The revolution of beat-to-beat wireless bidirectional communication between intra-cardiac devices

Comment on ‘A Dual-Chamber Leadless Pacemaker’ recently published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2300080 The Aveir DR i2i study was an industry-sponsored, prospective, multi-centre, uncontrolled study to evaluate the safety and performance of a dual-chamber leadless pacemaker (LP) system.1 The Aveir DR i2i system consists of two LPs to be implanted percutaneously in the right atrium and right ventricle, in order to eliminate transvenous leads and device pocket. They link like two components of a wireless network to coordinate their separate sensing and rate-adaptive, atrioventricular (AV)-synchronous pacing functions. The primary safety endpoint was freedom from serious adverse events related to the procedure or the device within 90 days after implantation. The first primary performance endpoint was a combination of adequate atrial capture threshold and atrial sensing amplitude at the 3-month visit. The second primary performance endpoint was at least 70% AV synchrony at the 3-month visit. An independent data and safety monitoring board reviewed and evaluated the study data for participant safety and study conduct. Among the 300 patients (mean age 69 ± 13 years, males 62%) enrolled over 7 months across 55 centres with a conventional indication for dual-chamber pacing, 190 (63%) had sinus-node dysfunction and 100 (33%) had AV block as the primary indication to pacemaker implantation. Only 8.7% had undergone previous extraction of a transvenous lead or LP. The implantation procedure was successful in 295 patients (98%); intraprocedural repositioning (≥1) of the atrial and ventricular device was required in 72 (24%) and 40 patients (13%), respectively. By 3 months, the primary safety endpoint was met by 271 patients [90%; 95% confidence interval (CI), 87–94] compared with the performance goal of 78% (P < .001). A total of 35 procedure-related serious adverse events occurred in 29 patients. The most common adverse event was procedural atrial fibrillation (nine patients, 3% of the overall population). The LP dislodgement rate was 1.7%, and in all five patients, the dislodged LP was retrieved successfully and re-implanted during the initial procedure. Two cardiac pericardial effusions, as procedure-related major adverse events, occurred in two patients (0.6%). None of the four deaths (1.3%) that occurred during follow-up (between 46 and 86 days after implantation) were considered to be device or procedure related; specifically, two deaths occurred after cardiac arrest, one was related to a malignant tumour and the other to sepsis. The first primary performance endpoint was met in 90% (95% CI, 87–94), exceeding the 82.5% performance goal (P < .001). The second primary performance endpoint was observed in 97% (95% CI, 95–99), against the performance goal of 83% (P < .001). Fifteen patients had missing data on LP AV synchrony, for whom a multiple imputation method was used. The mean AV synchrony percentage remained above 95% in each posture evaluated and in different gaits. The Aveir DR i2i study is the first-in-human experience with a modular dual-chamber LP with bidirectional wireless communication that met the primary safety and performance endpoints at 3 months in patients with indications for dual-chamber pacing.1 Leadless pacemaker systems represent an important evolution in the field of cardiac pacing; these innovative devices are self-contained intra-cardiac pacemakers implanted by using a femoral percutaneous approach, with complete elimination of transvenous leads and the generator pocket. As a result, the use of the LP system reduces the long-term risk of infection and lead malfunction, which affects up to one in six patients within 3 years of implantation.2,3 In this regard, the 2021 European Society of Cardiology guidelines recommend LP when no upper extremity venous access is available or when there is a high risk of infection (Class 2a recommendation) and as an alternative to single chamber pacing depending on life expectancy and shared decision-making (Class 2b).4 Currently, LPs are available for right ventricular pacing with the significant limitation of serving a minority (15%–30%) of total pacemaker recipients in Western countries, i.e. mostly patients with chronic atrial fibrillation and AV block.3 The Aveir DR i2i study aimed to expand the benefits of leadless pacing to a larger population including patients with node dysfunction and AV block, with only a minority of patients presenting with high risk of infection at the time of admission. Regarding the safety endpoint, the incidence of acute complications was similar to that observed in studies of transvenous dual-chamber pacemakers,5,6 although this single-group study does not provide a direct comparison of LP with a conventional transvenous pacemaker. Notably, there were no procedure-related deaths, and serious cardiac injury (pericardial effusion) occurred in 0.6% of patients compared with 0.8% lead perforation in a recent meta-analysis of conventional pacing studies.7 Furthermore, as reported by observational studies,8,9 single-chamber right ventricular LPs were shown to have fewer associated complications than conventional transvenous pacemakers. However, the authors observed a higher-than-expected incidence of dislodgement during and after the implantation procedure (1.7%), as compared with 1.1% in the initial study of the ventricular LP.9 In particular, there was a high rate of atrial LP repositioning. From a technical viewpoint, there are three aspects of the procedure that require special attention: (i) the thinner right atrial wall compared with the right ventricle wall and consequent special care in attaching the LP helix to the right atrium; (ii) the arrhythmogenic mechanical effects of atrial LP resulting in the onset of atrial fibrillation; and (iii) the procedural workflow, including implantation, long-term retrievability and replacement of the Aveir DR system. Accordingly, considerable background with LP and rigorous training of all investigators was required before enrolment. Leadless pacing is an innovative technology for which the learning curve has been included in clinical trials. Advanced technical skills associated with the cost of this new system could limit its widespread adoption in clinical practice. Regarding the performance endpoint, this study showed the feasibility of a wireless connection between atrial and ventricular devices. The bidirectional communication modality is an emerging technical innovation that uses sub-threshold electrical signals conducted between the two intra-cardiac LPs through blood and myocardial tissue on a beat-by-beat basis. This innovative modality contributes to the AV synchrony endpoint achieved in 97% of the Aveir DR i2i study. These results are in agreement with the preclinical animal study10 demonstrating a 99% success rate of beat-to-beat wireless communication in synchronized, dual-chamber DDD LP at 13 weeks after implantation. On the other hand, inadequate atrial pacing threshold and sensing were found in 28 patients (9%), and no data on ventricular sensing and thresholds are available. The main limitations of the study are represented by the small sample size, uncontrolled nature, and short-term follow-up. Although the chronic pacing performance and battery longevity of right ventricular LP are reliable at least in the medium term,8 data on dual-chamber LP are needed. Particularly, data on dual-chamber LP dependency status are lacking with limited assessment of battery longevity and rate-responsive capability. In addition, longer follow-up of patients undergoing dual-chamber LP is needed to definitively assess long-term complication rate and the benefits of LP in terms of pocket or lead infections, especially in patients with risk factors for device infection (chronic renal failure, immunodepression, and diabetes). The technical feasibility of dual-chamber LP will also create new questions regarding management strategies at the end of expected battery life. Finally, current transvenous devices have reached a high level of pacing algorithms that are hardly comparable with the LP system. In this regard, further randomized controlled studies are needed to understand which patients are best served by LP technology and which will be better served by traditional transvenous devices, for example, patients who need conduction system pacing. The wireless cardiac pacing revolution has just begun. Supplementary data are not available at European Heart Journal online. M.V. has no conflicts of interest to report. M.L.N. received educational grant from Biotronik, Boston Scientific and grant from Impulse Dynamics.