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Ambulatory atrioventricular synchronous pacing over time using a leadless ventricular pacemaker: Primary results from the AccelAV study

Open AccessPublished:September 05, 2022DOI:https://doi.org/10.1016/j.hrthm.2022.08.033

      Background

      Previous studies demonstrated that accelerometer-based, mechanically timed atrioventricular synchrony (AVS) is feasible using a leadless ventricular pacemaker.

      Objective

      The purpose of this study was to determine the performance of a leadless ventricular pacemaker with accelerometer-based algorithms that provide AVS pacing.

      Methods

      AccelAV was a prospective, single-arm study to characterize AVS in patients implanted with a Micra AV, which uses the device accelerometer to mechanically detect atrial contractions and promote VDD pacing. The primary objective was to characterize resting AVS at 1 month in patients with complete atrioventricular block (AVB) and normal sinus function.

      Results

      A total of 152 patients (age 77 ± 11 years; 48% female) from 20 centers were enrolled and implanted with a leadless pacemaker. Among patients with normal sinus function and complete AVB (n = 54), mean resting AVS was 85.4% at 1 month, and ambulatory AVS was 74.8%. In the subset of patients (n = 20) with programming optimization, mean ambulatory AVS was 82.6%, representing a 10.5% improvement (P <.001). Quality of life as measured by the EQ-5D-3L (EuroQol Five-Dimensions Three-Level questionnaire) improved significantly from preimplant to 3 months (P = .031). In 37 patients with AVB at both 1 and 3 months, mean AVS during rest did not differ (86.1% vs 84.1%; P = .43). There were no upgrades to dual-chamber devices or cardiac resynchronization therapy through 3 months.

      Conclusion

      Accelerometer-based mechanical atrial sensing provided by a leadless pacemaker implanted in the right ventricle significantly improves quality of life in a select cohort of patients with AV block and normal sinus function. AVS remained stable through 3 months, and there were no system upgrades to dual-chamber pacemakers.

      Keywords

      Introduction

      Although pacemakers have made a transformational impact on patients with bradyarrhythmias, extensive advances in device technology over the past 60 years have not eliminated the significant complications primarily associated with the pocket or leads of transvenous systems.
      • Udo E.O.
      • Zuithoff N.P.
      • van Hemel N.M.
      • de Cock C.C.
      • Hendriks T.
      • Doevendans P.A.
      • Moons K.G.
      Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOLLOWPACE study.
      Leadless devices were developed to overcome these complications and improve patient outcomes and satisfaction. Data from the Micra Post-Approval Registry suggest a 63% reduction in complications relative to transvenous pacemakers.
      • El-Chami M.F.
      • Al-Samadi F.
      • Clementy N.
      • et al.
      Updated performance of the Micra transcatheter pacemaker in the real-world setting: a comparison to the investigational study and a transvenous historical control.
      In addition, a 2-year follow-up claims-based analysis demonstrated a 38% reduction in system revisions compared to transvenous devices.
      • El-Chami M.F.
      • Bockstedt L.
      • Longacre C.
      • et al.
      Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up.
      Unfortunately, the use of single-chamber pacemakers is limited to a small percentage of pacemaker implantations due to the need for atrial pacing in patients with sinus node dysfunction as well as the recognized benefits of atrioventricular synchrony (AVS).
      • Hoijer C.J.
      • Brandt J.
      • Willenheimer R.
      • Juul-Moller S.
      • Bostrom P.A.
      Improved cardiac function and quality of life following upgrade to dual chamber pacing after long-term ventricular stimulation.
      • Lamas G.A.
      • Orav E.J.
      • Stambler B.S.
      • et al.
      Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in the Elderly Investigators.
      • Nielsen J.C.
      • Andersen H.R.
      • Thomsen P.E.
      • et al.
      Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single-chamber atrial or ventricular pacing.
      The MARVEL 2 (Micra Atrial tRacking using a Ventricular accELerometer 2) study assessed the ability to provide AV synchronous pacing by mechanically sensing atrial contractions from a Micra leadless pacemaker implanted in the right ventricle (RV).
      • Steinwender C.
      • Khelae S.K.
      • Garweg C.
      • et al.
      Atrioventricular synchronous pacing using a leadless ventricular pacemaker: results from the MARVEL 2 study.
      The algorithm facilitated AVS of >70% in 95% of patients with complete atrioventricular block (AVB) at rest, with an improvement in stroke volume. Because MARVEL 2 assessed AVS for a relatively brief period at rest, it is important to extend the investigation to assess the maintenance of mechanical atrial sensing over time. Real-world settings are associated with greater variations in heart rate, patient movement, atrial and ventricular arrhythmias, and lifestyle and medication changes, all of which may affect the ability to accurately track atrial signals and maintain a high percentage of AVS.
      The AccelAV (Accelerometer Sensing for Micra AV) study was designed to assess AVS prospectively over time and in an ambulatory setting with variations in heart rate and patient movement. The study also measured changes in stroke volume and quality of life (QoL). An important substudy, AccelAV Optimize, assessed the efficacy of prescribed programming changes on AVS in an ambulatory setting.

      Methods

      Study design

      The AccelAV study was a prospective, nonrandomized, multicenter clinical trial conducted in the United States and Hong Kong. The primary aim of the AccelAV study was to characterize chronic AVS in patients implanted with Micra™ AV (Model MC1AVR1, Medtronic, Inc., Minneapolis, MN). Micra AV is implanted in the RV and uses the device’s accelerometer to mechanically sense atrial contractions and facilitate VDD pacing, promoting AVS in patients with normal sinus function. A detailed description of the device’s algorithm has been provided previously.
      • Steinwender C.
      • Khelae S.K.
      • Garweg C.
      • et al.
      Atrioventricular synchronous pacing using a leadless ventricular pacemaker: results from the MARVEL 2 study.
      ,
      • Chinitz L.
      • Ritter P.
      • Khelae S.K.
      • et al.
      Accelerometer-based atrioventricular synchronous pacing with a ventricular leadless pacemaker: results from the Micra atrioventricular feasibility studies.
      In brief, the detection algorithm uses programmable blanking periods and threshold values to identify signal components from the device’s accelerometer corresponding to passive ventricular filling (A3) and atrial contraction (A4) to provide VDD pacing and promote AVS. In addition, the device incorporates a rate smoothing algorithm for periods of intermittent undersensing and has 2 mode switching algorithms, one to enable automatic switching to VVI-40 to promote intrinsic ventricular activation during periods of 1:1 AV conduction and the second to provide VVIR pacing in order to maintain adequate heart rate during periods of high activity. The study protocol was approved by local ethics committees at each participating institution. All patients provided written informed consent.

      Patients and procedures

      The AccelAV study enrolled patients with a history of AVB who were ≥18 years old and planned to undergo implantation of a Micra AV for an approved indication. After obtaining informed consent, baseline procedures (including QoL assessment [EQ-5D-3L (EuroQol Five-Dimensions Three-Level questionnaire)]) were performed and medical history obtained. Patients were then implanted with a Micra AV following the standard of care at each institution. A specialized Holter monitor capable of storing accelerometer waveforms, electrograms, device markers, and electrocardiograms (ECGs) was placed on the patient after implant for approximately 60 minutes during the device’s auto-setup phase. The device’s auto-setup runs for 30 minutes in VDI mode and chooses the accelerometer combination with largest A4 amplitude and initializes the A3 threshold, A4 threshold, and A3 window end parameters.
      Within 48 hours of implantation, echocardiograms were collected from each patient during VVI and VDD pacing following a standardized echo protocol. Measurements of left ventricular outflow tract (LVOT) velocity–time integral (VTI) during 6 cardiac cycles were made by an echocardiography core laboratory (United Heart and Vascular Clinic, St. Paul, MN) blinded to patient and pacing mode.
      At the follow-up visits (1 and 3 months postimplant), patients completed the EQ-5D-3L and the specialized Holter monitor was placed on the patient for the duration of the follow-up visit. After Holter monitor placement, the device was programmed to VDI mode for approximately 5 minutes while the patient was resting in a supine or sitting position. The atrial sensing parameters were adjusted if needed to improve AVS, and the patient was programmed to VDD mode and rested in a consistent supine or sitting position. At the 1-month visit, patients continued to wear the Holter monitor for approximately 24 hours after leaving the study clinic. Patients exited the study at the conclusion of their 3-month visit.
      After the 3-month visit, the subset of patients in complete AVB with normal sinus function at their 1-month visit were invited to participate in the AccelAV Optimize substudy in which the patients repeated the 20-minute resting and 24-hour ambulatory Holter monitoring periods following a prescribed set of programming recommendations designed to optimize ambulatory AVS. The primary recommendation was to program a fixed A3 threshold approximately 1.0 m/s2 greater than the isolated accelerometer A3 signal to aid in tracking sinus rate between 80 and 110 bpm (for detailed recommendations see the Supplemental Methods).
      All adverse events and patient deaths were reviewed by an independent clinical events committee (CEC) composed of physicians not participating in the AccelAV study. The CEC adjudicated each adverse event for its relationship to the Micra AV system or procedure. In addition, the CEC determined whether each related adverse event was a major complication, defined as requiring invasive intervention that resulted in hospitalization, prolonged hospitalization by >48 hours, death, system revision, or permanent loss of device function.

      Endpoints

      The primary endpoint was to characterize the rate of AVS during the 20-minute resting period at 1 month postimplant. Secondary endpoints included characterizing the stability of AVS during rest between 1 and 3 months; AVS during a 24-hour ambulatory period at 1 month postimplant; and change in stroke volume as measured by LVOT VTI during VDD pacing compared with VVI pacing. Cardiac cycles were defined as synchronous if a ventricular marker followed the P wave by ≤300 ms regardless of underlying rhythm (eg, premature atrial and ventricular events were included). The protocol prespecified that primary and secondary endpoints be assessed among patients with complete AVB and normal sinus function. Other endpoints included EQ-5D-3L health status (U.S. valuation)
      • Shaw J.W.
      • Johnson J.A.
      • Coons S.J.
      US valuation of the EQ-5D health states: development and testing of the D1 valuation model.
      and visual analog score.

      Statistical analysis

      Based on the MARVEL 2 study results,
      • Steinwender C.
      • Khelae S.K.
      • Garweg C.
      • et al.
      Atrioventricular synchronous pacing using a leadless ventricular pacemaker: results from the MARVEL 2 study.
      a sample size of 150 patients with a Micra AV implant attempt was expected to provide at least 50 patients with a predominant heart rhythm of complete AVB and normal sinus function at 1 month postimplant. A sample size of 50 patients with complete AVB and normal sinus function was postulated to allow the AVS percentage during rest to be estimated with precision of 3.5% (ie, distance between point estimate and 2-sided lower 95% confidence interval [CI]).
      At each visit, each patient’s predominant heart rhythm was classified as complete AVB with normal sinus function, intact AV conduction, or other (eg, atrial arrhythmias, sinus node dysfunction, other AVB) based on the distribution of PR and PP intervals during the auto-setup (implant visit) or initial VDI and 20-minute resting period (1- and 3-month visits). Additional details for assessing synchrony are provided in the Supplemental Methods.
      AVS percentage was computed within each patient, visit, and procedure step (20-minute resting period, 24-hour ambulatory period) by dividing the total number of AV synchronous cycles by the total number of cardiac cycles. For patients with complete AVB and normal sinus function, logistic regression models using generalized estimating equations were used to estimate the AVS percentage across all patients. Similar models were used to compare AVS percentage between the 20-minute resting periods at 1 and 3 months, and between the 24-hour ambulatory period between the 1-month and Optimize substudy visits.
      LVOT VTI during VDI and VDD pacing were compared using a paired t test among patients with complete AVB and normal sinus function at implantation who had an absolute heart rate difference <15 bpm within each pacing mode. Linear models accounting for repeated measures were used to compare the EQ-5D health status and visual analog score at baseline at each follow-up visit.
      All analyses were performed using SAS Version 9.4 (SAS Institute, Cary, NC) or R (www.r-project.org). P <.05 was considered significant.

      Results

      Patients

      A total of 157 patients from 20 centers in the United States and Hong Kong were enrolled in the AccelAV study from June 2020 through September 2021. Of the 157 patients, 152 underwent a Micra AV implant attempt and were successfully implanted. Patients implanted with the device were an average of 77 ± 11 years and 48% were female with multiple comorbidities. Nearly one-fourth of patients (23.7%) were deemed precluded from transvenous pacing by the implanting physician (Table 1). Of the 152 implanted patients, 130 (85.5%) completed the 3-month follow-up period, with 6 of the 22 premature study exits associated with the coronavirus disease 2019 (COVID-19) pandemic. The remaining premature exits were due to patient withdrawal (8), patient lost to follow-up (4), patient condition (2), and death (2; see section on Safety).
      Table 1Patient baseline characteristics
      Implanted (n = 152)Evaluable for primary objective (n = 54)
      Age (y)77.2 ± 10.877.0 ± 14.2
      Female73 (48.0)30 (55.6)
      BMI
      Body mass index (BMI) not available for 4 subjects in the implanted cohort and 1 subject in the primary objective cohort.
      28.3 ± 7.028.4 ± 7.5
      Comorbidities
       Hypertension121 (79.6)41 (75.9)
       Atrial fibrillation20 (13.2)7 (13.0)
       Diabetes62 (40.8)19 (35.2)
       Coronary artery disease65 (42.8)12 (22.2)
       Myocardial infarction11 (7.2)0 (0.0)
       COPD29 (19.1)9 (16.7)
       Dialysis13 (8.6)3 (5.6)
       Preclusion for transvenous pacing36 (23.7)16 (29.6)
      Cardiac perforation risk
      Risk for cardiac perforation based on scoring system of Piccini et al.10
       Low72 (47.4)21 (38.9)
       Medium39 (25.7)16 (29.6)
       High37 (24.3)16 (29.6)
       Unavailable4 (2.6)1 (1.9)
      Device location
       RVOT2 (1.3)1 (1.9)
       RV high septum22 (14.5)6 (11.1)
       RV mid septum88 (57.9)31 (57.4)
       RV low septum29 (19.1)11 (20.4)
       RV apex11 (7.2)5 (9.3)
      Predominant rhythm at 1 month
      Complete AV block with normal sinus function56 (36.8)54 (100.0)
      Intact AV conduction42 (27.6)0 (0.0)
      Other32 (21.1)0 (0.0)
      First-degree AV block16 (10.5)0 (0.0)
      Second-degree AV block9 (5.9)0 (0.0)
      Other7 (4.6)0 (0.0)
      Not available
      For the 22 patients with no 1-month predominant rhythm assessment, 9 exited before 1 month, 1 died before 1 month, 3 missed the visit, 4 did not wear the Holter monitor, and 5 had poor Holter telemetry.
      22 (14.5)0 (0.0)
      Values are given as mean ± SD or n (%).
      AV = atrioventricular; COPD = chronic obstructive pulmonary disease; RV = right ventricle; RVOT = right ventricular outflow tract.
      Body mass index (BMI) not available for 4 subjects in the implanted cohort and 1 subject in the primary objective cohort.
      Risk for cardiac perforation based on scoring system of Piccini et al.
      • Piccini J.P.
      • Cunnane R.
      • Steffel J.
      • et al.
      Development and validation of a risk score for predicting pericardial effusion in patients undergoing leadless pacemaker implantation: experience with the Micra transcatheter pacemaker.
      For the 22 patients with no 1-month predominant rhythm assessment, 9 exited before 1 month, 1 died before 1 month, 3 missed the visit, 4 did not wear the Holter monitor, and 5 had poor Holter telemetry.

      AV synchrony at rest

      Among the 139 patients who completed the 1-month study visit, 54 with complete AVB and normal sinus function had at least 500 cardiac cycles during the 20-minute resting period meeting the prespecified criteria for analysis of the study’s primary objective (Supplemental Figure S1). AVS percentage at rest was 85.4% (95% CI 81.1%–88.9%; median 90.0%) during VDD pacing, with 85.2% of patients achieving >70% resting AVS (Figure 1) during a median of 100% [interquartile range 99.7%–100%] ventricular pacing. Reasons for <70% resting AVS were multifactorial and included high and/or variable sinus rates, low A4 signal amplitude, and suboptimal programming.
      Figure thumbnail gr1
      Figure 1Resting atrioventricular (AV) synchronous pacing percentage. AV synchronous pacing percentage during VDD mode during 20-minute resting period at 1 month postimplant in 54 patients with complete AV block and normal sinus function. Black line in the boxplot represents the median; edges of the box denote the interquartile range. Open circles indicate individual patients. Blue circle represents the average. Error bars are 95% confidence intervals. Black horizontal dashed line is 70%.
      Of the 54 patients with complete AVB and normal sinus function, 37 remained in the same rhythm at the 3-month visit (Supplemental Table S1). Among these patients, average AVS during rest at 1 month was 86.1% (95% CI 81.2%–89.9%; median 90.0%) compared to 84.1% (95% CI 78.3%–88.6%; median 87.9%) at 3 months, representing a nonsignificant change of –2.0% (95% CI –6.8% to 2.9%; P = .43) (Figure 2).
      Figure thumbnail gr2
      Figure 2Resting atrioventricular (AV) synchronous pacing at 1 and 3 months postimplant in 37 patients with complete AV block and normal sinus function at both visits. Left: AV synchrony at 1 and 3 months. Gray lines indicate individual patient values. Blue line connects averages; red line connects medians. Right: Change in AV synchrony from 1 to 3 months. Red circles are individual patients; blue circle is the average change. Error bars are 95% confidence intervals.

      Ambulatory AV synchrony

      At the 1-month visit, average ambulatory AVS collected on the 24-hour Holter recording during >4.6 million cardiac cycles in 54 patients with complete AVB and normal sinus function was 74.5% (95% CI 70.4%–78.2%; median 75.0%) during a median of 91,321 cardiac cycles (Supplemental Figure S2). Median percent ventricular pacing was 99.8% [interquartile range 99.2%–99.9%] during this same period. A detailed graphic from an ambulatory Holter recording is shown in Supplemental Figure S3.
      A total of 23 patients with complete AVB and normal sinus function at the 1-month visit participated in the Optimize substudy and underwent Holter monitoring for a second time an average of 9.5 ± 4.7 months after their main study 1-month visit. At the substudy visit, 20 patients remained in complete AVB and normal sinus function, 1 had intact AV conduction, and 2 had other rhythms. Among the patients with complete AVB and normal sinus function at both visits, ambulatory AVS percentage increased significantly (P <.001) from 71.9% (95% CI 63.4%–79.1%; median 75.9%) to 82.6% (95% CI 75.8%-87.7%; median 85.3%) following the prescribed programming recommendations (Figure 3A). The improved AVS after optimized programming was most pronounced during elevated sinus rates between 80 and 110 bpm (Figure 3B). Supplemental Table S2 provides a summary of the programming changes.
      Figure thumbnail gr3
      Figure 3A: Ambulatory atrioventricular (AV) synchronous pacing during a 24-Hour period at 1 month and after programming optimization at the Optimize substudy visit (n = 20 patients). Left: Ambulatory AV synchrony at 1 month and the substudy visit. Gray lines indicate individual patient values. Blue line connects averages; red line connects medians. Right: Change in AV synchrony from 1 month to the substudy visit. Red circles are individual patients; blue circle is the average change. Error bars are 95% confidence intervals. B: Ambulatory AV synchronous pacing by sinus rate during a 24-hour period at 1 month and after programming optimization at the Optimize substudy visit (n = 20 patients). Lines connect average AV synchrony by sinus rate. Error bars represent 95% confidence intervals. Gray bars indicate the percentage of total cardiac cycles across both visits within each sinus rate category.

      Cardiac output

      At implantation, 78 patients were in complete AVB with normal sinus function, of whom 67 had paired LVOT VTI measurements in VDI and VDD modes. Among these patients, LVOT VTI increased by 2.1 cm (95% CI 1.0–3.1; P <.001) during VDD pacing from an average of 22.2 ± 6.8 cm during VVI pacing. A similar increase of 2.3 cm (95% CI 1.5–3.1; P <.001) during VDD pacing from an average 21.4 ± 5.9 cm was observed in the subset of 47 patients with heart rates within 15 bpm during both pacing modes adhering to the echo protocol (Supplemental Figure S3).

      QoL

      QoL as measured by the EQ-5D-3L health status and visual analog score improved significantly from baseline values by 3 months postimplant among all implanted patients with assessments as well as within the subset of 54 patients with complete AVB and normal sinus function at 1 month (Table 2). At 1 month, there was no association between AVS percentage at rest among patients with complete AVB and normal sinus function EQ-5D-3L health status (r = –0.09; P = .51) or visual analog scale (r = 0.14; P = .30) (Supplemental Figure S4).
      Table 2Quality of life as measured by the EQ-5D-3L by visit
      All patientsPatients with complete AV block and normal sinus function at 1 month
      VisitnMean ± SDDifference (95% CI)P valuenMean ± SDDifference (95% CI)P value
      Health status (US valuation)
       Baseline1510.78 ± 0.23540.77 ± 0.24
       1 month1390.84 ± 0.190.05 (0.02–0.09).003540.83 ± 0.190.05 (-0.01–0.11).085
       3 months1300.84 ± 0.180.06 (0.02-0.09).001500.84 ± 0.160.07 (0.01–0.13).031
      Visual analog scale
       Baseline15165.0 ± 22.55467.3 ± 21.9
       1 month13975.1 ± 19.89.9 (5.9–13.8)<.0015477.0 ± 18.39.7 (4.0–15.3)<.001
       3 months13076.6 ± 18.011.5 (7.5–15.5)<.0015078.6 ± 14.112.0 (6.2–17.8)<.001
      AV = atrioventricular; CI = confidence interval.

      Safety

      There were 14 major complications experienced by the 152 patients with an implant (Table 3), including 4 pericardial effusions. Three occurred in patients at medium or high risk for perforation, and 1 occurred in a low-risk patient based on preimplant risk score.
      • Piccini J.P.
      • Cunnane R.
      • Steffel J.
      • et al.
      Development and validation of a risk score for predicting pericardial effusion in patients undergoing leadless pacemaker implantation: experience with the Micra transcatheter pacemaker.
      One perforation in a 92-year-old woman with a high baseline risk for pericardial effusion, including body mass index of 18.6 and history of congestive heart failure, coronary artery disease, previous leadless pacemaker, and transcatheter aortic valve replacement, resulted in death after tether release and delivery sheath removal. Pericardiocentesis was performed, but surgical repair was not attempted. During the procedure, the device was deployed twice in the RV apical septum. The other perforations (3) resolved after pericardiocentesis. Two patients, both with baseline left ventricular ejection fraction <50%, experienced acute heart failure events, with both events occurring 2 days postimplant. Both events were resolved with intravenous furosemide. One patient experienced an elevated threshold 1 day postimplant and had the device percutaneously explanted and replaced. There were no device upgrades to dual-chamber device or cardiac resynchronization therapy (CRT) reported during the follow-up period.
      Table 3Major complications related to the system or procedure
      Adverse event key termImplanted (n = 152)Evaluable for primary objective (n = 54)
      Total events14 (14, 9.2%)5 (5, 9.3%)
      Events at groin puncture site0 (0, 0%)0 (0, 0%)
      Cardiac effusion/perforation4 (4, 2.6%)
      One cardiac effusion/perforation event resulted in patient death.
      0 (0, 0%)
      Elevated threshold1 (1, 0.7%)1 (1, 1.9%)
      Cardiac rhythm disorder4 (4, 2.6%)1 (1, 1.9%)
      Other5 (5, 3.3%)3 (3, 5.6%)
      Acute left ventricular failure1 (1, 0.7%)0 (0, 0%)
      Cardiac failure acute1 (1, 0.7%)1 (1, 1.9%)
      Pericarditis1 (1, 0.7%)0 (0, 0%)
      Peripheral vein occlusion1 (1, 0.7%)1 (1, 1.9%)
      Thrombocytopenia1 (1, 0.7%)1 (1, 1.9%)
      Event rates are given as the number of events (number of unique patients with event, % of unique patients with event).
      One cardiac effusion/perforation event resulted in patient death.
      One additional death occurred 127 days postimplant in an 83-year-old man due to aortic valve thrombosis and was considered not related to the system or procedure by the CEC.

      Discussion

      There are several important findings from this study of accelerometer-based, mechanically delivered AV synchronous pacing using a single device implanted in the RV. First, AVS was 86.1% at rest among patients with AVB and remained stable through 3 months (84.1%; P = .43), with ambulatory AVS assessed over a 24-hour period of 74.8%. Second, QoL as measured by the EQ-5D-3L health status and visual analog score improved significantly from baseline values by 3 months postimplant among all patients with completed assessments. Third, cardiac output represented by LVOT VTI also increased significantly during VDD pacing compared to the VVI mode. Finally, there were no upgrades to dual-chamber devices or CRT reported during the 3-month follow-up period. This reflected the absence of major complications related to pacemaker syndrome or RV pacing. In addition to corroborating the level of AVS and increase in stroke volume observed in MARVEL 2, the present study expands on the body of knowledge through the prospective evaluation of the maintenance of AVS over time and during activities of daily living.
      Building on successful programming strategies learned during the initial release of the device, the Optimize substudy looked at 20 patients with complete AVB and normal sinus rhythm at the 1-month visit who underwent programming changes to enhance A4 signal recognition. The primary enhancement was utilization of a fixed A3 threshold to improve tracking in the A3 window. With this programming, ambulatory AVS percentage increased significantly from 71.9% to 82.6%, similar to AVS at rest, with the most pronounced increase during elevated sinus rates between 80 and 110 bpm. Similar findings were reported by Neugebauer et al
      • Neugebauer F.
      • Noti F.
      • van Gool S.
      • et al.
      Leadless atrioventricular synchronous pacing in an outpatient setting: early lessons learned on factors affecting atrioventricular synchrony.
      in an outpatient setting, in which the investigators were able to improve median AVS with a second optimization session occurring between 1 and 3 months after implantation. Collectively, these findings suggest that programming optimization can improve AVS and should be routinely performed as needed.
      Previous studies have shown that patient selection is critical to achieve the benefits of leadless devices. Kowlgi et al
      • Kowlgi G.N.
      • Tseng A.S.
      • Tempel N.D.
      • et al.
      A real-world experience of atrioventricular synchronous pacing with leadless ventricular pacemakers.
      reported that congestive heart failure and pulmonary hypertension may affect mechanical sensing of atrial contraction, possibly by altering thoracic impedance. An analysis of MARVEL 2 data showed that a low A4 amplitude was inversely related to atrial function assessed by E/A ratio and was directly related to atrial contraction excursion and atrial strain on echocardiography.
      • Garweg C.
      • Khelae S.K.
      • Steinwender C.
      • et al.
      Predictors of atrial mechanical sensing and atrioventricular synchrony with a leadless ventricular pacemaker: results from the MARVEL 2 Study.
      Specifically, a multivariable lasso regression model found coronary artery bypass graft surgery history, higher E/A ratio, lower atrial contraction excursion, and lower atrial strain all were associated with low A4 amplitude. The model also showed that low sinus rate variability (SDSD <5 bpm) combined with E/A ratio <0.94 predicts high AVS (>90%) with >90% probability.
      The percentage of synchronous contraction required to maintain a clinical benefit over time is unknown but most likely is not 100%. Previous reports have shown that atrial undersensing associated with conventional transvenous VDD pacing systems resulted in minimal clinical impact in patients with high-degree AVB.
      • Marchandise S.
      • Scavee C.
      • le Polain de Waroux J.B.
      • de Meester C.
      • Vanoverschelde J.L.
      • Debbas N.
      Long-term follow-up of DDD and VDD pacing: a prospective non-randomized single-centre comparison of patients with symptomatic atrioventricular block.
      ,
      • Schaer B.A.
      • Weinbacher M.
      • Zellweger M.J.
      • Sticherling C.
      • Osswald S.
      Value of VDD-pacing systems in patients with atrioventricular block: experience over a decade.
      In the present study, we observed an increase in stroke volume with AV synchronous pacing. Additionally, QoL improved after device implant, and there were no system revisions or device upgrades related to pacemaker syndrome. Although these results are reassuring, assessment of these findings over a longer period of time is warranted. The ongoing Micra AV Post-Approval Registry (ClinicalTrials.gov Identifier: NCT04253184) will assess the rate of system upgrade through 3 years.
      The results of the present study demonstrate the ability to achieve sustained AVS from a single device implanted in the RV. Although it may be preferable to implant a dual-chamber transvenous system in patients who will benefit from AVS with exercise, elderly patients with complete heart block might do well with this technology despite the lack of 100% AVS. Although AVS levels may be lower than with traditional dual-chamber transvenous devices, the benefits associated with leadless devices may outweigh those of transvenous devices given the substantial reduction in complications associated with a single device leadless technology. Despite the overall reduction in complications with leadless technology, pericardial effusion has been identified as a potentially serious complication,
      • Hauser R.G.
      • Gornick C.C.
      • Abdelhadi R.H.
      • Tang C.Y.
      • Casey S.A.
      • Sengupta J.D.
      Major adverse clinical events associated with implantation of a leadless intracardiac pacemaker.
      and it is important to not overlook the potential risk for this complication, especially in high-risk patients. A recent analysis of the global Micra VR clinical trials found that pericardial effusion risk was <1% in low-risk patients and increased with baseline risk level.
      • Piccini J.P.
      • Cunnane R.
      • Steffel J.
      • et al.
      Development and validation of a risk score for predicting pericardial effusion in patients undergoing leadless pacemaker implantation: experience with the Micra transcatheter pacemaker.
      In line with these findings, 75% (3/4) of pericardial effusions in the present study occurred in patients with medium/high elevated baseline risk. Therefore, attention to procedural technique training to mitigate the risk of pericardial effusion, (eg, use of contrast and advanced imaging to confirm septal placement and reduce recapturing; immediate access to echocardiography equipment and pericardiocentesis kits; recognizing clinical signs and symptoms of pericardial effusion), particularly among high-risk patients, is warranted. Ultimately, selection of this technology will require consideration of the need for higher degrees of AVS vs the benefits of leadless pacing over transvenous pacing.

      Study limitations

      There are several limitations that should be acknowledged when considering the data from this study. Although evaluation of AVS using surface ECG to identify P waves regardless of underlying rhythm (eg, premature atrial and ventricular events were included) provides a robust measure of device performance compared to device collected diagnostics alone, surface ECG was collected only during 24-hour Holter monitoring and may not reflect the total variability in use conditions experienced by patients in the longer term. Because all patients with complete AVB and normal sinus function at 1 month did not participate in the Optimize substudy, the effect of selection bias cannot be eliminated when evaluating the impact of programming changes on ambulatory AVS. Although only 1 system revision and no upgrades to dual-chamber or CRT devices were observed in the study, the follow-up period was relatively short. Thus, the longer-term performance and tolerability of these devices await the results of larger ongoing studies (eg, Micra AV Post-Approval Registry; ClinicalTrials.gov Identifier: NCT04253184). Finally, although it is encouraging that QoL improved for study participants after implant, the lack of a control group makes it difficult to put these findings in context and specifically determine whether the improvement was due to AVS vs an increase in heart rate, although previous reports suggest AVS contributes to QoL improvements.
      • Hoijer C.J.
      • Brandt J.
      • Willenheimer R.
      • Juul-Moller S.
      • Bostrom P.A.
      Improved cardiac function and quality of life following upgrade to dual chamber pacing after long-term ventricular stimulation.

      Conclusion

      Accelerometer-based, mechanical atrial sensing significantly improves stroke volume, providing AVS at rest that is stable through 3 months in patients with AVB and normal sinus rhythm and a leadless pacemaker implanted in the RV. Ambulatory AVS improved to >80% with programming optimization. The therapy was well tolerated and improved QoL during follow-up. There were no system upgrades to dual-chamber pacemakers.

      Appendix Supplementary data

      References

        • Udo E.O.
        • Zuithoff N.P.
        • van Hemel N.M.
        • de Cock C.C.
        • Hendriks T.
        • Doevendans P.A.
        • Moons K.G.
        Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOLLOWPACE study.
        Heart Rhythm. 2012; 9: 728-735
        • El-Chami M.F.
        • Al-Samadi F.
        • Clementy N.
        • et al.
        Updated performance of the Micra transcatheter pacemaker in the real-world setting: a comparison to the investigational study and a transvenous historical control.
        Heart Rhythm. 2018; 15: 1800-1807
        • El-Chami M.F.
        • Bockstedt L.
        • Longacre C.
        • et al.
        Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up.
        Eur Heart J. 2022; 43: 1207-1215
        • Hoijer C.J.
        • Brandt J.
        • Willenheimer R.
        • Juul-Moller S.
        • Bostrom P.A.
        Improved cardiac function and quality of life following upgrade to dual chamber pacing after long-term ventricular stimulation.
        Eur Heart J. 2002; 23: 490-497
        • Lamas G.A.
        • Orav E.J.
        • Stambler B.S.
        • et al.
        Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in the Elderly Investigators.
        N Engl J Med. 1998; 338: 1097-1104
        • Nielsen J.C.
        • Andersen H.R.
        • Thomsen P.E.
        • et al.
        Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single-chamber atrial or ventricular pacing.
        Circulation. 1998; 97: 987-995
        • Steinwender C.
        • Khelae S.K.
        • Garweg C.
        • et al.
        Atrioventricular synchronous pacing using a leadless ventricular pacemaker: results from the MARVEL 2 study.
        JACC Clin Electrophysiol. 2020; 6: 94-106
        • Chinitz L.
        • Ritter P.
        • Khelae S.K.
        • et al.
        Accelerometer-based atrioventricular synchronous pacing with a ventricular leadless pacemaker: results from the Micra atrioventricular feasibility studies.
        Heart Rhythm. 2018; 15: 1363-1371
        • Shaw J.W.
        • Johnson J.A.
        • Coons S.J.
        US valuation of the EQ-5D health states: development and testing of the D1 valuation model.
        Med Care. 2005; 43: 203-220
        • Piccini J.P.
        • Cunnane R.
        • Steffel J.
        • et al.
        Development and validation of a risk score for predicting pericardial effusion in patients undergoing leadless pacemaker implantation: experience with the Micra transcatheter pacemaker.
        Europace. 2022; 24: 1119-1126
        • Neugebauer F.
        • Noti F.
        • van Gool S.
        • et al.
        Leadless atrioventricular synchronous pacing in an outpatient setting: early lessons learned on factors affecting atrioventricular synchrony.
        Heart Rhythm. 2022; 19: 748-756
        • Kowlgi G.N.
        • Tseng A.S.
        • Tempel N.D.
        • et al.
        A real-world experience of atrioventricular synchronous pacing with leadless ventricular pacemakers.
        J Cardiovasc Electrophysiol. 2022; 33: 982-993
        • Garweg C.
        • Khelae S.K.
        • Steinwender C.
        • et al.
        Predictors of atrial mechanical sensing and atrioventricular synchrony with a leadless ventricular pacemaker: results from the MARVEL 2 Study.
        Heart Rhythm. 2020; 17: 2037-2045
        • Marchandise S.
        • Scavee C.
        • le Polain de Waroux J.B.
        • de Meester C.
        • Vanoverschelde J.L.
        • Debbas N.
        Long-term follow-up of DDD and VDD pacing: a prospective non-randomized single-centre comparison of patients with symptomatic atrioventricular block.
        Europace. 2012; 14: 496-501
        • Schaer B.A.
        • Weinbacher M.
        • Zellweger M.J.
        • Sticherling C.
        • Osswald S.
        Value of VDD-pacing systems in patients with atrioventricular block: experience over a decade.
        Int J Cardiol. 2007; 122: 239-243
        • Hauser R.G.
        • Gornick C.C.
        • Abdelhadi R.H.
        • Tang C.Y.
        • Casey S.A.
        • Sengupta J.D.
        Major adverse clinical events associated with implantation of a leadless intracardiac pacemaker.
        Heart Rhythm. 2021; 18: 1132-1139