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\begin{document}

\title{Leadless versus Transvenous Single-Chamber Ventricular Pacemakers: Three
Year Follow-Up of the Micra CED Study}



\author[1]{George Crossley}%
\author[2]{Jonathan Piccini}%
\author[3]{Colleen Longacre}%
\author[3]{Lucas Higuera}%
\author[3]{Kurt Stromberg}%
\author[4]{Mikhael El-Chami}%
\affil[1]{Vanderbilt University Medical Center}%
\affil[2]{Duke Clinical Research Institute}%
\affil[3]{Medtronic Inc}%
\affil[4]{Emory University School of Medicine}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} The Micra Coverage with Evidence Development (CED)
Study is a novel comparative analysis of Micra (leadless VVI) and
transvenous single-chamber ventricular pacemakers (transvenous VVI)
using administrative claims data. \textbf{Objective:} To compare chronic
complications, device reinterventions, heart failure hospitalizations,
and all-cause mortality after 3 years of follow-up.~ \textbf{Methods:}
U.S. Medicare claims data linked to manufacturer device registration
information were used to identify Medicare beneficiaries with a \emph{de
novo} implant of either a Micra VR leadless VVI or transvenous VVI
pacemaker from March 9, 2017-December 31, 2018. Unadjusted and
propensity score overlap-weight adjusted Fine-Gray competing risk models
were used to compare outcomes at 3 years.~~ \textbf{Results:} Leadless
VVI patients (N=6,219) had a 32\% lower rate of chronic complications
and a 41\% lower rate of reintervention compared with transvenous VVI
patients (N=10,212) (chronic complication hazard ratio {[}HR{]} 0.68;
95\% CI, 0.59-0.78; reintervention HR 0.59; 95\% CI 0.44-0.78).
Infections rates were significantly lower among patients with a leadless
VVI (\textless{}0.2\% versus 0.7\%, P\textless{}0.0001). Patients with a
leadless VVI also had slightly lower rates of heart failure
hospitalization (HR 0.90; 95\% CI 0.84-0.97). There was no difference in
the adjusted 3-year all-cause mortality rate (HR 0.97; 95\% CI,
0.92-1.03).~ \textbf{Conclusion:} This nationwide comparative evaluation
of leadless VVI versus transvenous VVI \emph{de novo} pacemaker implants
demonstrated that the leadless group had significantly fewer
complications, reinterventions, heart failure hospitalizations, and
infections than the transvenous group at 3 years, confirming that the
previously reported shorter-term advantages associated with leadless
pacing persist and continue to accrue in the medium-to-long-term.%
\end{abstract}%



\sloppy


\textbf{Introduction}

The Micra Coverage with Evidence Development (CED) Study is a novel
comparative analysis of Micra (leadless VVI) and transvenous
single-chamber ventricular pacemakers (transvenous VVI) using Medicare
administrative claims data. This unique study allows the Centers for
Medicare and Medicaid Services (CMS) to provide coverage for leadless
pacemakers while continuing to assess the performance of the technology
as it becomes more widely implemented in real-world
practice.\textsuperscript{1} The acute (30-day), 6-month, and 2-year
outcomes have been previously reported,\textsuperscript{2,3} with
leadless VVI associated with higher rates of acute pericardial effusion
(0.8\% vs. 0.4\%), but lower rates of chronic complications and
reinterventions at both 6 months and 2 years of follow-up (31\% lower
rate of chronic complications (3.6\% vs. 6.5\%) and 38\% lower rate of
device reintervention (3.1\% vs. 4.9\%) at 2 years). The Micra CED Study
results have been consistent with the findings of the Micra
transcatheter pacing system (TPS) investigational device exemption (IDE)
study\textsuperscript{4} and Micra leadless pacemaker post-approval
registry (Micra PAR),\textsuperscript{5} demonstrating the utility of
real-world data in complementing traditional clinical and registry
studies as a source of evidence for insight into utilization, safety,
and outcomes in general practice. The Micra CED Study will continue to
follow leadless pacing patients in the Medicare population until CMS
determines there is enough evidence to support or negate national
coverage, making it a valuable source of evidence for comparative
performance of leadless and transvenous pacemakers into the medium- and
long-term. The study design also allows for the comparison of relevant
health care utilization endpoints. In the present analysis, we compare
for the first time rates of heart failure hospitalization between
patients implanted with a leadless VVI vs. transvenous VVI pacemaker.
The objective of this analysis is to compare and report on chronic
complications, device reinterventions, heart failure-related
hospitalizations, and all-cause mortality between leadless VVI and
transvenous VVI pacemakers after 3-years of study follow-up.

\textbf{Methods}

The overall Micra CED Study design has been described
previously.\textsuperscript{2,3,6} The purpose of the study is to
evaluate complications, utilization, and outcomes of the leadless VVI
pacing system in the US Medicare population. The primary objectives of
the Micra CED study were to estimate the acute (30-day) complication
rate and the 2-year survival rate associated with the leadless pacing
system. The study uses manufacturer device registry information to
identify Medicare beneficiaries implanted with a Micra leadless
pacemaker (Model MC1VR01, Medtronic, Inc) using a previously-described-
linking algorithm.\textsuperscript{6} The study also identifies a
contemporaneous cohort of patients implanted with a transvenous VVI
pacemaker from any manufacturer during the study period directly from
their Medicare claims. The study was approved by the Western
Institutional Review Board with a waiver of informed consent and is
registered on ClinicalTrials.gov (NCT03039712).

\emph{Data and Cohort Identification}

For this analysis, Medicare claims (inpatient, outpatient, and carrier)
and enrollment data were used to identify Medicare fee-for-service (FFS)
beneficiaries implanted with a leadless VVI or transvenous VVI pacemaker
from March 9, 2017 (the first date of Medicare coverage for leadless VVI
pacemakers) through December 31, 2018. Pacemaker implants were
identified using the International Classification of Diseases,
10\textsuperscript{th} Revision, Procedure Coding System (ICD-10) and
the Current Procedural Terminology (CPT) codes for inpatient and
outpatient implants respectively (\textbf{Appendix Table 1} ). The index
date for outcomes ascertainment was defined as the date of each
patient's first observed pacemaker implant procedure during the study
period. Patients with evidence of a prior cardiovascular implantable
electronic device (CIED) were excluded to facilitate comparison
of\emph{de novo} pacemaker implants and to reduce the risk of
misattribution of outcomes related to a prior device. Patients with less
than 12 months of continuous enrollment in FFS Medicare were excluded to
ensure that patient baseline clinical and demographic characteristics
could be adequately captured. Among the patients implanted with a
transvenous VVI pacemaker, the cohort was limited to patients implanted
in facilities with evidence of leadless implants over the same time
period, to increase the likelihood that patients in the study cohort
would have had access to and a chance to receive either system.
See\textbf{Appendix Figure 1} for the study cohort diagram.

\emph{Baseline and Implant Encounter Characteristics}

Patient demographic characteristics (age, sex, US region) were
ascertained using data from the CMS enrollment file. Patient baseline
comorbidities were defined as the presence of diagnosis and procedure
codes on any encounter claim during the 12 months prior to implant (see
full ICD-10 and CPT code list in \textbf{Appendix 2} .) Comorbidities
included end-stage renal disease (ESRD), renal dysfunction, coronary
artery disease, peripheral vascular disease, tricuspid valve disease,
atrial fibrillation, left bundle branch block, supraventricular
tachycardia, ventricular arrythmia, steroid use, diabetes, heart
failure, chronic obstructive pulmonary disease, hyperlipidemia, and
hypertension. History of any cardiovascular events and procedures (acute
myocardial infarction, coronary artery bypass graft, transcatheter
aortic valve, and percutaneous coronary intervention) were also
included. A Charlson Comorbidity Index (CCI) score was also calculated
for each patient.\textsuperscript{7} Characteristics of the implant
encounter hospitalization were also identified, including whether the
implant occurred in the inpatient or outpatient hospital setting,
whether the patient was admitted for the implant procedure
hospitalization through the emergency department, whether the patient
was implanted during the weekend, the time from admission to the implant
procedure, and whether the patient had a concomitant cardiac procedure
(transcatheter aortic valve replacement or atrial fibrillation ablation)
during the pacemaker implant procedure.

\emph{Outcomes}

This analysis focuses on chronic complications, device reinterventions,
heart failure-related hospitalizations and all-cause mortality at 3
years as acute complications have been reported
previously.\textsuperscript{2} Chronic complications have been reported
previously and include those prospectively defined using the relevant
ICD-10 and CPT codes as complications most likely attributable to the
implant procedure or device itself that may continue to occur or persist
outside the time period of the implant procedure. These included
embolism, thrombosis, device-related complications, including device
breakdown, dislodgment, infection, and pocket complications,
pericarditis, and hemothorax (\textbf{Appendix Table 2} ). Device
reinterventions were identified using the relevant procedure codes and
were defined as system revision, lead revision or replacement, system
replacement (e.g. replacing a leadless VVI with another leadless VVI),
system removal, switch to the alternative type of system (i.e. switch
from leadless VVI to transvenous VVI or transvenous VVI to leadless
VVI), upgrade to a dual chamber system, or upgrade to a cardiac
resynchronization therapy (CRT) device. A post-hoc composite endpoint of
any reinterventions requiring a wholly new device (composite of
replacement, system switch, removal, upgrade to dual chamber system,
upgrade to CRT) was also defined. The rationale for defining this
post-hoc endpoint was that these types of reinterventions are
particularly burdensome and costly to patients, providers, and payers.
Date of death was determined from the Medicare Beneficiary Summary File.

A heart failure-related hospitalization was defined as an inpatient
hospitalization with an ICD-10 diagnosis code for heart failure in the
primary position on an inpatient claim following discharge from the
implant procedure hospitalization or encounter. A composite endpoint of
heart failure hospitalization or death was also defined, as this is a
common measure in the heart failure literature.\textsuperscript{8} These
heart failure hospitalization endpoints were newly-defined for the
present analysis and were not previously reported on in the Micra CED
Study.\textsuperscript{2,3} Similar to reporting on upgrades to CRT,
heart failure hospitalizations can provide evidence of and serve as a
proxy measure for pacing-induced cardiomyopathy or potentially worsening
heart failure among pacemaker patients and may be useful for evaluating
long-term device performance. This novel endpoint is designed to be
hypothesis generating and is the first health care utilization-related
endpoint reported from the Micra CED Study. Medicare claims were
available through December 31, 2020; patients alive and without an event
were censored on that date.

\emph{Statistical Analysis}

The statistical adjustments used in the analysis were prespecified and
have been used for all comparative analyses of the Micra CED Study
cohort. Propensity score overlap weights\textsuperscript{9,10} were used
to account for differences in baseline and encounter characteristics
between the leadless-VVI and transvenous-VVI cohorts. Unadjusted and
overlap-weight adjusted 3-year complication, reintervention, and heart
failure hospitalization rates were estimated using the cumulative
incidence function. Fine-Gray competing risk models were used to compare
the unadjusted and adjusted risk for 3-year chronic complications,
device reinterventions, and heart failure hospitalizations between study
groups, and Cox proportional hazards models were used to compare
all-cause mortality and the composite of heart failure hospitalization
and all-cause mortality through 3 years. A sub-analysis of the heart
failure hospitalization endpoints was also conducted among patients in
the study cohort without a history of heart failure at baseline. Because
heart failure hospitalizations are not a primary or pre-specified
secondary endpoint of the Micra CED Study, the inclusion of this
endpoint is designed to be hypothesis-generating. Thus, no statistical
correction for the additional endpoint was made and all endpoints were
evaluated at a significance level of P\textless{}.05 and all P values
were 2-tailed. Events occurring in between one and 10 patients were
suppressed to protect beneficiary privacy as required by
CMS.\textsuperscript{11} All statistical analyses were conducted in SAS
version 9.4 (SAS Institute).

\textbf{Results}

There were 6,219 leadless and 10,212 transvenous \emph{de novo} implant
procedures identified during the study period contributing to the
analysis cohort (\textbf{Table 1} ). Patient baseline characteristics of
this cohort have been previously reported.\textsuperscript{3} Compared
with transvenous, patients implanted with a leadless VVI pacemaker were
more likely to have ESRD (12.0\% vs. 2.3\%, P\textless{}0.001), renal
dysfunction (48.8\% vs. 42.1\%, P\textless{}0.001), and a higher mean
Charlson Comorbidity Index score (5.1\selectlanguage{ngerman}±3.4 vs. 4.6±3.0,
P\textless{}0.001). Mean follow-up time for patients implanted with a
leadless VVI pacemaker was 675 days, compared to 727 days for
transvenous (P\textless{}0.001). After applying the propensity score
overlap weights, all measured baseline and encounter characteristics
were well balanced with all standardized mean differences near zero.
There were 2,937 patients implanted with a leadless VVI pacemaker and
4,821 patients implanted with a transvenous VVI pacemaker in the
sub-analysis of heart failure hospitalization endpoint analysis cohort
without a prior history of heart failure.

\emph{Chronic Complications}

\textbf{Table 2} shows the adjusted rates for chronic complications and
reinterventions. Chronic complication rates were significantly lower in
patients implanted with a leadless VVI pacemaker compared with the
transvenous (adjusted, 4.9\%, vs. 7.1\%, P\textless{}0.0001), driven by
lower device-related complication rates (adjusted 2.6\% vs. 5.2\%,
P\textless{}0.0001). In the time-to-event model, patients implanted with
a leadless pacemaker had significantly fewer overall chronic
complications at 3 years compared with patients implanted with a
transvenous pacemaker (\textbf{Figure 1A} ; unadjusted hazard ratio (HR)
0.73; 95\% CI 0.64--0.84, P= \textless{}0.0001; adjusted HR 0.68; 95\%
confidence interval (CI) 0.59--0.78, P\textless{} 0.0001). Unadjusted
chronic complication rates are shown in \textbf{Appendix Table 3.}

\emph{Reinterventions}

Reintervention rates were also significantly lower in the patients
implanted with a leadless VVI pacemaker compared with the transvenous
(adjusted, 3.6\%, vs. 6.0\%, P=0.0002). System revisions, removals, and
upgrades to both dual chamber and CRT devices were significantly lower
in the patients implanted with a leadless VVI pacemaker compared with
the transvenous, while system replacements were significantly higher.
For the composite endpoint of reinterventions requiring a new device
(inclusive of system removal, system replacement, system switch or
upgrade to dual chamber or CRT), patients implanted with a leadless VVI
pacemaker had significantly fewer reinterventions requiring a new device
(adjusted, 3.6\% vs. 5.0\%, P=0.02). In the time-to-event model,
patients implanted with a leadless pacemaker had a lower rate of
reintervention compared with patients implanted with a transvenous
pacemaker (\textbf{Figure 1B} ; unadjusted HR 0.60; 95\% CI 0.45--0.80,
P=0.0006; adjusted HR 0.59; 95\% CI 0.44--0.78, P=0.0002). Unadjusted
reintervention rates are shown in \textbf{Appendix Table 3.}

\emph{Heart Failure Hospitalizations and All-Cause Mortality}

Heart failure hospitalization rates were slightly lower among patients
implanted with a leadless VVI pacemaker compared to transvenous in the
overall patient cohort (adjusted, 19.9\% vs. 22.0\%, P=0.005) as well as
among patients without prior history of heart failure (adjusted, 11.2\%
vs. 13.6\%), P=0.003) (\textbf{Appendix Table 4} ). In the time-to-event
models, patients with a leadless pacemaker had a slightly, but
significantly lower, rate of heart failure hospitalization compared with
patients implanted with a transvenous pacemaker through 3 years
(\textbf{Figure 1C} ; unadjusted HR 0.90; 95\% CI 0.84--0.97, P=0.006;
adjusted HR 0.90; 95\% CI 0.83--0.97, P=0.005). Among patients without
history of heart failure, the lower rates among patients implanted with
a leadless VVI pacemaker were more pronounced (unadjusted HR 0.83; 95\%
CI 0.72--0.94, P=0.005; adjusted HR 0.81; 95\% CI 0.71--0.93, P=0.003)
(\textbf{Appendix Figure 2} ).

The unadjusted 3-year all-cause mortality rate was significantly greater
in the patients implanted with a leadless VVI pacemaker compared with
the transvenous (HR, 1.09; 95\% CI, 1.03-1.15, P=0.003); however, there
was no difference in the adjusted 3-year all-cause mortality rate
between leadless and transvenous (\textbf{Figure 1D} ; HR, 0.97; 95\%
CI, 0.92-1.03, P=0.32) after accounting for differences in baseline
characteristics.

For the composite endpoint of time to heart failure hospitalization or
death, there was no difference in the unadjusted rates for either the
full cohort or those patients without history of heart failure (full
cohort: unadjusted HR 1.03; 95\% CI 0.98-0.1.08, P=0.28; sub-cohort:
unadjusted HR 1.00, 95\% CI 0.93-1.08, P=0.98). After statistical
adjustment, there were small differences, with patients implanted with a
leadless VVI pacemaker having slightly lower rates than transvenous
(full cohort: adjusted HR 0.94; 95\% CI 0.89-0.99, P=0.01; sub-cohort:
adjusted HR 0.92, 95\% CI 0.85-0.99, P=0.03) (\textbf{Appendix Figures
3A and 3B} ).

\textbf{Discussion}

In this nationwide comparative evaluation of 6,219 leadless VVI versus
10,212 transvenous VVI \emph{de novo} pacemaker implants, leadless VVI
pacemakers were associated with a 32\% reduction in the rate of chronic
complications and a 41\% reduction in the rate of reintervention at 3
years. These results build off of the published 2-year results of the
Micra CED Study, which showed a 31\% reduction in complications and a
38\% reduction in reinterventions at 2 years in this
cohort.\textsuperscript{3} Lower rates of complications among leadless
pacing patients have now been observed in both clinical trials and
real-world clinical practice.\textsuperscript{4,5} This present analysis
suggests the reductions in the risk of complications and reinterventions
associated with leadless pacing, previously seen at 6 months and 2 years
of follow-up, persist and continue to accrue in the medium-to-long-term.
This analysis provides valuable new information on the expected rate of
accrual of additional complications and need for system revision over
time. At the 3-year endpoint, most complications that patients continue
to experience are related to device (device breakdown, mechanical
failure, etc.) or pocket in the transvenous VVI arm. Because the
differential benefit of leadless pacing is largest with respect to these
device-related complications, it would be reasonable to assume that the
benefits observed at 2 and now 3 years would persist over longer time
horizons.

The present analysis also provides new insight into the robustness of
the 2-year results, particularly related to device reinterventions. This
present analysis found a 29\% lower rate of reinterventions requiring a
new device (device removal and replacement, and upgrades to dual-chamber
and CRT devices) among leadless VVI patients, demonstrating that the
lower rate of reintervention is not solely driven by the need for lead
revisions and lead-related reinterventions, which are less invasive and
costly than reinterventions requiring a whole new system.

As discussed in El-Chami et. al.,\textsuperscript{3} rates of device
reintervention can be influenced by both adverse events, like
pacing-induced cardiomyopathy, as well as patient selection. The
advantage that leadless pacemakers have in terms of absence of leads can
also be a limitation in that leadless pacemaker systems can be less
adaptable to modular upgrades, such as an addition of a CRT lead. The
current study shows no significant difference in all-cause mortality
after adjustment for differences in baseline patient characteristics and
a 10\% lower rate of heart failure hospitalizations at 3 years. These
results are comforting and suggest the reduction in reinterventions
observed among leadless-VVI patients are not coming at the expense of
worse pacing outcomes (such as untreated pacing-induced cardiomyopathy).
In fact, these results appear to bolster previous findings suggesting
lower rates of pacing-induced cardiomyopathy among patients implanted
with a leadless pacemaker, potentially due to greater frequency of
mid-septal placement associated with leadless
implants.\textsuperscript{12} It would be valuable to explore this
hypothesis further in a randomized clinical trial.

The Micra CED Study also continues to demonstrate the benefits of
leadless pacing with regards to device infection. While the total rate
of device infection requiring full device removal in the transvenous VVI
comparator arm is low (0.7\%), it is significantly higher than in the
leadless VVI arm. CMS reporting rules prevent us from displaying cell
values less than 10 in order to prevent patient identification. If we
assume that the value is actually 10, the infection rate requiring
device removal in the leadless group is only 0.16\%. Prior literature
has demonstrated the serious risk of patient mortality and other adverse
clinical and economic outcomes posed by device
infection.\textsuperscript{13}

To our knowledge, this is the first analysis to report on heart failure
hospitalizations among leadless pacing patients and is possible because
the large sample size and long-term follow-up of the Micra CED study
allows for the capture of an adequate number of events of interest. The
ability to capture and report on this endpoint highlights some of the
significant advantages of using real-world data to supplement
traditional clinical studies for post-market device evaluation.

\emph{Limitations}

There are several limitations inherent to this observational study using
administrative data. First, Medicare administrative claims data are a
secondary database used primarily for billing purposes, not for clinical
research purposes; therefore, traditional clinical adjudication is not
conducted. It is possible that reinterventions, complications, or
comorbidities could be missed, improperly coded, or inadequately
documented in administrative claims. However, our prior analyses suggest
that this probability is low,\textsuperscript{6} and, if anything,
claims-based studies tend to overestimate adverse
events.\textsuperscript{14} We would also not expect this to have a
differential impact between the two study arms. Second, as with any
observational study, the possibility of residual confounding following
statistical adjustment for measured confounders cannot be completely
eliminated. Third, because our study does not include device
interrogation data, we are unable to assess variables such as programmed
lower rates, pacing thresholds, and battery longevity which may be of
particular interest when assessing the need for device reintervention.
Finally, due to data availability, this analysis is limited to the
Medicare FFS population and does not capture outcomes beyond December
31, 2020.

\textbf{Conclusion}

In a real-world study of US Medicare patients, the leadless VVI
pacemaker was associated with a 32\% lower rate of chronic complications
(4.9\% vs. 7.1\%) and a 41\% lower rate of device reinterventions (3.6\%
vs. 6.0\%) at 3 years. Rates of heart failure hospitalization were
slightly lower among leadless VVI patients, and all-cause mortality
rates were similar among leadless VVI and transvenous VVI patients at 3
years, suggesting no trade-off between lower rates of device
reintervention and chronic right ventricular-only pacing outcomes for
patients. Infections rates were remarkably lower in the leadless group.
The Micra CED Study continues to illustrate the feasibility of utilizing
real-world data to generate evidence measuring the safety and
effectiveness of new technology and continues to complement existing
clinical evidence demonstrating the benefits of leadless pacing.

\textbf{Author Contributions:} All authors met the IJCME criteria for
authorship. All authors had access to the data according to the terms of
the data use agreement with CMS and all authors fully reviewed and vouch
for the accuracy of reported results. Academic authors had independent
final review and approval of publication.

\textbf{Data Availability Statement:} The authors are not owners of the
dataset (dataset is owned by the Centers for Medicare and Medicaid
Services) and do not have the right to share the data.

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  https://doi.org/10.1161/CIRCEP.119.008280.
\item
  El-Chami M, Piccini JP, Bockstedt L. In Reply: Leadless Pacing --
  Uncertainties Remain About Safety and Efficacy. JAMA Cardiology.
  Published Online: January 26, 2022. doi:10.1001/jamacardio.2021.5713.
\end{enumerate}

\textbf{Table 1: Baseline characteristics of patients undergoing\emph{de
novo} implantation with a leadless VVI pacemaker vs. a transvenous VVI
pacemaker}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Patient Characteristics} & \textbf{Leadless VVI (N=6,219)} &
\textbf{Transvenous VVI (N=10,212)} & \textbf{P-Value}\tabularnewline
\midrule
\endhead
\textbf{Demographic characteristics} & & &\tabularnewline
Age & 79.5 \selectlanguage{ngerman}± 9.5 & 82.0 \selectlanguage{ngerman}± 8.1 & \textless{}.0001\tabularnewline
Female, N (\%) & 2741 (44.1\%) & 4412 (43.2\%) & 0.28\tabularnewline
Midwest & 1,351 (21.7\%) & 2191 (21.5\%) & 0.69\tabularnewline
South & 2506 (40.3\%) & 3904 (38.2\%) & 0.01\tabularnewline
West & 1,307 (21.0\%) & 1,842 (18.0\%) & \textless{}.0001\tabularnewline
Northeast & 1,051 (16.9\%) & 2,266 (22.2\%) &
\textless{}.0001\tabularnewline
\textbf{Encounter characteristics} & & &\tabularnewline
Inpatient implant & 3,309 (53.2\%) & 5,790 (56.7\%) &
\textless{}.0001\tabularnewline
Days to implant & 2.5\selectlanguage{ngerman}±5.3 & 1.9\selectlanguage{ngerman}±3.6 & \textless{}.0001\tabularnewline
Weekend implant & 163 (2.6\%) & 353 (3.5\%) & 0.003\tabularnewline
Admission through the ED & 745 (12.0\%) & 1,105 (10.8\%) &
0.02\tabularnewline
\textbf{Clinical Characteristics} & & &\tabularnewline
ESRD & 744 (12.0\%) & 238 (2.3\%) & \textless{}.0001\tabularnewline
Diabetes & 2,805 (45.1\%) & 4,222 (41.3\%) &
\textless{}.0001\tabularnewline
Atrial fibrillation & 5,066 (81.5\%) & 9,088 (89.0\%) &
\textless{}.0001\tabularnewline
Congestive heart failure & 3,282 (52.8\%) & 5,391 (52.8\%) &
0.98\tabularnewline
Chronic Obstructive Pulmonary Disease & 1,931 (31.1\%) & 2,975 (29.1\%)
& 0.01\tabularnewline
Chronic steroid use & 246 (4.0\%) & 327 (3.2\%) & 0.01\tabularnewline
Coronary Artery Disease & 3,489 (56.1\%) & 5,447 (53.3\%) &
0.001\tabularnewline
Supraventricular tachycardia & 476 (7.7\%) & 534 (5.2\%) &
\textless{}.0001\tabularnewline
Ventricular arrythmia & 979 (15.7\%) & 1,403 (13.7\%) &
0.0004\tabularnewline
Hyperlipidemia & 4,770 (76.7\%) & 7,578 (74.2\%) & 0.0003\tabularnewline
Left bundle branch block & 334 (5.4\%) & 543 (5.3\%) &
0.88\tabularnewline
Peripheral vascular disease & 1,685 (27.1\%) & 2,736 (26.8\%) &
0.67\tabularnewline
Prior coronary artery bypass graft & 929 (14.9\%) & 1,460 (14.3\%) &
0.26\tabularnewline
Prior acute myocardial infarction & 1,242 (20.0\%) & 1,680 (16.5\%) &
\textless{}.0001\tabularnewline
Prior percutaneous coronary intervention & 979 (15.7\%) & 1,416 (13.9\%)
& 0.001\tabularnewline
Renal dysfunction & 3,034 (48.8\%) & 4,294 (42.1\%) &
\textless{}.0001\tabularnewline
Tricuspid valve disease & 1,795 (28.9\%) & 2,945 (28.8\%) &
0.97\tabularnewline
Transcatheter Aortic Valve Replacement & 106 (1.7\%) & 154 (1.5\%) &
0.33\tabularnewline
Concomitant atrial\textsuperscript{\textbf{+}} ablation & 861 (13.8\%) &
1,125 (11.0\%) & \textless{}.0001\tabularnewline
Concomitant TAVR & 170 (2.7\%) & 474 (4.6\%) &
\textless{}.0001\tabularnewline
Charlson Comorbidity Index & 5.1 \selectlanguage{ngerman}± 3.4 & 4.6 \selectlanguage{ngerman}± 3.0 &
\textless{}.0001\tabularnewline
Follow-up time (days) & 675 \selectlanguage{ngerman}± 364 & 727 \selectlanguage{ngerman}± 366 &
\textless{}.0001\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{\textbf{+}} Concomitant procedures are defined as those
occurring during the implant encounter. Atrial ablation includes CPT
codes 93650, 93653, 93656, 93657, 02583ZZ with diagnosis of atrial
fibrillation and may include atrial fibrillation as well as
atrio-ventricular node ablation

\textbf{Table 2. Adjusted reintervention and chronic complication rates
at 3-years in leadless VVI versus transvenous VVI pacemaker patients}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
& \textbf{Leadless VVI (N=6,219)} & \textbf{Leadless VVI (N=6,219)} &
\textbf{Transvenous VVI (N=10,212)} & \textbf{Transvenous VVI
(N=10,212)} & \textbf{Leadless VVI vs. Transvenous VVI} &
\textbf{Leadless VVI vs. Transvenous VVI}\tabularnewline
\midrule
\endhead
& \textbf{Observed Events (\%\textsuperscript{+})} & \textbf{3-Year
Adjusted CIF Estimates (95\% CI)} & \textbf{Observed Events
(\%\textsuperscript{+})} & \textbf{3-Year Adjusted CIF Estimates (95\%
CI)} & \textbf{Relative Risk Reduction (95\% CI)} &
\textbf{P-Value}\tabularnewline
\textbf{Chronic Complications} & & & & & &\tabularnewline
\textbf{Overall complications} & 310 (5.0\%) & 4.9\% (4.6\% - 5.2\%) &
699 (6.8\%) & 7.1\% (6.7\% - 7.6\%) & 32\% (22\% - 41\%) &
\textless{}.0001\tabularnewline
\textbf{Embolism and Thrombosis} & \textless{}11 (\textless{}0.2\%)* & *
& 28 (0.3\%) & 0.3\% (0.3\% - 0.3\%) & 56\% (6\% - 79\%) &
0.03\tabularnewline
Thrombosis due to cardiac device & \textless{}11 (\textless{}0.2\%)* & *
& 24 (0.2\%) & 0.2\% (0.2\% - 0.3\%) & 57\% (-2\% - 82\%) &
0.06\tabularnewline
Embolism due to cardiac device & \textless{}11 (\textless{}0.2\%)* & * &
\textless{}11 (\textless{}0.1\%)* & * & 16\% (-397\% - 86\%) &
0.85\tabularnewline
\textbf{Device-related complications++} & 172 (2.8\%) & 2.6\% (2.5\% -
2.7\%) & 538 (5.3\%) & 5.2\% (5.1\% - 5.3\%) & 51\% (41\% - 59\%) &
\textless{}.0001\tabularnewline
Breakdown & 91 (1.5\%) & 1.5\% (1.4\% - 1.8\%) & 218 (2.1\%) & 2.4\%
(2.1\% - 2.7\%) & 34\% (14\% - 50\%) & 0.002\tabularnewline
Dislodgement & 24 (0.4\%) & 0.4\% (0.3\% - 0.5\%) & 128 (1.3\%) & 1.3\%
(1.2\% - 1.6\%) & 71\% (53\% - 82\%) & \textless{}.0001\tabularnewline
Other mechanical failure & 64 (1.0\%) & 1.0\% (0.9\% - 1.2\%) & 117
(1.2\%) & 1.4\% (1.2\% - 1.6\%) & 26\% (-3\% - 47\%) &
0.08\tabularnewline
Infection & \textless{}11 (\textless{}0.2\%)* & * & 66 (0.7\%) & 0.7\%
(0.6\% - 0.9\%) & 96\% (82\% - 99\%) & \textless{}.0001\tabularnewline
Pain due to device & 0 (0.0\%) & * & \textless{}11 (\textless{}0.1\%)* &
* & * & NE\tabularnewline
Stenosis due to device & 29 (0.5\%) & 0.5\% (0.4\% - 0.6\%) & 37 (0.4\%)
& 0.4\% (0.3\% - 0.5\%) & -28\% (-113\% - 23\%) & 0.34\tabularnewline
Pocket complications & N/A & N/A & 146 (1.4\%) & 1.5\% (1.3\% - 1.7\%) &
NE & NE\tabularnewline
\textbf{Other complications} & 145 (2.3\%) & 2.1\% (2.0\% - 2.2\%) & 156
(1.5\%) & 1.5\% (1.4\% - 1.6\%) & -39\% (-76\% - -9\%) &
0.01\tabularnewline
Pericarditis & 104 (1.7\%) & 1.7\% (1.4\% - 1.9\%) & 84 (0.8\%) & 0.9\%
(0.8\% - 1.0\%) & -93\% (-161\% - -42\%) &
\textless{}.0001\tabularnewline
Hemothorax & 45 (0.7\%) & 0.7\% (0.6\% - 0.8\%) & 81 (0.8\%) & 0.9\%
(0.7\% - 1.0\%) & 22\% (-18\% - 48\%) & 0.24\tabularnewline
\textbf{Reinterventions} & & & & & &\tabularnewline
\textbf{Any reintervention} & 199 (3.2\%) & 3.6\% (3.2\% - 3.9\%) & 548
(5.4\%) & 6.0\% (5.5\% - 6.5\%) & 41\% (22\% - 56\%) &
0.0002\tabularnewline
\textbf{System reinterventions} & & & & & &\tabularnewline
Revisions & 11 (0.2\%) & 0.2\% (0.1\% - 0.3\%) & 59 (0.6\%) & 0.6\%
(0.5\% - 0.8\%) & 70\% (40\% - 85\%) & 0.0007\tabularnewline
Lead-related reinterventions & N/A & N/A & 69 (0.7\%) & 0.7\% (0.6\% -
0.9\%) & NE & NE\tabularnewline
Replacement & 74 (1.2\%) & 1.2\% (1.0\% - 1.5\%) & 53 (0.5\%) & 0.5\%
(0.4\% - 0.7\%) & -124\% (-290\% - -28\%) & 0.005\tabularnewline
System switch (replacement with opposite type of device) & 24 (0.4\%) &
0.5\% (0.4\% - 0.7\%) & 31 (0.3\%) & 0.4\% (0.3\% - 0.5\%) & -36\%
(-145\% - 25\%) & 0.31\tabularnewline
Removal & * & * & 88 (0.9\%) & 1.0\% (0.8\% - 1.2\%) & 98\% (83\% -
100\%) & 0.0002\tabularnewline
\textbf{Upgrades} & & & & & &\tabularnewline
Dual-chamber & 26 (0.4\%) & 0.5\% (0.3\% - 0.6\%) & 83 (0.8\%) & 0.9\%
(0.7\% - 1.1\%) & 49\% (15\% - 70\%) & 0.01\tabularnewline
CRT & 76 (1.2\%) & 1.5\% (1.3\% - 1.7\%) & 194 (1.9\%) & 2.2\% (1.9\% -
2.6\%) & 35\% (15\% - 50\%) & 0.002\tabularnewline
\textbf{Composite of reinterventions requiring new device+++} & 198
(3.2\%) & 3.6\% (3.2\% - 4.0\%) & 449 (4.4\%) & 5.0\% (4.5\% - 5.5\%) &
29\% (6\% - 46\%) & 0.02\tabularnewline
\bottomrule
\end{longtable}

CIF, Cumulative Incidence Function; CRT, Cardiac Resynchronization
Therapy, N/A: Not applicable; NE: Not estimable.

\textsuperscript{\textbf{+}} Observed percentage defined as number of
events divided by number of patients.

\textbf{++} Includes complications related to the mechanical integrity
of the device or codes explicitly stating device relatedness (e.g.
device dislodgement, device infection, device pocket complication).

\textbf{+++} Includes replacement, system switch, removal, upgrade to
dual-chamber, and upgrade to CRT.

*CMS cell suppression requirement for cell values between 1 and 10.

\textbf{Figure Legends:~}

\textbf{Figure 1. Adjusted time to event plots for chronic
complications, device reinterventions, heart failure hospitalizations,
and all-cause mortality out to 3 years of follow-up in patients treated
with leadless VVI versus transvenous VVI pacing.~} A) Hazard ratio (HR)
and cumulative incidence function for 3-year chronic complications based
on the Fine-Gray competing risk model.~ B) HR and cumulative incidence
function for 3-year device reinterventions based on the Fine-Gray
competing risk model. B) HR and cumulative incidence function for 3-year
heart failure hospitalizations based on the Fine-Gray competing risk
model. D) HR and patient mortality rates based on the Cox proportional
hazards model. CI = 95\% confidence interval.\textbf{~}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1A-ChronicComps/Figure1A-ChronicComps}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1B-Reint/Figure1B-Reint}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1C-HFH/Figure1C-HFH}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1D-Mortality/Figure1D-Mortality}

\end{center}
\end{figure}

\selectlanguage{english}
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\end{document}

