Study Design and Oversight

The LEADLESS II trial is a prospective, nonrandomized, multicenter clinical study. The trial is currently ongoing and enrolling patients. The planned interim analysis, reported here, includes the primary analysis of efficacy and safety in the initial 300 patients who were followed for 6 months (the primary cohort) and outcomes for all 526 patients who were enrolled as of June 2015 (the total cohort).

This premarket study was sponsored by the manufacturer of the Nanostim leadless cardiac pacemaker (St. Jude Medical) and was approved by the Food and Drug Administration and the institutional review board at each participating center. An international steering committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org), with the participation of the sponsor, was responsible for the design and conduct of the study and the reporting of the findings. Monitoring and collection of the data and initial data analyses were performed by the sponsor in partnership with the steering committee. All the authors vouch for the completeness and accuracy of the data and analyses and for the fidelity of this report to the study protocol, available at NEJM.org. The first and last authors wrote the first draft of the manuscript, which was reviewed and edited by the other authors. The sponsor reviewed the manuscript before submission but was not involved in the writing of the manuscript or in the decision to submit it for publication.

Study Participants

After obtaining written informed consent, we enrolled patients with indications for permanent single-chamber ventricular pacing, including chronic atrial fibrillation with atrioventricular or bifascicular bundle-branch block, sinus rhythm with second-degree or third-degree atrioventricular block and a low level of physical activity or a shortened expected life span, or sinus bradycardia with infrequent pauses or unexplained syncope with an abnormal electrophysiological study. Patients were excluded if they had a mechanical tricuspid-valve prosthesis, pulmonary arterial hypertension, preexisting endocardial pacing or defibrillation leads, or an inferior vena cava filter or if they had undergone cardiovascular or peripheral vascular surgery within 30 days before enrollment (see the Supplementary Appendix for a full list of inclusion and exclusion criteria).

Device Implantation and Follow-up

Figure 1. Figure 1. The Leadless Cardiac Pacemaker. The Nanostim leadless cardiac pacemaker is shown attached to the right ventricular apex (Panel A). The cathode is in the center of the coiled spring, which affixes the device to the endocardium. The anode of the pacemaker is the uncoated part of the titanium case. The proximal portion of the device has a docking interface that enables attachment to the delivery and retrieval catheters. Chest radiographs of a patient who underwent implantation of this leadless cardiac pacemaker are shown in the posteroanterior (Panel B) and lateral (Panel C) projections. The arrows indicate the location of the device, which is situated in the region of the distal right ventricular septum and right ventricular apex.

The leadless cardiac pacemaker that we evaluated (Nanostim LP, St. Jude Medical) is an entirely self-contained, active-fixation, rate-adaptive pacemaker that is 42 mm in length and has a maximum diameter of 5.99 mm (Figure 1). The pacemaker is delivered to the right ventricle at the end of a percutaneous delivery catheter and is anchored in the right ventricular apex with the use of a helical screw-in fixation electrode at the distal end of the device. Further details regarding this pacemaker and its implantation technique are provided in , and in Figure S1 in the Supplementary Appendix.

After the device was implanted and before the patient was discharged from the hospital, the pacemaker was interrogated and the patient underwent chest radiography and standard 12-lead electrocardiography. Subsequent follow-up assessments were performed at 2 weeks, 6 weeks, 3 months, 6 months, and every 6 months thereafter. The programming of the pacemaker was left to the physician’s discretion.

Primary Efficacy and Safety End Points

Figure 2. Figure 2. Enrollment, Study Intervention, and Follow-up. The first 300 enrolled patients made up the primary cohort; data from these patients were analyzed for the primary efficacy and safety end points at 6 months, as prespecified in the protocol. An additional 226 patients were enrolled as part of the ongoing trial; data from these patients were analyzed together with data from the primary cohort that had extended follow-up beyond 6 months. This total cohort of 526 patients was assessed for device-related and non–device-related serious adverse events.

The primary outcome analysis was a prespecified assessment of the primary efficacy and safety end points in the first 300 patients who were followed for 6 months (primary cohort) (Figure 2). The composite primary efficacy end point was both a therapeutically acceptable pacing capture threshold (≤2.0 V at 0.4 msec) and a therapeutically acceptable sensing amplitude (R wave ≥5.0 mV, or a value equal to or greater than the value at implantation) through 6 months. The primary safety end point was freedom from device-related serious adverse events during the initial 6 months after implantation.

All adverse events were adjudicated by an independent clinical-events committee (see the Supplementary Appendix). A serious adverse event was defined as any untoward medical occurrence that led to death or to a serious deterioration in the health of a patient that resulted in life-threatening illness or injury, permanent impairment of a body structure or a body function, inpatient or prolonged hospitalization, or a medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function. Serious adverse events were classified as device-related if they were considered by the clinical-events committee to be attributable to the investigational device or procedure.

Secondary Outcomes

The primary cohort was also evaluated for all non–device-related serious adverse events during 6 months of follow-up. Such events were considered to be unrelated to the investigational device or procedure. Because the LEADLESS II trial is ongoing, secondary analyses were performed on data from additional patients who were enrolled as of June 2015, combined with data from the first 300 patients, who had extended follow-up beyond 6 months (total cohort) (Figure 2). Additional analyses in the total cohort included determination of all device-related and non–device-related serious adverse events during follow-up and the influence of operator experience.

Statistical Analysis

We estimated that if 300 patients were followed for 6 months, the study would have 90% power, at a two-sided 5.0% significance level, to show rates of safety and efficacy that would be superior to predetermined performance goals for safety and efficacy. The performance goal for the primary efficacy end point of both a therapeutically acceptable pacing capture threshold and a therapeutically acceptable sensing amplitude through 6 months was 85%, and the study was powered under the assumption that the rate of this end point would be 91.5% or higher. The performance goal for efficacy was based on an ongoing pacemaker study (ClinicalTrials.gov number, NCT01576016) that is sponsored by St. Jude Medical. The performance goal for the primary safety end point of freedom from device-related serious adverse events through 6 months was 86%, and the study was powered under the assumption that the event-free rate would be 92%. (See the Supplementary Appendix for explanation of the performance goals.)

All the analyses were conducted with the use of exact confidence intervals for binomial proportions. The null hypotheses would be rejected if the lower boundaries of the two-sided 95% confidence intervals for the rate of the primary safety and efficacy end points would be greater than the respective performance goals. The primary safety and efficacy end points were assessed in the intention-to-treat population, which included the first 300 patients (primary cohort) who met the enrollment criteria and provided written informed consent and in whom the implantation of a leadless cardiac pacemaker was attempted. The primary efficacy end point was also analyzed in the subgroup of patients in whom implantation was successful. Statistical calculations were performed with the use of SAS software (SAS Institute) and were validated according to the operating procedures of the sponsor.