. These researchers also asked the sole manufacturer of the device for their list of known trials. Primary outcomes of interest were peak VO2, 6MWD, and QOL measured by MLWHFQ, and all data were received as individual patient and individual time point data-points; MDs and 95 % CIs were calculated for continuous data using a fixed-effects model. A total of 5 trials were identified, 4 randomized studies enrolling 801 subjects for all end-points of interest, and for peak VO2 alone (n = 60), there was an additional single arm non-randomized trial (FIX-HF-5C2) with a prospective comparison of its 24 week peak VO2 data compared with the control group of the FIX-HF-5C control patients. Pooled analysis showed that, compared with control, CCM significantly improved peak VO2 (MD +0.93, 95 % CI: 0.56 to 1.30 ml/kg/min, p < 0.00001), 6MWD (MD +17.97, 95 % CI: 5.48 to 30.46 m, p = 0.005), and QOL measured by MLWHFQ (MD -7.85, 95 % CI: -10.76 to -4.94, p < 0.00001). As a sensitivity analysis, these investigators excluded the FIX-HF-5C2 trial (only relevant for peak VO2), and the result was similar (MD +0.65, 95 % CI: 0.21 to 1.08 mL/kg/min, p = 0.004). The authors concluded that this meta‐analysis showed statistically significant and clinically worthwhile beneficial effects of CCM in improving functional capacity, exercise tolerance, and QOL in HF patients. Moreover, these researchers stated that larger, well‐conducted RCTs using a parallel double‐blind design are needed to examine the effect of CCM on major mortality and morbidity outcomes before CCM can be widely recommended as an effective therapeutic option for HF patients. However, in those in whom conventional interventions are failing or contraindicated, these results suggested that worthwhile benefits could be expected. Studies in less compromised HF patients are also encouraged in order to explore a wider application of CCM in all stages of HF.
The authors stated that this meta-analysis had several drawbacks. Study cohorts are relatively young and predominantly male, thus, future data would be needed in older individuals and in more women. Patients with permanent AF were initially excluded because the original 3‐lead OPTIMIZER device required detection of an appropriately timed P wave as part of a safety algorithm that ensures CCM signals are never delivered during the vulnerable period where they might trigger an arrhythmia. New algorithms have been developed to overcome this issue, and the FIX‐HF‐5C2 study included 9 patients with AF. Furthermore, the 2‐lead system has been available and used in patients with AF in European Union for 10 years although, as of now, specific reports of the effects of CCM in patients with AF have not been completed. In addition, although no formal statistical heterogeneity was observed, the studies analyzed differed in study design limiting the ability to define representative results across different patient subgroups.
Matta and co-workers (2021) stated that CCM is a therapeutic option for patients suffering symptomatic CHF with reduced LVEF who are not eligible for cardiac resynchronization. Data on mid-term follow-up were limited to small observational studies. In a pilot study, these researchers examined the impact of CCM on QOL, symptoms, exercise tolerance and left ventricular function in patients with CHF and moderate-to-severe left ventricular systolic dysfunction. Patients suffering CHF with LVEF of less than 45% and NYHA class of greater than II despite optimal medical therapy, underwent CCM implantation. Enrolled patients underwent baseline and 3-, 6- and 12-months evaluation with ECG, echocardiogram, clinical assessment, 6MWD and MLWHFQ. A total of 10 patients underwent CCM implantation. All subjects were actively treated with the optimal pharmacological therapy as tolerated, and had at least 1 hospitalization for worsening HF during the previous year. After a mean follow-up of 15 months, 9 patients were alive, while 1 patient died for worsening HF precipitated by pneumonia. Among the remaining 9 patients, LVEF improved non-significantly from 29.4 ± 8 % to 32.2 ± 10 % (p = 0.092), 6MWD improved from 179 ± 73 m to 304 ± 99 m (p < 0.001), NYHA class reduced from 3.0 ± 0.4 to 1.6 ± 0.5 (p = 0.003) and MLWHFQ score improved from 59.6 ± 49 to 34.2 ± 32 (p = 0.037). Only 2 patients have been hospitalized during the 12 months. Overall, a net clinical benefit was detected in 6 out of 9 patients. The authors concluded that CCM could be effective in improving QOL, symptoms and exercise tolerance, and reduced hospitalizations in patients with symptomatic CHF on top of optimal medical and electrical therapy. Moreover, these researchers stated that a prospective registry has been designed to identify the subsets of patients gaining more benefit, and to evaluate the long-term effect of CCM on those clinical end-points.
Kuschyk et al (2021) examined long-term effects of CCM delivered by the Optimizer Smart system on QOL, LVEF, mortality and HF and cardiovascular hospitalizations. These researchers noted that CCM-REG is a prospective registry study including 503 patients from 51 European centers. Effects were examined in 3 terciles of LVEF (less than or equal to 25 %, 26 % to 34 % and greater than or equal to 35 %) and in patients with AF and normal sinus rhythm (NSR). Hospitalization rates were compared using a Chi-square test. Changes in functional parameters of NYHA class, MLHFQ and LVEF were assessed with Wilcoxon signed-rank test, and event-free survival (EFS) by Kaplan-Meier analysis. For the entire cohort and each subgroup, NYHA class and MLHFQ improved at 6, 12, 18 and 24 months (p < 0.0001). At 24 months, NYHA class, MLHFQ and LVEF showed an average improvement of 0.6 ± 0.7, 10 ± 21 and 5.6 ± 8.4 %, respectively (all p < 0.001). LVEF improved in the entire cohort and in the LVEF less than or equal to 25 % subgroup with AF and NSR. In the overall cohort, HF hospitalizations decreased from 0.74 [95 % CI: 0.66 to 0.82] prior to enrolment to 0.25 (95 % CI: 0.21 to 0.28) events per patient-year during 2-year follow-up (p < 0.0001). Cardiovascular hospitalizations decreased from 1.04 (95 % CI: 0.95 to 1.13) events per patient-year prior to enrolment to 0.39 (95 % CI: 0.35 to 0.44) events per patient-year during 2-year follow-up (p < 0.0001). Similar reductions of hospitalization rates were observed in the LVEF, AF and NSR subgroups. Estimated survival was significantly better than predicted by MAGGIC at 1 and 3 years in the entire cohort and in the LVEF 26 % to 34 % and greater than or equal to 35 % subgroups. The authors concluded that CCM therapy improved functional status, QOL, LVEF and, compared to patients' prior history, reduced HF hospitalization rates. Survival at 1 and 3 years was significantly better than predicted by the MAGGIC risk score.
The authors stated that the findings of this study were subject to the limitations of an observational, non‐randomized, registry study including the potential role of placebo effect. However, sustained improvements over 2 years in NYHA class, MLHFQ and, more objectively, LVEF, and the consistency of these findings among different patient subgroups suggested that clinical effects beyond placebo were operative. Furthermore, LVEF data were available only when this test was carried out as part of routine care, which accounted for the lower number of observations compared to NYHA class and MLHFQ that were collected at each visit . It should also be recognized that these findings were derived from completer analyses over time, which did not account for patients lost to follow‐up or who had died. Similarly, effects of CCM on hospitalization rates were based on comparison of patients' historical rates rather than on a parallel control group. However, similar findings were observed in the prior randomized clinical trial and had also been used as the primary analysis for other studies of HF therapies. Furthermore, changes in medications were not tracked during the follow‐up period; however, there was very high usage of diuretics (90.7 %), angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (90.7 %), beta‐blockers (95.6 %) and mineralocorticoid receptor antagonists (68.4 %). Accordingly, there would have been very little opportunity for meaningful additions of drugs to the population as a whole; thus, changes in medications would unlikely have contributed to the sustained improvements in clinical status and hospitalizations noted during follow‐up. Also noted that during the period of data collection neither sacubitril/valsartan nor sodium-glucose co‐transporter 2 inhibitors were in widespread use, so these medications did not factor into the results. Finally, interpretation of effects on survival was based on the MAGGIC risk score, not a parallel control group . However, the MAGGIC score incorporates values of 13 independent, readily obtained clinical parameters. This is the most comprehensive and generalizable risk score currently available in the literature that has been based on 39,372 patients from 30 studies with a median follow‐up of 2.5 years. Furthermore, the score was prospectively validated in a study of 51,043 patients. The MAGGIC score does not reflect the use of ICDs.
Dobrovolskaya et al (2021) analyzed echocardiographic parameters that reflect LV myocardial contractility, using a novel method for evaluation of myocardial performance in patients with CHF and AF during heart contractility modulation (HCM). Standard echocardiographic parameters and indexes of myocardial strain and work were analyzed for 66 patients (52 men and 14 women; median age of 60 [54 to 66] years). A total of 36 patients had paroxysmal AF and 30 patients had permanent AF. All patients had CHF with a duration of 17 [4 to 60] months; duration of AF was 12 [6 to 36] months. At baseline, the LVEF was 33 [27 to 37] %. After 1 year of HCM, LVEF significantly increased from 33 [27 to 37] to 38 [33 to 44] % (р = 0.001). In addition, there were improvements in the myocardial global longitudinal strain (from -6.00 [ -8 to -4] to -8 [-10 to -6] %; р = 0.001) and parameters of myocardial work, including the global work efficiency (from 74 [65 to 79] to 80 [73; to 87] mm Hg%; р = 0.001), global constructive work (from 699 [516 to 940] to 882 [714 to 1,242] mm Hg%; р = 0.001), and global myocardial work index (from 460 [339 to 723] to 668 [497 to 943] mm Hg%; р = 0.001). A segmentary analysis of LV work parameters showed positive changes in the myocardial constructive work in the area of the interventricular septal apical segment (at baseline, 844 [614 to 1224]; after HCM, 1,027 [800 to 1,520] mm Hg%; р = 0.05) and the medium segment of the LV antero-septal wall (at baseline, 593 [312 to 1,000]; after HCM, 877 [494 to 1,145] mm Hg%; р = 0.05). The authors concluded that this method for analysis of the myocardial work provided a more detailed examination of LV structural and functional re-modeling and mechanisms for its effects on the LV contractile function in patients with CHF. These investigator stated that this method is promising and merits further study in various clinical situations.
Furthermore, an UpToDate review on “Investigational and emerging strategies for management of heart failure” (Colucci, 2021) lists “cardiac contractility modulation” as one of the investigational and emerging strategies. It states that “Cardiac contractility modulation (CCM) is a device-based therapy for HF that mildly improves functional measures but an effect on long-term clinical outcomes has not been established and there is a significant risk of complications … CCM is an option in patients with HFrEF with NYHA functional class III or IV symptoms despite optimal medical therapy. However, there are several limitations to the widespread use of CCM: the data regarding outcomes with CCM are limited and there is risk of bias due to lack of full blinding (i.e., control subjects did not receive a generator implant), and outcomes less susceptible to lack of blinding such as all-cause death and survival free of hospitalization were not improved. Accordingly, CRT, which has more extensive supporting data, is the preferred approach in patients who qualify for CRT”.
Nolan et al (2022) discussed the implications of recent technological advances in the care of patients with HF. These investigators stated that novel cardiac devices and technologies may offer an opportunity to improve outcomes. Baroreflex activation therapy and CCM may improve myocardial contractility by altering neurohormonal stimulation of the heart. Implantable pulmonary artery monitors and bi-atrial shunts may prevent HF admissions by altering the trajectory of progressive congestion. Phrenic nerve stimulation offers potentially effective treatment for co-morbid conditions. Smartphone applications offer an intriguing strategy for improving medication adherence. The authors concluded that novel HF technologies offer promise for reducing this public health burden. Moreover, these researchers stated that RCTs are needed for examining the future role of these novel therapies.
Zhang et al (2022) stated that metabolic re-modeling contributes to the pathological process of HF. In a rabbit model of chronic HF, these researchers examined the effects of CCM on myocardial metabolic re-modeling. The HF in rabbit model was established by pressure up-loading and then CCM was applied. These investigators evaluated the cardiac structure and function by echocardiography, serum BNP level, and hematoxylin and eosin and Masson's trichrome staining. They detected the accumulation of glycogen and lipid droplets in myocardial tissues by periodic acid-Schiff and Oil Red O staining. Then, these researchers measured the contents of glucose, free fatty acid (FFA), lactic acid, pyruvate, and adenosine triphosphate (ATP) levels in myocardial tissues by corresponding kits and the expression levels of key factors related to myocardial substrate uptake and utilization by Western blotting were analyzed. CCM significantly restored the cardiac structure and function in the rabbit model with HF. CCM therapy further decreased the accumulation of glycogen and lipid droplets. In addition, CCM reduced the contents of FFA, glucose, and lactic acid, and increased pyruvate and ATP levels in HF tissues. The protein expression levels related to myocardial substrate uptake and utilization were markedly improved with CCM treatment by further activating adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-α signaling pathways.
In a prospective, multi-center, single-arm, pilot study, Linde et al (2022) examined the potential benefits of CCM in patients with HFpEF. This trial enrolled patients with HFpEF and NYHA class II or III. Echocardiographic parameters were measured by an echo core laboratory to determine study eligibility. After CCM device implantation, patients were followed for 24 weeks. A total of 47 patients (mean age of 74.3 ± 4.4 years, 70.2 % women) were enrolled, with LVEF of 59 ± 4.4 %, 63.8 % with hypertension, 46.8 % with AF, 40.4 % with diabetes, 31.9 % with at least 1 HF hospitalization in the previous year, 61.7 % in NYHA class III, and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of 48.9 ± 21.7. The primary effectiveness endpoint (mean change in the KCCQ overall summary score) improved by 18.0 ± 16.6 points (p < 0.001) and there was an event-free rate of 93.6 % for the primary safety endpoint (device- and procedure-related complications), as adjudicated by an independent physician committee. The authors concluded that the findings of this pilot study showed that the benefits of CCM may extend to the HFpEF patient population. The significant improvement in health status observed, with no obvious impact on safety, suggested that the use of CCM for patients with HFpEF could prove to be promising.
The OPTIMIZER Integra CCM-DTM System
The OPTIMIZER Integra CCM-D System (CCM-D System) is an implantable cardiac device system that combines an ICD and CCM into 1 device. It is being studied in an ongoing, prospective, single-arm, multi-center study of 300 subjects who will be followed for at least 2 years with an estimated completion date of December 2025 (NCT05855135). The objective of the study is to examine how safely and effectively the CCM-D can convert induced ventricular fibrillation and spontaneous ventricular tachycardia and/or ventricular fibrillation (VT/VF) episodes in subjects with Stage C or D heart failure who remain symptomatic despite being on guideline-directed medical therapy (GDMT), are not indicated for CRT, and have HF with reduced LVEF (40 % or less).
Roger et al (2018) noted that CCM is an electrical-device therapy for patients with HFrEF. Patients with LVEF of 35 % or less also have indication for an ICD, and in some cases subcutaneous ICD (S-ICD) was selected. In a non-randomized, single-center study, these researchers hypothesized that CCM and S-ICD can be combined to work safely and effectively. They reported on 20 patients with HFrEF and LVEF 35 % or less who received CCM and S-ICD. To exclude device interference, patients received intra-operative cross-talk 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. 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; 3 patients experienced a total of 6 episodes of sustained VT, all successfully treated with 1st ICD shock. One case received an inappropriate shock unrelated to the concomitant CCM; 1 patient received an LVAD, so CCM and S-ICD were discontinued. The authors concluded that CCM and S-ICD could be successfully combined in patients with HFrEF. S-ICD and CCM remained effective when used together, with no interference affecting their function.
These researchers stated that this study presented experience with the combination of CCM and S‐ICD in a small cohort of patients (n = 20) from a single site. It presented limited data on clinical outcome in a non-randomized, non-controlled manner. These investigators stated that further multi-center studies are needed to examine the long‐term impact of combining these 2 technologies in support of patients with HFrEF and LVEF of 35 % or less, who comprise a large segment of the chronic HF population.
Li et al (2023) stated that CCM offers a novel therapeutic avenue for patients with HF, especially those unresponsive to CRT within specific QRS duration ranges. These investigators elucidated CCM's mechanistic underpinnings, its impact on myocardial function, and utility across patient demographics. However, CCM is limited by insufficient data on mortality and hospitalization rate reductions, as well as the need for specialized device implantation skills. While prevailing research has concentrated on left ventricular effects, a knowledge gap persists for other patient subsets. These researchers stated that future inquiries should address combinatory treatment strategies, extended usage and the impact of AF on device implantation. Such expanded studies could refine therapeutic outcomes and widen the scope of beneficiaries.
Pipilas et al (2024) noted that CCM is a FDA-approved device-based therapy for patients with HF. The system delivers bi-phasic electric stimulation to the ventricular myocardium during the absolute refractory period to augment left ventricular contraction. CCM therapy promotes acute and chronic changes at the cellular level, resulting in favorable re-modeling throughout the myocardium. CCM improves QOL, HYHA functional class, LVEF, peak oxygen uptake, and the composite end-point of cardiovascular death and HF hospitalizations. This review focused on the biological basis, indications, and evidence for CCM, as well as the future applications of this technology. The authors concluded that there is robust evidence to suggest improved QOL and functional status with CCM; however, future trials are needed to confirm benefits on mortality, hospitalization, and the use of CCM in patients with HFpEF.
Yuecel et al (2024) stated that cardiac implantable electrical devices can affect renal function via hemodynamic improvements. The CCM is a device-based therapeutic option for patients with symptomatic chronic HF (CHF) despite optimized medical treatment. The long-term cardio-renal interactions for CCM-treated patients are yet to be described. In this study, CCM recipients (n = 187) from the Mannheim Cardiac Contractility Modulation Observational Study (MAINTAINED) were examined in the long-term (up to 60 months) for changes in serum creatinine, estimated glomerular filtration rate (eGFR), other surrogate markers of renal function, and the chronic kidney disease (CKD) stage distribution. With regard to renal function at baseline, subjects were further grouped to either advanced CKD (aCKD, CKD stage 3 or higher, eGFR less than or equal to 59 ml/min/1.73 m2, n = 107) or preserved renal function and mild CKD (pCKD, CKD stages 1 to 2, eGFR of greater than or equal to 60 mL/min/1.73 m2, n = 80). The groups were compared for differences regarding renal function, NYHA functional class, bi-ventricular systolic function, HF hospitalizations, as well as other parameters in the long-term (60 months). CKD stage distribution remained stable during the entire follow-up (p = 0.65). An increase in serum creatinine (1.47 ± 1 versus 1.6 ± 1 mg/dL) with a corresponding decline of eGFR (58.2 ± 23.4 versus 54.2 ± 24.4 mL/min/1.73 m2, both p < 0.05) were observed after 60 months but not before for the total cohort, which was only significant in pCKD patients in terms of group comparison. Mean survival (54.3 ± 1.3 versus 55.3 ± 1.2 months, p = 0.53) was comparable in both groups. Improvements in NYHA functional class (3.11 ± 0.46 versus 2.94 ± 0.41 – 2.28 ± 0.8 versus 1.94 ± 0.6) and LVEF (24.8 ± 7.1 % versus 22.9 ± 6.6 % – 31.1 ± 11.4 5 versus 35.5 ± 11.1 %) were likewise similar after 60 months (both p < 0.05). The aCKD patients suffered from more HF hospitalizations and ventricular tachycardias during the entire follow-up period (both p < 0.05). The authors concluded that the renal function parameters and CKD stage distribution might remain stable in CCM treated HF patients in the long-term, who experienced improvements in LVEF and NYHA functional status, regardless of their renal function before. An impaired kidney function might be associated with further cardiovascular co-morbidities and more advanced HF before CCM, and could be an additional risk factor of HF complications afterward.
The authors stated that this study had several drawbacks. First, these investigators reported retrospective and non-controlled data, which were assessed from a mono-centric registry. Due to those limitations, these researchers deferred conclusions based on survival rates and comparisons to predicted mortality. Second, the assessed renal values could be influenced by several other factors, and as such, even if the authors described medical therapies initiated after CCM, the renal function outcomes might have been influenced positively and negatively by other factors. All of which, especially age-related deterioration of eGFR, must be considered for the interpretation of these findings. Third, although the delivery rates of CCM have been described in this study, further aspects of the CCM therapy, such as the number or activity status of the leads or the influence of CCM leads on tricuspid valve regurgitation were not considered. Similarly, patients with other cardiac implantable electrical devices (CIEDs) such as CRTs might have experienced benefits from these devices as well. Fourth, the lack of assessments other than blood values. To describe renal function as exactly as possible, urine volume and proteinuria/albuminuria should be considered, especially in order to diagnose CKD stage 1 and stage 2, which could not be diagnosed using eGFR alone. On the other hand, both CKD stages were grouped together, addressing this potential study bias. The assessed eGFR could not exactly reflect the measured GFR from a 24-hour urine collection. Furthermore, daily fluctuations of the eGFR and further renal retention parameters could not totally be excluded. Although grouping to either aCKD or pCKD was based on nephrology society definitions of impaired renal function, the more granular assessment would be description of each CKD stage alone (e.g., end-stage renal disease [ESRD] patients should be evaluated as carrying a different risk status than CKD stage 3a patients). However, the number of patients with CKD stage 4 or stage 5 was too low to warrant independent assessments in the authors’ mono-centric approach.
References
The above policy is based on the following references:
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