Authors: Hamidreza Soleimani, Parham Dastjerdi, Negin Sadat Hosseini Mohammadi, Soroush Najdaghi, Hedieh Shayesteh, Delaram Narimani Davani, Hirad Yarmohammadi, Masoud Eslami, Reza Mollazadeh
Categories: Topics in Review, Leadless cardiac pacemaker, Transcatheter pacing system, Complications, Safety, Efficacy
Source: Heart Rhythm O2
Authors: Hamidreza Soleimani, Parham Dastjerdi, Negin Sadat Hosseini Mohammadi, Soroush Najdaghi, Hedieh Shayesteh, Delaram Narimani Davani, Hirad Yarmohammadi, Masoud Eslami, Reza Mollazadeh
Leadless pacemakers (LPs) are emerging as a transformative alternative to traditional transvenous pacemakers (TVPs) for managing brady-arrhythmias. Unlike TVPs, LPs eliminate the need for leads and subcutaneous generator pockets, addressing complications.
This meta-analysis aimed to evaluate the safety and efficacy of LPs, including Micra (Medtronic) and Aveir VR (Abbott) devices, in comparison to TVPs.
A systematic review and meta-analysis were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Overall, 55 studies involving 286,349 patients met the inclusion criteria.
LPs demonstrated significantly lower risks of pneumothorax (relative risk [RR], 0.29; P = .019, event 0.14% [LP] vs 0.93% [TVP], number needed to treat [NNT] = 128) and lead dislodgement (RR, 0.21; 95% confidence interval, 0.16–0.28; P < .0001, event 0.36% [LP] vs 2.29% [TVP], NNT = 52) compared with TVPs, with negligible infection rates. However, LPs were associated with higher risks of cardiac tamponade (RR, 2.36; P = .007, event 0.84% [LP] vs 0.46% [TVP], number needed to harm [NNH] = 265) and access site complications (RR, 2.82; P < .0001, event 2.03% [LP] vs 0.62% [TVP], NNH = 71).
LPs offer distinct advantages over TVPs, including reduced risks of certain complications and improved procedural efficiency.
Key Teaching Points ▪Leadless pacemakers (LPs) are being recognized as a promising alternative to traditional transvenous pacemakers (TVPs) for the treatment of brady-arrhythmias and heart block.▪Elimination of leads and the subcutaneous generator in LPs may significantly decrease the risk of complications commonly associated with TVPs.▪An updated meta-analysis of 55 studies involving 286,349 patients was performed which revealed that LPs have substantially lower rates of pneumothorax (Relative risk [RR], 0.29) and lead dislodgement (RR, 0.21), with negligible infection rates.▪Despite their advantages, LPs carry higher risks of early cardiac tamponade (RR, 2.36) and access site complications (RR, 2.82), although no significant differences were found in procedure duration, fluoroscopy time, impedance, or pacing capture threshold compared to TVPs.▪Although LP present a significant advancement in cardiac pacing technology by reducing certain risks associated with traditional methods, careful consideration of their potential complications is essential for optimal patient selection and management.
Leadless pacemakers (LPs) have emerged as a transformative alternative to traditional transvenous pacemakers (TVPs) for treating brady-arrhythmias. In contrast to TVPs, which rely on a pulse generator and leads to connect with the heart, LPs are fully self-contained, eliminating the need for leads and subcutaneous generator pockets.^1^ TVPs carry a 7.8%–12.4% risk of serious complications within 90 days, with nearly half related to the lead or generator. Long-term risks remain at 1%–2% per year, mainly because of lead failure and infection, with 1 in 6 patients experiencing a serious complication by year 3.^2^^,^^3^ Rare complications, such as the embolization of broken lead fragments, may require complex interventions like valve replacement or lead extraction, further emphasizing the limitations of traditional TVP.^4^ TVPs are also associated with an incidence rate of up to 6% for right ventricular perforation, further underscoring the risks of conventional system.^5^ In comparison, LPs streamlined, percutaneous design offers significant clinical advantages, particularly in reducing risks associated with TVP implantation, such as lead dislodgement, pocket infections, and generator-related complications. However, potential concerns with LPs include limited pacing options, challenges with device retrieval, and the need for long-term data on safety and performance.^6^
Since the introduction of cardiac pacemakers, substantial efforts have been made to enhance the efficacy, durability, and safety of pacing therapy. Currently, 2 single-chamber LP systems are available on the The Micra Transcatheter Pacing System (Medtronic) and the Aveir (Abbott). Micra VR, the primary single-chamber LP currently in use, has shown promising outcomes in initial clinical trials; however, its adoption has been approached cautiously because of device-specific limitations.^7^ The Aveir VR pacemaker, approved by the United States Food and Drug Administration in April 2022,^8^ showed promising safety and feasibility results in the LEADLESS-II trial, particularly in real-world settings.^9^ However, broader evaluations in diverse clinical populations are still needed to confirm its safety and efficacy profile.
This report presents an updated systematic review and meta-analysis of recent studies, incorporating expanding on previous meta-analyses by newly published data to provide a more current comparison between LPs and TVPs in terms of clinical end points related to safety and efficacy.^10^^,^^11^ The analysis focuses exclusively on single-chamber LPs, the Micra Transcatheter Pacing System (Medtronic) and the Aveir (Abbott), and does not include Nanostim devices owing to their withdrawal from the market and distinct performance profile. By pooling evidence from an expanded patient cohort and examining both short- and long-term complications, this analysis seeks to offer robust insights into the comparative effectiveness of LPs, supporting the evolving standards of care in pacemaker therapy.
This systematic review and meta-analysis was conducted according to guidelines set by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).^12^ The study protocol was submitted to PROSPERO online database and was assigned the study registration ID: CRD42024602484. Authors attest that the research reported has adhered to ethical guidelines and that the authors are in compliance with the regulations of Tehran university of medical sciences review boards. Informed consent was taken from the patients in the studies included.
In October 2024, a comprehensive search strategy was created and implemented across the PubMed, EMBASE, Scopus, and Cochrane databases, including all articles published in these sources up to the date of the search. Furthermore, relevant studies and reviews on the topic were evaluated for potential inclusion by examining their reference lists. The search strategy employed a comprehensive combination of keywords and controlled vocabulary (eg, MeSH and Emtree terms), including terms such as “leadless pacemaker,” “conventional pacemaker,” “Micra,” “Aveir VR,” and other related phrases. The search details are in Supplementary Material.
All studies that reported outcomes in patients who had undergone the implantation of an LP were eligible for inclusion, regardless of study design (ie, randomized controlled trials or observational studies, both comparative and non-comparative). Single-arm, non-comparative studies were used to estimate pooled effects proportions; whereas 2-arm studies were used to perform comparative meta-analysis and construct forest plots. Studies involving pediatric populations, patients with endocarditis, patients undergoing valvular procedures, and those who had received heart transplants were not included. Conference abstracts, case reports, reviews, non-English studies, and animal studies were also excluded. To ensure consistent application of the exclusion criteria, only studies with sufficient methodological and clinical information were considered eligible. Studies had to clearly report the study design, patient population, intervention (including LP type), and at least 1 clinical outcome of interest to be included (eg, complications, device performance, or survival). During full-text screening, any studies lacking critical data necessary to confirm inclusion/exclusion criteria were excluded to maintain comparability across the dataset.
Search results were imported into the Rayyan web application for data collection and extraction.^13^ Two expert researchers (NSHM, and PD), independently reviewed the titles and abstracts of all retrieved citations to identify eligible studies. They also independently evaluated the full texts of selected citations. In cases of disagreement, studies were discussed until a consensus was reached. If consensus could not be reached, the study was excluded; however, all disagreements were successfully resolved through discussion. The same 2 researchers compiled and cross-verified the extracted data to ensure accuracy and consistency.
In the subsequent phase, data from the eligible studies were extracted using a standardized data collection form created in Microsoft Excel (Microsoft Corporation, Redmond, WA). The collected data included a variety of variables such as author names, publication years, study designs, sample sizes, follow-up durations, participant ages, gender distributions, baseline characteristics (comorbidities, indication for pacing, etc.) and information regarding primary and secondary outcomes.
This review included studies reporting outcomes on Micra VR or Aveir VR LPs. We excluded studies focusing solely on Nanostim models, which were recalled owing to battery depletion issues. Additionally, in studies that provided results from multiple types of devices, we did not extract or analyze data pertaining to Nanostim devices.
In this study, we evaluated both safety and efficacy outcomes. The primary safety outcome was the total complication rate, which was extracted directly from the included studies when reported as such. The secondary safety outcomes included access site complications, lead dislodgement, total infection rates, endocarditis incidence, total fluoroscopy time, total procedure time, and the rates of procedural pneumothorax, pericardial effusion (PE), and tamponade. For efficacy, the primary outcome was all-cause mortality, chosen because of its consistent reporting across the largest number of studies and minimal missing data. Secondary efficacy outcomes included the pacing device’s capture threshold and impedance. The definitions of each outcome were accepted as reported in the individual studies, and these study-level definitions formed the basis of our analyses.
The risk of bias for non-randomized studies was assessed using the Risk Of Bias In Non-randomized Studies Of Interventions (ROBINS-I) tool, which evaluates potential bias by comparing each included study to a hypothetical pragmatic randomized trial.^14^ 2 authors (PD and NSHM) independently assessed the studies across 3 low risk of bias, some concerns, or high risk of bias. Any disagreements were resolved through consensus between the authors. The quality of the evidence was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology.^15^
Risk ratio (RR) with 95% confidence intervals (CIs) were calculated for each outcome. Given the expected significant heterogeneity among studies, we employed a random-effects model to aggregate effect size from studies with 2 comparative arms. The restricted maximum likelihood estimator was used to determine the heterogeneity variance (τ2).^16^ We applied Knapp-Hartung adjustments to compute the CI for the pooled effect.^17^ For studies lacking comparative arms, the proportions of reported outcomes were pooled using a generalized linear mixed-effects model with logit transformations.
To assess the robustness of our findings and detect any influential studies, we performed a Leave-One-Out (LOO) sensitivity analysis, wherein each study was sequentially excluded from the meta-analysis, and the pooled result recalculated. Importantly, no studies were removed or excluded based on their outcomes or effect size—this method is purely exploratory and automated, allowing for assessment of each study’s impact on heterogeneity and significance. Although omission of certain studies slightly modified effect sizes and heterogeneity, these changes did not alter the overall direction or interpretation of the results. Additionally, we carried out a subgroup analysis based on the type of device and the duration of follow-up, categorizing studies with <1 year of follow-up as short-term and those with >1 year as long-term.
To further investigate the factors influencing study outcomes and explore potential sources of heterogeneity across studies, we conducted a meta-regression analysis. This analysis aimed to assess the association between key covariates—patient age, percentage of male patients, proportion of patients with diabetes, and proportion of patients with hypertension—and the primary safety and efficacy outcomes.
All statistical analyses were conducted using the R software (R for Windows, version 4.1.3) and R Studio version 1.1.463 (Posit PBC), using packages tidyverse, meta, and robvis.18, 19, 20, 21
The initial search identified 3647 records across PubMed, Scopus, Cochrane, and Embase. After removing 1289 duplicates, 2358 articles were screened by title and abstract. Of these, 207 studies underwent full-text review, resulting in 55 studies meeting the inclusion criteria (Figure 1). The included studies, published between 2015 and 2024, represented various countries, with most conducted in the United States, followed by European countries, Japan, and other international collaborations. In total, 286,349 patients were analyzed across both the LP and TVP groups, of which 88,377 were in the LP group. The studies included various designs, with 33 retrospective studies, 20 prospective studies, and 2 case series. Several studies focused solely on the LP group, whereas others provided comparative data between LP and TVP groups, all of which were limited to single-chamber devices in both arms. Details of the included studies are summarized in Table 1.Figure 1PRISMA flow diagram of search strategy and trial selection.Table 1Studies of transvenous and leadless pacemakers included in systematic reviewAuthor (y)Study DesignSingle/Double ArmSample SizeGroup 1Group 1 sample sizeGroup 2Group 2 sample sizeFollow-Up TimeMale, %Male, %Age, mean ± SDAge, mean ± SDHeart failure, %Heart failure, %HTN, %HTN, %CAD,%CAD,%DM, %DM, %AF, %AF, %LVEF%, Mean ± SDLVEF, Mean ± SDReported outcomesGroup 1Group 2Group 1Group 2Group 1Group 2Group 1Group 2Group 1Group 2Group 1Group 2Group 1Group 2Group 1Group 2Panico (2024)Retrospective, propensity-matched, cohort studyDouble-arm178Micra89TVP8927 (28) months657077.3 ± 9.877.9 ± 8.67063N/AN/A575576746967N/AN/APneumothoraxInfectionPericardial effusionAccess site complicationsEndocarditisTokavanich (2023)Retrospective, cohort studyDouble-arm76Micra41Aveir266 months666978 (10)70 (15)N/AN/A6154N/AN/A2442N/AN/AN/AN/AProcedure timeFluoroscopy timePacing capture thresholdImpedanceKumar (2020)Prospective, non-randomized, cohort studySingle-arm28Micra28N/AN/A3 years71N/A71.71 ± 8.4N/AN/AN/A78.5N/A39.28N/A46.5N/A28.5N/A52.85 ± 4.17N/AProcedure timeFluoroscopy timePacing capture thresholdBreeman (2023)Retrospective, cohort studySingle-arm179Micra+Nanostim179N/AN/A44 ± 26 months65N/A79 ± 9N/AN/AN/A53N/A30N/A20N/AN/AN/AN/AN/APacing capture thresholdImpedanceSultan (2024)Retrospective, cohort studySingle-arm188Micra188N/AN/A723.4 ± 597.9 days57N/A79.7 ± 8.6N/A26N/AN/AN/A35N/A23N/AN/AN/A55N/APericardial effusionFluoroscopy timeAll-cause mortalityAccess site complicationsPacing capture thresholdHofer (2023)Retrospective, cohort studySingle-arm220Micra220N/AN/A30 days66N/A80.6 ± 7.7N/AN/AN/AN/AN/A35.5N/A22.3N/A79.5N/A55 ± 10N/AProcedure timePericardial effusionFluoroscopy timeImpedanceAccess site complicationsSterliński (2024)Retrospective, cohort studySingle-arm28Aveir28N/AN/A3 (4) days57.1N/A75 (10)N/AN/AN/AN/AN/AN/AN/AN/AN/A78.5N/A55 (11)N/AProcedure timeImpedancePacing capture thresholdFluoroscopy timeNair (2023)Retrospective, cohort studySingle-arm167Aveir167N/AN/A30 days56.6N/A74 (16)N/AN/AN/AN/AN/AN/AN/AN/AN/A47.3N/AN/AN/APericardial effusionImpedancePacing capture thresholdDislodgementRitter (2015)Prospective, cohort studySingle-arm140Micra140N/AN/A3 months60.7N/A77.0+10.2N/A9.3N/A79.3N/A31.4N/A24.3N/AN/AN/AN/AN/AProcedure timeFluoroscopy timePericardial effusionImpedancePacing capture thresholdAccess site complicationsTachibana (2020)Retrospective, cohort studyDouble-arm62Micra27TVP356 months44.44090.1 ± 3.590.9 ± 4.1N/AN/A69.4N/AN/AN/A11.3N/AN/AN/A61.4 ± 8.3N/AProcedure timeInfectionFluoroscopy timeEndocarditisDislodgementPacing capture thresholdImpedanceAccess site complicationsMartinez-Sande (2021)Prospective, cohort studyDouble-arm443Micra198TVP24522.3 ± 15.9 months62.127.379.2 ± 6.683.5 ± 8.923.227.380.863.3N/AN/A34.825.7N/AN/A59.8 ± 7.956.9 ± 8.6TamponadePneumothoraxPericardial effusionDislodgementEndocarditisAll-cause mortalityAccess site complicationsPiccini (2021)Retrospective, cohort studyDouble-arm15426Micra5746TVP96626 months56.356.679.4 ± 9.582.0 ± 8.152.652.9N/AN/A5653.4N/AN/A81.489.1N/AN/APneumothoraxPericardial effusionAccess site complicationsPalmisano (2022)Prospective, propensity-matched, cohort studyDouble-arm2669Micra665TVP200439 months69.561.173.9 ± 13.872.5 ± 13.317.914.674.762.5N/AN/A24.420.66743.455.6 ± 8.158.4 ± 8.5TamponadePneumothoraxInfectionDislodgementAccess site complicationsKhan (2024)Retrospective, cohort studySingle-arm29005Micra+Aveir11815N/AN/AN/A55.7N/A77.5 ± 5.4N/A51.9N/A84.3N/A42N/A9N/AN/AN/AN/AN/ATamponadePericardial effusionAll-cause mortalityAccess site complicationsTotal complicationsHaddadin (2022)Retrospective, cohort studySingle-arm7821Micra7821N/AN/A30 days55.8N/A75.5 ± 12.3N/A53.2N/A82.1N/AN/AN/A37.9N/A53.2N/AN/AN/ATamponadeInfectionPericardial effusionAll-cause mortalityAccess site complicationsTotal complicationsDislodgementChen (2021)Prospective, clinical trial studySingle-arm81Micra81N/AN/A8.7 ± 1.5 months49.4N/A68.6 ± 11.8N/A1.2N/A64.2N/A33.3N/A25.9N/A44.4N/AN/AN/AProcedure timeFluoroscopy timeImpedancePacing capture thresholdAccess site complicationsEl Amrani (2019)Prospective, non-randomized, cohort studySingle-arm129Micra129N/AN/A342 ± 279 days44.76N/A84.8 ± 4.4N/A38.8N/A83.2N/AN/AN/A32.8N/A48.5N/A59 ± 7.9N/ATamponadePericardial effusionTotal complicationsImpedanceProcedure timeAccess site complicationsPacing capture thresholdCrossley (2024)Retrospective, cohort studyDouble-arm115271Micra7471TVP1078006 months51.753.279.0 ± 10.278.7 ± 8.041.430.689.789.649.548.646.238.340.345.1N/AN/APericardial effusionAll-cause mortalityAccess site complicationsTotal complicationsDislodgementInfectionGarg (2020)Prospective, non-randomized, cohort studySingle-arm2814Micra2814N/AN/A36 months60.1N/A75.7 ± 12.7N/A15.7N/A69.8N/A25.1N/A27.4N/AN/AN/A55.0 ± 8.2N/AProcedure timePericardial effusionInfectionFluoroscopy timeAll-cause mortalityAccess site complicationsTotal complicationsGarweg (2017)Prospective, cohort studySingle-arm66Micra66N/AN/A10.4 ± 6.1 months69.7N/A79.1 ± 9.7N/A21.2N/A72.7N/A43.9N/A24.2N/A71.2N/A55.6 ± 5.6N/AProcedure timeImpedanceFluoroscopy timePacing capture thresholdDuray (2017)Prospective, non-randomized, clinical trial studySingle-arm726Micra726N/AN/A16.4 ± 6 4.9 months55.8N/A75.9 ± 10.9N/A15.6N/A69.6N/A36.2N/A17.7N/A44.3N/AN/AN/AImpedanceAccess site complicationsPacing capture thresholdCrossley (2023)Retrospective, cohort studyDouble-arm16431Micra6219TVP10212675 ± 364 Days55.956.879.5 ± 9.582.0 ± 8.152.852.8N/AN/A56.153.345.141.381.589N/AN/AInfectionDislodgementTotal complicationsVincent (2022)Retrospective, case-control matching, cohort studyDouble-arm16825Micra16825TVP565845In-hospital outcomes55.256.975.4 ± 12.873.0 ± 13.555.151.885.783.645.348.639.236.663.644.5N/AN/ATamponadeInfectionEndocarditisAll-cause mortalityAccess site complicationsTotal complicationsDenman (2018)Prospective, cohort studySingle-arm79MicraN/AN/AN/A12 months66N/A78 ± 8.9N/AN/AN/AN/AN/AN/AN/AN/AN/AN/AN/A58 ± 8.15N/AProcedure timeFluoroscopy timeImpedancePacing capture thresholdValiton (2018)Retrospective, cohort studySingle-arm92MicraN/AN/AN/A12.4 ± 7.4 months65N/A80.3 ± 11.1N/AN/AN/AN/AN/A46.7N/AN/AN/AN/AN/A57 ± 10N/ATamponadeInfectionProcedure timeImpedanceFluoroscopy timePacing capture thresholdAll-cause mortalityAccess site complicationsShantha (2023)Retrospective, matched, cohort studyDouble-arm50Micra25Aveir258 weeks525273 ± 1273 ± 16N/AN/A485624288327288N/AN/AFluoroscopy timeImpedancePacing capture thresholdProcedure timeTamponadePericardial effusionAll-cause mortalityClement (2021)Retrospective, cohort study (Micra Transcatheter Pacing System Post-Approval Registry)Single-arm99Micra99N/AN/A19 (40) months52N/A75 ± 13N/A32N/AN/AN/AN/AN/A28N/A53N/AN/AN/ATamponadePericardial effusionAll-cause mortalitySchiavone (2023)Retrospective, cohort study (International Leadless Pacemaker Registry)Single-arm1154Micra1154N/AN/AN/A35.7N/A77.1 ± 13.0N/A10.5N/A53.4N/A23N/A22.3N/A51.4N/AN/AN/AFluoroscopy timeAccess site complicationsTamponadePericardial effusionDislodgementBodin (2022)Retrospective, propensity-matched, cohort study (PMSI Registry)Double-arm2688LPM2688N/AN/A6.2 ± 8.7 months58.659.773.5 ± 15.273.5 ± 17.249.7546970.83433.230.43255.559.2N/AN/ATamponadePneumothoraxInfectionEndocarditisAll-cause mortalityLenormand (2023)Retrospective, cohort studySingle-arm400Micra400N/AN/A16 (29) months57N/A77 ± 12N/A43N/AN/AN/AN/AN/A32N/A62N/AN/AN/ATamponadeInfectionPericardial effusionPacing capture thresholdAll-cause mortalityBertelli (2022)Prospective, cohort studyDouble-arm344Micra72TVP27222.8 ± 2.6 months645979.5 (2.5)85.0 (1.0)6459N/AN/AN/AN/A26.41880.696.357 (3)59 [2]TamponadePericardial effusionInfectionProcedure timeImpedancePacing capture thresholdAccess site complicationsFluoroscopy timeGulletta (2022)Retrospective, cohort study (International LEAdless PacemakEr Registry)Single-arm1154MicraN/AN/AN/A837.5 (579) days64.1N/A76.6 ± 13.7N/A10.5N/A53.9N/A23.1N/A22.3N/A59N/A55.66 (8.89)N/AProcedure timeFluoroscopy timePericardial effusionImpedancePacing capture thresholdDislodgementAccess site complicationsTamponadeSaleem-Talib (2019)case seriesSingle-arm19Micra19N/AN/AN/A52.6N/A77.5 ± 9.6N/AN/AN/AN/AN/AN/AN/AN/AN/A100N/AN/AN/AFluoroscopy timePacing capture thresholdJohar (2018)case seriesSingle-arm9Micra9N/AN/AN/A55.5N/A73N/AN/AN/AN/AN/AN/AN/AN/AN/A66.6N/AN/AN/AFluoroscopy timeTotal complicationsProcedure timeMitacchione (2024)Retrospective, cohort study (International LEAdless PacemakEr Registry)Single-arm1748Micra1748N/AN/A39 (41) months60.2N/A80 (12)N/A13.8N/A66.4N/A24.3N/A24.1N/AN/AN/AN/AN/ATamponadeInfectionPericardial effusionFluoroscopy timeAccess site complicationsTotal complicationsAll-cause mortalityDislodgementFleur (2018)Prospective, propensity-matched, cohort studyDouble-arm440Micra+Nanostim220TVP220599 (456) days60.960.578 (14)77 (13)109.565.966.4101018.218.273.269.5N/AN/APneumothoraxPericardial effusionInfectionDislodgementAll-cause mortalityAccess site complicationsAlhuarrat (2023)Retrospective, propensity-matched, cohort studyDouble-arm35430Micra7780TVP27650in-hospital outcomes575677.1 ± 12.181.3 ± 9.44145858642413733N/AN/AN/AN/AInfectionAll-cause mortalityAccess site complicationsZucchelli (2020)Retrospective, cohort studyDouble-arm200Micra100TVP10012 months776777.46 ± 9.5878.78 ± 9.78N/AN/A726422172223N/AN/A56.09 ± 8.1454.83 ± 6.75PneumothoraxPericardial effusionDislodgementEndocarditisImpedancePacing capture thresholdTotal complicationsAll-cause mortalitySasaki (2022)Retrospective, cohort studyDouble-arm116Micra58TVP582 years384081 ± 882 ± 655625820223427N/AN/A63 ± 1063 ± 9TamponadePneumothoraxDislodgementInfectionKatsuki (2022)Retrospective, cohort studyDouble-arm929Micra368TVP5611.7 years485084.7 ± 7.177 ± 9.5231965671418141519360.0 ± 11.261.9 ± 8.7N/ATam (2024)Prospective, non-randomized, cohort studyDouble-arm262Micra139Aveir1233 MonthsN/AN/A80.5 ± 8.7379.7 ± 8.034N/AN/AN/A25N/AN/AN/A50N/AN/AN/AN/AKnops (2023)Prospective, cohort studySingle-arm300Aveir300N/AN/A3 Months62.3N/A69.2 ± 13.5N/A12.3N/A67N/A34N/A25N/AN/AN/A59.6 ± 6.9N/APericardial effusionDislodgementAll-cause mortalityAccess site complicationsTotal complicationsGarweg (2024)Retrospective, cohort study (Micra AV registry)Double-arm3468Micra801TVP26673 years42.244.974.1 ± 15.171.1 ± 12.19.91568.367.222.838.429.721.925.736.657.9 ± 8.9N/ATamponadePericardial effusionImpedancePacing capture thresholdAll-cause mortalityAccess site complicationsTotal complicationsRoberts (2022)Retrospective, cohort study (Micra MAP EMEA registry)Single-arm928Micra928N/AN/A9.7 ± 6.5 months62.4N/A76.3 ± 13.2N/A8.3N/A64.9N/A19.9N/A30.2N/A55.9N/AN/AN/ATamponadeInfectionPericardial effusionImpedanceAccess site complicationsTotal complicationsAll-cause mortalityPacing capture thresholdReynolds (2015)Prospective, non-randomized, cohort studySingle-arm725Micra725N/AN/A6 months58.8N/A75.9 ± 10.9N/A17N/A78.6N/A28N/A28.6N/A72.6N/A58.8 ± 8.8N/APericardial effusionImpedancePacing capture thresholdAll-cause mortalityTotal complicationsEl-Chami (2024)Prospective, non-randomized, cohort studyDouble-arm1809N/AN/AN/AN/A51.1 (42.6) months61.2N/A75.6 ± 13.4N/A15.4N/A64.9N/A22N/A26.5N/A62.6N/AN/AN/ATamponadeInfectionPericardial effusionDislodgementAccess site complicationsDa Costa (2017)Prospective, cohort studyDouble-arm14Micra14N/AN/A3 months50N/A75 ± 10N/A57N/A86N/A21.5N/A43N/A64N/A60 ± 7N/AImpedancePacing capture thresholdPalmisano (2022)Prospective, cohort studySingle-arm782Micra782N/AN/A20 months68.4N/A75.6 ± 12.4N/A17.1N/A81.3N/AN/AN/A28.3N/A66.2N/A55.3 ± 7.7N/ATamponadeDislodgementAccess site complicationsImpedanceTachibana (2020)Retrospective, cohort studyDouble-arm62Micra27TVP356 months44.44090.1 ± 3.590.9 ± 4.1N/AN/A66.771.4N/AN/A3.717.13771.462.7 ± 7.260.3 ± 9.1Procedure timeEndocarditisDislodgementPacing capture thresholdAccess site complicationsImpedanceHindricks (2024)Prospective, cohort studySingle-arm381Aveir381N/AN/A6 months61.7N/A69.3 ± 13.6N/AN/AN/AN/AN/AN/AN/AN/AN/A3.46N/A60.1 ± 6.7N/AImpedancePacing Capture thresholdMararenko (2023)Retrospective, cohort studyDouble-arm21782LPM4105TVP17677N/A81.1918.8178.28 ± 10.3681.71 ± 7.8918.1181.89N/AN/AN/AN/AN/AN/AN/AN/AN/AN/ATamponadePneumothoraxAll-cause mortalityRusso (2022)Retrospective, non-randomized, cohort studySingle-arm140Micra140N/AN/A606.5 ± 265.9 days64.3N/A76.7 ± 11.24N/AN/AN/A70N/A29.3N/A30.7N/A4.78N/AN/AN/AProcedure timeImpedanceFluoroscopy timeAll-cause mortalityAccess site complicationsDislodgementPacing capture thresholdPericardial effusionMitacchione (2023)Retrospective, non-randomized, cohort studySingle-arm1179Micra1179N/AN/A25 (15) months64.3N/A80 (11)N/AN/AN/A56.7N/A25.4N/A23.8N/AN/AN/A56.0 (9)N/AAll-cause mortalityPagan (2020)Retrospective, non-randomized, cohort studyDouble-arm302Micra183TVP11924 hours of implant51.940.389.5 ± 3.489.9 ± 3.416.98.476.088.24140.320.821.880.373.957.1 ± 11.157.8 ± 10.8Procedure timePericardial effusionFluoroscopy timeDislodgementAccess site complicationsImpedanceAndo (2023)Prospective, non-randomized, cohort studySingle-arm300Micra300N/AN/A30 days and 6 months51.3N/A82.6 ± 9.7N/AN/AN/A57N/A12.7N/A23.3N/A59N/A61.6 ± 9.5N/APericardial effusionDislodgementAccess site complicationsTotal complicationsData were expressed as median (interquartile range) or as the mean ± standard deviation (SD), or as a percentage (%)AF = atrial fibrillation; CAD = coronary artery disease; DM = diabetes mellitus; HTN = hypertension.
The quality assessment of the included studies was conducted using the ROBINS-I tool. Of the 55 studies, most demonstrated a “Moderate” risk of bias across most domains. Specifically, 24 studies were rated as having a “Serious” overall risk of bias, 4 studies were rated as having a “Critical” risk, and the remaining studies had a “Moderate” risk. Supplemental Figure 1 provides a detailed breakdown of the quality assessment results for each study.
In the single-arm analysis of LP studies, the pooled proportion of infections across 7 studies was 0.00 (95% CI, 0.00–0.00; I^2^ = 0%) (Supplemental Figure 2). Subgroup analysis by follow-up duration showed a pooled infection rate of 0.00 (95% CI, 0.00–0.00; I^2^ = 0%) for short-term follow-up and 0.00 (95% CI, 0.00–0.01; I^2^ = 20%) for long-term follow-up (Supplemental Figure 3), highlighting a consistently low rate of infections across different study durations.
In the double-arm analysis, 10 studies were included, with an overall RR for infection of 0.72 (95% CI, 0.22–2.35; P = .59; I^2^ = 100%, event 6.6% [LP] vs 2.02% [TVP]), suggesting no statistically significant difference between the LP and TVP groups (Figure 2A). Subgroup analyses based on follow-up duration showed that in the short-term, the RR was 1.99 (95% CI, 0.26–15.20; P = .52; I^2^ = 79%), whereas in the long-term follow-up, the RR was 0.40 (95% CI, 0.27–0.60; P < .0001; I^2^ = 36%) (Supplemental Figure 4), indicating a trend toward a lower infection risk with LP over longer durations, although not statistically significant. Subgroup analysis based on study design revealed an RR of 0.98 (95% CI, 0.21–4.53; I^2^ = 99.8%) in retrospective studies and an RR of 0.22 (95% CI, 0.04–1.24; I^2^ = 0%) in prospective studies, without a statistically significant difference between subgroups (P = .21). The LOO sensitivity analysis showed no substantial changes in the pooled effect size when individual studies were omitted, affirming the robustness of the findings (Supplemental Figure 5).Figure 2Forest plots of outcomes comparing TVPs vs LPs. A: Infection. B: Tamponade. C: Pericardial Effusion. D: Pneumothorax.
Six studies were included in the double-arm analysis comparing LP and TVP groups. The overall RR for endocarditis was 0.72 (95% CI, 0.21–2.46; P = .61, I^2^ = 100%, event 10.6% [LP] vs 1.99% [TVP]), indicating no statistically significant difference in endocarditis risk between the LP and TVP groups (Supplemental Figure 6). Subgroup analysis by study design showed an RR of 0.71 (95% CI, 0.17–2.99; I^2^ = 99.8%) in retrospective studies and an RR of 0.41 (95% CI, 0.02–10.06) in the single prospective study, with no significant difference between subgroups (P = .76). In the LOO sensitivity analysis, omitting the Vincent et al^22^ study resulted in a notable shift in the pooled RR, which dropped to 0.51 (95% CI, 0.47–0.56; P < .0001, I^2^ = 0%), suggesting a statistically significant lower risk of endocarditis associated with LP when this study is excluded. Additionally, the heterogeneity reduced to I^2^ = 0%, indicating that the Vincent et al^22^ study contributed significantly to the observed heterogeneity in the overall analysis. The omission of other studies did not lead to substantial changes (Supplemental Figure 7).
In the single-arm analysis of LP studies, the pooled proportion of tamponade events across 12 studies was 0.01 (95% CI, 0.00–0.01; I^2^ = 75%), reflecting a low incidence of tamponade among LP patients (Supplemental Figure 8). 8 studies were included in the double-arm analysis comparing the LP and TVP groups. The overall RR for tamponade was 2.36 (95% CI, 1.26–4.43; P = .007, I^2^ = 50%, event 0.84% [LP] vs 0.46% [TVP], number needed to harm [NNH] = 265), indicating a statistically significant higher risk of tamponade in the LP group compared with the TVP group (Figure 2B). Subgroup analysis based on study design revealed an RR of 2.86 (95% CI, 1.77–4.61; I^2^ = 65.7%) in retrospective studies and an RR of 0.73 (95% CI, 0.16–3.34; I^2^ = 0%) in prospective studies.
The LOO sensitivity analysis revealed important nuances. Omitting the Mararenko et al^23^ study reduced heterogeneity to I^2^ = 8% while maintaining a statistically significant RR of 2.10 (95% CI, 1.40–3.17; P < .001), supporting the robustness of the increased tamponade risk associated with LP.^23^ Omitting the Vincent et al^22^ study, which contributed significantly to the overall weight (44.8%), resulted in a slightly reduced RR of 2.07 (95% CI, 0.76–5.62; P = .15, I^2^ = 45%). Although this RR still favored an increased risk with LP, the CI included 1, leading to a lack of statistical significance (Supplemental Figure 9).
In the single-arm analysis focusing exclusively on LP patients, the pooled proportion of PE across 20 studies was 0.01 (95% CI, 0.01–0.01; I^2^ = 93%) (Supplemental Figure 10). Subgroup analysis by device type indicated a PE rate of 0.01 (95% CI, 0.00–0.01; I^2^ = 0%) for the Aveir device and 0.01 (95% CI, 0.01–0.01; I^2^ = 93%) for the Micra device (Supplemental Figure 11). Subgroup analysis by follow-up duration indicated a pooled mortality of 0.01 (95% CI, 0.01–0.1; I^2^ = 75%) for short-term follow-up and 0.01 (95% CI, 0.00–0.03; I^2^ = 94%) for long-term follow-up (Supplemental Figure 12). Subgroup analysis based on study design showed an RR of 1.37 (95% CI, 0.95–1.97; I^2^ = 51.5%) in retrospective studies and an RR of 0.54 (95% CI, 0.20–1.43; I^2^ = 0%) in prospective studies, with no statistically significant difference between the subgroups (P = .08).
In the double-arm analysis comparing LP with TVP groups, 9 studies were included. The pooled RR for PE was 1.22 (95% CI, 0.84–1.77; P = .3; I^2^ = 38%, event 0.95% [LP] vs 1.02% [TVP]), indicating no statistically significant difference in the risk of PE between LP and TVP groups (Figure 2C). Subgroup analyses stratified by follow-up duration revealed varying outcomes. In the short-term follow-up, the RR was 1.19 (95% CI, 0.77–1.85; P = .44; I^2^ = 48%), whereas the long-term follow-up analysis indicated an RR of 0.56 (95% CI, 0.20–1.57; P = .27; I^2^ = 0%) (Supplemental Figure 13).
The LOO sensitivity analysis provided additional insights. Omitting the Garweg et al^24^ study reduced heterogeneity to I^2^ = 24%. It slightly altered the pooled RR to 1.30 (95% CI, 1.00–1.69; P = .05), reaching statistical significance, suggesting a marginally increased risk of PE associated with LP when this study is excluded. Additionally, omitting the Piccini et al^1^ study resulted in a lower pooled RR of 1.05 (95% CI, 0.85–1.29; P = .65), with heterogeneity reaching I^2^ = 0%. This aligns with the overall findings but remains statistically insignificant (Supplemental Figure 14).
For the outcome of pneumothorax, we analyzed data from 9 double-arm studies comparing LP to TVP. The overall pooled RR for pneumothorax was 0.29 (95% CI, 0.10–0.82; P = .019; I^2^ = 40%, event 0.14% [LP] vs 0.93% [TVP], number needed to treat [NNT] = 128), favoring LP over TVP and demonstrating statistical significance, suggesting a lower risk of pneumothorax associated with LP (Figure 2D). Subgroup analysis by study design showed consistent findings across retrospective (RR, 0.30; 95% CI, 0.06–1.40; I^2^ = 59%) and prospective (RR, 0.19; 95% CI, 0.02–1.56; I^2^ = 0%) studies, with no significant subgroup difference (P = .73). In the LOO sensitivity analysis, omitting the study by Piccini et al^1^ notably impacted heterogeneity, reducing the I^2^ to 0%. The pooled RR also decreased to 0.32 (95% CI, 0.20–0.53; P < .0001), maintaining statistical significance and further supporting a reduced risk of pneumothorax with LP (Supplemental Figure 15).
In the single-arm analysis of LP studies, 9 studies were included with a pooled dislodgement rate of 0.00 (95% CI, 0.00–0.01; I^2^ = 85%) (Supplemental Figure 16). Subgroup analysis by device type revealed a slight the Aveir subgroup, with 2 studies, showed a dislodgement rate of 0.03 (95% CI, 0.00–0.96; I^2^ = 68%), whereas the Micra subgroup demonstrated a pooled dislodgement rate of 0.00 (95% CI, 0.00–0.01; I^2^ = 54%) (Supplemental Figure 17).
9 studies comparing LP and TVP groups were included in the double-arm analysis. The overall RR for dislodgement was 0.21 (95% CI, 0.16–0.28; P < .0001; I^2^ = 0%, event 0.36% [LP] vs 2.29% [TVP], NNT = 52), favoring LP with a lower dislodgement risk than TVP (Figure 3A). Subgroup analysis based on follow-up duration demonstrated that the RR for dislodgement during short-term follow-up was 0.17 (95% CI, 0.12–0.24; P < .0001; I^2^ = 0%), significantly favoring LP. Similarly, the long-term follow-up analysis showed a statistically significant RR of 0.29 (95% CI, 0.19–0.44; P < .0001; I^2^ = 0%). (Supplemental Figure 18). Study design subgroup analysis showed similar results between retrospective (RR, 0.22; 95% CI, 0.16–0.31; I^2^ = 24%) and prospective (RR, 0.10; 95% CI, 0.02–0.52; I^2^ = 0%) studies, with no significant difference between subgroups (P = .35). In the LOO sensitivity analysis, omitting any individual study did not significantly alter the pooled RR or heterogeneity (Supplemental Figure 19).Figure 3Forest plots of outcomes comparing TVPs vs LPs. A: Dislodgement. B: Access Site Complications.
In the single-arm analysis of LP studies, 20 studies were included with a pooled rate of access site complications of 0.01 (95% CI, 0.01–0.02; I^2^ = 91%) (Supplemental Figure 20). 11 studies comparing LP and TVP groups were included in the double-arm analysis. The overall RR for access site complications was 2.82 (95% CI, 1.79–4.44; P < .0001; I^2^ = 71%, event 2.03% [LP] vs 0.62% [TVP], NNH = 71), favoring the TVP group and indicating a significantly higher risk of access site complications associated with LP (Figure 3B). Subgroup analysis based on study design revealed consistent findings, with retrospective studies showing a pooled RR of 3.27 (95% CI, 2.39–4.49; I^2^ = 75%) and prospective studies showing a pooled RR of 2.38 (95% CI, 0.56–10.17; I^2^ = 62%), with no statistically significant difference between subgroups (P = .68). In the LOO sensitivity analysis, removing individual studies did not result in substantial changes in the pooled RR, with values remaining within a similar range and retaining statistical significance, thereby confirming the robustness of the results (Supplemental Figure 21). funnel plot (Supplemental Figure 22) was generated to assess publication bias in the analysis of access site complications, showing a symmetric distribution of studies (P = .59), which suggests no significant publication bias.
In the single-arm analysis of LP studies, 11 studies were included with a pooled rate of total complications of 0.04 (95% CI, 0.02–0.06; I^2^ = 96%) (Supplemental Figure 23). The subgroup analysis by follow-up duration showed similar pooled rates for short-term (0.04 [95% CI, 0.03–0.06; I^2^ = 95%]) and long-term (0.03 [95% CI, 0.01–0.07; I^2^ = 98%]) follow-up periods (Supplemental Figure 24). 7 studies comparing LP and TVP groups were included in the double-arm analysis. The overall RR for total complications was 0.66 (95% CI, 0.35–1.25; P = .2; I^2^ = 92%, event 5.29% [LP] vs 9.87% [TVP]), indicating a nonsignificant trend favoring LP with a lower complication risk than TVP (Figure 4). In the subgroup analysis by follow-up duration, the pooled RR was 0.86 (95% CI, 0.46–1.58; P = .64; I^2^ = 97%) for short-term and 0.47 (95% CI, 0.25–0.90; P = .02; I^2^ = 83%) for long-term follow-up, with a significant reduction in complication risk in the long-term favoring LP (Supplemental Figure 25). Additionally, subgroup analysis by study design showed a pooled RR of 0.76 (95% CI, 0.29–1.96; I^2^ = 92.9%) for retrospective studies and 0.45 (95% CI, 0.32–0.65; I^2^ = 61.6%) for prospective studies.Figure 4Forest plot of Total Complications comparing LPs vs TVPs.
To explore potential sources of heterogeneity, we conducted a meta-regression analysis. Patient age (Beta: −0.01 ± 0.02; P = .64) and the proportion of male patients (Beta: −0.88 ± 2; P = .66) were not significant predictors of heterogeneity. However, the percentage of patients with diabetes was positively associated with total complications (Beta: 1.78 ± 0.75; P = .02), suggesting a higher risk in cohorts with more patients with diabetes. The proportion of patients with hypertension showed a potential inverse association (Beta: −2.85 ± 1.75; P = .1), although it did not reach statistical significance (Supplemental Figure 26A–D).
In the LOO sensitivity analysis, omitting the study by Alhuarrat et al^25^ resulted in a notable change, with the pooled RR becoming statistically significant at 0.57 (95% CI, 0.41–0.80; P < .01; I^2^ = 87%), indicating a significantly lower risk of total complications associated with LP when this study is excluded (Supplemental Figure 27).
The meta-analysis of all-cause mortality included data from both single-arm studies focusing exclusively on LP patients and double-arm studies comparing LP and TVP groups. In the single-arm analysis of LP studies, the pooled proportion of all-cause mortality across 14 studies was 0.08 (95% CI, 0.03–0.16; I^2^ = 99%) (Supplemental Figure 28). When analyzed by device type, the Aveir subgroup, with 1 study, had a mortality rate of 0.01 (95% CI, 0.00–0.03), whereas the Micra subgroup had a pooled mortality rate of 0.09 (95% CI, 0.04–0.18; I^2^ = 99%) (Supplemental Figure 29). Subgroup analysis by follow-up duration indicated a pooled mortality of 0.04 (95% CI, 0.01–0.11; I^2^ = 97%) for short-term follow-up and 0.08 (95% CI, 0.03–0.19; I^2^ = 95%) for long-term follow-up (Supplemental Figure 30).
8 studies were included in the double-arm analysis, which compared LP and TVP groups. The overall RR for all-cause mortality was 1.23 (95% CI, 0.64–2.37; P = .54; I^2^ = 100%, event 5.67% [LP] vs 1.48% [TVP]), indicating no statistically significant difference between the LP and TVP groups (Figure 5). Subgroup analyses based on follow-up duration showed differing for short-term follow-up, the RR was 1.96 (95% CI, 1.01–3.81; P = .46; I^2^ = 99%), whereas the long-term follow-up analysis yielded an RR of 0.57 (95% CI, 0.35–0.92; P = .02; I^2^ = 79%) (Supplemental Figure 31), suggesting a potential mortality benefit for the LP group in the long term. Moreover, study design subgroup analysis revealed a pooled RR of 1.44 (95% CI, 0.63–3.29; I^2^ = 99.7%) for retrospective studies and 0.75 (95% CI, 0.36–1.59; I^2^ = 80.4%) for prospective studies, with no statistically significant difference between the subgroups (P = .26).Figure 5Forest plot of all-cause mortality comparing LPs vs TVPs.
To further explore sources of heterogeneity, we conducted a meta-regression analysis. Age (Beta: 0.03 ± 0.34; P = .92), the proportion of male patients (Beta: −11.2 ± 11.31; P = .32), and the proportion of patients with hypertension (Beta: 1.72 ± 4.89; P = .73) were not significant predictors of mortality. However, the percentage of patients with diabetes was significantly associated with increased all-cause mortality (Beta: 10.64 ± 4.85; P = .03), suggesting that diabetic status may play a role in mortality risk among these patients (Supplemental Figure 32A–D).
In the LOO sensitivity analysis, omitting individual studies did not lead to significant shifts in the pooled effect size, confirming the robustness of the findings (Supplemental Figure 33).
In the single-arm analysis of LP studies, a total of 22 studies were included, yielding a pooled mean pacing capture threshold of 0.63 (95% CI, 0.55–0.72; I^2^ = 97%) Figure 6A (Supplemental Figure 34). In the subgroup analysis by device, the Aveir studies demonstrated a pooled mean threshold of 0.72 (95% CI, 0.47–0.96; I^2^ = 87%), whereas the Micra subgroup had a slightly lower threshold of 0.61 (95% CI, 0.53–0.70; I^2^ = 96%), as shown in Supplemental Figure 35. Further subgroup analysis by follow-up duration indicated that short-term follow-ups had a pooled mean pacing capture threshold of 0.64 (95% CI, 0.55–0.73; I^2^ = 96%), compared with 0.62 (95% CI, 0.51–0.73; I^2^ = 97%) for long-term follow-ups (Supplemental Figure 36).Figure 6Forest plots of TVP vs. LP. (A) pacing capturing threshold, (B) Impedance, (C) mean difference of procedure time, (D) Mean difference of fluoroscopic time.
Three studies were included in the double-arm analysis comparing LP to TVP. The overall mean difference (MD) in the pacing capture threshold was −0.03 (95% CI, −0.25 to 0.19; I^2^ = 89%), showing no statistically significant difference between LP and TVP groups (Supplemental Figure 37A). Subgroup analysis by follow-up duration revealed an MD of 0.37 (95% CI, −0.14 to 0.88; I^2^ = 99%) in the short-term group and 0.07 (95% CI, −0.49 to 0.63; I^2^ = 82%) in the long-term group, both without statistical significance (Supplemental Figure 38). In the LOO sensitivity analysis, removing individual studies did not substantially alter the pooled MD, with consistently non-significant values within a similar range (Supplemental Figure 39). For the Micra vs Aveir comparison, the pooled MD in pacing capture thresholds at implantation was −0.22 (95% CI, −0.30 to −0.14; I^2^ = 0%), favoring Micra with a statistically significant lower threshold. At 3 months, the MD was −0.08 (95% CI, −0.16 to −0.00; I^2^ = 0%), also favoring Micra without a statistically significant difference (Supplemental Figure 40).
In the single-arm analysis of LP studies, 20 studies were included with a pooled mean impedance of 621.85 (95% CI, 581.17–662.53; I^2^ = 97%) (Supplemental Figure 41). Subgroup analysis by device type showed a pooled mean impedance of 625.99 (95% CI, 406.89–845.09; I^2^ = 96%) Figure 6B for the Aveir device and 621.79 (95% CI, 580.53–663.05; I^2^ = 98%) for the Micra device (Supplemental Figure 42). A further subgroup analysis by follow-up duration revealed a mean impedance of 723.10 (95% CI, 670.93–775.28; I^2^ = 99%) for short-term follow-up and 616.08 (95% CI, 578.19–653.96; I^2^ = 97%) for long-term follow-up (Supplemental Figure 43).
In the double-arm analysis comparing LP to TVP, 4 studies were included, with an overall MD in impedance of 54.78 (95% CI, −28.8 to 138.35; I^2^ = 94%), showing no statistically significant difference between the 2 groups (Supplemental Figure 37B). Subgroup analysis by follow-up duration yielded an MD of 59.79 (95% CI, −16.42 to 136.0; I^2^ = 91%) for short-term follow-up and -8.68 (95% CI, −89.09 to 71.47; I^2^ = 94%) for long-term follow-up, both indicating no significant difference in impedance (Supplemental Figure 44). The LOO sensitivity analysis, excluding the study by Tachibana et al^26^, resulted in a significant MD of 89.31 (95% CI, 23.38 to 155.25; I^2^ = 91%) (Supplemental Figure 45). For the comparison between Micra and Aveir devices, the pooled MD in impedance at implantation was 68.79 (95% CI, −145.39 to 282.97; I^2^ = 96%), favoring Aveir, though not statistically significant. At 3 months, the MD was −16.34 (95% CI, −113.65 to 80.97; I^2^ = 72%), favoring Micra, also without statistical significance (Supplemental Figure 46).
The single-arm analysis included 15 studies reporting procedure time for LPs, yielding a pooled mean procedure time of 42.21 minutes (95% CI, 34.37–50.05; I^2^ = 100%) (Supplemental Figure 47). In the double-arm analysis, 4 studies comparing procedure durations between LP and TVP were pooled, resulting in an MD of −12.99 minutes (95% CI, −35.44 to 9.46; I^2^ = 99%), favoring LP with shorter procedure times. Although, this was not statistically significant (Supplemental Figure 37C). However, omitting the Bertelli et al^27^ study in the LOO sensitivity analysis led to a statistically significant MD of −23.44 minutes Figure 6C (95% CI, −33.73 to −13.15; I^2^ = 84%) (Supplemental Figure 48).
Seventeen studies were included in the single-arm analysis of LP studies, resulting in a pooled fluoroscopy duration of 7.09 minutes (95% CI, 5.17–9.02; I^2^ = 100%) (Supplemental Figure 49). In the double-arm analysis, 3 studies comparing the LP and TVP groups were analyzed, yielding an overall MD in fluoroscopy duration of 2.19 minutes (95% CI, −1.02 to 5.40; I^2^ = 98%), Figure 6D indicating no statistically significant difference in fluoroscopy time between LP and TVP (Supplemental Figure 37D). The LOO sensitivity analysis revealed no substantial change in the overall MD when individual studies were removed. However, omitting the Bertelli et al^27^ study notably reduced heterogeneity to I^2^ = 5%. (Supplemental Figure 50). For the comparison between Micra and Aveir devices, the pooled MD in fluoroscopy duration was −2.92 minutes (95% CI, −6.83 to 1.00; I^2^ = 93%), favoring Micra, though not statistically significant (Supplemental Figure 51).
The certainty of evidence was assessed using the GRADE approach. The certainty was rated moderate for tamponade, pneumothorax, dislodgement, and PE, indicating moderate confidence in the estimated effects. Outcomes such as total complications, access site complications, all-cause mortality, infection, fluoroscopy duration, and impedance were rated as having low certainty, mainly because of concerns regarding the risk of bias and inconsistency. Very low certainty was assigned to endocarditis, pacing capture threshold, and procedure duration, primarily because of the serious risk of bias, inconsistency, and imprecision. Detailed GRADE assessments for all outcomes are presented in Supplementary Table 1.
This systematic review and meta-analysis, comprising 55 studies with a total of 286,349 patients, offers a comprehensive comparison between LPs and traditional TVPs in terms of clinical outcomes. To our knowledge, this study is the first to analyze the safety and efficacy of the Aveir LP in comparison with the Micra and TVPs. Key findings include the (1) LPs demonstrated a significantly reduced risk of pneumothorax and lead dislodgement, suggesting they may offer an enhanced safety profile over TVPs; (2) all-cause mortality, infection, endocarditis, and PE rates were comparable between LP and TVP groups. Although subgroup analyses showed a directional trend suggesting a possible long-term benefit with LPs, this observation should be interpreted cautiously. Further studies are needed to substantiate this potential association; and (3) LPs were associated with a higher incidence of cardiac tamponade and access site complications, underscoring the need for careful patient selection and procedural caution with these devices.
A recent nationwide study by Bodin et al^28^ in 2022 demonstrated that patients with LPs had a reduced rate of all-cause and cardiovascular death within the first 30 days post-implantation. However, during extended follow-up (mean: 8.6 ± 10.5 months), the risk of all-cause mortality was elevated in the unmatched LP cohort relative to TVP patients, with no significant difference observed for cardiovascular death or endocarditis.^28^ In contrast, the Micra CED Study reported no significant difference in adjusted 3-year all-cause mortality rates between patients with ventricular LP and TVP, presenting a hazard ratio of 0.97 (95% CI, 0.92–1.03). This suggests that although LPs may reduce procedural complications, they do not consistently confer a mortality benefit compared with transvenous devices.^29^ A meta-analysis by Oliveira et al^10^ also supported these findings, revealing no significant difference in overall all-cause mortality in unadjusted analyses and similarly nonsignificant results in multivariate-adjusted studies.
In our analysis of all-cause mortality, the single-arm study of LP patients revealed a pooled mortality rate of 0.08 (95% CI, 0.03–0.16); Micra demonstrated a higher rate than Aveir, although there was only 1 study reporting this outcome for the Aveir device compared with 13 studies for the Micra device. Mortality was lower in the short-term compared with long-term follow-up. In the double-arm comparison of LPs and TVPs, the overall RR for mortality was 1.23 (95% CI, 0.64–2.37), indicating no significant difference between the 2 groups. However, subgroup analysis showed a potential long-term mortality benefit for LPs, suggesting a lower mortality risk in the long term compared with TVPs.
Clinical observations revealed that the Micra atrioventricular LP exhibited a lower major complication rate at 12 months (range, 1.5%–3.7%), in contrast to the rate for dual-chamber TVPs (range, 7.6%–8.8%).^24^^,^^30^ Additionally, across 5 years, the Micra LP maintained a major complication rate of 4.5%, lower than the 8.5% observed in transvenous systems.^31^ Recent research showed that traditional pacemakers, with a complication rate of up to 15% within 3 years, faced issues largely related to infections and lead-related complications—risks largely mitigated by leadless systems, which avoid pocket hematomas and lead dislodgement.^32^^,^^33^ Revision rates were notably lower for the Micra LP (1.5% vs 5.5% for TVPs), highlighting the reliability of LP systems in clinical practice.^24^
Nevertheless, LPs are not without limitations. Previous studies, including those by Chaika et al,^34^ indicated an increased risk of access site complications and higher in-hospital mortality with LPs. These complications stem from the challenges of percutaneous insertion, including femoral vascular complications, the need for intra-operative repositioning, and a moderate risk of cardiac perforation leading to PE and tamponade. The slightly higher perforation risk observed with LPs likely reflects the learning curve associated with this novel technology.^5^ This underscores the need for refined procedural techniques and improved patient selection criteria for LPs. It is important to recognize that the choice of vascular access site carries distinct clinical implications. Subclavian vein catheterization has been associated with a lower risk of bloodstream infection and symptomatic thrombosis compared with jugular or femoral access. However, it carries a higher risk of pneumothorax owing to its anatomical proximity to the lung apex. In contrast, femoral access eliminates the risk of pneumothorax but may be associated with vascular site complications such as hematoma or infection. Understanding these differences is essential for weighing the risks and benefits of each access approach in clinical practice.^35^
Infection rates, however, remain notably low in LPs, as exemplified by Micra and Aveir systems, which reported negligible infections in long-term follow-ups. LPs also demonstrate minimized risks for endocarditis and pneumothorax, attributable to their design that eliminates leads, a common site of bacterial colonization. However, they present risks like right ventricular-only pacing, perforation, unclear lifecycle management, and lack of defibrillator integration.^36^
In comparative analyses by Oliveira et al,^10^ LPs demonstrated a lower risk for overall complications, lead dislodgement, and pneumothorax. However, they presented a higher risk for PE and tamponade. A meta-analysis by Gangannapalle et al^11^ confirmed similar patterns, with LPs associated with reduced total complications, device-related issues, and risks for pneumothorax and endocarditis but an increased risk for PE.
In our analysis of LPs-related complications, the infection rate across the included studies was negligible, with no significant difference in infection risk compared with TVPs. Regarding endocarditis, there was no significant difference between LPs and TVPs, though the removal of a study^22^ after LOO sensitivity analysis suggested a lower risk of endocarditis with LP. For tamponade, LP showed a higher risk. PE risks were similar between LPs and TVPs. Although subgroup analyses stratified by follow-up duration showed directionally different results—with the short-term group slightly favoring TVPs and the long-term group favoring LPs—neither reached statistical significance, and thus no definitive advantage can be concluded. LPs, however, demonstrated a significantly lower risk of pneumothorax compared with TVPs.
Dislodgement rates were lower with LPs, especially in the long term. Access site complications were higher in LPs compared with TVPs, and the total complication rate was slightly lower for LPs, with a significant reduction in long-term complications. These findings highlight both the advantages and risks of LPs compared with TVPs, with certain complications favoring LPs and others favoring TVPs.
The overall safety of LPs has been a growing focus in cardiac pacing research, with studies highlighting their feasibility and favorable safety profiles.^10^^,^^25^^,^^37^^,^^38^ Expanding on this evidence, our results suggested a trend toward fewer complications with LPs compared with TVPs, although the difference is not statistically significant. When assessing follow-up duration, short-term outcomes indicate a similar complication risk between the 2 devices. However, in the long term, LPs demonstrate a clear reduction in complications, suggesting a potential advantage. Although ongoing research will continue to refine patient selection and long-term outcomes, current evidence supports their safety and expanding clinical adoption.
Comparing device efficiencies, in a cohort of 67 included patients, Micra VR exhibited a lower capture threshold relative to Aveir VR, indicating potential pacing efficiency advantages.^39^ Both devices showed parity in R-wave sensing and pacing percentage over time, with comparable impedance values recorded at implantation and subsequent follow-up intervals. Additionally, the Micra VR demonstrated a shorter procedural time than Aveir VR, potentially reducing radiation exposure owing to shorter fluoroscopy time.^39^
In a systematic review and meta-analysis by Ohn et al,^40^ findings indicated no significant difference in device performance between LPs and TVPs at the time of implantation regarding lead threshold. However, on follow-up, LPs showed a significant reduction in lead threshold. In terms of R-wave sensing, there was no difference between the 2 groups both at implantation and follow-up. Additionally, TVPs demonstrated a higher lead impedance during implantation, but no significant difference was observed during follow-up. In our analysis, the pooled capture threshold MD was −0.03 (95% CI, −0.25 to 0.19), with no significant difference between LPs and TVPs. There were no significant differences in impedance, procedure duration, or fluoroscopy time between LPs and TVPs.
Although the difference in procedural duration and fluoroscopy time between LPs and TVPs was not statistically significant, this finding should be interpreted with caution. Procedural metrics may be influenced by heterogeneity in operator experience and institutional familiarity with the respective device platforms. In particular, newer systems such as the Aveir may be subject to a learning curve, wherein implantation efficiency could improve with cumulative procedural exposure. As the technology matures and operator experience accumulates, these procedural metrics may evolve, underscoring the need for future studies to more accurately assess procedural performance over time.
Our study carries significant clinical implications, providing important insights into the safety and efficacy of LPs compared with TVPs, particularly with regard to long-term outcomes. Notably, most of the significant findings, including the reduced risks of pneumothorax and lead dislodgement with LPs, and the increased risk of cardiac tamponade, were supported by moderate-certainty evidence. These results indicate that LPs offer a clinically relevant safety advantage by reducing complications related to traditional transvenous leads, such as pneumothorax and lead dislodgement. However, this advantage must be carefully weighed against the increased incidence of cardiac tamponade. Although this risk remains a key concern, it may in part reflect the novelty of the technology and varying levels of operator experience. It is plausible that, with further refinements in device design and growing operator familiarity, the risk of cardiac tamponade associated with LP implantation may decline. Nonetheless, this remains a theoretical consideration and requires validation in future studies. It is important to highlight that the evidence regarding access site complications, although statistically significant, was rated as low certainty, which should be considered when interpreting this finding. This underscores the importance of meticulous patient selection and procedural expertise when opting for LP implantation. Several other outcomes demonstrated low or very low certainty, mostly relating to secondary outcomes without significant associations.
Furthermore, as LPs gained widespread adoption, our analysis includes data from both high-volume, experienced centers and those with limited prior experience. This diverse representation helps account for variability related to the implanter learning curve, thereby strengthening the generalizability of our findings across different clinical settings. By highlighting both the advantages and risks associated with LPs, our study provides critical evidence to inform clinical decision-making, guiding practitioners in optimizing patient selection, and procedural strategies to maximize safety and efficacy in real-world practice.
Our meta-analysis has several limitations. First, all included studies were observational, limiting our ability to control for confounding factors and draw causal conclusions. Second, most studies focused on the Micra LP, which may not fully represent other devices like Aveir, affecting the generalizability of our results. Additionally, owing to the small number of studies reporting Aveir outcomes, we were unable to perform a rigorous meta-analysis for all outcomes in the comparison of Aveir vs Micra, which limits the depth of our device-specific findings. Third, there was heterogeneity in follow-up durations and the proportion of genders across studies, although subgroup analyses by follow-up duration and device type, and the inclusion of both single-arm and comparative studies, helped address these factors. Fourth, we were unable to perform subgroup analyses on different RV pacing subtypes, such as single-chamber and dual-chamber pacing, which could have provided additional insights. The reason for this limitation is the fact that the double-arm studies included in our meta-analysis predominantly compared single-chamber TVPs to single-chamber LPs, maintaining clinical comparability between groups. Moreover, inconsistencies in defining pacing capture thresholds (eg, ≤2 V vs 1.5 V) could introduce variability and limit the robustness of our findings. Sensitivity parameters such as R-wave sensing were not consistently available across the included studies, and therefore could not be systematically assessed. An additional limitation is the current inability of LPs to support conduction system pacing, such as His-bundle or left bundle branch pacing, which are increasingly recognized for their physiological benefits. Because LPs are typically implanted in the right ventricular septum or apex, they do not directly engage the native conduction pathways, potentially limiting their utility in patients requiring more physiologic pacing strategies.^41^ Future advancements in leadless pacing technology may address this gap. Finally, excluding abstracts and conference proceedings may have introduced publication bias, although fully published studies are generally more reliable. Further studies, particularly on devices like Aveir, are essential to refine our findings and guide clinical practice.
In conclusion, our systematic review and meta-analysis highlight the distinct advantages and limitations of LPs compared with TVPs. LPs demonstrated reduced risks of pneumothorax, lead dislodgement, and total complications over the long term, underscoring their safety profile. However, higher risks of cardiac tamponade and access site complications emphasize the need for cautious patient selection. Although LPs offer comparable mortality rates and infection risks to TVPs, their procedural efficiency and low complication rates position them as a promising alternative.
To advance the field, future prospective studies are warranted to evaluate long-term outcomes with greater control for confounders, standardize reporting metrics such as pacing capture thresholds, and differentiate complication risks between femoral and subclavian access. Comparative data on the 2 available leadless devices, Micra and Aveir, remain scarce. In this review, we included all available evidence to compare them, but the small number of studies limits the strength of any conclusions. Dedicated head-to-head trials with larger and more diverse populations are needed to better define device-specific outcomes and guide clinical practice. Furthermore, studies examining long-term outcomes as operator experience increases and implantation techniques improve will be critical to understanding the evolving safety and efficacy profile of leadless pacing systems.