Medical Policy

This document addresses wireless left ventricular (LV) pacing for cardiac resynchronization therapy (CRT). Wireless LV pacing for CRT has been proposed as an alternative to conventionally delivered CRT as a treatment of heart failure.

Investigational and Not Medically Necessary:

Wireless left ventricular pacing for CRT is considered investigational and not medically necessary for all indications, including heart failure.

Conventional CRT involves biventricular pacing to help improve heart rhythm and symptoms associated with arrhythmias. In CRT, a small pacemaker is inserted just below the collarbone with three wires that will detect heart rate irregularities and emit tiny pulses of electricity to correct them (resynchronizing the heart). Wireless LV pacing for CRT has been proposed as an alternative to conventional CRT; however, there have been a limited number of studies published in the peer-reviewed literature addressing the use of this technology.

Wireless LV pacing for CRT

In 2013, Auricchio and colleagues published the results of a study that investigated the safety and performance of the WiCS^®-LV system, now known as the WiSE^™ CRT System (EBR Systems, Inc., Sunnyvale, CA). The authors evaluated the technology in 3 individuals in three different circumstances: an individual with an implanted cardioverter defibrillator (ICD) upgraded to CRT, another individual with an implanted CRT defibrillator (CRT-D) with exit block in the coronary sinus (CS) lead, and a third individual with an implanted CRT-D who was a non-responder. At 6 months post-procedure, all 3 individuals retained capture, New York Heart Association (NYHA) functional class “significantly changed (Pre: III in two patients, and IV in one patient; Post: I in one patient, II in one patient, and II–III in one patient), and LV ejection fraction increased from 23.7 ± 3.4% to 39 ± 6.2% (p<0.017)” (Auricchio, 2013). The results of this study are limited by the low quality design including small sample size, lack of blinding, and no control group.

Auricchio and colleagues reported on the Wireless Stimulation Endocardially for CRT (WiSE-CRT) study (2014). This multicenter, prospective, and observational feasibility study was designed to enroll 100 individuals in up to 12 centers; however, only 17 individuals were enrolled from 6 centers. Of the 17 individuals enrolled, 13 (76.5%) individuals received device implants. Reasons for device implantation included: individuals with failed CS lead implantation for CRT (n=7); individuals with an implanted CRT device and were not responding to CRT (n=2); and individuals with an implanted pacemaker or implantable cardioverter-defibrillator who met the standard indications for CRT (n=8). The primary endpoints were biventricular pacing capture on 12-lead electrocardiogram (EKG) analysis at 1 month and serious adverse events. Secondary endpoint was evaluation at 6 months. At 1 month, biventricular pacing was recorded in 83% (n=10) of the individuals and at 6 months, it was recorded in 92% (n=11) of the individuals. One individual had a non-functional device due to battery depletion at the 6-month follow-up. Serious adverse event rate at 1 month was 35%. This included three peri-operative pericardial effusions (18%), one of which resulted in death (6%). At the 6-month follow-up, 8 individuals (66%) had a NYHA functional class change, and LV ejection fraction significantly increased by 6 points (p<0.01). Limitations to this study include small sample size, and no control group or blinding.

In 2017, Reddy and colleagues published the outcomes of the Safety and Performance of Electrodes implanted in the Left Ventricle (SELECT-LV) study, which was a prospective, multicenter, non-randomized trial that investigated the safety and performance of the WiSE-CRT system in individuals (n=35) who had a standard indication for CRT, but failed conventional CRT [difficult CS anatomy (n=12; 34%), failure to respond to conventional CRT (n=10; 29%), high CS pacing threshold or phrenic nerve capture at low outputs (n=5; 14%), CS lead dislodgment or lead failure (n=3; 9%), prior infection or upper extremity venous occlusion (n=3; 9%), or other (n=2; 6%)]. The WiSE-CRT system was successfully implanted into 33 (97.1%) individuals for LV endocardial wireless pacing. The primary endpoints were biventricular pacing capture on EKG analysis at 1 month, and device-related complications from implant to 24 hours post-implant and from 24 hours post-implant to 30 days. Biventricular pacing capture was achieved in 33 individuals (97%). Due to defective transmitters, 2 of the 33 (5.7%) individuals did not achieve biventricular pacing. There were 3 (8.6%) individuals with device-related events within 24 hours. One individual died as a result of complications from cardiac arrest due to ventricular fibrillation during the electrode implant procedure. Prior to the introduction of the sheath into the left ventricle, another individual experienced embolization of the electrode to the left tibial artery during the exchange of the dilator and the catheter. The third individual required surgical repair after the formation of a femoral artery fistula. There were 8 (22.9%) individuals with device-related events between 24 hours and 30 days. These events included stroke (basilar artery) in conjunction with warfarin noncompliance (n=1), femoral pseudoaneurysm (n=2), pocket hematoma (generator) (n=1), suspected infection (generator site) (n=3), and death following ventricular fibrillation during the initial implant procedure as previously described (n=1). The secondary endpoints, which were evaluated at 6 months, were change in the clinical composite score (all-cause mortality, heart failure hospitalization, NYHA functional class, and global assessment), and change in echocardiographic left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF). The clinical composite score improved in 28 (84.8%) individuals. This change was largely driven by an improvement in NYHA functional class (n=22; 66.7%) and an improvement in quality of life scores (n=23; 69.7%). “Using the responder criteria for LVESV (≥ 15% relative reduction), LVEDV (≥ 10% relative reduction), and LVEF (≥ 5% absolute increase), positive echocardiographic responses to CRT were observed in 52% (n=3), 40% (n=10), and 66% (n=21) of patients, respectively” (Reddy, 2017). This study resulted in serious adverse events in a third of treated individuals. Furthermore, interpretation of study results is limited by a small sample size, lack of blinding, and no control group.

In a 2022 study, Okabe and colleagues presented short-term data regarding the WiSE-CRT system in centers without prior implant experience. The systems were implanted during the roll-in phase of SOLVE-CRT trial. Participants were followed for 6 months. There were 31 participants who had the implanted system with 29 completing the 6 month follow-up. The primary safety endpoint included type I complications (defined as those caused by a component of the device or specific procedure-related events). Primary efficacy endpoint was the mean percentage change in LVESV from baseline to 6 months. In terms of efficacy, 14 participants demonstrated ≥1 NYHA class improvement. None of the participants reported worsening symptoms. There were three (10%) reported type I complications (intermittent loss of capture, embolization of inadequately anchored LV electrode, and an infected wound). Limitations include lack of randomization and no comparator group.

A 2022 meta-analysis performed by Cang and colleagues reported on whether participants can benefit from WiSE-CRT as a rescue therapy for heart failure. The analysis included five studies with a total of 175 participants. Study participants had failed conventional CRT procedures, had no response to CRT, or needed an upgraded device. Follow-up time for all studies was 6 months. Four of the studies included QRS duration, which showed a mean decrease of -38.21 ms. The five studies included assessment of LVEF with echocardiography showing reduced LVEDV(mean difference -24.02ml) and reduced LVESV (mean difference -23.47ml). NYHA class was reported in three of the studies. One study reported 50% of participants with moderate or marked improvement. Another study reported 69.7% of participants had great or moderate improvement. The third study reported 46.7% of participants had ≥1 NYHA class improvement. Safety outcomes were reported by three studies which included 53 device or procedure-related adverse events (30%). Limitations include non-randomized studies and follow-up time of 6 months.

LV Endocardial Pacing

LV endocardial pacing (LVEP) presents a possible alternative to conventional CRT. There are several techniques with multiple variations that achieve LVEP, such as the atrial transeptal approach and the trans-ventricular apical approach. While the majority of studies on this alternative are case series, there have recently been some larger studies assessing LVEP.

In 2016, Morgan and colleagues released the results of the ALternate Site Cardiac ResYNChronization (ALSYNC) study, which was an international multicenter prospective study that assessed the safety and efficacy of LVEP using a single-incision, pectoral, atrial transseptal approach. Between March 2011 and July 2013, individuals who had either a failed previous conventional LV lead implantation, suboptimal CS anatomy, or were a CRT non-responder were enrolled in the study (n=138). The primary objective was freedom from complications greater than or equal to 70% related to the lead, the lead delivery system, or the implant procedure at the 6-month follow-up. Complications were defined as “any transseptal implant tool, transseptal implant procedure, or LVEP lead-related adverse event resulting in patient death, confirmed stroke, termination of significant device function, or any invasive intervention (including administration of intramuscular and parental fluids)” (Morgan, 2016). Of the 138 individuals enrolled in the study, LVEP lead implantation was performed in 132 individuals. Of those individuals who were not included in the results analysis, 2 were excluded from the analysis due to left superior vena cava, 1 died before the planned implant, and 3 did not have an implant due to thrombus in the left atrium. LVEP lead implantation was successful in 118 individuals (89%; 95% confidence interval [CI], 83–94%). The primary objective, freedom from complications as previously defined, was 82.2% at 6 months (95% CI, 75.6–88.8%). Adverse events included 5 post-procedure strokes (95% CI, 1.1–6.3), 14 transient ischemic attack (TIA) episodes observed in 9 individuals (95% CI, 3.6–17.6), and 23 deaths during study follow-up due to heart failure, renal failure, pulmonary failure, cancer, and sudden cardiac death (mortality rates at 6, 12, and 24 months after first implant attempt were 8.3%, 14.4%, and 18.4%, respectively). None of the deaths were due to a primary objective complication. Clinical outcomes during follow-up assessments at 6 months included 55% of individuals with a reduction in LV end-systolic volume (LVESV) of at least 15% (p<0.0001), 59% of individuals with an improvement of at least one NYHA class (p<0.0001), 33% of individuals with an improvement of mitral valve regurgitation by at least one class (p=0.035), 64% of individuals with at least a 5% absolute increase in LVEF (p<0.0001), and 44% of individuals with at least a 60-meter increase in the 6-minute walking test (p=0.004). While this study did not have a control group and randomization, it did show significant results that demonstrate clinical feasibility of LVEP as an alternative to conventional CRT.

Gamble and colleagues (2018) performed a systematic review and meta-analysis evaluating the benefits and risks of LVEP as an alternative to conventional CRT. The literature search yielded 23 studies published between 1999 and 2016 with a total of 384 individuals. There were 5 case reports, 15 case series, 2 retrospective case series, and 1 prospective clinical trial, which was the ALSYNC study that was previously described. While most individuals in the studies had a history of a failed CS implant of an LV lead for CRT, 10% of individuals were non-responders to CRT. The LVEP techniques used in the studies were trans-atrial septal (n=20), trans-ventricular apical (n=1), and trans-ventricular septal (n=2). Sixteen studies reported clinical response outcomes, defined as improvement of at least one NYHA class, for 262 individuals (68%). Of the 262 individuals, 191 individuals (73%) had a positive clinical response; however, due to the wide and uneven distribution of the range of reporting between studies, the meta-analysis estimate of response was 82% (95% CI, 71-89%). No significant difference in clinical response was found between LVEP techniques (p=0.2). A significant difference in clinical response was found between the ALSYNC study (59%) and the remainder of the studies (92%) (p=0.02), which may be due to the large number of non-responders to CRT in the ALSYNC group. Non-responders to CRT are less likely to show improvement due to various reasons such as comorbidities. Another possible reason for the significant difference in clinical response found between the ALSYNC study and the remaining studies is smaller studies typically have less bias-resistant designs. In regards to thromboembolic complications, which were reported by all studies, “the rate of stroke was 2.5 events per 100 patient years (95% CI, 1.5–4.3), and TIA 2.6 (1.1–6.1). The mortality rate was 4.5 (1.5–13.6) per 100 patient years” (Gamble, 2018). No significant difference was found in relation to complications and LVEP technique (p=0.7). The authors noted that clinical response rates and complication rates in this meta-analysis were comparable to other studies, including a large meta-analysis, on conventional CRT. While the sample size of this meta-analysis is small, which limits available data for analysis, the data shows that LVEP results in similar clinical response outcomes and complication rates making LVEP a viable alternative to conventional CRT.

In 2024, Singh published additional results of the SOLVE-CRT study, a prospective multicenter, double-blind, randomized clinical trial (RCT) assessing the safety and efficacy of the WiSE CRT System. It was originally designed as a randomized, multinational, double-blind study to enroll 350 participants from up to 45 centers. Participants were stratified into 3 groups, nonresponders, previously untreatable (PU), or high-risk upgrades (HRU). The PU group had full or partial CRT system implanted but were not receiving CRT because of lead issues preventing effective device functioning. Participants in the HRU group included those in whom a standard CRT upgrade was not advisable due to relative contraindication. This group also included participants with a leadless intracardiac pacemaker requiring upgrade to CRT. All participants underwent device implantation and were randomized in a 1:1 ratio to treatment (system-on) or control (system-off) groups. At 6 months, all participants were unblinded and the control group was given the option to have their device activated. Unblinded follow-up continued at 6-month intervals through year 2 and at 12-month intervals thereafter. Part 1, the study roll-in, was described above (Okabe, 2022). Part 2, the randomized portion of the trial enrolled 108 participants. A total of 99 participants had successful implants with 52 randomized to the control group and 47 to the treatment group. In the control group, 48 participants completed the 6-month follow-up (3 died, 1 withdrew) and in the treatment group, 43 participants completed 6-month follow-up (3 died, 1 withdrew). Part 3, the open label single arm phase, enrolled 75 participants, all of whom had successful implants and 69 completed the 6-month follow-up (1 died, 5 withdrew). The prespecified interim safety analysis included data from all participants in the randomized and single-arm parts of the trial (n=183; 108 randomized and 75 single-arm). The efficacy analysis included only PU and HRU group participants, including all single-arm (n=75) and those randomized to the treatment group from the PU and HRU groups (n=25) for a total of 100 participants. Among the 183 participants in the safety analysis, there were 44 nonresponders, 110 PU, and 29 HRU. Among the 100 in the efficacy analysis, there were 75 PU and 25 HRU. Of the safety participants, 162 were followed up through 6 months (88.5%), 10 died (5.5%), 5 withdrew due to unsuccessful implant attempts (2.7%), and 6 withdrew for reasons such as heart transplant (3.1%). Of the 100 efficacy participants, 91 completed 6-month follow-up (91.0%), 3 died (3.0%), 3 had an unsuccessful implant attempt (3.0%), and 3 withdrew due to infection or LV assist device (3.0%). In the efficacy population, the mean percent change in LV end systolic volume (LVESV) was -16.4% (95% CI, −21.0% to −11.7%) with an upper confidence bound below the −9.3% performance goal (p=0.003). This met the final primary efficacy end point. In the safety population, there was an 80.9% rate of freedom from type 1 complications (T1Cs) with a lower bound of the 1-sided 98.8% CI of 73.4%, above the 70% performance goal (p<0.001). This also met the interim primary safety end point. Since both the prespecified interim safety and final efficacy end points were met, the trial was stopped early. With regard to secondary end points, an acoustic pacing capture threshold (APCT) of less than 2.9 mJ was achieved in 95.2% (95% CI, 88.1%-98.7%) of participants. The authors concluded this demonstrated that thresholds were sufficiently low. The percentage biventricular pacing was 93.1% (95% CI, 90.3%-95.9%). In a responder analysis, 46.1% of participants had 5% or more increase in LVEF (95% CI, 35.4%-57.0%) and 65.5% had a 5-point increase or more in the Kansas City Cardiomyopathy Questionnaire (KCCQ) (95% CI, 54.6%-75.4%). The mean increase in KCCQ score was 15.3 (95% CI, 11.2%-19.5%). Other echocardiographic changes included the absolute reduction in LVESV of -25.1 mL (95% CI, −32.4 to −17.9) and in LV end diastolic volume (LVEDV) of -25.4 mL (95% CI, −28.4 to −22.5). The mean absolute increase in LVEF was 5.2% (95% CI, 4.7%-5.7%). Overall, 55% of participants’ NYHA class improved, 41% were unchanged, and 3.4% worsened by 1 class. The paced QRS duration shortened by a mean of 39.3 (SD, 23.3) milliseconds. The authors concluded that their study, “has demonstrated that leadless LV endocardial pacing with the WiSE CRT system is associated with a reduction in LVESV in patients with HF. This novel system may represent an alternative to conventional CRT implants in some HF patient populations.”

Summary

The majority of published studies evaluating the WiSE CRT system have included small sample sizes, no method of randomization, and an absence of a comparison control group. Other issues include, high rates of serious adverse events including death, and questions relating to generalizability (for example, procedure feasibility outside of academic research institutions). Individuals who are not candidates for or have failed conventional CRT may be eligible for LVEP, which has demonstrated comparable results with conventional CRT. Additional well-designed studies are required to demonstrate long-term safety and efficacy of wireless LV pacing for CRT for heart failure.

The WISE CRT System was evaluated in the investigational device exemption Stimulation Of the Left Ventricular Endocardium for Cardiac Resynchronization Therapy in non-responders and previously untreatable patients (SOLVE-CRT) clinical trial. While the results of this trial have now been published (and are described above), FDA approval has yet to be granted for any wireless CRT for LV pacing device.

Wireless LV pacing for CRT has been proposed as an alternative to conventionally delivered CRT through transvenous LV lead positioning as a treatment of heart failure. Devices that provide wireless LV pacing for CRT are co-implanted with a pacemaker, ICD, or CRT device. An implanted pulse transmitter senses the right ventricular pacing signal from the co-implanted device. This prompts the transmitter to generate ultrasound that is detected by an electrode implanted on the LV endocardial wall, which converts the ultrasound to an electrical pacing pulse thereby stimulating the LV.

Congestive heart failure (CHF) or 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.

Ventricular fibrillation (Vfib or VF): A condition in which the heart's electrical activity becomes disordered. When this happens, the heart's lower (pumping) chambers contract in a rapid, unsynchronized fashion (the ventricles "quiver" rather than beat) and the heart pumps little or no blood.

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. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace. 2014; 16(5):681-688.
2. Auricchio A, Delnoy PP, Regoli F, et al. First-in-man implantation of leadless ultrasound-based cardiac stimulation pacing system: novel endocardial left ventricular resynchronization therapy in heart failure patients. Europace. 2013; 15(8):1191-1197.
3. Cang J, Liu Y, Zhu D, et al. WiSE CRT is beneficial for heart failure patients as a rescue therapy: evidence from a meta-analysis. Front Cardiovasc Med. 2022; 9:823797.
4. Gamble JHP, Herring N, Ginks M, et al. Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis. Europace. 2018; 20(1):73-81.
5. Morgan JM, Biffi M, Gellér L, et al. ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy. Eur Heart J. 2016; 37(27):2118-2127.
6. Okabe T, Hummel JD, Bank AJ, et al. Leadless left ventricular stimulation with WiSE-CRT System - Initial experience and results from phase I of SOLVE-CRT Study (nonrandomized, roll-in phase). Heart rhythm. 2022; 19(1):22-29.
7. Reddy VY, Miller MA, Neuzil P, et al. Cardiac resynchronization therapy with wireless left ventricular endocardial pacing: the SELECT-LV study. J Am Coll Cardiol. 2017; 69(17):2119-2129.
8. Singh JP, Abraham WT, Auricchio A, et al. Design and rationale for the stimulation of the left ventricular endocardium for cardiac resynchronization therapy in non-responders and previously untreated patients (SOLVE-CRT) trial. AM Heart J. 2019; 2017:13-22.
9. Singh JP, Rinaldi CA, Sanders P, et al; SOLVE-CRT Investigators. Leadless ultrasound-based cardiac resynchronization system in heart failure. JAMA Cardiol. 2024; 9(10):871-879.
10. Singh JP, Walsh MN, Kubo SH, et al. Modified design of stimulation of the left ventricular  endocardium for cardiac resynchronization therapy in nonresponders, previously untreatable and high-risk upgrade patients (SOLVE-CRT) trial. Am Heart J. 2021; 235:158-162.

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. Journal of the American College of Cardiology. 2022; 79(17):e263-e421.

1. National Heart, Lung and Blood Institute. Heart failure. March 24, 2022. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF_WhatIs.html. Accessed on November 11, 2024.

WiCS-LV System
WiSE CRT System

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.