Early Performance of a Miniaturized Leadless Cardiac Pacemaker

The Micra Transcatheter Pacing Study

Philippe Ritter; Gabor Z. Duray; Clemens Steinwender; Kyoko Soejima; Razali Omar; Lluís Mont; Lucas VA Boersma; Reinoud E. Knops; Larry Chinitz; Shu Zhang; Calambur Narasimhan; John Hummel; Michael Lloyd; Timothy Alexander Simmers; Andrew Voigt; Verla Laager; Kurt Stromberg; Matthew D. Bonner; Todd J. Sheldon; Dwight Reynolds

Disclosures

Eur Heart J. 2015;36(37):2510-2519. 

In This Article

Methods

Study Design and Oversight

The trial is a prospective, multi-site, single-arm, worldwide clinical study evaluating the safety and efficacy of the TPS. Briefly, the study will implant up to 720 patients at up to 70 centres worldwide. All participants must satisfy standard criteria for de novo pacemaker implantation with Class I or II indications and provide written informed consent. The trial design is described in detail elsewhere.[9] The trial is sponsored by the manufacturer, Medtronic. The protocol was approved by the Ethics Committee at each participating institution and associated national and local regulatory agencies. Data of this ongoing study are collected by trained centre personnel, and data integrity maintained via programmatic edit checks and source data verification by the sponsor. Safety and trial conduct oversight are provided by an independent data monitoring committee.

Study Device and Implant Procedure

The transcatheter pacing system is a 0.8 cc, 2.0 g, self-contained, hermetically enclosed capsule, single-chamber ventricular pacemaker with functionality and features similar to existing ventricular pacemakers, inclusive of rate responsive pacing and automated pacing capture threshold management. The device is 25.9 mm in length, with an outer diameter of 6.7 mm. A nominal pulse width duration of 0.24 ms was chosen since it is near the chronaxie of the strength duration curve.[10] Utilizing a pulse width near the chronaxie should minimize pacing energy and improve battery longevity. By design, it is conditionally safe for full body magnetic resonance imaging in 1.5 and 3.0 Tesla scanners. The device is fixated via four electrically inactive protractible nitinol tines located on the distal end of the device (Figure 1).

Figure 1.

Transcatheter pacing system single-chamber ventricular pacemaker. Illustration of transcatheter pacing system positioned in the RV apex. RV, right ventricle.

The TPS is tethered to and sits in a cup at the distal end of a steerable transfemoral catheter delivery system and placed through the femoral vein using a 23 French internal diameter/27 French outer diameter introducer (Figure 2). The introducer is advanced using a guide-wire and dilator into the right atrium. The guide-wire and dilator are then removed, and the steerable delivery system catheter with TPS preloaded and tethered is then advanced into the RV. Transcatheter pacing system is deployed by retraction of the device-containing cup at the distal end of the delivery catheter positioned against the RV endocardium with fixation into the myocardium by the associated protraction of the nitinol tines (Figure 3). The delivery catheter is then withdrawn several centimetres and the fixation confirmed by a 'pull and hold' test. The tether is pulled until counter movement of the heartbeats can be felt and the tine deflection can be observed fluoroscopically, with the tethering material still connected to the TPS. Although bench testing has shown a single tine engaged in tissue holds the device securely within the myocardium with a high margin of safety, it is recommended that two tines are engaged for further security of fixation. Therefore, investigators are requested to check fluoroscopically that at least two tines are engaged within the myocardium before releasing the device; otherwise, the device should be retracted and repositioned to another position within the RV. Once the device is placed in the RV and adequate device fixation verified, electrical measurements (pacing thresholds, pacing impedance, R-wave amplitude) are checked. Inadequate fixation (e.g. device tines engage into the trabeculae rather than RV myocardial wall) will be apparent via unacceptable electrical measurements and possibly failed pull and hold test. In case of persistence of high thresholds after two to three deployments, investigators were advised to remove the transcatheter delivery system in order to check for thrombus covering the tip electrode, and, if found, to carefully remove the thrombus. No specific implant location is recommended as the device can be placed at various anatomical RV positions. However, it is suggested to avoid placement at the free wall to minimize risk of effusion.

Figure 2.

Transcatheter pacing system delivery system. Tools needed to deliver transcatheter pacing system, from bottom to top: needle and guide-wire, introducer with dilator, delivery catheter with transcatheter pacing system retracted within the distal tube of the delivery system. Insert: transcatheter pacing system with Euro dollar to indicate scale.

Figure 3.

Transcatheter pacing system deployment. Step 1, upper panel: the device is fully retracted within the delivery system. The distal end of the catheter is placed at the targeted site of the RV. Step 2, middle panel: the device is deployed and its tines penetrate the myocardium. Step 3, lower panel: the delivery catheter is pulled back from the device, which is still retained by a tether. After fixation and electrical checks, the tether will be cut and removed, as will the delivery system be. RV, right ventricle.

After adequate electrical measurements are obtained, the tether is cut and the delivery system is removed. Haemostasis is achieved via various closure methods, determined by implanter. Post-procedural haemostasis and peri-procedural antibiotics and anticoagulation are at implanter discretion with the exception that intra-procedural heparinized flushing of the introducer is recommended in all patients.

Therapy Initiation and Follow-up

Enrolled patients undergo system implant attempt and then are followed, including adverse event and device evaluation, at implant, hospital discharge, 1, 3, 6, and 12 months post-implant. Implanted patients are evaluated semi-annually until trial closure. Cardiovascular, procedure, and system-related adverse events are adjudicated by an independent clinical events committee.

Initially, pacemaker-dependent patients were excluded. Twenty-five implanted patients underwent 24 h ambulatory ECG and device function (markers and EGMs) monitoring (Model ER220, Medtronic plc, Mounds View, MN, USA). After comprehensive review of the ambulatory ECG and safety data by the trial's independent data monitoring committee, allowance of pacemaker-dependent patients was determined.

Early Performance Objectives

Early performance objectives, the subject of this report, were assessed once the 60th patient completed the 3-month post-implant visit. At that point, 140 patients had been implanted (Figure 4). The safety objective was assessed in all 140 implanted patients, and the efficacy objective was assessed in the 60 subjects who had been followed through 3 months. These early performance objectives were required to obtain CE mark:

Figure 4.

Flow diagram of patients analysed. Flow diagram from patients implanted by 11 August 2014 and analysed for early performance objectives.

  1. The early safety performance objective was to demonstrate that the freedom from unanticipated serious adverse device events (USADEs) was significantly >85% in all implanted patients once 60 patients were followed through 3 months. The early safety performance objective was assessed in all 140 implanted patients. USADEs are defined as serious adverse events related to the use of the TPS not previously identified in nature, severity, or degree of incidence. USADEs were selected for the early safety assessment endpoint since the risk profile of transvenous pacemaker lead systems has been well-established. Thus, the rate of USADEs was selected to characterize unforeseen risk associated with TPS.

  2. The early efficacy performance objective was to demonstrate that the mean pacing capture threshold at pulse duration of 0.24 ms was significantly lower than 2 V in the 60 patients who completed the 3-month follow-up visit. Meeting this objective ensures TPS would have battery longevity estimation as expected.

In addition to the USADE early performance objective, all adverse events from the 140 implanted patients were carefully described and reviewed by the Data Monitoring Committee.

Statistical Methods

A sample size of 60 patients successfully implanted with TPS and followed for at least 3-months post-implant provided more than 90% power at a type I error level of 0.025 to test the null hypothesis associated with the early performance efficacy objective assuming the true mean 3-month pacing capture thresholds is 1.0 V with a standard deviation of 0.5 V. This sample size provided more than 90% power for testing the early performance safety objective since all patients with an implant attempt at the time the 60th 3-month visit was accrued would be included in the analysis of the safety objective.

The Kaplan–Meier method was pre-specified as the method for evaluating the safety objective so all patients with an implant attempt could be included in the analysis. However, since no USADEs were observed, the exact binomial test comparing the observed 3-month USADE free rate to the null value of 85% was used to evaluate the safety objective and derive the lower 97.5% confidence interval (CI). A one-sample t-test comparing the observed mean 3-month pacing capture threshold to the null value of 2.0 V was used to test the efficacy objective. In addition, paired t-tests were used to compare electrical variables measured at implant and the 3-month visit. Statistical calculations were performed using SAS (SAS Institute, Cary, NC, USA) or R (www.r-project.org) and validated per the sponsor's operating procedures. The procedure duration was defined as the time from the insertion of the TPS introducer to removal. Time to hospital discharge was defined as the number of days from implant to hospital discharge.

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