Author + information
- Received September 5, 2018
- Revision received December 13, 2018
- Accepted December 16, 2018
- Published online February 18, 2019.
- Mikhael F. El-Chami, MDa,∗ (, )
- Nicolas Clementy, MDb,
- Christophe Garweg, MDc,
- Razali Omar, MDd,
- Gabor Z. Duray, MDe,
- Charles C. Gornick, MDf,
- Francisco Leyva, MDg,
- Venkata Sagi, MDh,
- Jonathan P. Piccini, MDi,
- Kyoko Soejima, MDj,
- Kurt Stromberg, MSk and
- Paul R. Roberts, MDl
- aDivision of Cardiology, Section of Electrophysiology, Emory University Hospital, Atlanta, Georgia
- bCentre Hospitalier Régional Universitaire de Tours-Hôpital Trousseau, Tours, France
- cUniversitaire Ziekenhuizen Leuven–Campus Gasthuisberg, Leuven, Belgium
- dCardiac Vascular Sentral, Kuala Lumpur, Malaysia
- eClinical Electrophysiology Department of Cardiology, Medical Centre, Hungarian Defence Forces, Budapest, Hungary
- fMinneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, Minnesota
- gAston Medical Research Institute, Aston Medical School, Aston University, Birmingham, United Kingdom
- hSouthern Heart Group, Jacksonville, Florida
- iDuke University Medical Center, Durham, North Carolina
- jKyorin University Hospital, Tokyo, Japan
- kMedtronic, Mounds View, Minnesota
- lUniversity Hospital Southampton National Health Service Foundation Trust, Southampton, United Kingdom
- ↵∗Address for correspondence:
Dr. Mikhael El-Chami, Division of Cardiology-Section of Electrophysiology, Emory University, 550 Peachtree Street Northeast, Atlanta, Georgia 30308.
Objectives This study sought to report periprocedural outcomes and intermediate-term follow-up of hemodialysis patients undergoing Micra implantation.
Background Leadless pacemakers may be preferred in patients with limited vascular access and high-infection risk, such as patients on hemodialysis.
Methods Patients on hemodialysis at the time of Micra implantation attempt (n = 201 of 2,819; 7%) from the Micra Transcatheter Pacing Study investigational device exemption trial, Micra Transcatheter Pacing System Continued Access Study Protocol, and Micra Transcatheter Pacing System Post-Approval Registry were included in the analysis. Baseline characteristics, periprocedural outcomes, and intermediate-term follow-up were summarized.
Results Patients on hemodialysis at the time of Micra implantation attempt were on average 70.5 ± 13.5 years of age and 59.2% were male. The dialysis patients commonly had hypertension (80%), diabetes (61%), coronary artery disease (39%), and congestive heart failure (27%), and 72% had a condition that the implanting physician felt precluded the use of a transvenous pacemaker. Micra was successfully implanted in 197 patients (98.0%). Reasons for unsuccessful implantation included inadequate thresholds (n = 2) and pericardial effusion (n = 2). The median implantation time was 27 min (interquartile range: 20 to 39 min). There were 3 procedure-related deaths: 1 due to metabolic acidosis following a prolonged procedure duration in a patient undergoing concomitant atrioventricular nodal ablation and 2 deaths occurred in patients who needed surgical repair after perforation. Average follow-up was 6.2 months (range 0 to 26.7 months). No patients had a device-related infection or required device removal because of bacteremia.
Conclusions Leadless pacemakers represent an effective pacing option in this challenging patient population on chronic hemodialysis. The risk of infection appears low with an acceptable safety profile. (Micra Transcatheter Pacing Study; NCT02004873; Micra Transcatheter Pacing System Continued Access Study Protocol; NCT02488681; Micra Transcatheter Pacing System Post-Approval Registry; NCT02536118)
Patients with end-stage renal disease (ESRD) are 5-fold more likely to require pacing for the treatment of bradyarrhythmia than the general population is (1). Transvenous (TV) pacing leads may cause subclavian vein stenosis in up to 70% of patients with a permanent pacemaker (PPM) on hemodialysis (2). Whereas central venous stenosis is often asymptomatic in the general population, it is frequently associated with symptoms in ESRD patients due to the higher flow associated with arteriovenous access (3). More importantly, central venous stenosis or occlusion could compromise the function of dialysis access and make implanting a TV-PPM challenging (2,4,5). These patients often have had multiple dialysis catheters leading to subclavian vein stenosis or occlusion (6,7). This could prevent access to the right atrium and right ventricle from the upper venous circulation. Another important consideration in this patient population is the risk of bacteremia associated with accessing dialysis catheters or arteriovenous fistulas or grafts (5,8). Bacteremia in this setting not uncommonly leads to seeding of the TV hardware (8,9).
By eliminating the need for subclavian venous access and reducing the risk of infection, leadless pacemakers offer an attractive alternative to traditional TV-PPM in this patient population. We sought to report on the safety and intermediate-term outcomes of dialysis patients enrolled in the Micra Transcatheter Pacing Study’s investigational device exemption (IDE) trial, Micra Transcatheter Pacing System Continued Access (CA) Study Protocol, and Micra Transcatheter Pacing System Post-Approval Registry (PAR) (10–12).
Study design and oversight
Patients with a history of renal dysfunction requiring dialysis at their baseline visit were identified from the Micra IDE study, Micra CA study, and Micra PAR. The design and results of the Micra IDE study have been previously reported (10). Briefly, the Micra IDE study evaluated the safety and performance of the Micra system and was used to secure regulatory approval for the Micra Transcatheter Pacing System (TPS) (Medtronic, Mounds View, Minnesota). The Micra CA study was conducted to allow for continued access to the Micra TPS while under review by the U.S. Food and Drug Administration. The design of the Micra PAR study and initial results have also been previously reported (12,13). The aim of the Micra PAR is to further evaluate short- and long-term safety and performance of the Micra TPS when used as intended in real-world clinical practice following commercial release. The 9-year Micra PAR follow-up period is ongoing.
All 3 studies were prospective, nonrandomized, and enrolled patients that met class I or II guideline recommendations for ventricular pacing (14) with no comorbidity restrictions. Patients with an existing pacemaker or implantable cardioverter-defibrillator were excluded from the Micra IDE study, but were allowed to participate in the Micra CA and PAR studies. All 3 studies were sponsored by Medtronic. The protocols were approved by the ethics committee at each center, and all patients provided written informed consent. Adverse events were adjudicated by a clinical events committee composed of independent physicians.
The objective of this analysis was to evaluate the performance and safety of the Micra TPS system when used to treat bradyarrhythmias for ESRD patients requiring dialysis. Safety was assessed by summarizing the rate of major complications through 12 months post-implantation, defined as events related to the Micra TPS device or implantation procedure and resulting in death, permanent loss of device function, hospitalization, prolonged hospitalization by 48 h or more, or system revision. Medical history characteristics, implantation characteristics, and electrical performance were also evaluated.
All patients enrolled in the Micra IDE, CA, or PAR studies with renal dysfunction requiring dialysis at baseline were included in the analysis. Summary statistics were obtained and reported using mean ± SD for continuous variables and frequencies and percentages for categorical variables. The rate of major complication through 12 months post-implantation and its 95% confidence interval were computed using the Kaplan-Meier method for patients on dialysis and not on dialysis at baseline. Additionally, the Cox proportional hazard model and Fine-Grey competing risk model, which models the risk for major complication in the presence of the competing risk of death unrelated to the Micra system or procedure, were used to compare the risk for major complication through 12 months between those patients on and not on dialysis at baseline. All analyses were conducted with SAS (version 9.4, SAS Institute, Cary, North Carolina) or the R statistical package (R Project for Statistical Computing, Vienna, Austria).
The Micra IDE and CA databases were locked prior to reporting their results. The Micra PAR database was frozen for analysis on April 3, 2018. A total of 2,819 patients underwent a Micra implantation attempt across the 3 studies, of which 201 dialysis patients (7%) were identified from 94 centers. Of the 201 dialysis patients, 28, 28, and 145 were from the Micra IDE, CA, and PAR studies representing, respectively, 3.9%, 10.1%, and 8.0% of each study’s population. Average follow-up for this cohort was 6.2 months (range 0 to 26.7 months), with 50 patients having more than 12 months of follow-up; though 45 patients had not yet had post-implantation follow-up at the time of the analysis. Mean follow-up time for the 2,615 patients in the nondialysis cohort was 9.0 ± 7.7 months (range 0 to 30.0 months). Baseline characteristics are summarized in Table 1. The mean age was 70.5 ± 13.5 years and 66% of patients had a history of atrial tachyarrhythmias, 61% had diabetes, and 80% had hypertension. Additionally, 15% of patients had a previously implanted cardiac implantable electronic device. Dialysis patients were younger and less likely to have a history of atrial arrhythmia, but they tended to have more comorbidities including: cardiomyopathy, congestive heart failure, coronary artery disease, hypertension, and diabetes.
Indications for pacing and device implantation
Permanent atrial fibrillation (AF) with bradyarrhythmia was the main indication for pacing (45.3%), followed by arteriovenous block (25.4%), and sinus node dysfunction (17.4%) (Table 1). A larger percentage of non-dialysis patients had a primary pacing indication of permanent AF with bradyarrhythmia (64.2%), while a lower percentage of patients had pacing indications associated with arteriovenous block (11.2%) and sinus node dysfunction (11.5%).
Of the 201 dialysis patients, the implanting physician indicated the presence of a condition that precluded transvenous pacing in 144 patients (72%). Of those precluded for TV pacing, common reasons included the need to preserve venous access (79%) followed by prior infection (20%) and venous occlusion (17%) (Table 2).
Micra was successfully implanted in 197 of the 201 patients (98.0%). The number of deployments required for implantations was ≤3 for 167 of the 186 patients (89.8%) with deployment number reported. Two patients had elevated thresholds despite multiple attempts to achieve acceptable electrical parameters. Two patients developed a pericardial effusion requiring surgical repair and subsequently died. Consequently, the implantation procedures failed in these 4 cases. The median implantation duration was 27 min (interquartile range: 20 to 39 min) with a median fluoroscopy time of 6 min (interquartile range: 4 to 10 min).
There were 11 major complications in 9 patients (4.5%) adjudicated as related to the Micra device or procedure (Table 3). These complications were reported previously as part of Micra IDE and PAR articles (10,13). All 11 major complications occurred within 25 days of implantation. The major complications included 4 device pacing issue events (2 intermittent loss of capture, 1 dislodgement without embolization, 1 device embolization during implantation attempt), 2 cardiac effusion/perforation events, 1 vascular pseudoaneurysm, 1 infection (abdominal wall), and 3 other events (including 1 instance of metabolic acidosis, 1 complication of device removal, and 1 drop in blood pressure). There were 76 major complications adjudicated as related to the device or procedure in 69 patients in the nondialysis cohort (2.6%) (Table 3). At 12 months, the Kaplan-Meier estimated major complication rate was 4.9% (95% CI: 2.6% to 9.4%) for patients on dialysis at baseline and 3.2% (95% confidence interval [CI]: 2.5% to 4.0%) for patients not on dialysis at baseline (Figure 1). Both the Cox proportional hazards model and the Fine-Gray competing risks model indicated an elevated risk for major complication among patients on dialysis versus those that were not, but in both cases the difference was not significant (Cox model: hazard ratio: 1.8; 95% CI: 0.9 to 3.7; p = 0.088, and Fine-Gray model: hazard ratio: 1.8; 95% CI: 0.9 to 3.6; p = 0.100).
There was 1 dislodgement without embolization. The device was attached to the RV myocardium in proximity to the papillary muscle. This device was retrieved and reimplanted 50 days after the original implantation procedure. Another device embolized during implantation, it was snared and retrieved. This patient received another Micra device during the same procedure. These dislodgments were previously reported as part of the Micra PAR article (13).
The abdominal wall infection was related to a percutaneous retrieval attempt on the day of implantation due to elevated thresholds. During the retrieval, the device became entangled in the patient’s inferior vena cava filter (a contraindication for a Micra implant), causing vascular trauma requiring surgical repair. A second Micra device was successfully implanted on the same day. This soft tissue infection was treated successfully with antibiotics. No bacteremia or device involvement were noted.
Three of the major complications resulted in death among the 201 dialysis patients. These complications were also previously reported (10,13). One patient developed acidosis after a prolonged Micra and concomitant arteriovenous nodal ablation procedure. This patient died during hospitalization from severe acidosis and a refractory sepsis-like picture. There was no pericardial effusion and no retroperitoneal hemorrhage identified and the Micra pacemaker was functioning normally at the time of death. Two perforation events required surgical repair, but ultimately led to death. The first perforation occurred in a 65-year-old woman with a low body mass index (17.6 kg/m2) and hypertension. After multiple attempts to deploy the Micra device without successfully engaging the tines, an echocardiogram revealed a pericardial effusion. The RV perforation was repaired surgically, but the patient experienced extensive blood loss and was pronounced dead the same day despite administration of blood products. The second perforation event occurred in a 76-year-old woman with hypertension and diabetes. This patient had a complicated post-operative course and developed sepsis 2 weeks later with documented bacteremia and died approximately 3 weeks following the implantation attempt due to septic shock. There were also 3 reported procedure-related deaths in the nondialysis patients, which have been previously reported (13). Briefly, these deaths were due to pulmonary edema, retroperitoneal bleeding (in a patient undergoing concomitant arteriovenous nodal ablation), and heart failure.
One additional patient developed a pericardial effusion requiring a pericardiocentesis. This complication did not meet the pre-specified major complication definition. The total rate of perforation in this cohort was 1.5% (1.0% for perforations meeting the major complication definition). In comparison, the rate was 1.1% (0.8% meeting major complication definition) in patients not requiring dialysis at baseline (p = 0.21 and p = 0.27, respectively).
No patient had a device-related infection or required device removal due to bacteremia.
Device electrical performance
The mean pacing capture threshold was 0.65 ± 0.56 V at 0.24 ms (n = 156) at implantation and remained stable through 12 months of follow-up (0.66 ± 0.45 V; n = 48) (Figure 2A). The mean impedance was 696 ± 187 Ω at implantation and 566 ± 94 at 12 months (Figure 2B). The mean R-wave amplitude was 11.1 ± 5.3 mV at implantation and 13.8 ± 6.0 mV at 12 months (Figure 2C).
This is the first report on the outcome of dialysis patients implanted with leadless pacemakers. In this study of 201 dialysis patients, there are several notable findings. First, implantation success in this cohort was high (98%) and is comparable with the overall Micra implantation experience: Micra IDE (99.2%) and PAR (99.1%) (10,11). Second, Micra pacing thresholds and sensing were excellent and remained stable during follow-up. Third, although the major complication rate was slightly higher for patients on dialysis (4.9%) compared with those not on dialysis (3.2%), the rate was relatively low for both groups and did not differ significantly in this dataset of 2,819 patients. However, 3 procedure-related mortalities were observed among the dialysis patients. Finally, and perhaps most importantly, during a total of 103.5 patient-years of follow-up, the rate of device infection was extremely low in this very high-risk patient population, through mid-term follow-up.
Although the overall safety profile was comparable to the overall Micra experience, patient deaths did occur. One death was due to an underlying systemic illness (potentially sepsis) manifesting as acidosis and AF with rapid ventricular response without any evidence of mechanical complication attributed to the procedure. The remaining 2 deaths, however, were related to perforations that required surgical repair. The rate of perforation in this cohort was 1.5% (1.0% meeting major complication definition) compared with 1.1% (0.8% meeting major complication definition) in patients not requiring dialysis at baseline.
As highlighted here, the most important finding in this study was the absence of device-related infection or bacteremia that required device removal. This finding potentially highlights an advantage of leadless pacing in this setting. TV device-related infection occurs in 8% of dialysis patients (15). Dialysis-access infection and related bacteremia often result in lead-related endocarditis and require extraction of TV pacing leads (16–18). TV lead extraction in dialysis patients with bacteremia is associated with an increase in short-term and intermediate-term mortality (19,20). The Micra leadless pacemaker not only eliminates pocket-related infections but also may have the potential advantage of minimizing the chance of device seeding in the setting of bacteremia. This is probably related to the small surface area of Micra and its tendency for complete or near-complete endothelialization (21,22).
Another important advantage of leadless pacing in dialysis patients is the sparing of access to the central venous system. This is an obvious advantage, as a functioning dialysis access site is the lifeline of this population. Dialysis accesses often malfunction, resulting in these patients having to rely on a new arteriovenous fistula or graft in the contralateral shoulder (23). Keeping subclavian veins patent by avoiding the use of TV leads is therefore important in this patient population. This was noted in our study as 57% of patients underwent Micra implantation to preserve venous access for dialysis and another 12% underwent Micra implantation due to the presence of an occluded/stenosed subclavian vein (Table 3).
Less than one-half (44.5%) of patients had permanent AF with bradycardia as an indication for pacing, whereas the remainder had an intact sinus node mechanism (Table 2). In the Micra IDE study and PAR, 64% and 57.7% of patients, respectively, had permanent/persistent AF. It is conceivable that physicians were more likely to choose the Micra device (a single-chamber pacemaker) in ESRD patients despite an intact sinus node function because of the advantages of a leadless system in this setting.
We did note a periprocedural mortality of 1.5% in this cohort. Patients on dialysis have significant comorbidities including cardiomyopathy, heart failure, coronary artery disease, and diabetes. These comorbidities could predispose this cohort to higher rate of perioperative adverse events. For example, in a study examining outcomes of implantable cardioverter-defibrillator recipients, patients with ESRD had 5-fold higher in-hospital mortality as compared to patients not on dialysis (1.9% vs. 0.4%, p < 0.0001) (24). Similarly, patients with chronic kidney disease undergoing percutaneous coronary intervention had higher in-hospital mortality than patients without chronic kidney disease (5.7% vs. 1.2%, p < 0.001) (25).
This is the first report on the outcomes of ESRD patients after leadless pacemaker implantations. The choice of leadless over TV-PPM was left to the discretion of the implanting physician. Whereas leadless pacemakers have several potential advantages in this patient population, their advantage over TV-PPM has not been studied in a randomized trial. In addition, the nonrandomized nature of the trial does not rule out selection bias as a possible confounder. For those patients from the IDE trial, there is potential for referral bias; however, IDE patients composed 3.9% of the dialysis cohort, minimizing this potential bias. As the mean follow-up duration was shorter in the dialysis cohort, it is plausible that the major complication rate may continue to rise; however, in prior analyses, we have found that the majority of major complications occur within 30 days of implantation (11,13).
The Micra leadless pacemaker is a reasonable pacing option in patients with ESRD on hemodialysis and it appears to have an acceptable safety profile through mid-term follow-up. The absence of device infection during a mean follow-up of 6.2 months and the sparing of upper venous circulation are significant advantages of leadless pacing in this population.
COMPETENCY IN MEDICAL KNOWLEDGE: The present study demonstrates the safety and effectiveness of leadless pacemakers in patients on hemodialysis at the time of implantation. The absence of device infection during follow-up and the sparing of upper venous circulation are significant advantages of leadless pacing in this population.
TRANSLATIONAL OUTLOOK: While our results demonstrate advantages of leadless pacemakers versus TV pacemakers in this patient population, further investigation is required to determine long-term outcomes.
The authors thank Dedra Fagan of Medtronic for assistance in the preparation of this manuscript.
The Micra Transcatheter Pacing Study, Micra Transcatheter Pacing System Continued Access Study Protocol, and Micra Transcatheter Pacing System Post Approval Registry are funded by Medtronic. Dr. El-Chami is a consultant for Medtronic and Boston Scientific. Dr. Clementy has received consulting fees from Medtronic. Dr. Garweg has received consulting fees from Medtronic and Biotronic. Dr. Omar has received honoraria for speaking engagements on behalf of the Speakers Bureaus of Boehringer Ingelheim, Boston Scientific, and Medtronic. Dr. Duray has received research grants from Boston Scientific, Biotronik, and Medtronic; has received consulting fees from Bayer/Schering Pharma, Biotronik, Boehringer Ingelheim, Medtronic, Abbott, and St. Jude Medical; and is a member of the Micra Study steering committee. Dr. Gornick owns stock in Medtronic. Dr. Leyva has received consulting fees from Medtronic, Boston Scientific, LivaNova, St. Jude Medical; and has received research grants from Boston Scientific, LivaNova, Medtronic, Abbott, Microport, and St. Jude Medical. Dr. Piccini has received consulting fees from ARCA Biopharma, Allergan, Biotronik, Boston Scientific, Gilead, Johnson & Johnson, Medtronic, Philips, Sanofi, GlaxoSmithKline, and Motif Bio. Dr. Soejima has received funding from Medtronic. Mr. Stromberg is an employee of and owns stock in Medtronic. Dr. Roberts has received consulting fees from Boston Scientific and Medtronic. Dr. Sagi has reported that he has no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- atrial fibrillation
- Continued Access
- confidence interval
- end-stage renal disease
- investigational device exemption
- Post-Approval Registry
- permanent pacemaker
- Transcatheter Pacing System
- Received September 5, 2018.
- Revision received December 13, 2018.
- Accepted December 16, 2018.
- 2019 American College of Cardiology Foundation
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