This study assesses the safety and efficacy of a novel, leadless, left ventricular endocardial pacing system for patients at high risk for a cardiac resynchronization therapy upgrade or whose coronary sinus lead placement/pacing with a conventional cardiac resynchronization therapy system has failed.
Key Points
Question
Is leadless left ventricular (LV) endocardial pacing using ultrasound energy safe and effective for providing cardiac resynchronization therapy (CRT) to patients whose conventional CRT using a coronary sinus lead failed?
Findings
In this prospective clinical trial (N = 183), 80.9% of patients were free from device- and procedure-related adverse events. The average improvement in mean LV end systolic volume was –16.4%.
Meaning
In this study, for patients with failed coronary sinus lead placement for CRT, a leadless LV pacing system using ultrasound energy holds promise as a viable alternative.
Abstract
Importance
Approximately 40% of patients with heart failure (HF) who are eligible for cardiac resynchronization therapy (CRT) either fail to respond or are untreatable due to anatomical constraints.
Objective
To assess the safety and efficacy of a novel, leadless, left ventricular (LV) endocardial pacing system for patients at high risk for a CRT upgrade or whose coronary sinus (CS) lead placement/pacing with a conventional CRT system failed.
Design, Setting, and Participants
The SOLVE-CRT study was a prospective multicenter trial enrolling January 2018 through July 2022, with follow-up at 6 months. Data were analyzed from January 17, 2018, through February 15, 2023. The trial combined data from an initial randomized, double-blind study (n = 108) and a subsequent single-arm part (n = 75). It took place at 36 centers across Australia, Europe, and the US. Participants were nonresponders, previously untreatable (PU), or high-risk upgrades (HRU). All participants contributed to the safety analysis. The primary efficacy analysis (n = 100) included 75 PU-HRU patients from the single-arm part and 25 PU-HRU patients from the randomized treatment arm.
Interventions
Patients were implanted with the WiSE CRT System (EBR Systems) consisting of a leadless LV endocardial pacing electrode stimulated with ultrasound energy delivered by a subcutaneously implanted transmitter and battery.
Main Outcomes and Measures
The primary safety end point was freedom from type I complications. The primary efficacy end point was a reduction in mean LV end systolic volume (LVESV).
Results
The study included 183 participants; mean age was 68.1 (SD, 10.3) years and 141 were male (77%). The trial was terminated at an interim analysis for meeting prespecified stopping criteria. In the safety population, patients were either New York Heart Association Class II (34.6%) or III (65.4%). The primary efficacy end point was met with a 16.4% (95% CI, −21.0% to −11.7%) reduction in mean LVESV (P = .003). The primary safety end point was met with an 80.9% rate of freedom from type I complications (P < .001), which included 12 study device system events (6.6%), 5 vascular events (2.7%), 3 strokes (1.6%), and 7 cardiac perforations which mostly occurred early in the study (3.8%).
Conclusions and Relevance
The SOLVE-CRT 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.
Trial Registration
ClinicalTrials.gov Identifier: NCT0292203
Introduction
Cardiac resynchronization therapy has conclusively demonstrated left ventricular (LV) reverse remodeling, improved functional status, and reduced hospitalizations and mortality in patients with heart failure (HF) with reduced ejection fraction (EF) and a prolonged QRS duration.1,2,3,4,5,6,7,8,9
Conventional cardiac resynchronization therapy (CRT) involves one lead in the right ventricle and another in the coronary sinus (CS). Biventricular pacing (BIVP) is rendered by pacing both simultaneously. However, positioning the lead within the coronary vein is not possible in 5% to 15% of patients due to anatomical constraints.10 Additionally, many patients have a suboptimal lead location and 30% to 40% are nonresponders.1,10,11,12 Surgical implantation of an epicardial lead is not optimal for patients with comorbidities. Moreover, evidence suggests that pacing the epicardium is not physiological.10,11,13
The WiSE CRT System is a novel leadless LV endocardial pacing system that delivers ultrasonic energy to a wireless receiver electrode implanted within the endocardium.1,10,11,14 The system consists of a battery connected to an ultrasound transmitter that is implanted subcutaneously and the electrode implanted in the LV endocardium (Figure 1). The system requires a co-implant (eg, pacemaker, defibrillator, or CRT) capable of right ventricular (RV) pacing. The transmitter senses the RV pacing spike of the co-implant and within approximately 5 milliseconds emits an ultrasonic pulse to the electrode, which is converted into electrical energy to pace the LV. The WiSE CRT System has the potential to overcome the anatomical constraints of the coronary venous system and enable patient-specific approaches to electrode placement across the LV endocardium. We present results from the SOLVE-CRT study that examined the safety and efficacy of the WiSE CRT System.15,16
Figure 1. WiSE Cardiac Resynchronization Therapy (CRT) System.
Existing co-implant device (pacemaker, implantable cardioverter defibrillator of CRT) providing right ventricular pacing (A); the receiver-electrode converts ultrasound into electrical energy to pace the LV from the endocardium (B); the battery powers the transmitter; implanted subcutaneously at the left midaxillary line (C); the phase array transmitter that is synchronized with right ventricular pacing pulse and transmits ultrasound energy to the receiver-electrode (D).
Methods
The SOLVE-CRT study was a prospective multicenter trial combining data from an initial randomized, double-blind study and a subsequent single-arm study and follows the reporting guidelines for nonrandomized studies as applicable.17 It was originally designed as a randomized, multinational, double-blind study to enroll 350 patients from up to 45 centers. There were 3 groups of patients, including nonresponders, previously untreatable (PU), or high-risk upgrades (HRU) (eTable 1 in Supplement 1). Previously untreated patients had a full or partial CRT system but were not receiving CRT because of a failed LV lead implantation or lead issues that resulted in the CS lead programmed “off” due to high threshold, noncapture, phrenic nerve pacing, or lead failure.
Patients in the HRU group included those in whom standard CRT upgrade was not advisable due to relative contraindication, such as risk of venous occlusion, pocket infection, or comorbidities. This group also included patients with a leadless intracardiac pacemaker requiring upgrade to CRT. A complete listing of inclusion and exclusion criteria16 are listed in eTable 1 in Supplement 1.
All patients underwent device implantation and were then randomized in a 1:1 ratio to treatment (system-on) or control (system-off) groups. At 6 months, patients were unblinded and the control group could have their device activated. Unblinded follow-up continued at 6-month intervals through year 2 and at 12-month intervals thereafter.
The first patient was enrolled in SOLVE-CRT in January 2018. Enrollment was severely impacted by the COVID-19 pandemic and was paused in March 2020 after 108 patients were enrolled. At that time, the investigators worked with the US Food and Drug Administration (FDA) to revise the clinical protocol, implementing a single-arm nonrandomized part to complete the study.16 Central to this strategy was a differentiation of the 3 original patient groups and the requirements for demonstration of safety and efficacy. For the patients in the PU and HRU groups, CRT was an approved therapy and the WiSE CRT System could be viewed as an alternate method of providing CRT when conventional CRT was not possible, so a single-arm study with an objective performance goal was appropriate. In contrast, the nonresponder group had suboptimal responses to conventional CRT due to a diverse set of pathophysiologic mechanisms. Thus, there was a different threshold for scientifically acceptable evidence for safety and effectiveness and this group was excluded from the study continuation.16 All versions of the study protocol were approved by relevant institutional review boards and the FDA under an Investigational Device Exemption application. All patients provided written informed consent.
Patient Disposition and Study Populations
The modified study design and patient disposition are shown in Figure 2. Overall, the SOLVE-CRT study enrolled 214 patients. Part 1 (roll-in) was designed for centers without prior experience and enrolled 31 patients. These results were published.18 Part 2 (randomized) enrolled 108 patients; 99 had successful implants with 52 randomized to control and 47 to treatment. In the control group, 48 completed the 6-month follow-up (3 died, 1 withdrew) and in the treatment group, 43 completed 6-month follow-up (3 died, 1 withdrew). Part 3 (single-arm) enrolled 75 patients; all had successful implants and 69 completed the 6-month follow-up (1 died, 5 withdrew).
Figure 2. Modified Study Design and Patient Disposition at 6 Months.
Part 2, randomization phase, was suspended in March 2020 due to the COVID-19 pandemic with 108 patients enrolled. To accommodate COVID-19 restrictions, the single-arm part (part 3) was instituted, and the inclusion criteria no longer included nonresponders. Twenty-five patients from part 2 were in the treatment arm subset of previously untreatable or high-risk upgrade patients. Seventy-five patients were enrolled in part 3, single arm. The safety population includes all patients enrolled in part 2 and part 3, while the efficacy population includes all patients enrolled in part 3 plus the subset of part 2 matching the indication.
aNot included in the analysis.
Data from all participants in the randomized and single-arm parts were included in the prespecified interim safety analysis (n = 183; 108 randomized and 75 single-arm). The efficacy analysis was composed of only patients in the PU and HRU groups, including all single-arm patients (n = 75) and patients randomized to the treatment group from the PU and HRU groups (n = 25) for a total of 100 patients.
Study End Points
Primary Safety
The primary safety end point for the SOLVE-CRT study was freedom from type I complications (T1Cs) through 6 months compared with a performance goal of 70%.16 Type I complications included adverse events caused by any component of the investigational system (transmitter, battery, electrode, delivery catheter, or programming software) or specific procedure-related events, such as electrode complications, vascular events, stroke, pericardial effusion, and pocket-related events. Type II complications included other procedure-related events not specifically caused by the study device, type III included events related to new disease, and type IV included events related to preexisting conditions (eMethods 6 in Supplement 1).
The performance goal was based on a review of the incidence rate of possible complications incurred by each device component and a literature search of related technologies, such as CRT, percutaneous coronary interventions, ventricular tachycardia ablations, and transcatheter aortic valve replacements (eTables 2 and 3 in Supplement 1).16
Primary Efficacy
The primary efficacy end point for the SOLVE-CRT study was the mean relative (percentage) change in LVESV from baseline to 6 months compared with a performance goal of –9.3%. All echocardiograms were evaluated by a blinded echocardiographic core lab.
The rationale for this end point was based on evidence that it is the most reliable measure of clinical benefit of CRT.19,20,21,22 The performance goal of –9.3% relative reduction was derived from the lower confidence bound of a meta-analysis of LVESV reduction in control groups reported in 4 randomized CRT trials (eTable 4 and eFigure 1 in Supplement 1).8,23,24,25
Secondary Efficacy End Points
Secondary efficacy end points were measured at 6 months and included the proportion of patients with an acoustic pacing capture threshold (APCT) less than 2.9 mJ, the proportion of patients with APCT stability (defined as a less than a 3 × relative change from predischarge), percent BIVP (ejection fraction responder analysis for 5% or more absolute increase), and Kansas City Cardiomyopathy Questionnaire (KCCQ) responder analysis for 5 points or more absolute increase.
Statistical Analysis
The overall sample size was driven by the requirements for the primary safety end point. The expected rate of freedom from T1Cs was 77% (lower confidence limit = 70%). The sample size of 300 patients provided approximately 85% power for a fixed sample-size analysis, based on an exact binomial test of proportions with a 1-sided .05 α level.
Spending across the analysis points was controlled using the O’Brien-Fleming spending function. The critical 1-sided α levels for testing safety at the interim and final analyses were 0.0121 and 0.0463. Based on these parameters, a 1-sided 98.8% CI was constructed for the primary safety end point at this interim analysis.
A gatekeeping approach was used to control the type I error rate for the 2 primary end points (eTable 5 though eTable 7 in Supplement 1). The final efficacy and interim safety analyses were conducted after completion of the 6-month follow-up visit for the first 75 patients enrolled in the single-arm part. This yielded 100 patients for the primary efficacy analysis (25 randomized; 75 single arm) and 183 patients for the interim safety analysis (108 randomized; 75 single arm).
The comparison of the mean percent change in LVESV with the performance goal of –9.3% was based on the upper bound of a 95% 2-sided CI using the t distribution. Primary safety analysis consisted of calculating the 1-sided lower confidence bound from the exact binomial distribution and comparing that to the 70% freedom from T1Cs performance goal. Secondary end points were assessed in the efficacy population and reported as frequencies and proportions or means and SDs, as appropriate, with nominal 95% CIs for the mean or proportion. The widths of CIs for secondary end points and other exploratory analyses were not adjusted for multiplicity.
Results
Baseline Characteristics
Baseline characteristics of the 183 patients in the safety analysis and 100 patients in the efficacy analysis are presented in Table 1. The safety and efficacy populations were similar. In the safety population, the mean age was 68.1 years and 141 patients were male (77%), 63 patients had New York Heart Association (NYHA) Class II disease (34.6%), and 119 had Class III disease (65.4%). The etiology of cardiomyopathy was similarly distributed between ischemic and nonischemic causes. Baseline LVEF (LV ejection fraction), LV end diastolic volume (LVEDV), and LVESV were consistent with patients with advanced HF (eTable 8 and eTable 9 in Supplement 1).
Table 1. Baseline Characteristics.
| Variable | No. (%) | |
|---|---|---|
| Safety population (n = 183) | Efficacy population (n = 100) | |
| Age, y, mean (SD) | 68.1 (10.28) | 68.2 (10.47) |
| Sex | ||
| Female | 42 (23) | 24 (24) |
| Male | 141 (77.0) | 76 (76.0) |
| BMI,a mean (SD) | 30.8 (5.75) | 30.6 (5.45) |
| SBP, mm Hg, mean (SD) | 119.2 (18.69) | 117.5 (17.68) |
| DBP, mm Hg, mean (SD) | 70.3 (10.58) | 69.5 (10.45) |
| HR, bpm, mean (SD) | 70.0 (10.59) | 70.4 (10.25) |
| CRT indication | ||
| Class I | 126 (68.9) | 64 (64.0) |
| Class IIa | 57 (31.2) | 36 (36.0) |
| Patient subpopulations | ||
| Nonresponder | 44 (24.6) | 0 (0) |
| Previously untreatable | 110 (60.1) | 75 (75.0) |
| Failed CS lead implant | 68 (37.2) | 48 (48.0) |
| CS lead turned off | 42 (23.0) | 27 (27.0) |
| High-risk upgrade | 29 (15.8) | 25 (25.0) |
| NYHA class | ||
| Class II | 63 (34.6) | 35 (35.0) |
| Class III | 119 (65.4) | 65 (65.0) |
| Rhythm disorders | ||
| History of atrial tachyarrhythmia | 92 (50.3) | 52 (52.0) |
| History of ventricular tachyarrhythmia | 67 (36.6) | 34 (34.0) |
| Type of cardiomyopathy | ||
| Nonischemic cardiomyopathy | 94 (51.4) | 50 (50.0) |
| Ischemic cardiomyopathy | 87 (47.5) | 50 (50.0%) |
| Co-implant | 183 (100.0) | 100 (100.0) |
| Pacemaker | 28 (15.3) | 21 (21.0) |
| ICD | 69 (37.7) | 48 (48.0) |
| CRT-P | 11 (6.0) | 4 (4.0) |
| CRT-D | 124 (67.8) | 59 (59.0) |
| Medical condition/prior surgery | ||
| Cardiac valve surgical history | 19 (10.4) | 14 (14.0) |
| Cerebrovascular disease history | 28 (15.3) | 16 (16.0) |
| Baseline kidney function (eGFR), mean (SD) | 64.3 (22.20) | 64.3 (21.95) |
| Chronic obstructive pulmonary disease | 25 (13.7) | 11 (11.0) |
| Systemic hypertension | 99 (54.1) | 63 (63.0) |
| Diabetes | 64 (35.0) | 31 (31.0) |
| Insulin dependent | 21 (11.5) | 8 (8.0) |
| Noninsulin dependent | 43 (23.5) | 23 (23.0) |
| Sleep apnea | 43 (23.5) | 24 (24.0) |
| Echo, baseline, mean (SD) | ||
| LVESV, mL | 151.1 (67.21) | 146.3)71.51) |
| LVEDV, mL | 210.4 (77.76) | 206.8 (83.58) |
| LVEF, % | 29.8 (7.90) | 31.1 (7.89) |
| Other baseline measures, mean (SD) | ||
| Paced QRS, ms | 183.8 (25.94) | 184.9 (24.72) |
| KCCQ Overall Summary Score | 54.7 (22.90) | 57.2 (21.38) |
| NT-proBNP, pg/mL | 1626.2 (2172.41) | 1761.6 (2463.09) |
| Baseline medications | ||
| ACE or ARB or ARNI | 168 (91.8) | 96 (96.0) |
| ACE inhibitor | 59 (32.8) | 30 (30.0) |
| Angiotensin receptor blocker | 74 (40.4) | 38 (38.0) |
| Angiotensin receptor-neprilysin inhibitor | 68 (37.2) | 44 (44.0) |
| β-Blocker | 174 (95.1) | 94 (94.0) |
| Aldosterone antagonist | 115 (62.8) | 58 (58.0) |
| Sodium-glucose cotransporter-2 inhibitor | 6 (3.3) | 6 (6.0) |
| Diuretic | 145 (79.2) | 81 (81.0) |
| Digitalis | 11 (6.0) | 6 (6.0) |
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor/neprilysin inhibitor; BMI, body mass index; CS, coronary sinus; CRT, cardiac resynchronization therapy; CRT-D, CRT-defibrillator; CRT-P, CRT-pacemaker; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HR, heart rate; ICD, implantable cardioverter defibrillator; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure.
Calculated as weight in kilograms divided by height in meters squared.
Background medical therapy reflected contemporary medication trends. Notably, 168 patients were taking an ACE, ARB, or ARNI (91.8%). Sixty-eight patients (68%) were taking ARNI (37.2%), 115 (62.8%) were taking aldosterone antagonists, and 174 (95.1%) were taking β-blockers, consistent with maximal guideline-directed medical therapy prior to enrollment.
Indications for CRT and Patient Classifications
There were Class I indications for CRT in 68.9% and Class IIa in 31.2% of patients (Table 1).26 Among the 183 patients in the safety analysis, there were 44 nonresponders, 110 PU, and 29 HRU. Among the 100 patients in the efficacy analysis, there were 75 PU and 25 HRU (eTable 10 in Supplement 1).
Patient Follow-Up
Of the 183 safety patients, 162 were followed up through 6 months (88.5%), 10 patients died (5.5%), 5 were withdrawn due to unsuccessful implant attempts (2.7%), and 6 were withdrawn for reasons such as heart transplant (3.1%). Of the 100 efficacy patients, 91 completed 6-month follow-up (91.0%), 3 died (3.0%), 3 had an unsuccessful implant attempt (3.0%), and 3 were withdrew due to infection or LV assist device (3.0%).
Procedure Times
In the safety population, mean procedure times were 1.4 (SD, 0.6) hours for transmitter/battery implantation and 1.1 (SD, 0.6) hours for electrode placement. The electrode was placed via either a retrograde transaortic approach (57.3%) or an atrial transseptal approach (42.7%).
Primary End Points
In the efficacy population, the mean percent change in LVESV was −16.4% (95% CI, −21.0% to −11.7%) with an upper confidence bound below the −9.3% performance goal (P = .003), meeting the final primary efficacy end point (Figure 3A). In the safety population, there was an 80.9% (148 of 183) rate of freedom from T1Cs with a lower bound of the 1-sided 98.8% CI of 73.4%, above the 70% performance goal (P < .001), meeting the interim primary safety end point (eTable 11 in Supplement 1). Since both the prespecified interim safety and final efficacy end points were met, the trial was concluded.
Figure 3. Percent Change in Left Ventricular End Systolic Volume (LVESV) at 6 Months vs Performance Goal and LVESV, Left Ventricular End Diastolic Volume (LVEDV), and Left Ventricular Ejection Fraction (LVEF) Baseline vs 6-Month Follow-Up.
A, The intent-to-treat change in LVESV of −16.4% is shown. The upper boundary of the 2-sided 95% CI was used as the cutoff for meeting the prespecified efficacy objective.
aThe P value is based on a 1-sample t test.
bThe nominal P values are based on paired t tests comparing 6 months with baseline values for LVESV (mL), LVEDV (mL), and LVEF (%). These nominal P values are not adjusted for multiplicity.
Table 2 provides additional details on T1Cs at 6 months. There were 12 patients with study device system events (6.6%), including 7 in whom the electrode was not anchored, 3 who did not achieve BIVP due to difficulties with the acoustic window, 1 transmitter revision, and 1 episode of ventricular tachycardia requiring cardioversion. Five patients had vascular events (2.7%), including 2 groin hematomas, 1 ischemic limb, and 2 retroperitoneal bleeds. Three patients had strokes (1.6%). The strokes occurred early in the study (2018 to 2019); 2 led to the patient’s death and 1 resolved with sequalae.
Table 2. Summary of Type I Complications.
| Type I complicationsa | No. of patients (%) [No. of events] |
|---|---|
| Type I | 35 (19.1) [43] |
| Study device system event | 12 (6.6) [12] |
| Electrode not anchored | 7 (3.8) |
| No biventricular capture | 3 (1.6) |
| Transmitter revision | 1 (0.5) |
| Ventricular tachycardia | 1 (0.5) |
| Vascular event | 5 (2.7) [5] |
| Groin hematoma | 2 (1.1) |
| Ischemic leg | 1 (0.5) |
| Retroperitoneal bleed | 2 (1.1) |
| Stroke and other thromboembolic events (eg, TIA) | 3 (1.6) [3] |
| Cardiac perforation | 7 (3.8) [7] |
| Surgically repaired | 4 (2.2) [4] |
| Pericardiocentesis | 3 (1.6) [3] |
| Pocket events | 12 (6.6) [15] |
| Hematoma, conservative treatment | 3 (1.6) |
| Hematoma requiring transfusion | 1 (0.5) |
| Infection | 4 (2.2) |
| Transmitter revision, uneventful | 1 (0.5) |
| Transmitter revision, pneumothorax | 1 (0.5) |
| Battery revision due to erosion | 2 (1.1) |
| Other (anemia postoperative) | 1 (0.5) [1] |
Abbreviation: TIA, transient ischemic attack.
Six months after the electrode implant procedure, per statistical analysis plan.
In addition, 7 patients had cardiac perforations (3.8%). Four perforations required surgical intervention (2.2%) and 3 were treated with pericardiocentesis (1.6%). The cardiac perforations occurred early in the study (2018 to 2019) and in response, refresher training on an implant simulator prior to every implant and use of real-time echocardiography were implemented. These mitigations reduced the rate of cardiac perforations, with only 2 reported in the single-arm part of the study (2.7%), neither of which required surgical intervention. Twelve patients had pocket events (6.6%), including 4 infections, 4 hematomas, 2 transmitter revisions, and 2 battery revisions.
Secondary End Points
An APCT of less than 2.9 mJ was achieved in 95.2% (95% CI, 88.1%-98.7%) of participants, demonstrating that thresholds were sufficiently low. The percentage BIVP was 93.1% (95% CI, 90.3%-95.9%). For responder analyses, 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 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) (Figure 3B) and in LVEDV of −25.4 mL (95% CI, −28.4 to −22.5) (Figure 3C). The mean absolute increase in LVEF was 5.2% (95% CI, 4.7%-5.7%) (Figure 3D) (eTable 12, eFigure 2, and eFigure 3 in Supplement 1.
Overall, 55% of participants’ NYHA class improved, 41% were unchanged, and 3.4% worsened by 1 class (eFigure 4 in Supplement 1). The paced QRS duration shortened by a mean of 39.3 (SD, 23.3) milliseconds (eFigure 5 in Supplement 1).
Discussion
The SOLVE-CRT study prospectively evaluated the role of a novel leadless LV endocardial CRT system (WiSE CRT System) in patients whose conventional CRT implant failed due to lead issues (PU) or who could not be upgraded to a standard CRT system due to known contraindications (HRU). This study showed that leadless ultrasound-based endocardial pacing is feasible and clinically efficacious with a high implant success rate (95.5%), an 80.9% freedom from T1Cs, enhanced functional status of patients as reflected by NYHA class and KCCQ scores, evidence of LV reverse remodeling with a mean reduction of 16.4% in LVESV, and shortening of QRS duration by a mean of 39.3 milliseconds.
Epicardial Lead Location vs Endocardial Electrode Placement and Physiology
Traditional CRT implant involves placing a lead in the CS; however, 30% to 40% of patients do not respond.1,10,11,12 Furthermore, an additional 10% are unable to receive CRT due to anatomical challenges limiting access to the CS, phrenic nerve stimulation, or high-pacing thresholds.27,28 Previous strategies to overcome these challenges included surgically placed epicardial leads or transvenous LV endocardial leads, which are both associated with multiple complications.29,30
The WiSE CRT electrode implanted within the left ventricle is small (0.91 cm in length; 0.27 cm in diameter) with a woven polyester jacket that promotes endothelialization31,32 to prevent clot formation. The WiSE CRT System enables patient-specific endocardial positioning of the electrode, unconstrained by the coronary venous anatomy and without the risks of lead fractures, venous obstruction, mitral regurgitation, and endocarditis.
The present study has demonstrated that the WiSE CRT System can produce equivalent clinical results as seen with conventional CRT in terms of reverse remodeling and improved functional status in patients who were unable to be treated or upgraded with their conventional pacing devices. As such, the WiSE CRT System fills an important unmet need.
Value of Endocardial Pacing
Conventional CS pacing is nonphysiological as the electrical wavefront starts in the epicardium and moves to the endocardium. Normal physiological activation of the heart is the opposite. There is increased interest in pacing the endocardium directly due to the immediate capture of the conduction system and superior hemodynamic effects.11,13,29 Additional comparisons are needed.14
Complications
Adverse events were adjudicated by an independent clinical events committee. The results are comparable with prior studies of patients undergoing an upgrade to CRT who had a major complication rate of 18.7%33 and for patients treated with a transvenous LV endocardial lead who had a complication rate of 17.8%.29
As is typical in initial studies with a novel device, observed complication rates were higher in the early phases and decreased over time. This can be attributed to a protocol change that allowed transseptal access, which reduced the complications associated with arterial access, enhanced training including the use of simulator models, and mandated use of real-time echocardiography.
Clinical Implications
This novel technology using ultrasound energy disrupts the conventional pacing paradigm while allowing for leadless pacing within the LV endocardium. There are several aspects of the WiSE CRT System that favorably impact the leadless future for cardiac pacing. The electrode implanted in the LV is efficiently endothelialized—without the need for prolonged anticoagulant therapy. The system has been used in Europe and Australia in patients with an intracardiac RV pacemaker who are eligible for a CRT upgrade to provide totally leadless CRT pacing.34,35
A feasibility study has shown promise in delivering the WiSE electrode directly into the left bundle branch area to achieve conduction system pacing.36 Compared with conventional epicardial CRT, this is considered more physiologic and may have greater efficacy. Additional clinical studies are needed to evaluate the effects of the WiSE CRT System in CSP.
Limitations
The SOLVE-CRT study was initiated as a randomized clinical trial. Through the challenges of the COVID-19 pandemic, the protocol was revised with approval from the FDA to include a single-arm part that no longer included the nonresponder cohort.16 This trial is limited by the absence of randomization, a limited overall trial size, and a 6-month follow-up period, so robust conclusions regarding comparative efficacy with other implant strategies cannot be drawn. Furthermore, in the absence of blinding, it is very difficult to interpret the changes in NYHA and KCCQ. Also, patients who were considered nonresponders were not included in the efficacy analysis, so this study cannot make any comment on clinical efficacy in nonresponders.
There are some technological challenges worth noting. The system requires a focused beam of ultrasound energy to target the electrode and, thus, is dependent on implanting the transmitter in an intercostal space that is free of lung encroachment. Also, the battery and transmitter are additional components that the patient must carry, requiring 2 separate chest wall incisions.
Conclusions
In this nonrandomized study, the SOLVE-CRT study has demonstrated that leadless ultrasound-based LV endocardial pacing with the WiSE CRT system is associated with a reduction in LVESV. This is a novel technology that allows the delivery of CRT in patients with HF who meet the standard criteria for CRT but who cannot be treated with conventional CRT.
eMethods 1. Study Investigators and Steering Committee Members
eMethods 2. Supplementary Methods
eMethods 3. Full Inclusion and Exclusion Criteria
eMethods 4. Objective Performance Criteria
eMethods 5. Echocardiography Core Lab
eMethods 6. Statistical Methods
eMethods 7. System Description and Implant
eMthods 8. Acoustic Pacing Capture Threshold
eMethods 9. Supplementary Baseline Information
e Results
eTable 1. SOLVE-CRT Study Full Inclusion and Exclusion Criteria
eTable 2. Historical Complication Rates
eTable 3. Six-month Mortality Rates from CRT Trials
eTable 4. Literature Support for Primary Efficacy Performance Goal
eTable 5. Type I Error Rates by Data Analysis
eTable 6. Interim Analysis Plan
eTable 7. Poolability Testing Across Study Part (II vs. III), Geography, and Site
eTable 8. Supplemental Baseline Characteristics
eTable 9. Co-implant Details
eTable 10. Summary of Patient CRT Indications and Groups
eTable 11. Primary Safety Sensitivity Analysis - Kaplan-Meier Analysis of Freedom
eTable 12. Change in Secondary Endpoints and Ancillary Values from Baseline to 6 Months
eFigure 1. Control Group Meta-Analysis Results for LVESV % Relative Change
eFigure 2. Secondary Endpoints and Ancillary Values from Baseline to 6 Months
eFigure 3. Change in LVESV, LVESD, and LVEF Baseline to 6 Months
eFigure 4. Change in NYHA Classification from Baseline to 6 Months (n = 88)
eFigure 5. QRS Duration (ms) at Baseline (RV paced) and 6 Months (BiVP)
eReferences
Supplementary appendix
SOLVE-CRT Statistical Analysis Plan
SOLVE-CRT Study Protocol
Data sharing statement
References
- 1.Abraham WT, Fisher WG, Smith AL, et al. ; MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation . Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-1853. doi: 10.1056/NEJMoa013168 [DOI] [PubMed] [Google Scholar]
- 2.Cleland JG, Daubert JC, Erdmann E, et al. ; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators . The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-1549. doi: 10.1056/NEJMoa050496 [DOI] [PubMed] [Google Scholar]
- 3.McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA. 2007;297(22):2502-2514. doi: 10.1001/jama.297.22.2502 [DOI] [PubMed] [Google Scholar]
- 4.Bristow MR, Saxon LA, Boehmer J, et al. ; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators . Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-2150. doi: 10.1056/NEJMoa032423 [DOI] [PubMed] [Google Scholar]
- 5.Rivero-Ayerza M, Theuns DA, Garcia-Garcia HM, Boersma E, Simoons M, Jordaens LJ. Effects of cardiac resynchronization therapy on overall mortality and mode of death: a meta-analysis of randomized controlled trials. Eur Heart J. 2006;27(22):2682-2688. doi: 10.1093/eurheartj/ehl203 [DOI] [PubMed] [Google Scholar]
- 6.Auricchio A, Stellbrink C, Sack S, et al. ; Pacing Therapies in Congestive Heart Failure (PATH-CHF) Study Group . Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol. 2002;39(12):2026-2033. doi: 10.1016/S0735-1097(02)01895-8 [DOI] [PubMed] [Google Scholar]
- 7.Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol. 2003;42(8):1454-1459. doi: 10.1016/S0735-1097(03)01042-8 [DOI] [PubMed] [Google Scholar]
- 8.Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C; REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group . Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008;52(23):1834-1843. doi: 10.1016/j.jacc.2008.08.027 [DOI] [PubMed] [Google Scholar]
- 9.Moss AJ, Hall WJ, Cannom DS, et al. ; MADIT-CRT Trial Investigators . Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361(14):1329-1338. doi: 10.1056/NEJMoa0906431 [DOI] [PubMed] [Google Scholar]
- 10.Derval N, Steendijk P, Gula LJ, et al. Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol. 2010;55(6):566-575. doi: 10.1016/j.jacc.2009.08.045 [DOI] [PubMed] [Google Scholar]
- 11.Spragg DD, Dong J, Fetics BJ, et al. Optimal left ventricular endocardial pacing sites for cardiac resynchronization therapy in patients with ischemic cardiomyopathy. J Am Coll Cardiol. 2010;56(10):774-781. doi: 10.1016/j.jacc.2010.06.014 [DOI] [PubMed] [Google Scholar]
- 12.Gold MR, Daubert C, Abraham WT, et al. The effect of reverse remodeling on long-term survival in mildly symptomatic patients with heart failure receiving cardiac resynchronization therapy: results of the REVERSE study. Heart Rhythm. 2015;12(3):524-530. doi: 10.1016/j.hrthm.2014.11.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Padeletti L, Pieragnoli P, Ricciardi G, et al. Acute hemodynamic effect of left ventricular endocardial pacing in cardiac resynchronization therapy: assessment by pressure-volume loops. Circ Arrhythm Electrophysiol. 2012;5(3):460-467. doi: 10.1161/CIRCEP.111.970277 [DOI] [PubMed] [Google Scholar]
- 14.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. doi: 10.1016/j.jacc.2017.02.059 [DOI] [PubMed] [Google Scholar]
- 15.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 untreatable patients (SOLVE-CRT) trial. Am Heart J. 2019;217:13-22. doi: 10.1016/j.ahj.2019.04.002 [DOI] [PubMed] [Google Scholar]
- 16.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. American Heart Journal. 2021;235:158-162. doi: 10.1016/j.ahj.2021.02.008 [DOI] [PubMed] [Google Scholar]
- 17.Reeves BC, Gaus W. Guidelines for reporting non-randomised studies. Forsch Komplementarmed Klass Naturheilkd. 2004;11(suppl 1):46-52. [DOI] [PubMed] [Google Scholar]
- 18.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. doi: 10.1016/j.hrthm.2021.06.1195 [DOI] [PubMed] [Google Scholar]
- 19.White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987;76(1):44-51. doi: 10.1161/01.CIR.76.1.44 [DOI] [PubMed] [Google Scholar]
- 20.Konstam MA, Udelson JE, Anand IS, Cohn JN. Ventricular remodeling in heart failure: a credible surrogate endpoint. J Card Fail. 2003;9(5):350-353. doi: 10.1054/j.cardfail.2003.09.001 [DOI] [PubMed] [Google Scholar]
- 21.Ypenburg C, van Bommel RJ, Borleffs CJ, et al. Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up. J Am Coll Cardiol. 2009;53(6):483-490. doi: 10.1016/j.jacc.2008.10.032 [DOI] [PubMed] [Google Scholar]
- 22.Yu CM, Bleeker GB, Fung JW, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112(11):1580-1586. doi: 10.1161/CIRCULATIONAHA.105.538272 [DOI] [PubMed] [Google Scholar]
- 23.Young JB, Abraham WT, Smith AL, et al. ; Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators . Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial. JAMA. 2003;289(20):2685-2694. doi: 10.1001/jama.289.20.2685 [DOI] [PubMed] [Google Scholar]
- 24.Abraham WT, Young JB, León AR, et al. ; Multicenter InSync ICD II Study Group . Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004;110(18):2864-2868. doi: 10.1161/01.CIR.0000146336.92331.D1 [DOI] [PubMed] [Google Scholar]
- 25.Solomon SD, Foster E, Bourgoun M, et al. ; MADIT-CRT Investigators . Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy. Circulation. 2010;122(10):985-992. doi: 10.1161/CIRCULATIONAHA.110.955039 [DOI] [PubMed] [Google Scholar]
- 26.Epstein AE, DiMarco JP, Ellenbogen KA, et al. ; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society . 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 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 and the Heart Rhythm Society. Circulation. 2013;127(3):e283-e352. doi: 10.1161/CIR.0b013e318276ce9b [DOI] [PubMed] [Google Scholar]
- 27.Chung ES, Leon AR, Tavazzi L, et al. Results of the predictors of response to CRT (PROSPECT) trial. Circulation. 2008;117(20):2608-2616. doi: 10.1161/CIRCULATIONAHA.107.743120 [DOI] [PubMed] [Google Scholar]
- 28.León AR, Abraham WT, Curtis AB, et al. ; MIRACLE Study Program . Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2,000 patients from a multicenter study program. J Am Coll Cardiol. 2005;46(12):2348-2356. doi: 10.1016/j.jacc.2005.08.031 [DOI] [PubMed] [Google Scholar]
- 29.Morgan JM, Biffi M, Gellér L, et al. ; ALSYNC Investigators . 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. doi: 10.1093/eurheartj/ehv723 [DOI] [PubMed] [Google Scholar]
- 30.Buiten MS, van der Heijden AC, Klautz RJM, Schalij MJ, van Erven L. Epicardial leads in adult cardiac resynchronization therapy recipients: a study on lead performance, durability, and safety. Heart Rhythm. 2015;12(3):533-539. doi: 10.1016/j.hrthm.2014.11.004 [DOI] [PubMed] [Google Scholar]
- 31.Auricchio A, Delnoy PP, Butter C, et al. ; Collaborative Study Group . 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. doi: 10.1093/europace/eut435 [DOI] [PubMed] [Google Scholar]
- 32.Butter C, Georgi C, Stockburger M. Optimal CRT implantation-where and how to place the left-ventricular lead? Curr Heart Fail Rep. 2021;18(5):329-344. doi: 10.1007/s11897-021-00528-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Poole JE, Gleva MJ, Mela T, et al. ; REPLACE Registry Investigators . Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. Circulation. 2010;122(16):1553-1561. doi: 10.1161/CIRCULATIONAHA.110.976076 [DOI] [PubMed] [Google Scholar]
- 34.Sidhu BS, Gould J, Porter B, et al. Completely leadless cardiac resynchronization defibrillator system. JACC Clin Electrophysiol. 2020;6(5):588-589. doi: 10.1016/j.jacep.2020.02.012 [DOI] [PubMed] [Google Scholar]
- 35.Carabelli A, Jabeur M, Jacon P, et al. European experience with a first totally leadless cardiac resynchronization therapy pacemaker system. Europace. 2021;23(5):740-747. doi: 10.1093/europace/euaa342 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Elliott MK, Jacon P, Sidhu BS, et al. Technical feasibility of leadless left bundle branch area pacing for cardiac resynchronization: a case series. Eur Heart J Case Rep. 2021;5(11):ytab379. doi: 10.1093/ehjcr/ytab379 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods 1. Study Investigators and Steering Committee Members
eMethods 2. Supplementary Methods
eMethods 3. Full Inclusion and Exclusion Criteria
eMethods 4. Objective Performance Criteria
eMethods 5. Echocardiography Core Lab
eMethods 6. Statistical Methods
eMethods 7. System Description and Implant
eMthods 8. Acoustic Pacing Capture Threshold
eMethods 9. Supplementary Baseline Information
e Results
eTable 1. SOLVE-CRT Study Full Inclusion and Exclusion Criteria
eTable 2. Historical Complication Rates
eTable 3. Six-month Mortality Rates from CRT Trials
eTable 4. Literature Support for Primary Efficacy Performance Goal
eTable 5. Type I Error Rates by Data Analysis
eTable 6. Interim Analysis Plan
eTable 7. Poolability Testing Across Study Part (II vs. III), Geography, and Site
eTable 8. Supplemental Baseline Characteristics
eTable 9. Co-implant Details
eTable 10. Summary of Patient CRT Indications and Groups
eTable 11. Primary Safety Sensitivity Analysis - Kaplan-Meier Analysis of Freedom
eTable 12. Change in Secondary Endpoints and Ancillary Values from Baseline to 6 Months
eFigure 1. Control Group Meta-Analysis Results for LVESV % Relative Change
eFigure 2. Secondary Endpoints and Ancillary Values from Baseline to 6 Months
eFigure 3. Change in LVESV, LVESD, and LVEF Baseline to 6 Months
eFigure 4. Change in NYHA Classification from Baseline to 6 Months (n = 88)
eFigure 5. QRS Duration (ms) at Baseline (RV paced) and 6 Months (BiVP)
eReferences
Supplementary appendix
SOLVE-CRT Statistical Analysis Plan
SOLVE-CRT Study Protocol
Data sharing statement