Leadless Pacemakers For Cardiac Implantable Electronic Devices

The Rise of Pacemaker Implantations

Question:

Discuss about the Scientific and Clinical Evidence of Pacemakers.

In 1950's, Elmquist and Senning at the Karolinsika Hospital, Stockholm, successfully implanted the first ever epicardial system by thoracotomy [1]. Since then, substantial improvements have been made in pacemaker technology, leading to highly sophisticated, entirely endocardial, transvenous systems. Over the past years, the rate of pacemaker implantation has accelerated to approximately 700,000 per year [2]. The same studies show that in United States of America (USA) the implantation rate per year is 250,000, in Europe, implantation rate in 18 countries stands at 938 units per million of the residents annually.

Population aging and great suggestions for the implant of the CIEDs (cardiac implantable electronic devices) are the primary reasons for the progressive increase of the CIDs, PMs, and tools for the CRT [3]. The latest statistics show that since 2005 to 2008, the rate of CIEDs implants have significantly increased, particularly in European countries, with a higher demand for ICDs than for PMs [4].

Despite the progress, pacemaker therapy is still associated with non-negligible peri and post-procedural complications, with transvenous lead remaining the major challenge in the pacing technology [5]. Many implantation processes may result in complications such as pneumothorax, lead dislodgement, cardiac perforation, and tamponade, among other impediments. Complications such as venous thrombosis, significant regurgitation of the tricuspid valve are usually associated with lead pacemaker's implantation [6]. Also, first failure due to insulation problems, the first fracture was reported to be 13% of the total patient who underwent first pacemaker implantation [7]. Modern technological advancement such as leadless pacemaker system, which is implantable in the right ventricle is a significant step towards reducing pacemaker lead-related complications.

At present, only two types of leadless pacing systems are available; the NanostimTM  Leadless Pacemakers System (LCP) introduced in 2012, and the MicraTM Transcatheter Pacing System (TPS) launched in 2013 [8]. Although both systems have received a CE mark, only Micra-TPS is approved for use in the USA by FDA (Food and Drug Administration). Both systems are entirely intracardiac having the generator, the pacing and sensing electrodes incorporated into a capsulated partition implanted straight in the right ventricular wall [9]. The cathode, located on the distal end in both systems is steroid eluting, suitable for reducing inflammation. In the Micra-TPS, the anode is made of titanium ring in the proximal part of the case, while on the Nanostim-LCP, the nearly entire surface can function as an anode. The features of both devices are displayed in Table 1 [10].

Challenges with Traditional Pacemaker Therapy

After selecting the target region for implantation, the Nanostim-LCP is tightened by rotation, while in the Micra-TPS, tightening is done by retraction of the outer sheath and, hence fixing the pacemaker in place [11]. Liberation of the pacemaker from the delivery catheter then follows, though there is still a connection through tethering mechanism. This allows for testing of both pacemaker parameters (sensing, threshold testing, and impendence) as well as stability. Once the sensing and pacing parameters are satisfactory, the system is finally released from the delivery catheter as illustrated in figure 1 [12].

The LEADLESS trial research about the effectiveness and safety of the Nanostim-LCP was the first study was done that was capable of showing results in humans [13] LEADLESS in itself is a potential, systematic, multicenter trial that was performed in three countries in Europe from December 2012 to April 2013. Patients are showing signs of cardiac pacing, for instance, permanent atrial fibrillation, coupled with atrioventricular block, a reasonable range of sinus beat with either second or third-degree atrioventricular block with a reduced level of physical activity were considered for the research [14]. Thirty-three patients of an average age of 82 were recruited for this study, and the participants each received Nanostim-LCP system [15]. The participants were followed-up for the 2nd, 6th and 12th week following implantation of the Nanostim-LCP system.

The safety target for the study was that the participants should be safe from adverse effects of pacemaker implantation after 90 days following implantation. Secondary performance outcome was based on the implants success rate, implant time and features of implant performance such as the threshold of pacing and racing, batter longevity, and rate responsive performance [16]. Based on the results, implantation success rate was recorded at 97% with 32 out of the 33 patients completing the studies. The procedure duration was averaged at 40 minutes. Ten patients who took part in the survey required repositioning of Nanostim-LCP, translating to 30% of the total patients. Complication free rate was recorded at 94%, taking into account 31 out of 33 patients. However, two serious issues were reported, a 70-year-old patient who experienced cardiac tamponade and right ventricle perforation was complicated with an ischemic stroke on the 5th day following implantation and succumbed to death In the second patient, implantation was performed on the LV (left ventricle) via a persistent foramen ovale. Throughout the entire process, no lead dislodgement was encountered [17]. The mean R-wave amplitude was 8.3mV, pacing threshold of 0.80V at 0.4-ms pulse width and impedance of 773Ohms was reported at implantation, and three months later, the parameters either remained stable or improved.

Advancements in Pacemaker Technology: Leadless Pacemaker Systems

After the 12 months follow up period elapsed, the average R-wave amplitude, impedance, mean pacing threshold was 10.3mV, 627Ohms, and 0.43V( at a 0.4-ms pulse width), respectively. Also, it was noted that after the 12 months, there was no complication related to the Nanostim-LCP device and battery exhaustion cases [17]. Based on the systematic randomized results of the LEADLESS trial, it can be deduced that safety and efficacy of the patient following leadless pacemaker system implantation are significantly improved and be a suitable alternative to the standard pacemakers. Unfortunately, due to the death of the patient because of cardiac tamponade, implementation of the leadless pacemaker system in the clinical field was temporarily paused. Later on, permission was granted following training of the physicians carrying out implantation [18].

LEADLESS II study (prospective, nonrandomized, multicenter trial) is underway. The research focuses on the clinical safety and efficacy of the Nanastim-LCP implantation in patients that need permanent single-chamber ventricular pacing [19]. The provisional outcome of the investigation that was recently reported consist of 527 patients who were recruited from 56 sites in the three European countries. The LEADLESS II consisted of subjects that were enrolled from February 2014 to June 2015. Based on the interim results, the success rate was at 95.8% representing 504 of 527 participants [19]. Implantation time took an average of 50 minutes. The primary cohort consisted of 300 patients, who were followed-up for six months. The provisional result reported 2.0V (at 0.4ms) and sensed amplitude 5.0mV following six months, which are both above the standard range.

The primary objective was that the patients should be safe from pacemaker device associated complications through the six months [19]. Significant adverse cases occurred in 6.5% of the total participants that included ventricular perforation, hemopericardium without the need of intervention, and pericardium tamponade requiring intervention. Device dislodgement was reported in 6 patients representing 1.5% of the subjects, in 4 cases, the devices migrated to the pulmonary artery, while in the remaining two patients, the invention migrated to the femoral vein. In all the 6 cases, the dislodged devices were successfully recovered. Vascular access complications were reported in 1.2% of the patients [20].

Prospective, nonrandomized, single group, multisite, international clinical study about the Micra Transcatheter Pacing System was carried in 19 countries globally. The purpose of the study was to evaluate the pacing performance of the system. Seven hundred and twenty-five patients underwent Micra-TPS implantation attempt carried at 56 sites within the countries [21]. The success rate of the Micra-TPS implantation was recorded at 99.2%, translating to 719 patients out of the total 725 subjects. Over the duration of the six months, significant complications rate was reported at 4% as compared to the 7.4% in the control group (hazard ratio 0.50, 95% CI(Confidence Interval) 0.33 to 0.75, p=0.001). The intervention group (underwent Micra-TPS implantation) consisted of older patients with comorbidities as compared to the control group (historical cohort). The decline of device-related complications in the intervention group was even much more evident when a matched unit was used for comparison [21]. The 4% complication rate was composed of 1.6% cardiac perforation, 0.7% access associated issues, 0.3% those with venous thromboembolism and 0.3% representing an increase in threshold stimulation in spite of an absence of dislodgement. Metabolic acidosis led to the death of one patient due to sepsis and renal failure. There were no cases of device-related complications. Regarding pericardial effusion, the intervention group reported 1.6% as compared to the 1.1% in the control group. However, the difference is statistically negligible. There were no cases of lead-related issues or device pocket infection which resulted in the lower rate of complication in comparison to the conventional intravenous pacemakers [21]. Electrical measurement done after six months, included intra-cardiac signal amplitude, stimulation threshold, and pacing impedance which either remained stable or improved in 98.3% of the patients.

Nanostim-LCP and Micra-TPS

Comparison of the two results is displayed in table 2. In summary, the in LEADLESS II Nanostim-LCP, the success rate of implantation was 95.8% representing 504 of the 526 patients. Implantation time took an average of 50 minutes. Primary efficacy following the six months was achieved in 270 patients of the total 300 patients (90%). Since the Nanostim-LCP implantation was unsuccessful 6.6% (270 of 289 patients), the primary met the end point (93.4%). Additionally, central safety endpoint was achieved in 280 out of the 300 participants (93.3%). Following six months, 6.7% of the patients experienced adverse effects, which constituted of 1.3% cardiac perforation, 1.7% device dislodgement with successful percutaneous withdrawal, 1.3% elevation in pacing threshold which needed device retrieval or replacement. The battery longevity approximation in LEADLESS Nanostim-LCP study was 15 years.

In the Micra Transcatheter pacing study, the success rate of device implantation was 99.2%, translating to 719 out of the 725 patients. Adverse complications were reported in 25 of the725 patients, with no evidence of device dislodgements. Control group recorded significantly higher number of complications (7%) as compared to the 4% of the intervention group. Significant complications reported include five groin puncture complication, 11 cardiac injuries, two thromboembolism issues, two pacing cases and eight general complications [22]. The rate of efficacy over the six months was 98.3% in 292 out of 297 patients followed up within the period. Battery life approximations following six months were 12.5 years. Therefore, it is evident that the results from the two studies, even though is a short-term data, reveal that leadless pacing system is a safer and more efficient alternative to conventional lead intravenous pacemakers [22].

Based on the interim results from clinical evaluation, there is a possibility of the leadless pacing gaining widespread adoption. This mainly depends on the practicability and ease of multi-chamber leadless stimulation. This is because the primary limitation of the leadless pacemakers is that they can be used single-chamber ventricular pacing [23]. Therefore, it may not be suitable for patients with sinus-node dysfunction and other conditions, who require multi-chamber pacing system. Long-term research is necessary to confirm the device performance regarding battery longevity, adequate sensing, the safety of retrieval, stable stimulation control, among other parameters. The two types of research also do not explain the destiny of the devices after reaching the end of service. They do not clarify whether the devices will be switched off, or retrieved during replacement implantation. Finally, the cost of the leadless pacemakers is much higher than that of the conventional pacemakers. Hence, many people cannot afford them.

Results of the LEADLESS Trial

Conclusion

Based on the research results and the early experience of first-generation leadless pacemakers, there is more potential to explore using this novel technology. The reduction of the device related complications gives leadless technology a favorable advantage. The introduction of the leadless technology in healthcare facilities present a promising future in dealing with cardiovascular complications. However, the first generation leadless pacemakers require further technological advancement for development of the dual-chamber pacing system. Also, randomized, the clinical trial is necessary to further determine the long-term safety, efficacy, and retrievability of the leadless pacing system. Regardless of the concerns, the preliminary results about the performance of the leadless pacing system are quite impressing, making the new technology an additional weapon in clinical practice. The technology is ideal for patients with complicated venous anatomy as well as patients in whom implantation of the conventional lead system is impossible.

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