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Novel therapies in cardiac rhythm managementThe start of the leadless eraTjong, F.V.Y.

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Citation for published version (APA):Tjong, F. V. Y. (2018). Novel therapies in cardiac rhythm management: The start of the leadless era.

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Download date: 04 Jul 2020

Chapter 9

Permanent Leadless Cardiac Pacemaker Therapy – A Comprehensive ReviewCirculation. 2017;135:1458-1470.

Fleur V.Y. Tjong, MD and Vivek Y. Reddy, MD

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AbstractA new technology, leadless pacemaker therapy, was recently introduced clinically to address lead- and pocket-related complications in conventional trans-venous pacemaker therapy. These leadless devices are self-contained right ventricular single-chamber pacemakers implanted using a femoral percutaneous approach. In this review of available clinical data on leadless pacemakers, early results with leadless devices are compared to historical results with conventional single-chamber pacing.

Both presently manufactured leadless pacemakers show similar complications, which are mostly related to the implant procedure – cardiac perforation, device dislocation, and femoral vascular access site compli-cations. When compared to conventional transvenous single-chamber pacemakers, slightly higher short-term complication rates have been observed: 4.8% for lead-less pacemakers versus 4.1% for conventional pacemak-ers. The complication rate of the leadless pacemakers is influenced by the implanter learning curve for this new procedure. No long-term outcome data are yet available for the leadless pacemakers. Larger leadless pacing trials, with long-term follow-up and direct randomized comparison with conventional pacing systems, will be required to define the proper clinical role of these leadless systems. Though current leadless pacemakers are limited to right ventricular pacing, future advanced, communicating, multi-component systems are expected to expand the potential benefits of leadless therapy to a larger patient population.

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IntroductionAnnually, approximately 1 million new pacemakers are implanted worldwide, of which 250,000 are implanted in the United States (1) for bradyarrhythmias and heart block (2). Since the first pacemaker implants almost six de-cades ago, conventional transvenous pacemaker therapy has evolved tremendously, improving quality of life and reducing mortality in some at-risk patients (2-5). Despite these developments, this life-improving therapy is still associated with significant complications, mostly related to the transvenous lead and the subcutaneous genera-tor pocket. Short-term complication rates as high as 8-12% have been reported (6, 7), and include pneumothorax, cardiac tamponade, pocket hematoma, and lead dislodgement (8-10). Transvenous leads can cause complications such as venous obstruction, tricuspid regurgitation and endocarditis (11, 12). Transvenous lead related endocar-ditis has been reported associated with a mortality risk as high as 12-31% (13, 14). In the long-term, these leads are also prone to insulation breaks and conductor fracture, requiring re-intervention that puts the patient at risk for significant morbidity (15, 16). Furthermore, 0.7 to 2.4% of patients encounter serious complications related to the subcutaneously-placed pulse generator: skin erosion, pocket infection and septicemia (17-20).

To address these lead- and device pocket- related issues, leadless pacemaker systems were conceptualized in the 1970s, (21, 22) and have been gradually developed. In 2012, a new single-chamber right ventricular leadless cardiac pacemaker was introduced (23-26). Development of these miniaturized devices was enabled by a number of advancements: i) improvements in battery technology to allow adequate pacemaker longevity despite its low profile and overall size, ii) advances in component design including miniaturization and low power utilization, iii) communication protocols to also minimize power utilization, and iv) practical catheter-based delivery tools to ne-gotiate the vasculature and cardiac anatomy and permit safe affixation to the myocardial wall. In this review, we describe the technology of the current clinically available leadless pacemaker devices, and compare early results with these devices to historical transvenous single-chamber pacemaker (VVI) cohorts.

Self-contained leadless pacemakers for right ventricular pacingTwo leadless pacing systems are currently clinically available: i) the Nanostim Leadless Cardiac Pacemaker (LCP; St. Jude Medical, USA), and ii) the Micra Transcatheter Pacing System (TPS; Medtronic, USA). Both are fully self-contained units capable of providing single-chamber right ventricular pacing, sensing and delivery of rate response. The Nanostim LCP received CE-mark in October 2013, and is currently awaiting US FDA approval. The Micra TPS received CE mark in April 2015 and FDA approval in April 2016. The two pacemakers are compared in Figure 1. The Nanostim is longer (42 mm vs. 25.9 mm), however, both displace similar volumes of 1.0cc and 0.8cc, respectively. The implant procedure for both systems is similar, utilizing a percutaneous femoral, catheter-based approach to introduce and advance the leadless pacemaker to the right ventricle (RV). The introducer sheaths are dedicated for the procedure and measure 18F (inner diameter) / 21F (outer diameter) for the LCP, and 23F (inner diameter)/27F (outer diameter) for the TPS. After the pacemaker is advanced to the RV, contrast is injected to opacify the RV and visualize the desired location. The pacemaker is deployed using either a screw-in helix (LCP) or nitinol tines (TPS) to actively fix the device to the myocardium. Both pacemakers utilize a sensor to provide rate response, albeit with varying approaches: a temperature-based sensor for the LCP, and a 3-axis accelerometer for the TPS. After electrical measurements are obtained, the stability of the fixated pacemaker is assessed by performing a gentle tug-test. Subsequently, the pacemaker is released from the delivery catheter by removing/unlocking the tether. To establish communication for interrogation and programming, two different technologies are used: the LCP uses conductive communication with five ECG surface electrodes to minimize battery drain, while the TPS uses the conventional approach of radiofrequency (RF) current.

One important feature of leadless pacemaker systems is their retrievability. The LCP system has a dedicated steerable retrieval catheter for this purpose. When the distal cap of the pacemaker is captured by the snare of the retrieval catheter, it is designed to be removed by rotating, and hence unscrewing the pacemaker count-er-clockwise. The TPS system does not have a dedicated retrieval system, but has been shown in some cases to be retrievable using a conventional gooseneck snare. After advancing the snare through the TPS delivery

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catheter, the cup of the delivery catheter is advanced while applying counter pressure and retracting the TPS to unfold the tines from the myocardium.

Figure 1

Clinical data on safety and performanceThe first human trial of leadless pacing therapy, the LEADLESS trial (23) (NCT 01700244) enrolled 33 patients at 3 centers between December 2012 and April 2013. Conducted to evaluate the clinical safety and performance of the Nanostim LCP, the patient and procedure characteristics are summarized in Supplemental Table 1. The LCP was implanted successfully in 32/33 (97%) patients. The overall complication-free rate was 94% (31/33) at 90 days of follow-up (Supplemental Table 2). One major complication occurred: a 70-year-old man with a history of atrial fibrillation experienced cardiac tamponade with hemodynamic collapse during LCP implantation and required urgent cardiac surgery. Five days later, this patient with a non-therapeutic INR level suffered an isch-emic stroke and died 2 weeks later. The subsequent 12-month follow-up of these first 31 patients demonstrated adequate chronic electrical performance and no device related complications (26).

A second clinical study, the FDA IDE trial, LEADLESS II (NCT 02030418), was prospectively performed in 56 centers in 3 countries (USA, Canada and Australia) to assess the safety and efficacy of the LCP system (24). The study enrolled 526 patients (mean age 75 ± 8 years, 62% male), 300 with a minimum follow-up of 6 months. The implantation success was 95.8% (504/526), mean procedure time was 28.6±17.8 min, and 70% of the patients did not require device repositioning. Device-related serious adverse events occurred in 34 (6.5%) patients. Peri-cardial effusion occurred in 1.5% for which all but 0.4% required intervention. Vascular complications occurred in 1.2% and device dislodgement in 1.1%. In the first 2 weeks after the device placement 4 LCPs dislodged to the pulmonary artery, and 2 to the right femoral vein. All were percutaneously removed, and new LCPs were implant-ed. In addition, 0.8% of patients required device retrieval due to elevated pacing thresholds (range 1-413 days). All complications are summarized in Supplemental Table 2.

The electrical performance improved from baseline to 12-months: mean R-wave amplitude increased from7.8 ± 2.9 mV to 9.2 ± 2.9 mV (p<0.01), mean impedance decreased from 700 ± 295 Ω to 456 ± 111 Ω (p<0.01), and the mean pacing capture threshold at 0.4 msec decreased from 0.82 ± 0.69 V to 0.58±0.31 V (p<0.01). The mean per-centage pacing at 12-month follow-up was 51.6 ± 39.1%. In a subgroup of 30 patients that underwent additional 24-hour Holter-monitoring, the mean ventricular pacing rate was 50.3 ± 39.9% (range 0-98%), the mean minimum

101Chapter 9

and maximum heart rates were 58.6 ± 9.2 BPM and 111.1 ± 21.1 BPM, no pauses exceeded 2.0 seconds, and there were no episodes of undersensing or failure to capture. T-wave oversensing was noted in 4 (13%) of the 30 patients, none led to symptoms or adverse events. Recently, a battery advisory with the Nanostim leadless pace-maker was issued by the manufacturer. In this initial communication, 7 of 1423 (0.5%) patients who had received an LCP device had a battery malfunction which occurred between 29 and 37 months post-implant. Additional follow-up will be necessary to fully appreciate the frequency of this issue. In these devices, PPM failure resulted from abrupt battery depletion culminating in loss of pacing and communication. This battery issue seems to be limited to the Nanostim LCP; there is no evidence of any similar battery issue with the Micra TPS device. This episode highlights the fact that, as with any cardiac implantable pacemaker (or defibrillator), malfunctions can occur, and prospective long-term registry data are critical before reaching definitive conclusions about a device’s performance.

The FDA IDE Micra TPS Trial (NCT 02004873) was also a global, multicenter prospective study to evaluate de-vice safety and efficacy (25). In total, 725 patients (mean age 75.9±10.9 years, 58.8% male) who met a Class I or II guideline indication for RV pacing were enrolled. In 99.2% of the patients, the implantation of the TPS was successful (n=719/725), with a mean procedure duration of 23.0 ± 15.3 min. Major device-related complications occurred in 25 (3.4%) of the 725 patients; including cardiac perforations in 1.5%, vascular complications in 0.7%, venous thromboembolism in 0.3%, and increased pacing thresholds in 0.3% of patients. No device dislodgements were observed. One patient, a 77-year old female with end-stage renal failure, who underwent concomitant AV nodal ablation during the transcatheter pacemaker implantation, died. This was thought to be related to metabolic acidosis due to a prolonged procedure time with underlying renal failure. The electrical performance of the TPS during 6 months of follow-up showed stable measurements between implant and 6-months: mean R-wave ampli-tude of 11.2 mV and 15.3 mV, mean pacing capture threshold (at 0.24 ms) of 0.63 V and 0.54 V, and mean pacing impedance of 724 Ω and 627 Ω, respectively.

Comparison of the leadless pacemaker systemsComplicationsOverall, the two leadless systems have demonstrated comparable performance and safety results. As expected, pneumothorax and pocket/lead infection did not occur. However, the leadless procedure was associated with femoral vascular complications unique to the percutaneous insertion of the device, the need to reposition the device intra-operatively and a moderate risk of cardiac perforation resulting in pericardial effusion. It is difficult to compare the complication rates of the two leadless pacemaker systems, because of several differences in the two study designs. The main difference in these two trials was the definition used for the primary safety outcome. The LEADLESS II study used the standard ISO 14555 3.36 definition of Serious Device Adverse Effects (SADE): adverse events leading to i) death, ii) serious deterioration in subject health resulting in either life-threatening illness, permanent impairment of body structure or function, inpatient or prolonged hospitalization, medical or surgical intervention to prevent lifethreatening illness or permanent impairment, or iii) fetal distress, death, birth defects. In contrast, the Micra TPS study used a self-defined endpoint named “Major Complications”; this was defined as adverse events that resulted in death, permanent loss of device function, hospitalization or prolonged hospitaliza-tion (>48 hrs) or a system revision (explant, reposition, replacement). Thus, adverse events requiring medical or surgical intervention but not leading to the criteria mentioned above would not been included. Indeed, if this Major Complication criteria were applied to the LEADLESS II study, the complication rate would have decreased from the reported 6.5% to 4.9%.

While the pericardial effusion rates for the devices were similar (1.5% in each), there was a difference in the device dislodgement rate between the LCP and TPS (2.3% vs 0%). This indicates that the screw-in fixation mechanism of the LCP may be at a higher risk for dislocation. The design of the LCP requires a balance between adequate fixation and excessive myocardial penetration. Excessive penetration may lead to cardiac perforation, while insufficient penetration risks device embolization. Achieving fixation of the LCP is experience-related. Indeed, evidence for this was seen in the ongoing European LEADLESS Observational Trial (NCT 02051972). In

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the early phase of this study in 2014, there were two instances of fatal pericardial tamponade, that resulted in a temporary pause of the European study, and subsequent enhanced physician training. The device dislodgement rates substantially reduced from 2 (1.4%) of 147 implants pre-pause to zero of 93 post-pause (27). Enhanced phy-sician training with a focus on performing a deflection test to test adequate fixation prior to device release, and electrical mapping of the myocardial tissue before fixation, was likely at least partly responsible for this substan-tial reduction in device dislodgement. This underscores the importance of proper physician training and highlights the inevitable occurrence of a learning curve with new technology. The occurrence of a learning curve was also demonstrated in the LEADLESS II trial, in which SADEs were less frequently observed after 10 implants peroperator (6.8% to 3.6%). In the Micra study, there was no evidence of a relationship between operator ex-perience and major complications (28). On the other hand, the investigators (25) were able to identify several characteristics of patients likely to experience cardiac injury (n=13/725, 1.7%): older age, female, low BMI, and chronic lung disease. If substantiated in larger studies, this information might help physicians in optimizing patient selection.

LongevityUsing the 6-month follow-up actual-use data, the estimated battery longevity was 15.0 years for the LCP and 12.5 years for the TPS. There are several important caveats to consider when interpreting these results. First, the projections are made using relative short-term data (6 months), limiting the robustness of extrapolation to long-term battery longevity. Indeed, previous studies with standard pacemakers have shown a discrepancy between estimations and actual battery longevity (13, 29). Furthermore, different methods to estimate battery longevity have been used for the two devices, with significant influence on projected longevity. The LCP used the (ISO standard) nominal settings of 100% pacing at 2.5V at 0.4ms at 60 BPM. The TPS used an alternative nominal setting of 100% pacing at 1.5V at 0.24ms at 60 BPM. If the TPS longevity estimate was instead calculated using the ISO nominal settings, the battery longevity drops to 4.7 years (30). On the other hand, the TPS has an auto-capture algorithm feature, which is not available in the LCP, optimizing the pacing output to 0.5V above the pacing threshold. Although this should prolong battery longevity significantly, it implies a smaller capture safety margin – an issue to consider in pacemaker-dependent patients. Ultimately, long-term battery longevity of these leadless devices will need to be scrutinized.

Retrievability vs AbandonmentBoth leadless pacemaker systems are designed to be retrieved if necessary, and recent publications support acute and mid-term retrievability (31-37). The LCP has a dedicated retrieval catheter available with either a single loop or tri-loop snare, and has a screw-in fixation mechanism that may facilitate atraumatic removal (Figure 2). The largest retrieval experience with the LCP includes 16 patients (77 ± 13 years, 75% male) who required device removal for either elevated pacing thresholds (8 patients), worsening heart failure (5 patients), failure to pace (1 patient), upgrade to defibrillator (1 patient), or elective explantation (1 patient). Catheter-based retrieval was successful in 15 out of 16 patients (94%) without the occurrence of retrieval-related SADEs (no pericardial effusions occurred). The mean time from implant to retrieval was 240 days (range 1 to 1188 days) (31).

While this experience includes only a small number of patients followed for a mean implant-to-retrieval time of less than a year, there is some pre-clinical evidence that retrieval of this device may be possible more long-term. In an ovine study, LCP retrieval was 100% successful in 8 sheep in which devices had been implanted for a mean of 2.3 ± 0.1 years (32). Pathological examination of these animals showed no visible tissue on the body on the LCPs, little fibrous tissue around the proximal docking button, and no evidence of pericardial perforation or adhesions at necropsy. Local endocardial response to the implanted LCP at the RV apex appeared limited, however some local-ized (sub)endocardial hemorrhage at the implant site was observed. The rate of fibrous tissue formation and extent of device encapsulation observed in this ovine model may or may not relate to human implants.

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Figure 2

Although, minimal fibrous tissue was observed on the retrieved LCPs in the human cases, fibrous device encap-sulation after only 19 months has been reported (38). There may be patient specific factors that influence the progression and rate of fibrous capsule formation, but additional information is required for full characterization.For the TPS system, 13 patients required a system revision due to elevated thresholds, pacemaker syndrome, need for biventricular pacing, or in one patient, device infection. Retrieval using a gooseneck snare was successful without complications in 8 of 10 patients in whom it was attempted. In the remaining 2, plus 3 others in whom retrieval was not attempted, the device was turned OFF and left in situ (37). Full encapsulation of the TPS has been observed and might complicate the recapture of the distal end of the device (39, 40). Given the smaller length of the TPS (relative to the LCP), this is not surprising. Considering the uncertainty of long-term retrieval due to device encapsulation, the optimal end-of-life (EOL) replacement strategy is yet to be defined. One strategy, which already has been exercised with the TPS, is to abandon a turned-off leadless pacemaker in the RV. The small volume of these leadless devices (0.8 - 1.0cc) accounts for < 2% the volume of a normal sized RV, (41) and is quite unlikely to cause hemodynamic compromise.

Pre-clinical studies showed the feasibility of multiple (up to 3) TPS implants in a porcine and human cadaveric mod-el (42, 43). Upon echocardiographic assessment in 14 minipigs, there were no significant changes in left ventricular ejection fraction or changes in tricuspid regurgitation. The mean length of device encapsulation after 215 ± 7 days was 14.3 ± 7.8 mm, which translates to little over half the length of the TPS (42). The vast clinical experience with transvenous pacemaker or defibrillator lead abandonment without reported detrimental effects on RV function support this strategy. Unknowns for this strategy are the maximum number of devices that can be placed in parallel mechanical or electrical interactions in the human anatomy.

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Historical VVI pacemaker cohortsA literature search was performed to identify all studies with single-chamber ventricular (VVI) pacemaker cohorts with: i) at least 100 patients enrolled, and ii) all complications were reported specifically for single chamber ven-tricular pacemakers. The study details, patient demographics and available procedure information are shown in Supplementary Table 1. Both randomized controlled trial data, and prospective / retrospective observational data were included, unavoidably introducing selection bias into the results. A total of 14,330 single chamber pace-maker patients (mean age 79.1 years, 55.8% male) from 10 studies (12, 44, 45, 4, 46, 5, 47-50) were evaluated. The complications were classified in two categories: short-term (≤2 months) and long-term complications (>2 months). In the overall cohort, short-term device related complications were reported in a total of 4.0% patients and were mostly related to the implant procedure: these included pneumothorax (0.6%), acute lead dislocation (0.4%), cardiac perforation (0.1%), and hematoma (0.3%) (Supplemental Table 2). Four of the 10 studies reported long-term complication rates in a total of 3176 patients with a mean follow-up of 66 months. Of these, 98 (3.1%) experienced a long-term complication, mostly related to the pacemaker pocket (e.g. infection/erosion 0.9%) or to the transvenous leads (0.6%). It should be noted that there were substantial differences in the complication rates in these individual studies: short-term complication rates ranged from 1.5% to 11.8%, and long-term complication rates ranged from 1.3% to 6.9%.

Comparison of leadless versus traditional VVI pacingThe patient and procedure characteristics are shown in Table 1. The short-term complication rate of the conven-tional pacemaker (4.0%) appears slightly superior to that observed for the leadless pacemakers (4.8%) (Table 2). Two important factors influence this difference. First, conventional pacemaker technology has matured over 50 years of development and its implantation technique is wellestablished. Conversely, leadless pacing is a novel technology for which the procedure learning curve was included in the clinical trials. Indeed, the mean number of procedures performed per operator in the LEADLESS II and Micra studies were only 5.3 and 7.7, respectively. Second, there may be some underreporting of complications in the transvenous pacemaker studies as these studies did not mandate careful follow-up with site-level independent monitoring, unlike the prospective leadless FDA IDE trials.

When assessing the types of complications, an increased risk is apparent of cardiac perforation and pericardial effusion with the leadless pacemakers (1.5% vs 0.1%). This may be partly related to the size of the fixation mechanism being more extensive with the leadless pacemakers, but the importance of a learning curve cannot be ignored. Furthermore, newer generations of device and delivery tools will invariably be designed to further decrease these risks. Finally, there is recent real-world data from a large US cohort (n=922,549) that has high-lighted an increasing rate of cardiac tamponade in patients after conventional pacemaker placement: from 0.26% in 2008 to 0.35% in 2012, translating to an increase in in-hospital mortality (51). This 35% increase in tamponade is thought to be related to an increase in the co-morbidity profile of the population of patients receiving pacemak-ers. Femoral vascular access site complications were unique to the leadless pacemakers (0.9% vs 0%), but typi-cally require only conservative management (e.g., extended pressure bandage). Acute device/lead dislodgement rates were similar between groups (0.5% vs 0.6%), but may be more threatening if leadless device embolizes to the pulmonary artery. As expected, pneumothorax development did not occur with leadless pacemaker implan-tation (1 instance of hemothorax was noted), but remains a challenge for transvenous pacemaker implantation despite an increased use of cephalic venous access (0% vs 0.6%). A difference in mean fluoroscopy times was observed between the leadless and transvenous pacemakers (11.0 min vs 3.7 min), but this may decrease as experience accrues.

No long-term outcome data are yet available for leadless pacemakers. Thus no comparison can be drawn between long-term outcomes of the leadless and conventional pacemaker systems. This is important since any potential advantage of leadless pacemakers is anticipated over the long-term, when complications related to the device pocket and leads of standard pacemakers occur. This was hinted at in two observations.

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Table 1

Table 1. Patient demographics and procedure characteristics

Leadless Pacemakers Transvenous VVI Pacemakers

Number of studies included 3 10

Years study duration 2012-2015 1984-2008

Study design Pros RCT, Pros, Retro

n 1284 14330

Mean FUP, months 7 16

Age, yr 75,9 79,1

Male, % 60,2 55,8

Indication VVIR VVI

AF + AVB, % 60,8 36,6

SND, % 24,8 16,7

SR + 2/3 AVB, % 12,4 41

Other 0 4,3

Comorbidity

CAD, % 32,3 35,1

CABG, % 16 3,6

MI, % 13,9 19,9

PCI, % 16,3 0,7

HT, % 79,1 33,7

DM, % 28 13,5

AF% 72,6 29

Stroke or TIA % n/a 9,2

COPD, % 12,4 n/a

Renal disease, % 20 10,8

Hyperlipidemia, % 67,5 n/a

Peripheral vascular disease, % 9,7 18,8

CHD, % 16,4 27,1

LVEF Baseline, % 58,3 n/a

Procedure

Implant success, % 97,8 n/a

Procedure time, min 25,4 38,7

Fluoro time, min 11 3,7

Repositions <1 time 70,2 n/a

Position of device

- RV apex 54,2 n/a

- RV apical septum 21,8 n/a

- RV outflow, septum, other 23.9 n/a

Electrical Performance

FUP duration, months 8,6 n/a

Baseline R-wave amplitude, mV 9,8 13,2

FUP R-wave amplitude, mV 12,7 n/a

Baseline pacing threshold, V@0.4ms 0,71 0,5

FUP R-wave amplitude, mV 0,55 n/a

Baseline impedance, Ohms 714 610

FUP impedance, Ohms 557 n/a

% Pacing Baseline 39 n/a

% Pacing FUP 51,6 n/a

Battery longevity, yr* 13,6 n/aLegend: n/a denotes no data was available, Retro = retrospective observational analysis, Pros = prospective observational analysis, RCT = randomized controlled trial, * = Estimated battery longevity at 6-month follow-up

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Table 2

First, the one year outcomes from the LEADLESS II LCP cohort were recently compared to a matched cohort of patients undergoing standard single-chamber pacemaker implantation; these data were obtained from the Truven MarketScan database, which tracks U.S. healthcare claims and Medicare supplemental insurance encounters (52). Briefly, from a total cohort of 120,556 patients undergoing pacemaker implantation between 2009 – 2014, 10,492 adult patients receiving single-chamber pacemakers were identified and matched for age, gender and var-ious co-morbidities to provide a propensity-matched cohort of 2,154 patients. This real-world experience revealed a 71% reduction in complications observed with LCP procedures relative to standard pacemakers, with substan-tial reductions seen in both short-term (defined as ≤1 month post-implant) and mid-term (defined as 1-24 months post-implant) complications. Second, a recent report compared the one-year outcomes from the Micra TPS cohort with a predefined historical control group of standard pacemaker patients (n=2,662 pts) (53). In addition to a 48% lower 1-year complications rate with the TPS patients relative to standard pacemakers, there were also 47% fewer hospitalization over the time period, driven in part by an 82% reduction in the need for pacemaker system revision. Of course, both of these reports are limited by their retrospective nature and the confounding possi-bility of bias attendant with such comparisons. It is clear that longer follow-up of leadless pacemaker patients is required to definitively appreciate long-term complication rates. Ultimately, randomized controlled studies comparing leadless and conventional pacemakers are necessary to fully assess their durability and relative role in clinical practice.

Clinical applicabilityAt this point, both leadless pacemaker systems are right ventricular single-chamber pacemakers only. Such devices serve a minority (15-30%) of total pacemaker recipients in Western countries (1) – mainly patients with

Table 2. Complications in Leadless Pacing Trials and historic VVI cohorts

Number of studies included 3 10

Short-term (≤2mo) complication rate, % 4.8 † 4.1

n 1284 14330

Mean FUP, mo 2 2.4

Cardiac perforation 1.5 0.1

Vascular complications 0.9 0

Arrhythmia 0.2 0

Acute lead/ device dislocation 0.5 0.4

Pneumo/hemothorax 0.1 0.6

Hemorrhage/hematoma 0 0.3

Tromboembolism 0.2 0

Pacemaker syndrome 0.1 0.1

Procedure-related death 0.1 0

Pacemaker infection 0 0.3

Pacemaker erosion 0 0

Wound/local infection 0 0.1

Lead-related re-intervention 0 1.5

Pacing threshold elevation requiring intervention 0.5 0

Other 1 0.2

Long-term (>2mo) complication rate, % 0.2 † 3.1

n 1284 3176

Mean FUP, mo 7 66

Pacing threshold elevation requiring intervention 0 0.3

Pacemaker erosion 0 0.4

Pacemaker infection 0 0.5

Device malfunction (inc malsensing, malpacing) 0 0.1

Lead-related re-intervention 0 0.3

Pocket revision 0 0.1

Other 0.2 * 0

† Complication rates are displayed as absolute event rates (number of patients with event/total number of patients)* Three patients (3/1284) were admitted for worsening heart failure

Leadless Pacemakers Transvenous VVI pacemakers

107Chapter 9

chronic atrial fibrillation and atrioventricular (AV) block. However, current guidelines for single-chamber pacing (2) also recommend consideration in patients with complete AV block who are elderly and have a low activity level, and patients with sinus node dysfunction and infrequent pauses. Indeed, if leadless pacing proves to be durable and at least as effective as transvenous pacing, its availability may broaden the use of single-chamber pacing to include patients who otherwise might receive a dual-chamber device. In the leadless studies, 60% of patients had chronic atrial fibrillation with AV block, 25% had high degree AV block, and 15% sinus node dysfunction. On the other hand, RV pacing can be detrimental in some patients, especially those with marginal ejection fractions in whom heart failure might develop (54).

Training for Leadless Pacemaker ImplantationOne important consideration is the manner of elaboration of this novel technology beyond the clinical trials to clinical practice. With regard to the physicians that should be performing leadless pacemaker implantation, it probably matters less the type – electrophysiologist, non-electrophysiologist pacemaker-implanting cardiologist, or cardiac surgeon. But it is important for the physician to have the necessary skills: i) technical, particularly catheter experience including vascular access / management, and catheter manipulation within the heart, and ii) cognitive, such as pacemaker indications, programming and troubleshooting. Given that the skills for acute device retrieval overlap with those for device implantation, it is less necessary to have experience with lead extraction – a somewhat specialized skill. Of course, it is unknown if additional skills will be required for long-term device retrieval. Once the operator is identified, the manufacturers have designed simulation systems for training the operator, including manipulating the catheter delivery tools on the benchtop; actual pre-clinical experience, while useful if possible, is probably not necessary. However, proctoring for device implantation should be mandatory for the initial procedures – at least for the first 10. The nature of the proctor is less critical – whether a physician or a properly-trained industry clinical specialist. Finally, given the differences between the implants from the various manufacturers, proctoring should be considered independently for each device; that is, proctored implants with one device should not “count” for the other device.

Future perspectivesTo expand the benefits of leadless pacing to more patients, efforts are being made to develop multicomponent, communicating leadless systems capable of performing dual chamber pacing and cardiac resynchronization therapy (Figure 3). While not strictly a self-contained leadless pacemaker system, another leadless pacing system that is being investigated clinically (55, 56) bears mentioning. This novel system consists of two components: i) a leadless pacing electrode (~0.05cc displacement) that is affixed to the endocardial left ventricular free wall,and ii) a subcutaneous ultrasonic transmitter and battery that synchronizes to a conventional right-sided pacing system and emits ultrasonic pulses. The pacing electrode converts this ultrasound energy into electrical stimuli resulting in left ventricular stimulation for cardiac resynchronization. A large multicenter FDA IDE clinical trial of this system is planned to commence by 2017.

Beyond pacing, it is also anticipated that leadless pacing may be combined with defibrillation therapy (Figure 3). Although there is no clinical experience with any such dedicated combination, there are reports of concomitant, but not communicative independent implantation of subcutaneous defibrillators and leadless pacemakers (57, 58). Furthermore, a third leadless pacemaker system that can deliver antitachycardia pacing when coupled with a subcutaneous defibrillator was successfully tested pre-clinically (59). Clinical trials of this combination therapy are expected to commence in 2017.

Beyond pacing and defibrillation, leadless device-to-device communication may enable the intriguing possibility of further integration with patient monitoring devices (Figure 3). For example, a congestive heart failure patient in the future might receive a communicative device system consisting of: i) right atrial, right ventricular and left ventricular leadless pacers for cardiac resynchronization, ii) a subcutaneous defibrillator for sudden death prophy-laxis, and iii) a pulmonary artery pressure monitor for heart failure monitoring.

108

ConclusionThe first two leadless pacemaker systems have demonstrated similar performance and initial promise of efficacy and safety. A significant implanter learning curve has been appreciated. No long-term performance data of the leadless systems are yet available to determine technological robustness. As leadless pacing matures, both in device technology and physician experience, procedure-related complications are likely to decrease. Randomized controlled trials comparing leadless and conventional devices are necessary to fully appreciate any differences between these technologies in clinical practice.

Figure 3

109Chapter 9

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Dimopoulos K, Donal E, Drexel H, Flachskampf FA, Hall R, Halvorsen S, Hoen B, Kirchhof P, Lainscak M, Leite-Moreira AF, Lip GY, Mestres CA, Piepoli MF, Punjabi PP, Rapezzi C, Rosenhek R, Siebens K, Tamargo J, Walker DM.2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015; 36:3075-128. 21. Spickler JW, Rasor NS, Kezdi P, Misra SN, Robins KE, LeBoeuf C. Totally selfcon-tained intracardiac pacemaker. J Electrocardiol 1970; 3:325–31. 22. Vardas PE, Politopoulos C, Manios E, Parthenakis F, Tsagarkis C. A miniature pacemaker introduced intravenously and implanted endocardially. Preliminary findings from an experimental study. Eur J CPE 1991; 1: 27–30. 23. Reddy VY, Knops RE, Sperzel J, Miller MA, Petru J, Simon J, Sediva L, de Groot JR, Tjong FV, Jacobson P, Ostrosff A, Dukkipati SR, Koruth JS, Wilde AA, Kautzner J, Neuzil P. Permanent leadless cardiac pacing: results of the leadless trial. Circulation 2014; 129:1466–71. 24. Reddy VY, Exner DV, Cantillon DJ, Doshi R, Bunch TJ, Tomassoni GF, Friedman PA, Estes NA 3rd, Ip J, Niazi I, Plunkitt K, Banker R, Porterfield J, Ip JE, Dukkipati SR; LEADLESS II Study Investigators. Percutaneous implantation of an entirely intracardiac leadless pacemaker. N Engl J Med 2015; 373:1125–35. 25. Reynolds D, Duray GZ, Omar R, Soejima K, Neuzil P, Zhang S, Narasimhan C, Steinwender C, Brugada J, Lloyd M, Roberts PR, Sagi V, Hummel J, Bongiorni MG, Knops RE, Ellis CR, Gornick CC, Bernabei MA, Laager V, Stromberg K, Williams ER, Hudnall JH, Ritter P; Micra Transcatheter Pacing Study Group. A leadless intracardiac transcatheter pacing system. N Engl J Med 2016; 374:533-41. 26. Knops RE, Tjong FV, Neuzil P, Sperzel J, Miller MA, Petru J, Simon J, Sediva L, de Groot JR, Dukkipati SR, Koruth JS, Wilde AA, Kautzner J, Reddy VY. Chronic performance of a leadless cardiac pacemaker: 1-year follow-up of the LEADLESS trial. J Am Coll Cardiol. 2015; 65:1497–504. 27. Nanostim Leadless Pacemaker System – FDA Panel pack for Circulatory Systems Devices Panel, meeting date February 18, 2016. Version 01/20/2016. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDe-vicesAdvisoryCommittee/CirculatorySystemDevicesPanel/UCM485095.pdf. 28. Kowal R, Soejima K, Ritter P, Duray GZ, Hudhall JH, Stromberg K, Reynolds D. Relationship between operator experience and procedure outcomes with the Micra transcatheter leadless pacing system. Heart Rhythm 2016; 13:S16. 29. Senaratne J, Irwin ME, Senaratne MP. Pacemaker longevity: are we getting what we are promised? Pacing Clin Electrophysiol. 2006; 29:1044-54. 30. Micra Product Specifications http://www.medtronic.com/content/dam/medtronic-com/products/cardiacrhythm/ pacemakers/micra-pacing-system/documents/2016-04-micra-specifica-tion-sheet.pdf. 31. Reddy VY, Miller MA, Knops RE, Neuzil P, Defaye P, Jung W, Doshi R, Castellani M, Strickberger A,

Mead HR, Doppalapudi H, Lakkireddy D, Bennett M, Sperzel J. Retrieval of the leadless cardiac pacemaker: A multicenter experience. Circ Arrhythm Electrophysiol. 2016; 9:e004626. DOI: 10.1161/CIRCEP.116.004626. 32. Koruth JS, Rippy MK, Khairkhahan A, Ligon DA, Hubbard CA, Miller MA, Dukkipati SR, Neuzil P, Reddy VY. Percutaneous Retrieval of Implanted Leadless Pacemakers: Feasibility at 2.5 Years Post-Implanta-tion in an In Vivo Ovine Model. JACCCEP. 2015; 1:563-570.33. Bonner MD, Neafus N, Byrd CL, Schaerf RH, Goode L. Extraction of the Micra Transcatheter Pacemaker System. Heart Rhythm 2014; 11:S342. 34. Koay A, Khelae S, Kok Wei K, Muhammad Z, Mohd R, Omar R. Treating an infected tran-scatheter pacemaker system via percutaneous extraction. HeartRhythm Case Reports 2016; 2:360–362. 35. Karim S, Adbelmessih M, Marieb M, Reiner E, Grubman E. Extraction of a Micra Transcatheter Pacing System: First-in-human experience. Heart Rhythm Case Reports 2016; 2:60–6236. Jung W, Sadeghzadeh G, Kohler J, Jackle S, Beyersdorf F, Siepe M. Successful retrieval of an active fixation leadless pacemaker in a 74-year-old woman 506 days post-implant. Europace. 2016 Jul 1. pii: euw196. [Epub ahead of print]37. Micra Transcatheter Pacing System – FDA Panel pack for Circulatory Systems Devices Panel, meeting date February 18, 2016. http://www.fda.gov/downloads/AdvisoryCom-mittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevic esAdvisoryCommittee/CirculatorySystem-DevicesPanel/UCM485094.pdf 38. Tjong FV, Stam OC, van der Wal AC, Beenen LF, Bouma BJ, de Groot JR, Wilde AA, Knops RE. Post mortem histopathological examination of a leadless pacemaker shows partial encapsulation after 19 Months.Circ Arrhythm Electrophysiol 2015; 8: 1293–5.39. Kypta A, Blessberger H, Lichtenauer M, Steinwender C. Complete encapsulation of a leadless cardiac pacemaker. Clin Res Cardiol. 2016; 105:94. 40. Kypta A, Blessberger H, Kammler J, Lichtenauer M, Lambert T, Silye R, Stein-wender C. First Autopsy Description of Changes 1 Year After Implantation of a Leadless Cardiac Pacemaker: Unexpected Ingrowth and Severe Chronic Inflammation. Can J Cardiol. 2015 Dec 29. pii: S0828-282X(15)01699-2. 41. Tamborini G, Marsan NA, Gripari P, Maffessanti F, Brusoni D, Muratori M, Caiani EG, Fiorentini C, Pepi M. Reference values for right ventricular volumes and ejection fraction with real-time three-dimensional echocardiography: evaluation in a large series of normal subjects. J Am Soc Echocardiogr. 2010; 23:109-15. 42. Chen K, Zheng X, Dai Y, Wang H, Tang Y, Lan T, Zhang J, Tian Y, Zhang B, Zhou X, Bonner M, Zhang S. Multiple leadless pacemakers implanted in the right ventricle of swine. Europace. 2016 Jan 31. pii: euv418. DOI: 10.1093/europace/euv418. 43. Omdahl P, Eggen MD, Bonner MD, Iaizzo PA, Wika K. Right Ventricular Anatomy Can Accommodate Multiple Micra Transcatheter Pacemakers. Pacing Clin Electrophysiol. 2016; 39:393-7. 44. Aggarwal RK, Connelly DT, Ray SG, Ball J, Charles RG. Early complica-tions of permanent pacemaker implantation: no difference between dual and single chamber systems. Br Heart J. 1995; 73:571-5. 45. Kiviniemi MS, Pirnes MA, Eränen HJ,

111Chapter 9

Kettunen RV, Hartikainen JE. Complications related to permanent pacemaker therapy. Pacing Clin Electrophysiol. 1999; 22:711-20. 46. Connolly SJ, Kerr CR, Gent M, Roberts RS, Yusuf S, Gillis AM, Sami MH, Talajic M, Tang AS, Klein GJ, Lau C, Newman DM. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med. 2000; 342:1385-91. 47. Wiegand UK, Bode F, Bonnemeier H, Eberhard F, Schlei M, Peters W. Long-term complication rates in ventricular, single lead VDD, and dual chamber pacing. Pacing Clin Electro-physiol. 2003; 26:1961-9. 48. Pakarinen S, Oikarinen L, Toivonen L. Short-term implantation-related complications of cardiac rhythm management device therapy: a retrospective single-centre 1-year survey. Europace. 2010; 12:103-8. 49. Van Eck JW, van Hemel NM, Zuithof P, van Asseldonk JP, Voskuil TL, Grobbee DE, Moons KG. Incidence and predictors of in-hospital events after first implantation of pacemakers. Europace. 2007; 9:884-9. 50. Kirkfeldt R, Johansen JB, Niel-sen JC. Conventional VVI pacing in Denmark. A benchmark for Leadless pacing Europace 2016; 18:i170 (59-03) 51. Moazzami K, Dolmatova E, Kothari N, Mazza V, Klapholz M, Waller AH. Trends in cardiac tamponade among recipi-ents of permanent pacemakers in the United States from 2008 to 2012. Article in Press. http://dx.doi.org/10.1016/j.jacep.2016.05.009 52. Reddy VY, Cantillon DJ, Exner DV, Banker R, Rashtian M, Niazi I, Ip JE, Plunkitt K, Tomassoni GF, Porterfield PA, Nabutovsky Y, Oza AL, Estes AM. A Comparative Study of Acute and Mid-Term Complications of Leadless vs Transvenous Pacemakers. Abstract presented at Heart Rhythm Society Annual Meeting 2016 as LBCT02-04, San Francisco, CA, USA. 53. Ritter P, Duray GZ, Yalagudri S, Omar R, Tolosana JM, Zhang S, Soejima K, Steinwender C, El-Chami M, Reynolds DW. Long-Term Performance of a

Transcatheter Pacing System: 12-month results from the Mi-cra Global Clinical Trial. Abstract presented at the European Society of Cardiology Annual Meeting 2016 as Late Breaking Clinical Trial Update 2234, Rome, Italy. 54. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol. 2009; 54:764-76. 55. Auricchio A, Delnoy PP, Butter C, Brachmann J, Van Erven L, Spitzer S, Moccetti T, Seifert M, Markou T, Laszo K, Regoli F; Collaborative Study Group. Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace. 2014; 16:681-8. 56. Reddy VY, Neuzil P, Riahi S, Søgaard P, Butter C, Schau T, Delnoy PP, van Erven L, Schalij M, Boersma LV. Wireless LV endocardial stimula-tion for CRT: primary results of the safety and performance of electrodes implanted in the left ventricle (SELECT-LV) study. Abstract presented at Heart Rhythm Society Annual Meeting 2015 as LBCT01- 05, Boston, MA, USA. 57. Tjong FV, Brouwer TF, Smeding L, Kooiman KM, de Groot JR, Ligon D, Sanghera R, Schalij MJ, Wilde AA, Knops RE. Combined leadless pacemaker and subcutaneous implantable defibril-lator therapy: feasibility, safety, and performance. Europace. 2016; 18:1740-1747. 58. Mondésert B, Dubuc M, Khairy P, Guerra PG, Gosselin G, Thibault B. Combination of a leadless pacemaker and subcutaneous defibrillator: first in-human re-port. Heart Rhythm Case Reports 2015; 6:469–71. 59. Tjong FV, Brouwer TF, Kooiman KM, Smeding L, Koop B, Soltis B, Shuros A, Wilde AA, Burke M, Knops RE. Communicating Antitachycardia Pacing-Enabled Leadless Pacemaker and Subcutaneous Implantable Defibrillator. J Am Coll Cardiol. 2016; 67:1865-6.

FundingDr. Tjong was supported by a personal NHI Research Fellowship from The Netherlands Heart Institute, Utrecht, The Nether-lands.

DisclosuresDr. Tjong has received modest consulting fees from St. Jude Medical and Boston Scientific. Dr. Reddy has received significant grant support and honoraria from St. Jude Medical, Medtronic and Boston Scientific.

112

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419

92-1

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1990

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519

88-1

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1998

1995

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2006

2003

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an/

a37

,9n/

an/

a39

38,7

Fluo

ro ti

me,

min

n/a

149

11n/

an/

an/

an/

an/

an/

a3,

8n/

an/

a3,

73,

7

Repo

sitio

ns <

1 tim

e70

70n/

a70

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Posi

tion

of d

evic

e

- RV

apex

n/a

3866

54n/

an/

an/

an/

an/

an/

an/

an/

an/

an/

an/

a

- RV

apic

al s

eptu

mn/

a19

2422

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

- RV

outfl

ow, s

eptu

m, o

ther

n/a

4310

24n/

an/

an/

an/

an/

an/

an/

an/

an/

an/

an/

a

Elec

tric

al P

erfo

rman

ce

FUP

dura

tion,

mon

ths

1212

68,

6n/

an/

an/

an/

an/

an/

an/

an/

an/

an/

an/

a

Base

line

R-w

ave

ampl

itude

, mV

n/a

7,8

11,2

9,8

n/a

n/a

n/a

n/a

n/a

n/a

13,2

n/a

n/a

n/a

13,2

FUP

R-w

ave

ampl

itude

, mV

10,3

9,2

15,3

12,7

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Base

line

paci

ng th

resh

old,

V@

0.4m

sn/

a0,

820,

630,

71n/

an/

an/

an/

an/

an/

a0,

45n/

an/

an/

a0,

5

FUP

R-w

ave

ampl

itude

, mV

0,43

0,58

0,54

0,55

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Base

line

impe

danc

e, O

hms

n/a

700

724

714

n/a

n/a

n/a

n/a

n/a

n/a

610

n/a

n/a

n/a

610

FUP

impe

danc

e, O

hms

627

456

627

557

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

% P

acin

g Ba

selin

e37

39n/

a39

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

% P

acin

g FU

Pn/

a52

n/a

52n/

an/

an/

an/

an/

an/

an/

an/

an/

an/

an/

a

Batte

ry lo

ngev

ity, y

r*n/

a15

12,5

13,6

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Lea

dles

s Pa

cem

aker

sTr

ansv

enou

s VV

I Pac

emak

ers

Lege

nd: n

/a d

enot

es n

o da

ta w

as a

vaila

ble,

Ret

ro =

retro

spec

tive

obse

rvat

iona

l ana

lysi

s, P

ros

= pr

ospe

ctiv

e ob

serv

atio

nal a

naly

sis,

RCT

= ra

ndom

ized

cont

rolle

d tri

al, *

= E

stim

ated

bat

tery

long

evity

at 6

-mon

th fo

llow

-up,

† =

Dem

ogra

phic

dat

a is

dis

play

ed fr

om e

ntire

stu

dy c

ohor

t, no

t sep

arat

ely

for V

VI

113Chapter 9

Supplementary Table 2

Supp

lem

enta

ry T

able

2. C

ompl

icat

ions

in L

eadl

ess

Paci

ng T

rial

s an

d hi

stor

ic c

ohor

ts

Stud

y LE

ADLE

SS

LEAD

LESS

IIM

icra

TPS‡

Tota

l UK

IUK

IIFi

nlan

d De

nmar

k CT

OPP

UKPA

CEGe

rman

yHe

lsin

ki§

FOLL

OWPA

CEDa

nish

Reg

istr

y§To

tal ‡

Shor

t-te

rm (<

2mo)

com

plic

atio

n ra

te,%

6,1

6,5

3,5

4,8

2,9

5,1

5,4

5,2

4,1

5,6

1,5

11,8

6,8

44,

1n

3352

672

512

8419

8543

126

211

514

7410

0981

419

627

977

6514

330

Mea

n FU

P, m

o2

22

22

22

22

0,2

23

03

2,4

Card

iac

perfo

ratio

n3

1,5

1,5

1,5

--

0,8

--

n/a

0,1

n/a

n/a

0,2

0,1

Vasc

ular

com

plic

atio

ns-

1,1

0,7

0,9

--

--

-n/

a-

n/a

n/a

-0

Arrh

ythm

ia-

0,6

-0,

2-

--

0,9

-n/

a-

n/a

n/a

-0

Acut

e le

ad/ d

evic

e di

sloc

atio

n-

1,1

-0,

51

-1,

91,

71,

4n/

a0,

4n/

an/

a-

0,4

Pneu

mo/

hem

otho

rax

-0,

2-

0,1

0,6

1,6

1,1

0,9

1,4

n/a

0,1

n/a

n/a

0,5

0,6

Hem

orrh

age/

hem

atom

a-

--

00,

50,

50,

4-

0,4

n/a

0,3

n/a

n/a

0,3

0,3

Trom

boem

bolis

m-

0,2

0,3

0,2

--

0,4

--

n/a

-n/

an/

a-

0Pa

cem

aker

syn

drom

e-

-0,

10,

1-

--

1,7

-n/

a0,

7n/

an/

a0,

010,

1Pr

oced

ure-

rela

ted

deat

h-

--

0,1

0,02

--

--

n/a

-n/

an/

a0,

010

Pace

mak

er in

fect

ion

--

-0

-0,

9-

--

n/a

-n/

an/

a0,

40,

3Pa

cem

aker

ero

sion

--

-0

-0,

7-

--

n/a

-n/

an/

a-

0W

ound

/loca

l inf

ectio

n-

--

00,

7-

--

-n/

a-

n/a

n/a

-0,

1Le

ad-re

late

d re

-inte

rven

tion

--

-0

-1,

4-

--

n/a

-n/

an/

a2,

41,

5Pa

cing

thre

shol

d el

evat

ion

requ

iring

inte

rven

tion

-0,

80,

30,

5-

--

--

n/a

-n/

an/

a-

0Ot

her

31,

50,

61

0,1

-0,

8-

0,9

n/a

-n/

an/

a0,

20,

2Lo

ng-t

erm

(>2m

o) c

ompl

icat

ion

rate

, %0

00,

40,

21,

3n/

a6,

96,

9n/

an/

a1,

4n/

an/

an/

a3,

1n

3352

672

512

8419

85n/

a26

211

5n/

an/

a81

4n/

an/

an/

a31

76M

ean

FUP,

mo

127

67

72n/

a27

64n/

an/

a63

n/a

n/a

n/a

65,7

Paci

ng th

resh

old

elev

atio

n re

quiri

ng in

terv

entio

n-

--

0-

n/a

3,8

-n/

an/

a-

n/a

n/a

n/a

0,3

Pace

mak

er e

rosi

on-

--

00,

5n/

a0,

8-

n/a

n/a

0,2

n/a

n/a

n/a

0,4

Pace

mak

er in

fect

ion

--

-0

0,4

n/a

1,5

2,6

n/a

n/a

0,3

n/a

n/a

n/a

0,5

Devi

ce m

alfu

nctio

n (in

c m

alse

nsin

g, m

alpa

cing

)-

--

00,

1n/

a-

0,9

n/a

n/a

0,4

n/a

n/a

n/a

0,1

Lead

-rela

ted

re-in

terv

entio

n-

--

00,

2n/

a0,

81,

7n/

an/

a0,

5n/

an/

an/

a0,

3Po

cket

revi

sion

--

-0

0,1

n/a

-1,

7n/

an/

a-

n/a

n/a

n/a

0,1

Othe

r-

-0,

40,

20,

1n/

a-

-n/

an/

a-

n/a

n/a

n/a

0- D

enot

es n

o (0

%) c

ompl

icat

ions

occ

urre

d, n

/a d

enot

es n

o da

ta w

as a

vaila

ble;

† T

otal

com

plic

atio

n ra

te c

an b

e lo

wer

than

sum

of p

eri-p

roce

dura

l and

long

-term

com

plic

atio

ns b

ecau

se m

ore

than

one

eve

nt c

ould

hav

e oc

curre

d in

one

pat

ient

‡ M

icra

Maj

or C

ompl

icat

ion

rate

s ar

e di

spla

yed

as a

bsol

ute

even

t rat

es (n

umbe

r of p

atie

nts

with

eve

nt/t

otal

num

ber o

f pat

ient

s); §

Sho

rt-te

rm c

ompl

icat

ion

rate

was

def

ined

as

< 3m

onth

s

Righ

t Ven

tric

ular

Lea

dles

s Pa

cing

VVI p

acem

aker