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Two landmark studies have been published in 2020 following the use of subcutaneous implantable cardioverter defibrillator (S-ICDs) as a primary prevention therapy for sudden cardiac death. Cardiac Rhythm News speaks to the researchers behind the PRAETORIAN and UNTOUCHED studies to understand what the findings mean for future S-ICD use, and the relative benefits of the device compared to transvenous ICD therapy.
The S-ICD has emerged as an alternative to transvenous implantable cardioverter-defibrillators (TV-ICDs) to prevent sudden cardiac arrest. Unlike the traditional TV-ICD, which involves placing leads directly into the heart, an S-ICD is implanted under the skin, leaving the heart and vasculature untouched, and providing protection with a less invasive implant procedure. This may reduce a number of the risks often associated with TV-ICD devices, which can include vascular injury, lead insertion complications, such as pneumothorax or myocardial perforation, lead-associated tricuspid regurgitation, and lead failure or device infection and its associated extraction risk.
S-ICD devices have been available for use in Europe since September 2009, and commercially in the USA since October 2012. More recent developments in the technology include the introduction of Boston Scientific’s third generation S-ICD, the EMBLEM MRI system, which received US Food and Drug Administration (FDA) approval and CE mark in 2016. Boston Scientific estimates that as many as 82,000 S-ICD devices have been implanted worldwide, but, until 2020, no randomised controlled trials had taken place to evaluate S-ICD therapy directly against the TV-ICD.
Reinoud Knops, Amsterdam University Medical Center, Department of Cardiology (Amsterdam, The Netherlands), was among the early adopters of S-ICD technology, and recognised the potential benefits of the device from its foundation. “I got interested in the S-ICD from the beginning because part of my job is not only implanting ICDs, but extracting them if there is a problem,” he tells Cardiac Rhythm News. “I noticed that when patients have ICD therapy for up to five-to-ten years, many come back to the hospital with lead fractures and then need an extra, invasive procedure to resolve that issue. When the S-ICD came on the market in 2009, it was immediately clear to me that at last there was a solution for the lead problems that we know of with TV-ICDs.”
Experience with S-ICDs
According to Knops, the characteristics of the S-ICD, as compared to transvenous devices, are particularly attractive in those with a higher infection risk—where device complications can be damaging—as well as potentially in younger and more active patient groups. However, he believed that the use of the device in the wider ICD population also justified clinical study. “After having gone through the initial learning curve, we have had a very good experience with the S-ICD, especially with regard to complications, and that really told us that we needed a large clinical trial, not only researching this device in this niche patient category—the high risk patient category—but in all patients that need ICD therapy,” he says. “That was the idea behind the PRAETORIAN trial.”
Prior to PRAETORIAN, Knops explains, only registry data existed to demonstrate the outcomes of S-ICDs, which had primarily covered young patients with relatively preserved left ventricular ejection fraction (LVEF), and showed a high shock efficacy and fewer ICD-related complications, but more inappropriate shocks than TV-ICDs.
PRAETORIAN was the first prospective, randomised comparison of S-ICD and TV-ICD therapy— involving 39 centres across Europe and the USA. Instigated by Knops and colleagues and starting in 2011, the study enrolled 849 patients with a class I or IIa indication for ICD therapy and without the need for pacing who were randomised to use either S-ICD or TV-ICD devices and followed for a median of four years. The four-year follow-up period is a key feature of PRAETORIAN, Knops says, “[it] is a relatively long period for an ICD study. I think that was important because obviously we do not treat our patients for only one or two years with ICDs, but for a much longer time.”
PRAETORIAN’s primary endpoint was a composite of the first occurrence of ICD complications and inappropriate shocks, which Knops and colleagues believed would demonstrate the non-inferiority of the S-ICD versus the TV-ICD with respect to major ICD-related adverse events. The baseline characteristics of the PRAETORIAN patient population were comparable to those of other major ICD trials, with the population around 20% female, a median age of 63 years (55‒70 years), almost 20% had a secondary prevention indication, and 69% had ischaemic cardiomyopathy with a median left ventricular ejection fraction of 30% (range: 25‒35%).
Learnings from PRAETORIAN
Results from the landmark study were presented by Knops in Spring 2020, in a late-breaking trial session at Heart Rhythm Society (HRS) 2020 Science, and published in the New England Journal of Medicine. What Knops and colleagues uncovered through the study is that in a general ICD-population, the S-ICD proved to be non-inferior to the transvenous device regarding major ICD-related adverse events, and that there were significantly fewer lead-related complications in patients treated with the S-ICD. The primary composite endpoint of inappropriate shocks and complications occurred in the TV-ICD arm in 15.7% of patients, and in 15.1% in the S-ICD. “At least we know that if you select the S-ICD in a general ICD population, that you are not worse off in the first four years than with a TV-ICD,” Knops says. Breaking this down further into the individual primary endpoint components sheds more light on the suitability of the device, based upon certain patient characteristics, he notes. “The device was designed to overcome lead-related complications, and if we look at that result, this was very positive for the S-ICD. After four years, there were 5.9% complications in the S-ICD arm and 9.8% in the TV-ICD arm. This was just not statistically significant, but an important trend towards fewer complications in the S-ICD group,” Knops comments. In particular, the data show a major difference in the numbers of lead-related complications—1.4% in the S-ICD arm versus 6.6% in the TV-ICD patients.
However, one area where the TV-ICDs did out-perform the S-ICD is in inappropriate shocks, with PRAETORIAN showing that in the S-ICD arm, inappropriate shocks occurred in 9.7% (approximately 2.4% per year) of patients, compared to 7.3% (approximately 1.8% per year) in the TV-ICD arm. Knops notes that the main driver of inappropriate shocks in the TV-ICD arm was atrial fibrillation and supraventricular tachycardia, while in the S-ICD arm, this was cardiac over-sensing. However, he believes that this can be explained. “During the study there were several software updates of the sensing algorithm of the S-ICD, and that has been proven to prevent more than 50% of inappropriate shocks. Most of the patients in this study did not have the benefit of the SMART Pass-enabled S-ICDs, so I think that is a large part of why this inappropriate shock rate is relatively high in the S-ICD arm, and if we could do the study again with modern S-ICD devices and programming options available, this would look much different,” he explains.
It is the difference in rates of complications between the two device categories that Knops believes is the core message of PRAETORIAN. “I think that complication difference in the study is really something we will be looking at for the next several decades when we use ICDs for our patients. It is very important to realise that inappropriate shocks usuallyare manageable, but complications are something you should consider when you select the patient for a certain therapy,” he says. Further to this, Knops believes that the relatively recent emergence of the S-ICD, compared to the well-established TV-ICD, could have a further bearing on the results. He says: “We kept track of the experience of the physicians that were implanting ICDs in this study and in the TV-ICD arm physicians had experience of hundreds, sometimes thousands, of ICD implants to their name, whereas with the S-ICD, some had only experience with a few devices when they entered this study.”
Regarding the implications that these findings have for clinician-practice, Knops says that the message is clear: “For mere sudden cardiac death prevention, please go forward and select the S-ICD, because it is the least invasive of the two therapies, and we have already seen that up to four years you have significantly less lead-related complications and a trend towards fewer complications overall. I think we have to realise that we are not treating our patients for four years, but hopefully for five, ten, or even more years, and that in the long run we really will see the benefit of that selection.
“These data support its high safety profile, and demonstrate that you are certainly not making a negative decision by selecting an S-ICD, because for the primary endpoint, your choice is non-inferior at four years. I am really confident that in the long term we will have a significant difference in overall complications.”
Further study of the patient population is being carried out through the PRAETORIAN XL trial, which will follow the PRAETORIAN cohort up to eight years. Knops believes this longer-term data will provide the clearest picture yet of the merits of S-ICD devices compared to the TV-ICD. “When we reach eight-year follow-up in this study, our monitored ICD data for study will be really unique, as there is no such study available with such a long follow-up for ICD therapy,” he says.
Latest generation S-ICDs under the microscope in UNTOUCHED
If the PRAETORIAN data provide important insight into the merits of S-ICD and its relative performance compared to TV-ICD devices, another study presented at HRS 2020 Science—UNTOUCHED—brings to the table key findings on the improvements in the technology found in the latest generation of devices.
“The major risks of the transvenous devices were avoided by the S-ICD, but before UNTOUCHED most of the studies had very selective groups of patients that tended to be younger without much heart disease. This was likely for concern that the absence of pacing modality in the S-ICD would limit the patients who may be appropriately treated with this device,” the principal investigator in the UNTOUCHED study, Michael Gold (Division of Cardiology, Medical University of South Carolina, Charleston, USA) informs Cardiac Rhythm News.
UNTOUCHED was a global, multicentre, prospective non-randomised study, evaluating the safety and efficacy of the EMBLEM S-ICD system for primary prevention of sudden cardiac death, specifically in patients with a left ventricular ejection fraction (LVEF) ≤35%. The study involved de novo implanted patients at 110 sites in the USA and Europe, who were followed for 18 months.
According to Gold, UNTOUCHED combined newer S-ICD technology, more aggressive programming, and sicker or higher risk patients. Registry data, used in the US Post Approval Study of the device, had demonstrated its use in sicker patients, he says, adding: “For UNTOUCHED, we wanted to take it to the next level, doing a prospective trial and only having high-risk, primary prevention patients. They had never had a previous cardiac arrest or ventricular tachycardia, and they had to have a low ejection fraction—below 35%—to be included.”
Gold says that the study team took a “prescriptive” approach to the programming of the S-ICD devices in the study, explaining: “It was the most aggressive programming used to date, such that no therapies were given at rates below 200bpm and the discrimination algorithm in the S-ICD was active until 250bpm. To take it one step further, we also used primarily the newer generation of devices that have enhanced discrimination by having a SMART Pass-enabled S-ICD system in them. We wanted to combine newer technology, more aggressive programming, and sicker or higher-risk patients, into a prospective trial.”
The study’s primary endpoint was an inappropriate shock-free rate at 18 months, with a performance goal of 91.6%. This goal was derived from the inappropriate shock rate of 94.6% measured in ICD patients in the comparator study, MADIT-RIT study arms B and C, in which cardiac resynchronisation therapy (CRT) was excluded. Secondary endpoints included the all-cause shock-free rate at 18 months, with a performance goal of 85.8%, and system and procedure-related complication rate at 30 days.
Implants were attempted in 1,116 patients, Gold explains, with endpoint analysis reported in 1,111 who received devices. Patients had an average age of 56, 25.7% (n=286) were female, and 87.6% (n=883) had heart failure. Primary endpoint results of UNTOUCHED showed an inappropriate shock-free rate of 95.9%, exceeding the performance goal of 91.6%. Patients with a history of atrial fibrillation, non-ischaemic aetiology, and lower ejection fraction were more likely to experience inappropriate shocks, the study found. Procedural characteristics that predicted fewer shocks for the patients were implantation using the three-incision technique, and implanting devices with a SMART Pass filter. Comparing the shock rates from recent S-ICD studies, there has been a progressive decrease in the number of inappropriate shocks recorded over time, it was noted. The secondary endpoint, the all-cause shock-free rate, stood at 90.6%, meeting its performance goal of 85.8%. Significant multivariable predictors of all-cause shocks include a history of atrial fibrillation and lower ejection fraction, Gold adds.
Commenting on the relevance of the findings, Gold says: “The results further extend what we know about the S-ICD and also compare very favourably with transvenous device studies. If we look at the initial IDE [investigational device exemption] study, the annual inappropriate shock rate was 13%, then with the European EFFORTLESS registry it is 8%, and with the US post approval study it was 4%, so we are feeling better about that as we go along. With the UNTOUCHED study, with the newest generation of devices, it was 2.4%, which again is much lower than anything seen previously. If we now compare that with transvenous studies, the annual rate in the MADIT RIT study was 5%, and other studies such as ADVANCE III were also hovering around 5%. With UNTOUCHED and the newest generation devices, it is about half that at 2.4%. Not only does it tell us that S-ICDs are safe, effective, and that they do not increase inappropriate shocks with modern programming and algorithms, but in fact they may reduce the risks of inappropriate shocks, which is very important.”
A clearer picture of the benefits offered by S-ICD technology
For Kenneth Stein, senior vice president and chief medical officer, Rhythm Management and Global Health Policy at Boston Scientific, the findings of the two studies—PRAETORIAN and UNTOUCHED—provide a clear picture of the advantages of the S-ICD. “Sometimes it is good to be lucky, and I think we got lucky that both of these trials were ready to report out at the same time, because it is really useful to look at the data put together,” he comments. “Between these two studies, there is a very high degree of assurance that the S-ICD is as effective as TV-ICDs in preventing death from cardiac arrest due to ventricular fibrillation. When programmed appropriately, the current generation with SMART Pass the risks of inappropriate shocks for patients are as low or even lower than they are with transvenous devices. Over the long run, these devices are going to be associated with a lower risk of serious complications.”
He adds: “Our hope is that the electrophysiology community is a community that really is very evidence-based in their approach to the treatment of patients, and having good large-scale randomised clinical trial data like PRAETORIAN, having a very large registry set of real-world data as in UNTOUCHED, will give those who have been sitting on the fence the comfort they need to offer S-ICD treatment as part of a shared decision-making process.”
Reinoud Knops (the primary investigator) and the Academic Medical Center in Amsterdam are the sponsors and owners of the PRAETORIAN study, which is investigator-sponsored research (ISR). Boston Scientific funded but did not control the protocol design, data collection, analysis, or the final publication of this study. Additionally, the UNTOUCHED trial is a Boston Scientific-sponsored study.