Medical Policy

This document addresses the use of cardiac contractility modulation therapy designed to treat chronic moderate-to-severe heart failure.

Investigational and Not Medically Necessary:

The use of cardiac contractility modulation therapy is considered investigational and not medically necessary for all indications, including but not limited to heart failure.

The use of cardiac contractility modulation (CCM) therapy has been proposed as a treatment option for individuals with moderate-to-severe heart failure (HF). In March 2019, the U.S. Food and Drug Administration (FDA) granted Impulse Dynamics breakthrough device exemption for the OPTIMIZER^® Smart Implantable Pulse Generator (Impulse Dynamics, Orangeburg, NY), with approved use in the treatment of individuals with chronic, moderate-to-severe (New York Heart Failure [NYHA] Class III or ambulatory Class IV) HF who remain symptomatic despite guideline-directed medical therapy (GDMT). Recipients must be in normal sinus rhythm with left ventricular ejection fraction (LVEF) from 25 to 45 percent and not considered a candidate for cardiac resynchronization therapy (CRT) to restore normal heart rhythm. The OPTIMIZER Smart System treatment, referred to as CCM, delivers electrical signals to the ventricles during the ventricular absolute refractory period. The expected result is improvement in 6-mintue hall walking distance, quality of life, functional status, and exercise tolerance. (Product Label Information, 2019).

The original technology for CCM was developed by Impulse Dynamics. The original device was evaluated in a trial by the FDA that did not demonstrate efficacy. The original FIX-HF-5 study used a broader group of HF participants and endpoints that were difficult to achieve in the clinical trial. Ultimately, the trial failed, but subgroup analysis of the FIX-HF-5 study showed which participants could possibly benefit from use of the device.

The FIX-HF-5 study was a phase II, prospective, unblinded, randomized study comparing CCM plus optimal medical treatment (OMT) to OMT alone in 428 participants. Subjects had NYHA functional class III or IV HF with ejection fraction (EF) of ≤ 45% (Abraham, 2015). The FIX-HF-5 study met its primary safety endpoint, but did not reach its primary efficacy endpoint, changes in ventilatory anaerobic threshold (VAT) of responders. However, significant improvements in primary and secondary efficacy endpoints, including the responders VAT endpoint, were met in a prespecified FIX-HF-5 subgroup analysis of individuals with EFs ranging from 25%-45% (n=221; p=0.001). Based on the subgroup analysis a new, prospective study was designed and conducted to confirm the efficacy of CCM in this population.

Abraham and colleagues (2018) reported results from the FIX-HF-5C confirmatory study (NCT01381172) to prospectively test the efficacy and safety of CCM in participants with NYHA functional class III or IV symptoms and EF 25-45%. A total of 160 participants were randomized to continue OMT (n=86) or CCM (treatment, n=74, unblinded) for 24 weeks. The primary efficacy endpoint was met with a peak Vo₂ between groups of 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min. The following secondary outcomes, 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 significantly better in the treatment group compared to the control group. Of the 68 (n=68/74 underwent implant in the treatment group) individuals implanted with the OPTIMIZER device, there were seven device-related events reported. There was a reduction in the composite of cardiovascular death and HF hospitalizations from 10.8% to 2.9% (p=0.048). There was one death related to sepsis at 164 days after device implantation in the treatment group following surgery for an incarcerated hernia. Long-term risks of infection cannot be known at this time. Additional studies are needed to confirm benefit outside of this small study population and beyond the 24-week follow-up in this study.

The FDA approval of the OPTIMIZER Smart System is based on preliminary findings reported of 389 participants with moderate-to-severe HF (FIX-HF-5 subgroup, n=229; FIX-HF-5C, n=160) from two randomized, multi-center clinical trials that have not been published in a peer-reviewed journal. Participants received OMT alone versus OMT plus implantation with an OPTIMIZER Smart System. Study inclusion criteria were NYHA function class III or ambulatory class IV with HF despite OMT, an EF ranging from 25-45% as determined by echocardiographic core laboratory, and normal sinus rhythm with QRS duration < 130 ms. Individuals who had an EF ≤ 35% were required to have an ICD unless there were extenuating circumstances. The primary effectiveness endpoint was met, with estimated mean difference in peak Vo₂ at 24 weeks between the CCM groups and control groups of 0.84 mL/kg/min with a Bayesian credible interval of (0.12, 1.55) mL/kg/min. “The probability that CCM is superior to control was 0.989, which exceeds the 0.975 criterion required for statistical significance of the primary endpoint.” Among the pooled data 60.1% (104/173) of participants in the CCM group and 34.9% (59/169) in the control group achieved ≥ 1 class improvement in NYHA at 24-week follow up period. At the 24-week follow-up, the change in Quality of Life measured by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ) total score between the groups in the pooled data, was -10.9 (95% confidence interval [CI]; -14.6, -7.2). The primary safety endpoint was met. “The complication-free proportion in the CCM group cohort was 89.7% (61/68) with lower confidence limit of 79.9% (one-sided alpha=0.025), which was greater than the pre-defined threshold of 70%. The majority of complications (5/7, 71.4%) were lead dislodgements.” Among the OPTIMIZER group and the control group, the freedom from death (98.3%, 95.3%; p=0.2549), cardiovascular death (100%, 96.5%; p=0.1198), composite rate of all-cause death or all-cause hospitalizations (78.1%, 77.7%; p=0.9437) and overall rate of adverse events and serious adverse events were similar at 24-weeks (Product Label Information, 2019).

According to the FDA Summary of Safety and Effectiveness Data (SSED) the FDA concluded that:

Even though the primary effectiveness endpoint (change in peak V02) met its pre-specified endpoint the clinical significance was questioned; primarily because the observed treatment difference was due to a decline from baseline in the control arm. The treatment arm, depending on analysis method, either showed a decline in peak Vo₂ or a marginal increase; making claims of increased exercise tolerance not justifiable.

Two subjective endpoints, Quality of life per the MLWHFQ, and the 6 minute hall walk, did show an improvement. However, the confidence intervals were somewhat wide; possibly due to the relatively small sample size and unblinded nature of the trial (control group did not receive a device). The latter raised the question among panel members if the positive outcomes for the subjective endpoints could be due to a placebo effect.

The 2022 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) Guideline for the Management of Heart Failure does not include recommendations for use of cardiac contractility modulation therapy as a treatment for HF (Heidenreich, 2022).

Giallauira and colleagues (2020) reported findings from a comprehensive meta-analysis of individual data from all known randomized trials. The authors reviewed the effects of CCM therapy on functional capacity and HF-related quality of life and found CCM promising. The authors concluded that:

Larger, well-conducted RCTs using a parallel double-blind design are needed in order to determine the effect of CCM on major mortality and morbidity outcomes before CCM can be widely recommended as an effective treatment option for HF patients.

In 2021, the European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure listed CCM as a device under evaluation for individuals with NYHA class III-IV HF. The committee concluded that the device was associated with small improvement in exercise tolerance and quality of life (McDonagh, 2021).

In summary, the current evidence base is insufficient to support the use of CCM therapy with the OPTIMIZER Smart System in individuals with chronic, moderate-to-severe HF. The current studies included relatively small sample size with short follow-up duration, therefore the long-term complications such as infection and lead fractures are unknown. Longer studies with larger and more representative populations are needed to confirm longer-term effects of CCM therapy on whether health outcomes are significantly improved relative to standard of care for HF management.

The OPTIMIZER Smart System is being studied in an ongoing prospective, multicenter, post approval study. The study is designed to evaluate the long-term safety and efficacy of the device as well as to rule out placebo effects and more precisely identify the group of individuals that most benefit from the device. The study-estimated enrollment is 620 participants, with estimated study completion date in March 2026.

According to the Centers for Disease Control (CDC) and Prevention nearly 6.2 million Americans are currently diagnosed with HF, and approximately 960,000 new cases are diagnosed each year (CDC, 2020). Approximately 50% of individuals with HF die within 5 years of diagnosis. As a result of HF, the weakened heart muscle causes inadequate filling of the left ventricle, as well as a backflow of blood into the left atrium, both resulting in decreased cardiac output and increased symptoms for the afflicted individual. Symptoms can include shortness of breath, fatigue, swelling in the ankles, feet, legs, abdomen, and veins in the neck. Currently there is no cure for HF; medical therapy includes a combination of diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta-blockers, and aldosterone antagonists. Some individuals may remain symptomatic, despite medical therapy. Ongoing studies evaluate other treatment options to assist physicians in the management of individuals with severe HF.

Bayesian hierarchical analysis: A statistical method providing estimates of post-analysis parameters based on frequencies observed in a prior analysis evaluated in a series of hierarchical models.

Guideline-directed medical therapy (GDMT): This term was adopted by the writing groups for the major specialty medical societies, (such as found in Tracy, 2012 and Yancy, 2013) in 2012; the term replaces and is synonymous with “Optimal medical therapy.”

Heart failure: A condition in which the heart no longer adequately functions as a pump. As blood flow out of the heart slows, blood returning to the heart through the veins backs up, causing congestion in the lungs and other organs.

New York Heart Association (NYHA) Definitions: The NYHA classification of heart failure is a 4-tier system that categorizes subjects based on subjective impression of the degree of functional compromise; the four NYHA functional classes are as follows:

• Class I - patients with cardiac disease but without resulting limitation of physical activity; ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain; symptoms only occur on severe exertion.
• Class II - patients with cardiac disease resulting in slight limitation of physical activity; they are comfortable at rest; ordinary physical activity (e.g., moderate physical exertion such as carrying shopping bags up several flights of stairs) results in fatigue, palpitation, dyspnea, or anginal pain.
• Class III - patients with cardiac disease resulting in marked limitation of physical activity; they are comfortable at rest; less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain.
• Class IV - patients with cardiac disease resulting in inability to carry on any physical activity without discomfort; symptoms of heart failure or the anginal syndrome may be present even at rest; if any physical activity is undertaken, discomfort is increased.

Ventilatory Anaerobic Threshold (VAT): The point in exercise testing at which anaerobic metabolism is detected by comparing oxygen consumption with CO2 production. VAT provides a measure of exercise capacity that has prognostic value for individuals with heart failure.

Vo₂: Oxygen uptake. This can be calculated using the Fick Equation (Vo₂ = [SV x HR] x [CaO2 - CvO2]) in which oxygen uptake equals stroke volume times the heart rate times the difference in oxygen concentration between arterial and venous blood. Vo₂ indicates functional aerobic capacity is widely used as a measure of cardiorespiratory fitness.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure codes or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Abraham WT, Kuck KH, Goldsmith RL, et al. A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation. JACC Heart Fail. 2018; 6(10):874-883.
2. Abraham WT, Lindenfeld J, Reddy VY, et al. A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with moderately reduced left ventricular ejection fraction and a narrow QRS duration: study rationale and design. J Card Fail. 2015; 21(1):16-23.
3. Anker SD, Borggrefe M, Neuser H, et al. Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction. Eur J Heart Fail. 2019; 21(9):1103-1113.
4. Giallauria F, Cuomo G, Parlato A, et al. A comprehensive individual patient data meta-analysis of the effects of cardiac contractility modulation on functional capacity and heart failure-related quality of life. ESC Heart Fail. 2020; 7(5):2922-2932.
5. Kadish A, Nademanee K, Volosin K, et al. A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. Am Heart J. 2011; 161(2):329-337.
6. Kloppe A1, Mijic D, Schiedat F, et al. A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: a preliminary report. Cardiol J. 2016; 23(1):114-119.
7. Müller D, Remppis A, Schauerte P, et al. Clinical effects of long-term cardiac contractility modulation (CCM) in subjects with heart failure caused by left ventricular systolic dysfunction. Clin Res Cardiol. 2017; 106(11):893-904.
8. Ponikowski P, Francis DP, Piepoli MF, et al. Enhanced ventilator response to exercise in patients with chronic heart failure and preserved exercise tolerance: maker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation. 2001; 103(7):967-972.
9. Wiegn P, Chan R, Jost C, et al. Safety, performance, and efficacy of cardiac contractility modulation delivered by the 2-lead Optimizer Smart System: The FIX-HF-5C2 Study. Circ Heart Fail. 2020; 13(4):e006512.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure. A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Amer Col Cardiol. 2022; 79:e263-e421.
2. Impulse Dynamics. Continued Access Protocol for the evaluation of the OPTIMIZER Smart System (FIX-HF-5CA). NLM Identifier: NCT03102437. Last updated November 23, 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03102437?term=OPTIMIZER+Smart+system&cond=heart+failure&rank=2. Accessed on July 6, 2023.
3. Impulse Dynamics. Evaluation of the safety and efficacy of the 2-lead OPTMIZER® Smart System (FIX-HF-5C2). NLM Identifier: NCT03339310. Last updated January 14, 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT03339310?term=OPTIMIZER+Smart+system&cond=heart+failure&rank=1. Accessed on July 6, 2023.
4. Impulse Dynamics. Post Approval Study (PAS) of the OPTIMIZER Smart and CCM therapy (PAS). NLM Identifier: NCT03970343. Last updated January 27, 2022. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03970343?term=CCM+Therapy+AND+OPTIMIZER&cond=Heart+Failure&draw=2&rank=1. Accessed on July 6, 2023.
5. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur. Heart J. 2021; 75(6):3599-3726.
6. Mozaffarian D, Benjamin EJ, Go AS, et al. AHA Statistical Update. Heart disease and stroke statistics – 2016 update a report from the American Heart Association. Circulation. 2015; 133:e38-e360.
7. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012; 60(14):1297-1313.
8. U.S. Food and Drug Administration (FDA). Pre Market Approval (PMA). Medical Devices. OPTIMIZER Smart System – No. P180036. Rockville, MD: FDA. March 21, 2019. Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P180036. Accessed on July 6, 2023.
9. U.S. Food and Drug Administration (FDA) Premarket Notification Database. Implantable Pulse Generator, OPTIMIZER Smart System. Summary of Safety and Effectiveness Data (SSED). No. P180036. Rockville, MD: FDA. March 21, 2019. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180036b.pdf. Accessed on July 6, 2023.
10. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017; 70:776-803.
11. Yancy CW, Jessup M, Bozkurt B, et al. 2013ACCF/AHA guideline for the management of heart failure. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013; 128:e240-e327.

1. Centers for Disease Control and Prevention. Heart failure. Last updated September 8, 2020. Available at: https://www.cdc.gov/heartdisease/heart_failure.htm. Accessed on July 6, 2023.
2. National Heart, Lung and Blood Institute. Heart failure. Last updated March 24, 2022. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html. Accessed on July 6,2023.

Cardiac Contractility Modulation (CCM) Therapy
Heart Failure
OPTIMIZER Smart Implantable Pulse Generator
OPTIMIZER Smart System

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