Cardiac Contractility Modulation (CCM) for Heart Failure

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A. Decision Cardiac Contractility Modulation (CCM) for heart failure (HF) management is covered under Coverage with Evidence Development (CED) according to the provisions in sections (B) and (C) below. B. Coverage Criteria The implantation of CCM is covered for HF management when furnished according to a Food and Drug Administration (FDA) market-authorized indication and all of the following conditions are met: 1. Patient Criteria Patients must meet the FDA market-authorized indications for use and remain symptomatic despite at least 3 months of optimized guideline-directed medical therapy (GDMT) as determined by the heart team prior to CCM implantation. Patients are excluded from coverage if they meet any of the following criteria: Meet any of the contraindications in the FDA labeling; or, Have had a heart transplant; or, Are younger than 18 years old. 2. CED Study Criteria The CCM and related items and services are furnished in the context of a CMS-approved CED study. CMS-approved CED study protocols must include only those patients who meet the criteria in section B.1 and include all of the following: a) Primary outcomes of all-cause mortality, HF hospitalizations, or a composite of these, through a minimum of 24 months. Each component of a composite outcome must be individually reported. b) An active comparator. c) A care management plan that identifies members, roles, and responsibilities of the clinical team that performs the follow-up CCM patient management. d) Design sufficient for subgroup analyses by: Age (Stratify <65, 65-74, 75+); Other clinically important patient demographic Ischemic cardiomyopathy versus non-ischemic cardiomyopathy; No CRT, CRT; Left ventricular ejection fraction (LVEF) ≥35% versus <35%; Systolic blood pressure greater than or equal to median versus less than median; Diabetic vs non-diabetic. e) In addition, CMS-approved CED studies must adhere to the scientific standards (criteria 1-17 below) that have been identified by the Agency for Healthcare Research and Quality (AHRQ) as set forth in Section VI. of CMS’ Coverage with Evidence Development Guidance Document , published August 7, 2024 (the “CED Guidance Document”). Sponsor/Investigator: The study is conducted by sponsors/investigators with the resources and skills to complete it successfully. Milestones: A written plan is in place that describes a detailed schedule for completion of key study milestones, including study initiation, enrollment progress, interim results reporting, and results reporting, to ensure timely completion of the CED process. Study Protocol: The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation. The published protocol includes sufficient detail to allow a judgment of whether the study is fit-for-purpose and whether reasonable efforts will be taken to minimize the risk of bias. Any changes to approved study protocols should be explained and publicly reported. Study Context: The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes. Study Design: The study design is selected to safely and efficiently generate valid evidence of health outcomes. The sponsors/investigators minimize the impact of confounding and biases on inferences through rigorous design and appropriate statistical techniques. If a contemporaneous comparison group is not included, this choice should be justified, and the sponsors/investigators discuss in detail how the design contributes useful information on issues such as durability or adverse event frequency that are not clearly answered in comparative studies. Study Population: The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention, particularly when there is good clinical or scientific reason to expect that the results observed in premarket studies might not be observed in older adults or subpopulations identified by other clinical or demographic factors. Subgroup Analyses: The study protocol explicitly discusses beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. In the protocol, the sponsors/investigators describe plans for analyzing demographic subpopulations as well as clinically-relevant subgroups as identified in existing evidence. Description of plans for exploratory analyses, as relevant subgroups emerge, are also included. Care Setting: When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care. Health Outcomes: The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions. Generally, when study sponsors propose using surrogate endpoints to measure outcomes, they should cite validation studies published in peer-reviewed journals to provide a rationale for assuming these endpoints predict the health outcomes of interest. The cited validation studies should be longitudinal and demonstrate a statistical association between the surrogate endpoint and the health outcomes it is thought to predict. Objective Success Criteria: In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision. li>Data Quality: The data are generated or selected with attention to provenance, bias, completeness, accuracy, sufficiency of duration of observation to demonstrate durability of health outcomes, and sufficiency of sample size as required by the question. Construct Validity: Sponsors/investigators provide information about the validity of drawing warranted conclusions about the study population, primary exposure(s) (intervention, control), health outcome measures, and core covariates when using either primary data collected for the study about individuals or proxies of the variables of interest, or existing (secondary) data about individuals or proxies of the variables of interest. Sensitivity Analyses: Sponsors/investigators will demonstrate robustness of results by conducting pre-specified sensitivity testing using alternative variable or model specifications as appropriate. Reporting: Final results are provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s primary completion date. Wherever possible, the study is submitted for peer review with the goal of publication using a reporting guideline appropriate for the study design and structured to enable replication. If peer-reviewed publication is not possible, results may also be published in an online publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with incomplete results). Sharing: The sponsors/investigators commit to making study data publicly available by sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. The study should comply with all applicable laws regarding subject privacy, including 45 CFR § 164.514 within the regulations promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient Records. Governance: The protocol describes the information governance and data security provisions that have been established to satisfy Federal security regulations issued pursuant to HIPAA and codified at 45 CFR Parts 160 and 164 (Subparts A & C), United States Department of Health and Human Services (HHS) regulations at 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient and HHS regulations at 45 CFR Part 46, regarding informed consent for clinical study involving human subjects. In addition to the requirements under 42 CFR and 45 CFR, studies that are subject to FDA regulation must also comply with regulations at 21 CFR Parts 50 and 56 regarding the protection of human subjects and institutional review boards, respectively. Legal: The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals, although it is acceptable for a study to test a reduction in toxicity of a product relative to standard of care or an appropriate comparator. For studies that involve researching the safety and effectiveness of new drugs and biological products aimed at treating life-threatening or severely-debilitating diseases, refer to additional requirements set forth in 21 CFR § 312.81(a). Consistent with section 1142 of the Act, AHRQ supports clinical research studies that CMS determines meet all the criteria and standards identified above. C. Other Uses of CCM 1) CCM for HF management is not covered for patients outside of a CMS-approved study. 2) Nothing in this NCD would preclude coverage of CCM for HF management through NCD 310.1 (Clinical Trial Policy) or through the Investigational Device Exemption (IDE) Policy. See Appendix A for Medicare National Coverage Determinations Manual language.

Decision Memo: Date: October 28, 2025 Final Decision Final Decision Coverage Criteria Patient Criteria CED Study Criteria Other Uses of CCM Clinical Review Background Heart Failure Definitions & Classification HF Prevalence, Incidence, and Mortality Rates Management of Heart Failure Cardiac Contractility Modulation for Heart Failure Food and Drug Administration Status Evidence Evidence Questions Technology Assessments Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) Clinical Literature Search Assessment of the Evidence Trial Design Study Population Background Medical Therapy Intervention Setting Outcomes Study Quality Synthesizing the Clinical Trial Evidence Evidence from observational studies, meta-analyses Limitations of Evidence Evidence-Based Guidelines Professional Society Recommendations / Consensus Statements / Other Expert Opinion Appropriate Use Criteria Public Comments Support for Medicare Coverage for CCM Non-Coverage for CCM Patient Criteria Physician/Facility Criteria CED Criteria for CCM Miscellaneous Comments CMS Coverage Analysis CMS Coverage Authority CMS Analysis for Coverage of CCM for HF Management Rationale for Coverage Requirements for CCM for HF Management (Patient, Physician, and CED Study criteria) Evidence Questions – Answered Benefit Category Shared Decision-Making History of Medicare Coverage Current National Coverage Request Timeline of NCA Milestones Appendices Appendix A: Medicare National Coverage Determinations Manual Language Appendix B: Referenced Materials Appendix C: Heart Failure Quality of Life and Functional Measures Bibliography Abbreviations used throughout the Decision Memorandum for Cardiac Contractility Modulation for Heart Failure Management Abbreviations 6MWT – Six-Minute Walk Test ACC – American College of Cardiology Foundation ACS – Acute Coronary Syndrome AE – Adverse Events AF – Atrial Fibrillation AHA – American Heart Association AHRQ- Agency for Healthcare Research and Quality ASC – Ambulatory Surgery Center ASE – American Society of Echocardiography CAD – Coronary Artery Disease CCM – Cardiac Contractility Modulation CHF – Congestive Heart Failure CI – Confidence Interval CKD – Chronic Kidney Disease CMS – Centers for Medicare & Medicaid Services CRT – Cardiac Resynchronization Therapy EF – Ejection Fraction EU – European Union FDA – Food and Drug Administration GDMT – Guideline-Directed Medical Therapy GFR – Glomerular Filtration Rate GLS – Global Longitudinal Strain HF – Heart failure HFimpEF – Heart Failure, Improved Ejection Fraction HFmrEF – Heart Failure, Mildly Reduced Ejection Fraction HFpEF – Heart Failure, Preserved Ejection Fraction HFrEF – Heart Failure, Reduced Ejection Fraction HFSA – Heart Failure Society of America HHS – U.S. Department of Health and Human Services HRS – Heart Rhythm Society ICD – Implantable Cardioverter Defibrillator ICM – Ischemic Cardiomyopathy IDE – Investigational Device Exemption IV – Intravenous KCCQ – Kansas City Cardiomyopathy Questionnaire KDIGO – Kidney Disease Improving Global Outcomes NICM – Non-Ischemic Cardiomyopathy LBBB – Left Bundle Branch Block LV – Left Ventricle LVEF – Left Ventricular Ejection Fraction LVMEE – Left Ventricular Myocardial Mechano-energetic Efficiency LVGLS – Left Ventricular Global Longitudinal Strain MA – Meta Analysis MACs – Medicare Administrative Contractors MAGGIC – Meta-Analysis Global Group in Chronic [Heart Failure] MCID – Minimum Clinically Important Difference MEE – Mechano-Energetic Efficiency MI – Myocardial infarction MLWHFQ – Minnesota Living With Heart Failure Questionnaire MS - millisecond NA – Not applicable NCA – National Coverage Analysis NCD – National Coverage Determination NR – Not reported NTproBNP – N-terminal pro-brain natriuretic peptide NYHA – New York Heart Association O 2 – Oxygen OMT – Optimal Medical Therapy pVO 2 – Peak oxygen consumption QoL – Quality of Life RBBB – Right Bundle Branch Block RCT – Randomized Controlled Trial RV – Right Ventricle RWE – Real-World Evidence SAE – Serious Adverse Event SCAI – Society for Cardiovascular Angiography and Interventions SCMR – Society for Cardiovascular Magnetic Resonance S-ICD – Subcutaneous implantable cardioverter defibrillator SD – Standard deviation SDM – Shared Decision-Making SHFM – Seattle Heart Failure Model TAPSE – Tricuspid Annular Plane Systolic Excursion US – United States Note – GDMT (Guideline-directed medical therapy) and OMT (Optimal Medical Therapy) are used interchangeably throughout this document. I. Final Decision A. Decision Cardiac Contractility Modulation (CCM) for heart failure (HF) management is covered under Coverage with Evidence Development (CED) according to the provisions in sections (B) and (C) below. B. Coverage Criteria The implantation of CCM is covered for HF management when furnished according to a Food and Drug Administration (FDA) market-authorized indication and all of the following conditions are met: 1. Patient Criteria Patients must meet the FDA market-authorized indications for use and remain symptomatic despite at least 3 months of optimized guideline-directed medical therapy (GDMT) as determined by the heart team prior to CCM implantation. Patients are excluded from coverage if they meet any of the following criteria: Meet any of the contraindications in the FDA labeling; or, Have had a heart transplant; or, Are younger than 18 years old. 2. CED Study Criteria The CCM and related items and services are furnished in the context of a CMS-approved CED study. CMS-approved CED study protocols must include only those patients who meet the criteria in section B.1 and include all of the following: a) Primary outcomes of all-cause mortality, HF hospitalizations, or a composite of these, through a minimum of 24 months. Each component of a composite outcome must be individually reported. b) An active comparator. c) A care management plan that identifies members, roles, and responsibilities of the clinical team that performs the follow-up CCM patient management. d) Design sufficient for subgroup analyses by: Age (Stratify < 65, 65-74, 75+); Other clinically important patient demographic Ischemic cardiomyopathy versus non-ischemic cardiomyopathy; No CRT, CRT; Left ventricular ejection fraction (LVEF) ≥35% versus < 35%; Systolic blood pressure greater than or equal to median versus less than median; Diabetic vs non-diabetic. e) In addition, CMS-approved CED studies must adhere to the scientific standards (criteria 1-17 below) that have been identified by the Agency for Healthcare Research and Quality (AHRQ) as set forth in Section VI. of CMS’ Coverage with Evidence Development Guidance Document , published August 7, 2024 (the “CED Guidance Document”). Sponsor/Investigator: The study is conducted by sponsors/investigators with the resources and skills to complete it successfully. Milestones: A written plan is in place that describes a detailed schedule for completion of key study milestones, including study initiation, enrollment progress, interim results reporting, and results reporting, to ensure timely completion of the CED process. Study Protocol: The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation. The published protocol includes sufficient detail to allow a judgment of whether the study is fit-for-purpose and whether reasonable efforts will be taken to minimize the risk of bias. Any changes to approved study protocols should be explained and publicly reported. Study Context: The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes. Study Design: The study design is selected to safely and efficiently generate valid evidence of health outcomes. The sponsors/investigators minimize the impact of confounding and biases on inferences through rigorous design and appropriate statistical techniques. If a contemporaneous comparison group is not included, this choice should be justified, and the sponsors/investigators discuss in detail how the design contributes useful information on issues such as durability or adverse event frequency that are not clearly answered in comparative studies. Study Population: The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention, particularly when there is good clinical or scientific reason to expect that the results observed in premarket studies might not be observed in older adults or subpopulations identified by other clinical or demographic factors. Subgroup Analyses: The study protocol explicitly discusses beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. In the protocol, the sponsors/investigators describe plans for analyzing demographic subpopulations as well as clinically-relevant subgroups as identified in existing evidence. Description of plans for exploratory analyses, as relevant subgroups emerge, are also included. Care Setting: When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care. Health Outcomes: The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions. Generally, when study sponsors propose using surrogate endpoints to measure outcomes, they should cite validation studies published in peer-reviewed journals to provide a rationale for assuming these endpoints predict the health outcomes of interest. The cited validation studies should be longitudinal and demonstrate a statistical association between the surrogate endpoint and the health outcomes it is thought to predict. Objective Success Criteria: In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision. li>Data Quality: The data are generated or selected with attention to provenance, bias, completeness, accuracy, sufficiency of duration of observation to demonstrate durability of health outcomes, and sufficiency of sample size as required by the question. Construct Validity: Sponsors/investigators provide information about the validity of drawing warranted conclusions about the study population, primary exposure(s) (intervention, control), health outcome measures, and core covariates when using either primary data collected for the study about individuals or proxies of the variables of interest, or existing (secondary) data about individuals or proxies of the variables of interest. Sensitivity Analyses: Sponsors/investigators will demonstrate robustness of results by conducting pre-specified sensitivity testing using alternative variable or model specifications as appropriate. Reporting: Final results are provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s primary completion date. Wherever possible, the study is submitted for peer review with the goal of publication using a reporting guideline appropriate for the study design and structured to enable replication. If peer-reviewed publication is not possible, results may also be published in an online publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with incomplete results). Sharing: The sponsors/investigators commit to making study data publicly available by sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. The study should comply with all applicable laws regarding subject privacy, including 45 CFR § 164.514 within the regulations promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient Records. Governance: The protocol describes the information governance and data security provisions that have been established to satisfy Federal security regulations issued pursuant to HIPAA and codified at 45 CFR Parts 160 and 164 (Subparts A & C), United States Department of Health and Human Services (HHS) regulations at 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient and HHS regulations at 45 CFR Part 46, regarding informed consent for clinical study involving human subjects. In addition to the requirements under 42 CFR and 45 CFR, studies that are subject to FDA regulation must also comply with regulations at 21 CFR Parts 50 and 56 regarding the protection of human subjects and institutional review boards, respectively. Legal: The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals, although it is acceptable for a study to test a reduction in toxicity of a product relative to standard of care or an appropriate comparator. For studies that involve researching the safety and effectiveness of new drugs and biological products aimed at treating life-threatening or severely-debilitating diseases, refer to additional requirements set forth in 21 CFR § 312.81(a). Consistent with section 1142 of the Act, AHRQ supports clinical research studies that CMS determines meet all the criteria and standards identified above. C. Other Uses of CCM 1) CCM for HF management is not covered for patients outside of a CMS-approved study. 2) Nothing in this NCD would preclude coverage of CCM for HF management through NCD 310.1 (Clinical Trial Policy) or through the Investigational Device Exemption (IDE) Policy. See Appendix A for Medicare National Coverage Determinations Manual language. II. Clinical Review A. Background 1. Heart Failure Definitions & Classification HF is a chronic syndrome in which the heart muscle is unable to pump enough blood to meet the body’s needs. This condition results in protean symptoms, including fatigue and shortness of breath, which limit an individual’s ability to engage in everyday physical activities such as walking or climbing stairs. As the end-stage manifestation of most forms of heart disease, HF is affected by traditional cardiovascular risk factors, including age, diabetes, hypertension, hyperlipidemia, smoking, and obesity. HF classification is commonly based on the left ventricular ejection fraction (LVEF), a measure of the fraction or percentage of blood volume pumped out of the heart with each contraction (Heidenreich et al., 2022). The most recent US and European diagnostic criteria for HF include three subtypes based on the LVEF (Ostrominski et al., 2024): HF with preserved ejection fraction (EF) (HFpEF), HR with mildly reduced EF (HFmrEF), and HR with reduced EF (HFrEF). In HFpEF, the LVEF is within the normal range of 50-70% and the muscles of the heart contract relatively normally but thickening of the heart muscle and diastolic dysfunction may result in high left ventricular (LV) filling pressures. In HFmrEF, the intermediary level between HFpEF and HFrEF, the LVEF is 41%-49%. In HFrEF, the LVEF is ≤ 40%, which indicates abnormalities in cardiac structure or functioning, including left ventricular dilatation. Of US adults with HF, approximately 41% have HFpEF, 14% have HFmrEF, and 45% have HFrEF (Bozkurt et al., 2023). The most recent US guidelines include a new subtype, HF with improved EF (HFimpEF), which indicates that the LVEF has improved from ≤ 40% to > 40% (Heidenreich et al., 2022). Based on a recent meta-analysis, the estimated prevalence of HFimpEF is 23% (He et al., 2021). HF classification is essential for treatment management, as it is predictive of adverse events (e.g., mortality and hospitalization) and the response to certain medical therapies (Dimond et al., 2024; He et al., 2021). The severity of HF symptoms is commonly classified using the New York Heart Association (NYHA) Functional Classification system (Holland et al., 2010). The purpose of the classification is to describe the impact of HF on a person’s physical activities using four categories: I=no limitation; II=slight limitation; III=marked limitation, but comfortable at rest; IV=unable to engage in any physical activity without discomfort and symptoms even at rest. Clinicians assign the classification based on how they interpret the symptoms reported by a patient, the patient’s medical history, and results from clinical tests on cardiac functioning (Holland et al., 2010). HF treatment recommendations are commonly based on the NYHA classification (Rohde et al., 2023). 2. HF Prevalence, Incidence, and Mortality Rates Approximately 6.7 million Americans are living with HF (Bozkurt et al., 2023), and the number is expected to grow through 2030. An estimated 650,000 new HF cases are diagnosed in the US each year (Malik et al., 2024), and the lifetime risk of HF in the US has increased from 1 in 5 to 1 in 4 (Bozkurt et al., 2023). For individuals aged 65 to 70 years, the estimated prevalence of HF is expected to increase (Bozkurt et al., 2023). The reported HF incidence and prevalence rates vary based on the timeframe and HF ascertainment methodology (Bozkurt et al., 2023). An analysis of Medicare claims data for beneficiaries indicates that the estimated incidence rate declined by over 25% from 2011 to 2016 (Khera et al., 2020). This decline occurred irrespective of sex or race/ethnicity (Khera et al., 2020). Over the nearly 20 years from 1999 to 2017, the estimated HF prevalence rate among adults aged 65 and older increased by over 15% (Bozkurt et al., 2023). In addition, the HF prevalence rate is expected to nearly double among 65- to 70-year-olds, from 4.3% in 2010 to 8.5% in 2030 (Bozkurt et al., 2023). Disparities exist between ethnic groups for the key indicators of HF population burden (including incidence, prevalence, and outcomes). Blacks and Hispanics have a higher prevalence of HF than Whites, and Black women have the highest prevalence of all racial and ethnic groups (Tsao et al., 2022). HFpEF is the most prevalent HF phenotype for White women, while HFrEF predominates among Black women (Mwansa et al., 2021). Compared with Hispanics and non-Hispanic Whites, Black individuals have a higher incidence of HF (Bozkurt et al., 2023). Black patients not only have a higher incidence of heart failure than other racial groups, but they also have higher admissions for HFrEF and worse overall survival (Lewsey & Breathett, 2021; Miller et al., 2021). The MESA (Multi-Ethnic Study of Atherosclerosis) study reported incidence rates per 1,000 person-years of 4.6 for Blacks, 3.5 for Hispanics, and 2.4 for non-Hispanic Whites (Bahrami et al., 2008). The HF prevalence rate among Black individuals increased from 2001 to 2016, compared to an unchanged prevalence rate for non-Hispanic White individuals. Black individuals with HF also experience a disproportionate prevalence of disability (Roger, 2021) and mortality (Glynn et al., 2019). The HF mortality rate is difficult to estimate because HF-related deaths tend to be greatly undercounted (Bozkurt et al., 2023). In 2020, 85,855 US deaths were attributed to HF, although the total number is likely to be closer to the 415,922 reported deaths with HF as a contributing cause of death. From 2000 to 2012, the estimated HF mortality rate declined but has increased since 2012 (Bozkurt et al., 2023). The HF mortality rate also varies by ethnicity, similar to the prevalence rates. In the longitudinal ARIC (Atherosclerosis Risk in Communities) study, the 30-day, 1-year, and 5-year case fatality rates after hospitalization for HF were 10.4%, 22%, and 42.3%, respectively, with Black individuals having a greater 5-year case fatality rate than White individuals (p < 0.05) (Loehr et al., 2008). Among Medicare beneficiaries, the age-adjusted HF mortality rate has increased, from 16.9% in 2011 to 20.4% in 2017 (Sidney et al., 2019). 3. Management of Heart Failure The treatment approaches overlap considerably across the LVEF spectrum (von Haehling et al., 2024). For all patients, the treatment of choice is a lifestyle change that addresses the underlying cause of HF. Patients are counseled to limit salt consumption, quit smoking, improve diet and exercise, and lose weight (Heidenreich et al., 2022; von Haehling et al., 2024). Medication management of HF includes diuretics, vasodilators, and renin-angiotensin-aldosterone system blockers (Heidenreich et al., 2022). For HFrEF, the use of β-blockers is recommended, either alone or as part of a quadruple therapy with angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors (Heidenreich et al., 2022). Quadruple therapy is estimated to reduce the hazard of cardiovascular death or HF hospitalization by up to 62% compared with limited conventional therapy (Vaduganathan et al., 2020). Recently, sodium-glucose cotransporter-2 inhibitors have reduced the combined risk of cardiovascular deaths and hospitalizations among individuals with HFmrEF (Solomon et al., 2022) and HFpEF (Anker et al., 2021; Solomon et al., 2022). Several medical devices, including an implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy (CRT), may also improve outcomes for HFrEF patients who are refractory to medical therapy (Heidenreich et al., 2022). ICDs are approved for use in patients with HFrEF who have persistently low LVEF despite guideline-directed medical therapy (GDMT) and life expectancy of at least one year for the primary prevention of sudden cardiac death (Butler et al., 2022). The devices detect potentially fatal arrhythmias and deliver high-energy electric shocks intended to reestablish a normal heart rhythm. Although ICDs prevent fatal arrhythmias and improve survival, they do not treat the symptoms of HFrEF. CRT devices may improve health outcomes for HF patients who have a QRS duration > 150 ms and an LVEF ≤ 35% despite GDMT (Henin et al., 2020). In these patients, CRT may improve coordination of left ventricular contraction and may meaningfully improve patients’ functional capacity, quality of life (QoL), and exercise tolerance while decreasing hospitalizations and mortality. However, for patients with a QRS duration < 130ms, data indicate that CRT is not beneficial and may cause harm (Ruschitzka, 2013). Additional data suggests patients with right bundle branch block (RBBB) experience minimal to no benefit from CRT (Zareba et al., 2011). 4. Cardiac Contractility Modulation for Heart Failure A CCM system consists of animplantable pulse generator, ventricular septal pacing leads, an external charger, and an external programming device. CCM devices deliver periodic, programmed electrical stimulation designed to alleviate symptoms associated with HF in order to improve QoL, restore functional capacity, and improve exercise tolerance. CCM delivers electrical stimuli to the ventricular septum during the absolute refractory period. As such, CCM is non-excitatory, meaning it does not trigger cardiac depolarization. The intent of CCM is not to cause the heart to contract, but rather to increase the strength of the heart’s contraction (Abraham et al., 2018; Wiegn et al., 2020). B. Food and Drug Administration Status The FDA granted breakthrough device status for the three-lead OPTIMIZER Smart System on July 31, 2015, and granted premarket approval on March 21, 2019. Subsequent FDA approvals for CCM removed the requirement of a right atrial lead (October 2019), allowed commercial distribution of the Optimizer Smart Mini System (July 2021), and removed the requirement for normal sinus rhythm (October 2021). As stated in the Summary of Safety and Effectiveness, the OPTIMIZER Smart System is currently FDA-indicated “to improve 6-minute hall walk distance, quality of life, 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 left ventricular ejection fraction ranging from 25% to 45%”. 1 III. Evidence This section provides a summary of the evidence considered during this review. The evidence presented here includes peer-reviewed publications of pertinent clinical research on CCM for HF management and evidence-based guidelines which we considered in our coverage analysis (See Section IV. B.). A detailed account of the methodological principles of study design that CMS uses to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions may be found in the CMS National Coverage Analysis Evidence Review Guidance Document , published August 7, 2024. A. Evidence Questions The following questions guide this review and analysis of the evidence on the clinical utility of CCM (e.g., OPTIMIZER Smart System) for moderate to severe chronic systolic heart failure (EF 25-45%) that remains symptomatic despite guideline-directed medical therapy. We answer these questions in Section IV.B.2. following the CMS coverage analysis. Question 1-Is the evidence sufficient to conclude that cardiac contractility modulation is reasonable and necessary for the treatment of Medicare beneficiaries with moderate to severe chronic systolic heart failure (EF 25-45%) that remains symptomatic despite guideline-directed medical therapy? Question 2-Is there evidence that specific characteristics or comorbidities make patients more or less likely to benefit from cardiac contractility modulation? Question 3-Are specific treatment conditions necessary to achieve cardiac contractility modulation outcomes similar to those demonstrated in the clinical studies reviewed in this analysis? B. Technology Assessments CMS did not request an external technology assessment (TA) on this issue. Our review did not identify any Cochrane or Evidence-based Practice Center (EPC) reviews of CCM for HF. C. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) A MEDCAC meeting was not convened on CCM for HF management. D. Clinical Literature Search A systematic literature review focused on CCM for HF management was undertaken to address the evidence questions in Section A above. Literature searches were conducted in PubMed, Scopus, Cochrane, and EMBASE was performed with the following search terms: (1) “cardiac contractility modulation;” (2) “optimizer smart;” or (3) “optimizer smart system.” The review included peer-reviewed English-language medical literature from January 1, 2008, to April 9, 2024. Of the references identified in the searches, 22 were deemed eligible for inclusion. An additional 2 studies were included in response to public comments in the initial public comment period. See Appendix B for summary tables outlining the characteristics of included studies and study outcomes. Of the 24 studies included in this review, three were randomized controlled trials (RCTs), one was a single-arm RCT extension study, one was an RCT post-hoc analysis, 18 were observational studies, and one was a meta-analysis. All reports included patient populations with moderate to severe chronic systolic heart failure (EF 25 – 45%). All patients were followed for 6 months – 5 years. The studies examined CCM therapy in patients with a wide range of NYHA, from class I-IV. Importantly, 960 patients were included in the six long-term registry-derived observational studies. See Table 1 for a list of devices used in the studies reviewed and the studies reviewed above for earlier iterations of CCM devices. Table 1. Optimizer Systems Used by Study Reference Optimizer Version Study CCM GDMT Study type Abraham et al. 2011 IV FIX-HF-5 109 97 RCT Kadish et al. 2011 IV FIX-HF-5 215 213 RCT Kuschyk et al. 2015 II or III - 81 - Retrospective cohort Müller et al. 2017 III CCM-HF 143 - CCM HF Registry Abraham et al. 2018 IV FIX-HF-5C 74 86 RCT Borggrefe et al. 2008 IV FIX-CHF-4 80 84 RCT Röger et al. 2017 III and IV - 48 - Prospective cohort Röger et al. 2018 III and IV - 20 - Prospective one-arm Anker et al. 2019 Smart CCM-REG 140 - Prospective registry Wiegn et al. 2020 Smart FIX-HF-5C2 60 - Nonrandomized one-arm Fastner et al. 2021 Smart MAINTAINED 174 - Retrospective registry Kuschyk et al. 2021 Smart CCM-REG 503 - Prospective registry Matta et al. 2021 Smart - 10 - Prospective cohort Ansari et al. 2022 Smart (CE mark) - 58 - Prospective cohort Fastner et al. 2022 Smart MAINTAINED 172 - Retrospective registry Giallauria et al. 2022 - - 861 - Meta-analysis through Jan. 2020 Masarone et al. 2022 Smart - 25 - Prospective cohort Yücel et al. 2022 II, III, IV, or Smart MAINTAINED 172 - Retrospective registry Linde et al. 2022 Smart 47 - Prospective pilot Davtyan, et al. 2023 IV (n=3) and Smart (n=8) NA 11 - Prospective cohort Masarone, et al. 2023 Smart - 30 - Prospective cohort Pavlovskaya, et al. 2023 IV (n=51) and Smart (n=8) - 59 - Prospective cohort Tint, et al. 2023 Smart - 19 - Prospective cohort Deak, et al. 2024 Smart - 31 - Prospective cohort Note: The 7 first rows (in gray) are previous versions of CCM devices Table 2 . Controlled trials reviewed to assess CCM (OPTIMIZER Smart System) for moderate to severe chronic systolic HF (EF 25 – 45%) that remains symptomatic despite GDMT Study Patients (CCM; control) 24-week Outcomes (CCM; control) Acronym Year Type Inclusion (n) Mean Age Male % ∆ pVO 2 ∆ NYHA ∆ 6MWT ∆ MLWHFQ FIX-CHF-4 2008 RCT (crossover) LVEF ≤35%, NYHA II/III 80; 84 58.9; 59.9 88.8; 81.0 Between-group difference 0.52* No significant between-group difference No significant between-group difference Between-group difference 2.93* FIX-HF-5 2011 RCT LVEF ≤35%, NYHA III/IV 215; 213 58.1; 58.6 73.5; 70.9 % responder 17.3; 13.7 % responder 49.2; 41.9** % responder 34.2; 29.5 % responder 56.1; 41.8** FIX-HF-5 subgroup analysis 2011 RCT LVEF ≥25%, NYHA III/IV 109; 97 58.7; 60.3 70.6; 78.4 % responder 19.2; 3.95** % responder 44.3; 23.2** % responder 37.1; 25.3 % responder 59.4%; 41.7* FIX-HF-5C 2018 RCT LVEF 25-45%, NYHA III/IV 68; 86 63.0; 63.0 73.0; 70.1 Between-group difference 0.836* % responder 81; 42*** Between-group difference 33.7** Between-group difference 11.7*** FIX-HF-5C2 (2-lead CCM vs FIX-HF-5C controls) 2020 Single-arm extension LVEF 25-45%, NYHA III/IV 60 66.3 88.3 Between-group difference 1.72*** % responder 83.1; 42.7*** NR NR Legend: 6MWT = 6-minute walk test; CCM = cardiac contractility modulation; LVEF = left ventricular ejection fraction; MLWHFQ = Minnesota Living With Heart Failure Questionnaire; NR = not reported; NYHA = New York Heart Association; pVO 2 = peak oxygen consumption; RCT = randomized control trial. Only significant results are designated by an asterisk; *p < 0.05; **p < 0.01; ***p < 0.001. The 4 first rows (in gray) are previous versions of CCM devices reviewed. E. Assessment of the Evidence Currently, the Optimizer Smart System is the only device that delivers CCM therapy. Previous versions of the Optimizer device, Optimizer II-IV, were evaluated in these three RCTs and three observational studies, as described below. The RCTs, sub-group analysis of RCT, and single-arm study are discussed here while the observational studies and meta-analysis are reviewed in another section of this document. The 3 randomized trials were: FIX-CHF-4 (Borggrefe et al., 2008) FIX-HF-5 (Kadish et al., 2011; Abraham et al., 2011 ) FIX-HF-5C (Abraham et al., 2018) Additionally, there was a subgroup analysis FIX-HF-5C2 (Single-arm extension of the FIX-HF-5C; Wiegn et al., 2020). Data from FIX-CHF-4 (Borggrefe et al., 2008) suggest that exercise tolerance and QoL improved when patients received 3-lead CCM therapy applied over a 3-month period in patients with LVEF ≤35%. FIX-HF-5 (Kadish et al., 2011), a larger trial of CCM compared with optimal medical therapy (OMT) among patients with LVEF ≤35%, did not meet its primary efficacy endpoint (ventilatory anaerobic threshold). A retrospective subgroup analysis of FIX-HF-5 suggested that patients with LVEF > 25% who received the 3-lead CCM therapy had significant improvements in QoL and exercise capacity (Abraham et al., 2011). The authors note that this peak VO 2 (exercise capacity) increase is relevant to improvements typically observed in CRT therapy. Data from FIX-HF-5C (Abraham et al., 2018), designed to confirm these results prospectively, also suggested that 3-lead CCM therapy improves QoL and exercise tolerance amongst patients with LVEF 25-45%. Wiegn et al. (2020) conducted FIX-HF-5C2 (NCT03339310), a single-arm extension of the FIX-HF-5C RCT. Data from FIX-HF-5C2 indicated statistically significant treatment effects in a similar patient population treated with 2-lead CCM therapy. Additionally, data from the major trials support the safety of CCM devices. Serious adverse events (SAEs) were seen at similar rates in the CCM and control groups in FIX-HF-5 and FIX-HF-5C (Abraham et al., 2011; Abraham et al., 2018; Kadish et al., 2011). Overall survival and hospitalization rates were similar for the CM and control group in FIX-HF-5C (Abraham et al., 2018). The primary safety endpoint in FIX-HF-5C2 was device- or procedure-related complications, which decreased the CCM-related complication rate compared to FIX-HF-5C (Wiegn et al., 2020). 1. Trial Design FIX-CHF-4 , the first RCT of CCM therapy, was a double-blind, double-crossover study. Subjects were randomly assigned to Group 1 (CCM ON for 3 months, CCM OFF for 3 months) or Group 2 (reversed treatment sequence). The co-primary endpoints were changes in peak VO 2 and Minnesota Living with Heart Failure Questionnaire (Borggrefe et al., 2008). FIX-HF-5 , the first US RCT of CCM therapy, was a prospective, randomized, unblinded, parallel-group, controlled trial comparing a group receiving optimal medical therapy (i.e., GDMT) versus a group receiving GDMT plus CCM (CCM group). FIX-HF-5 study was initiated as FIX-CHF-4 neared the end of its recruitment to confirm the safety and efficacy of CCM in a larger patient population. Along with its primary safety endpoint, FIX-HF-5 had a unique primary efficacy endpoint that required an intention-to-treat (ITT) responder analysis of VO 2 at an anaerobic threshold (Kadish et al., 2011). FIX-HF-5C (Abraham et al., 2018) was a confirmatory, prospective, multicenter, randomized, controlled, unblinded clinical trial comparing OMT versus OMT plus CCM. Subjects were randomly assigned to one of two treatment groups (CCM or Control) with an allocation ratio of 1:1. A prespecified Bayesian statistical approach was used to leverage data available from FIX-HF-5 to decrease the number of patients required for the confirmatory study. The Bayesian model incorporated the 160 subjects enrolled in FIX-HF-5C and a prior distribution of the treatment effect from the FIX-HF-5 subgroup. The FIX-HF-5 subgroup could contribute ≤ 30% weight to the overall assessment, ensuring that the prospective FIX-HF-5C data would not be dominated by the prior subgroup data. The primary endpoint was the model-based estimated mean difference in peak VO 2 at 24 weeks between the CCM and Control groups. Secondary efficacy endpoints were tested using non-Bayesian methods. FIX-HF-5C2 (Wiegn et al., 2020) was a single-arm, treatment-only, confirmatory extension study of subjects in a similar patient population as the FIX-HF-5C study to confirm the efficacy of a 2-lead CCM system. The same Bayesian statistical approach used for the primary analysis of the FIX-HF-5C study was incorporated for the FIX-HF-5C2 extension study, as were the data from the FIX-HF-5C study for comparison. 2. Study Population Baseline patient characteristics were similar across the controlled trials, with a few notable exceptions. FIX-CHF-4 (Borggrefe et al., 2008) included 164 HF subjects with LVEF ≤ 35% and NYHA class II or III symptoms who were ineligible for CRT. The authors did not specify why subjects were not eligible for CRT. The baseline QRS duration for all subjects was 118 ms. CRT therapy has a class I recommendation for patients with LVEF of ≤ 35% and QRS duration ≥ 150 ms (and left bundle branch block) and a class IIa indication for patients with LVEF < 35%, left bundle branch block, and QRS duration 120 to 149 ms (Heidenreich et al., 2022). FIX-HF-5 (Kadish et al., 2011) included 428 HF subjects with LVEF ≤35% but who were ineligible for CRT (defined as QRS duration ≤ 130 ms) and NYHA class III or IV symptoms refractory to GDMT. Similarly, FIX-HF-5C (Abraham et al., 2018) included 160 HF patients with QRS duration ≤ 130 ms and NYHA class III or IV symptoms refractory to GDMT but with LVEF between 25% and 45%. FIX-HF-5C2 (Wiegn et al., 2020) included the same patient population as FIX-HF-5C , with the addition of subjects with atrial fibrillation (15% in FIX-HF-5C2 vs. 0% in FIX-HF-5C ). The FIX-HF-5C2 study was conducted with a small sample of 60 patients. The three RCTs, FIX-CHF-4 (Borggrefe et al., 2008), FIX-HF-5 (Abraham et al., 2011; Kadish et al., 2011), and FIX-HF-5C (Abraham et al., 2018), enrolled 752 patients, of whom 369 were implanted with the device. The mean age of the patients ranged from 58.1 to 63.0 years, and the percentage of male patients ranged from 70.1% to 88.8%. It is important to note that the patient populations included in FIX-CHF-4 and FIX-HF-5 fall partially outside the patient population currently indicated for CCM therapy in the US (different LVEF range, QRS duration, and functional status). Table 3. Comparison of baseline patient characteristics in the FIX-CHF-4, FIX-HF-5, FIX-HF-5C and FIX-HF-5C2 trials. FIX-CHF-4 FIX-HF-5 FIX-HF-5C FIX-HF-5C2 CCM-sham (n=80) Sham-CCM (n=84) CCM (n=215) OMT (n=213) CCM (n=68) OMT (n=86) CCM (n=60) Age (yr) 58.9±9.8 59.9±10.0 58.1±12.8 58.6±12.2 63.0±11.0 63.0±11.0 66.3±8.9 Male (%) 88.8 81.0 73.5 70.9 73.0 70.1 88.3 QRS (ms) 119.9±28.3 116.3±26.6 101.6±15.3 101.5±12.8 103.0±13.0 103.6±12.1 101.2±12.3 LVEF (%) 29.3±6.6 29.8±7.8 25.7±6.6 26.1±6.5 33±6 33±5 34.1±6.1 NYHA Class (%) II 27.5 20.0 0.0 0.47 0.0 0.0 0.0 III 72.5 80.0 91.2 85.9 86.5 92.7 98.3 IV 0.0 0.0 8.8 13.6 13.5 9.3 1.7 Legend: CCM = cardiac contractility modulation; LVEF = left ventricular ejection fraction; ms = millisecond; NYHA = New York Heart Association; OMT = optimal medical therapy; yr = year. 3. Background Medical Therapy Table 4 . Baseline rates of GDMT and device implantations in the FIX-CHF-4, FIX-HF-5, FIX-HF-5C, and FIX-HF-5C2 trials. FIX-CHF-4 FIX-HF-5 FIX-HF-5C FIX-HF-5C2 CCM-sham (n=80) Sham-CCM (n=84) CCM (n=215) OMT (n=213) CCM (n=68) OMT (n=86) CCM (n=60) ACEi or ARB NR NR 91 91 82.4 83.7 75.0 ACEi 72.5 73 71 69 54.1 57.0 48.3 ARB 16 23 24 23 28.4 29.1 13.3 Beta Blocker 77.5 77 94 93 97.3 95.3 95.0 Diuretic 76 81 92 92 75.7 79.1 73.3 Second Diuretic NR NR NR NR 6.8 9.3 8.3 Ivabradine NR NR NR NR 2.7 4.7 5.0 Digoxin 39 42 39 46 13.5 9.3 6.7 Aldosterone Inhibitor 41 49 44 48 33.8 37.2 41.7 Hydralazine NR NR NR NR 5.4 11.6 5.0 Nitrates NR NR NR NR 24.3 30.2 18.3 Entresto NR NR NR NR 2.7 3.5 NR Calcium Channel Blocker NR NR NR NR 12.2 9.3 NR Anti-arrhythmic NR NR 17 14 17.6 14.0 31.7 Aspirin NR NR NR NR 73.0 68.6 NR Coumadin NR NR NR NR 9.5 5.8 NR Clopidogrel NR NR NR NR 20.3 29.1 NR ICD 67 57 96 95 87.8 84.9 88.3 Legend: ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CCM = cardiac contractility modulation; ICD = implantable cardioverter defibrillator; NR = not reported; all values reported as %. 4. Intervention Setting The four clinical trials were conducted in sites across the US and Europe. FIX-CHF-4 was conducted entirely within Europe, and FIX-HF-5 took place entirely within the US, while FIX-HF-5C and FIX-HF-5C2 took place at sites across both the US and Europe. CCM systems were implanted and study follow-up visits took place in the hospital (inpatient and outpatient) and Ambulatory Surgery Center (ASC) settings. 5. Outcomes A change in peak VO 2 was the primary efficacy endpoint for FIX-CHF-4, FIX-HF-5C, and FIX-HF-5C2. FIX-HF-5 had a unique primary efficacy endpoint that required an ITT responder analysis of VAT and considered a change in peak VO 2 to be a secondary efficacy endpoint. Changes in MLWHFQ, 6MWT, and NYHA class were included as secondary efficacy endpoints in all trials except for FIX-HF-5C2 ( FIX-CHF-4 included MLWHFQ as a co-primary efficacy endpoint). Primary safety outcomes included device-related complications, hospitalization, and mortality across all trials except for FIX-HF-5C2, which had a sole safety endpoint of device-related complications. All four trials had a 24-week follow-up duration for efficacy endpoints. FIX-HF-5 extended the follow-up period to 50 weeks for safety endpoints. 6. Study Quality Although all four studies reviewed above were multicenter and there was no evidence of selective outcome reporting, the RCTs were rated as low-quality overall. The main limitations were related to the high risk of bias, which reduced confidence in the strength of the evidence. Device trials typically have inherent restrictions on study design. As a result, sources of bias may affect internal and external validity quality assessments, such as lack of blinding and a lack of sham procedure (in some studies). Further downgrades in study quality were related to statistical imprecision (e.g., lack of any statistical analysis or wide variation around the effect estimate), low event rates, short follow-up duration, and/or small sample size. Below we review each study. 7. Synthesizing the Clinical Trial Evidence FIX-CHF-4 (Borggrefe et al., 2008), a double-blind, double-crossover trial, was performed in Europe in 164 subjects with LVEF ≤35% and NYHA Class II or III symptoms. Subjects were randomized to CCM ON or CCM OFF for 12 weeks in Phase 1, followed by the opposite treatment for 12 weeks in Phase 2. Peak VO 2 increased similarly for both groups during the first 12 weeks, 0.40 ( SD =3.0) compared to 0.37 ( SD = 3.3). During the next 12 weeks, peak VO 2 decreased when CCM was switched OFF (-0.86, SD = 3.06) and increased when CCM was switched ON (0.16, SD = 2.50). Similarly, MLWHFQ improved in both groups during the first 12 weeks (-12.06, SD = 15.33 vs. -9.70, SD =16.17), worsened when CCM was switched OFF (+4.70, SD =16.57) and improved when CCM was switched ON (-0.70, SD =15.13) in the second 12 weeks. The 3-lead CCM therapy for three months led to statistically significant improvements at 24 weeks in peak VO 2 (GDMT vs. CCM, O2/kg/min: M = -0.46, SD = 0.33 vs. M = 0.53, SD =0.45; t = 2.16, p = 0.032), and QoL (GDMT vs. CCM, MLWHFQ: M = -7.4, SD = 2.2 vs. M = -10.4, SD =2.1; t = 2.20, p = 0.030) among patients with LVEF ≤ 35%. Although the difference in peak VO 2 was statistically significant, it failed to meet the 6% criteria for a clinically significant change among patients with HF (3.1% = 0.46/13.9 ml O2/min/kg) at baseline (Corra et al., 2006). The authors noted a significant placebo effect (due to unblinding) may have accounted for similar efficacy results during the first phase. Overall, across both phases, statistically significant improvements were seen in mean VO 2 (p=0.03) and mean MLWHFQ (p=0.03) during CCM ON periods compared to CCM OFF periods. The authors found no significant carryover or period effects. SAEs were comparable between CCM ON and CCM OFF, with 45 events in 41 patients during CCM ON periods and 48 events in 40 patients during CCM OFF periods. The number of hospitalizations was also similar between periods, with 31 patients hospitalized in each. FIX-HF-5 ( Kadish et al., 2011), an unblinded, controlled trial, was performed in the US in 428 subjects with LVEF ≤35% and NYHA Class III or IV symptoms. Subjects were randomized to CCM plus GDMT or GDMT alone. The study did not meet its primary efficacy endpoint, an improvement in ventilatory anaerobic threshold (VAT) at 24 weeks. Both CCM and GDMT treatment arms saw a mean 0.14 mL/kg/min decrease in VAT, and the ITT responder analysis found the difference (17.7% vs. 12.2%) was not significant (p=0.314). However, compared to GDMT, CCM was seen to significantly improve peak VO 2 (p=0.024) and MLWHFQ (p < 0.0001) at 24 weeks. Subjects in the CCM arm experienced non-significantly higher rates of all-cause hospitalization and mortality rates (52% vs. 48%, Blackwelder test difference of 3.7% with upper 1-sided 95% CI of 11.7%, which was below the prespecified allowable 12.5%). SAEs were similar between treatment groups, with 341 events in 129 subjects in the CCM arm and 326 events in 115 subjects in the GDMT arm. The most frequent SAEs were general medical issues and worsening HF. Device-related SAEs occurred in 6% of patients, with lead dislodgement reported most frequently. A multi-regression analysis of FIX-HF-5 (Abraham et al., 2011) identified NYHA class III and LVEF ≥25% as significant predictors of CCM efficacy. This retrospective analysis examined CCM therapy for the subgroup of patients with ≥ 25% LVEF (CCM: 109; GDMT: 97). Analysis revealed statistically and clinically significant improvements compared to GDMT in peak VO 2 (1.31 mL/kg-1min-1, p = 0.001), VAT (p=0.03), and QoL (MLWHFQ: 10.8 points; p = 0.003). Subsequently, FIX-HF-5C was designed to confirm these results prospectively. FIX-HF-5C (Abraham et al., 2018) , an unblinded, controlled trial, was performed in the US and Europe in 160 subjects with LVEF between 25 and 45% and NYHA Class III or IV symptoms. Subjects were randomized to CCM plus GDMT or GDMT alone. The authors employed both a Bayesian and non-Bayesian (frequentist) approach to estimate their primary efficacy endpoint, the between-group differences in mean peak VO 2 at 24 weeks. Bayesian repeated measures linear modeling incorporated prior peak VO 2 data from FIX-HF-5 , favoring CCM therapy. The model-based estimated mean difference in pVO 2 at 24 weeks between CCM treatment and control groups was 0.84 mL/kg/min, with a 95% Bayesian credible interval (95% BCI) of 0.12-1.55 O2/kg/min. The primary endpoint posterior probability of CCM treatment superiority versus control was 0.989 and was noted to exceed the 0.975 criteria required for statistical significance. Sensitivity analyses showed that CCM maintained superiority after accounting for methods of imputing missing data and site-to-site heterogeneity. However, details were not provided to document the magnitude of this superiority. The frequentist linear mixed model estimate of the mean difference, which does not pull data from FIX-HF-5, was 0.79 mL/kg/min (95% confidence interval: -0.10 to 1.68). MLWHFQ (p < 0.001), 6MWT (p=0.02), and NYHA class (p < 0.001) responder rates were higher with CCM compared to GDMT, although variability around the point estimates for mean changes in 6MWT and MLWHFQ was relatively high. SAEs occurred in 27% and 22% of the CCM and GDMT groups, respectively, with device malfunction and general medical events reported most frequently in the CCM group and worsening HF and general medical events reported most frequently in the GDMT group. The CCM group had a 90% device- or procedure-related complication-free rate, with lead dislodgement accounting for five out of the seven complications observed. Although overall survival (98%, CCM vs. 95%, GDMT) and hospitalization-free survival (78% vs. 78%) were similar in both treatment arms, survival free from cardiac death and HF-related hospitalization was significantly improved in the CCM treatment arm (97% vs. 89%, p=0.036). A secondary analysis undertaken as part of the FIX-HF-5C study examined treatment effects in patients with LVEF < 35% versus LVEF ≥35% by pooling peak VO 2 , MLWHFQ, and NYHA functional class data from FIX-HF-5 and FIX-HF-5C . A total of 371 patients were included, of whom 275 were classified as LVEF < 35% and 96 as LVEF ≥35%. Subgroup analyses showed positive treatment effects in each efficacy parameter in CCM versus GDMT patients for both LVEF subgroups, with those classified as LVEF ≥35% experiencing greater improvements. While statistical significance was determined for the differences in mean change between CCM versus OMT within each LVEF subgroup, a statistical analysis of the differences between LVEF subgroups was unavailable. The absence of a statistical analysis between LVEF subgroups limits the interpretability of these findings (Abraham et al., 2018). Additionally, data from the three trials support the safety of the Optimizer IV device. The reported rates of SAEs were similar across the control groups in FIX-HF-5 (GDMT vs. CCM, events/patient-year: 1.505 vs.1.338) and FIX-HF-5C (GDMT vs. CCM, % of patients: 22 vs. 27%) (Abraham et al., 2018; Abraham et al., 2011; Kadish et al., 2011). Survival free of any hospitalization was also similar for the control groups in FIX-HF-5C (GDMT vs. CCM: 78% vs. 78%) (Abraham et al., 2018). FIX-HF-5C2 (Wiegn et al., 2020) , a single-arm, confirmatory extension study, was conducted on 60 subjects with LVEF between 25 and 45% and NYHA Class III or IV symptoms. All subjects received a 2-lead CCM system implant and were compared to control subjects from FIX-HF-5C . The studies were all performed with a 3-lead CCM system: one in the right atrium and two in the right ventricle (RV). This imposed a technical limitation on the use of CCM in patients with atrial fibrillation or atrial flutter. A 2-lead CCM device operates with ju