Leadless Trial: The First Leadless Self-Contained Pacemaker in Humans

Steven M. Stevens, MD, PhD

Review

Reddy V, Knops RE, Sperzel J, et al. Permanent leadless cardiac pacing: results of the LEADLESS Trial. Circulation. 2014;129:1466-1471.

Study Design

The LEADLESS Trial is the first safety trial in humans of the completely self-contained leadless cardiac pacemaker (LCP) (Nanostim Inc, Sunnyvale, California). LEADLESS was a non- randomized trial with 33 consecutive patients who had a VVIR pac- ing indication, most with atrial fibrillation (AF) and atrioventricular block. The 42-mm-long LCP device was placed with an 18F trans- femoral sheath to the right ventricular apex, and a helix was delivered in a similar screwing mechanism to traditional leads. A tether remains connected for testing once the LCP is delivered and the sheath is un- docked. Once in a satisfactory position, the tether cable is released. Snare retrieval devices are also supplied, and were required twice in this study to remove leads (1 from the left ventricle, and the other when the patient was implanted with an implantable cardiac defibril- lator [ICD] for ventricular tachycardia). The mean procedure time was 28 minutes (range, 11-74 minutes). The LCP communicates with a specialized programmer that sends 250-kHz pulses from skin elec- trodes to the device, but otherwise works like a traditional program- mer (Merlin Patient Care System model 3650, St. Jude Medical, St. Paul, MN). Functionally, the LCP works similar to a standard bipolar VVIR pacemaker, with similar lead characteristics, and a rate-respon- sive feature. The expected battery longevity is 8.4 years with 100% pacing. The trial investigators report a 97% implant success rate.

The 90-day safety data were comparable to traditional pacemaker implantation, with 2 overall complications: 1 from inadvertent left ventricular (LV) implantation and the other from right ventricular (RV) perforation, leading to patient death. There were 5 patients (15%) that required a second LCP to be implanted due to technical difficulties with implantation (inadvertent LV placement, malfunction of release knob, damage to helix, difficulty with wire deflection mechanism, and delivery sheath damage). Pacing characteristics, thresholds, R-wave amplitude, and impedance were as expected with a traditional pacemaker.

Commentary

A Potential Game Changer

Nanostim’s leadless self-contained pacemaker is the first major advance in pacemaker technology since the implantation of the first pacemaker in 1958. Until now, pacing the heart was synonymous with use of pacing leads and a pulse generator. By eliminating the need for a lead and the need to place the generator in a pocket, the risk of infection should theoretically be reduced without exposure to skin flora during incision, no risk of pocket hematoma or device erosion, and overall less surface area of the device to potentially become infected. Likewise, the leads, exposed to mechanical stress and required to bend in the heart and vasculature with each beat, are prone to fractures, insulation breaks, and connection problems, and may cause vascular thrombosis. Therefore, the concept of a small self-contained leadless pacemaker should eliminate many of the problems that are associ- ated with current pacemaker technology.

Nevertheless, any new solution to a problem will bring with it a new set of problems. The unfortunate case of cardiac tamponade leading to death in the LEADLESS trial was notable, and would be an unacceptable result of a traditional pacemaker implanta- tion. Rates of life-threatening events such as tamponade (0.13%-0.5%), pneumothorax (0.7%-2.3%), and infection (0.4%-0.9%) are all low for pacemaker implantation, but the mortality rate is even lower (0.2%-0.7%) and has been reported to be zero in many trials.^1-3 Therefore, the death of 1 of 33 patients in this trial, if demonstrated to persist, would be 3% in a larger population—an unacceptably high rate of mortality that suggests leadless pacing technology would not be viable in the near future.

The authors of the LEADLESS trial explain in great detail how the tamponade occurred, stating that the 18F sheath was not fully disengaged from the LCP and subsequently was advanced past the device while at the RV apex. They even detailed the amount of force on the LCP (4.6 g/mm²) compared with an ICD lead (5.5 g/ mm²) and demonstrated that the pressure exerted on the tissue at the tip of the LCP with the sheath attached is increased to 17.7 g/ mm². One can argue that, as experience with implanting the LCP accumulates, complications like this will be rare. But sadly, real- world experience will likely show a bimodal curve in the complication rate, with a second surge as less experienced operators start to implant LCPs. Tamponade is a reality in any intracardiac procedure. But not all tamponade is created equal, and certainly a perforation from a pacing lead, albeit traumatic, is rarely lethal and does not lead to sternotomy and death. This device is much larger than a pacemaker lead, with a diameter of 6 mm and an 18F delivery sheath, so when perforation occurs, one can predict it may be lethal, as was the case in the LEADLESS trial.

However, traditional pacemakers are also plagued with issues that cause frequent complications. Pocket-related problems include hematoma (2.9%), superficial infection (1%), and pacemaker erosion (1%), and can be painful and lead to repeat surgery. Lead related problems such as lead dislodgements (3.3%) 1 and lead fractures (1.5%) 2 often lead to reoperation (3.6%) 3 and sometimes expose patients to risks of extraction. Other than death, rates of overall complications related to pacemakers are high, ranging from 4% to 12%.⁴ Complications were rare in the LEADLESS trial (2/33). Further, the technical problems with LCP delivery described in the 5 cases where >2 LCPs were required will continue to be a real-world challenge.

In conclusion, a finished product that worked 97% of the time with a short procedural duration of 28 minutes suggests this technology is more than feasible. New challenges to be met with respect to LCPs will include dual-chamber and biventricular pacing, making this a potential game changer. This frontier can only be met once there is evidence that leadless pacemakers can be implanted without a significant risk of death, and it will need to be as durable as, or more durable than current pacemakers. This leads to an important question: while they were able to swiftly snare the LCP device in 2 patients in this trial (6 minutes for the misplaced LV lead removal), what will be the case in 6 months, 5 years, or 10 years? What will be the case when the battery runs out? It seems unreasonable to clutter the RV with multiple LCPs over a lifetime if extraction poses undue risk.)

Overall, the LEADLESS trial demonstrates an innovative and sweeping advance in cardiac pacing technology. The fate of this innovation as a true contender in the pacing world will depend on a reasonable safety record, which will need to exceed our expectations of traditional pacing with a lead and pulse generator. We look forward to future studies, including a randomized trial to help guide practice.

References

1. Udo EO, Zuithoff NP, van Hemel NM, et al. Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOL- LOWPACE study. Heart Rhythm. 2012;9:728-735.

2. Tobin K, Stewart J, Westveer D, Frumin H. Acute complications of permanent pacemaker implantation: their financial implication and rela- tion to volume and operator experience. Am J Cardiol. 2000;85:774-776, A779.

3. Kirkfeldt RE, Johansen JB, Nohr EA, Moller M, Arnsbo P, Nielsen JC. Risk factors for lead complications in cardiac pacing: a population-based cohort study of 28,860 Danish patients. Heart Rhythm. 2011;8:1622-

1628.

4. Parsonnet V, Bernstein AD, Lindsay B. Pacemaker-implantation compli- cation rates: an analysis of some contributing factors. J Am Coll Cardiol.

1989;13:917-921.

About the Authors

Steven M. Stevens, MD, is a clinical instructor at the UCLA Cardiac Arrhythmia Center. He received his MD from the University of Southern California Keck School of Medicine and completed his residency in internal medicine at the University of California San Francisco. Dr Stevens was chief cardiology fellow in his cardiovascular fellowship at Cedars-Sinai in Los Angeles, and completed an electrophysiology fellowship at UCLA. He was assisted in the writing of this article by Kalyanam Shivkumar, MD, PhD, professor of medicine and radiology and director of the UCLA Cardiac Arrhythmia Center and EP Programs at the UCLA Health System, David Geffen School of Medicine at UCLA, in Los Angeles, CA. He received his MD at the University of Madras. Dr Shivkumar was chief medical resident at the Henry Ford Hospital in Detroit, MI, and chief cardiology fellow at the UCLA School of Medicine. He received his PhD in Physiology from UCLA. Dr Shivkumar has received many research grants, several patents, and has lectured widely on electrophysiology.