Reinoud E. Knops

An Entirely Subcutaneous Implantable Cardioverter–Defibrillator

BACKGROUND Implantable cardioverter-defibrillators (ICDs) prevent sudden death from cardiac causes in selected patients but require the use of transvenous lead systems. To eliminate the need for venous access, we designed and tested an entirely subcutaneous ICD system. METHODS First, we conducted two short-term clinical trials to identify a suitable device configuration and assess energy requirements. We evaluated four subcutaneous ICD configurations in 78 patients who were candidates for ICD implantation and subsequently tested the best configuration in 49 additional patients to determine the subcutaneous defibrillation threshold in comparison with that of the standard transvenous ICD. Then we evaluated the long-term use of subcutaneous ICDs in a pilot study, involving 6 patients, which was followed by a trial involving 55 patients. RESULTS The best device configuration consisted of a parasternal electrode and a left lateral thoracic pulse generator. This configuration was as effective as a transvenous ICD for terminating induced ventricular fibrillation, albeit with a significantly higher mean (+/-SD) energy requirement (36.6+/-19.8 J vs. 11.1+/-8.5 J). Among patients who received a permanent subcutaneous ICD, ventricular fibrillation was successfully detected in 100% of 137 induced episodes. Induced ventricular fibrillation was converted twice in 58 of 59 patients (98%) with the delivery of 65-J shocks in two consecutive tests. Clinically significant adverse events included two pocket infections and four lead revisions. After a mean of 10+/-1 months, the device had successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. CONCLUSIONS In small, nonrandomized studies, an entirely subcutaneous ICD consistently detected and converted ventricular fibrillation induced during electrophysiological testing. The device also successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. (ClinicalTrials.gov numbers, NCT00399217 and NCT00853645.)

Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry

Aims The totally subcutaneous implantable-defibrillator (S-ICD) is a new alternative to the conventional transvenous ICD system to minimize intravascular lead complications. There are limited data describing the long-term performance of the S-ICD. This paper presents the first large international patient population collected as part of the EFFORTLESS S-ICD Registry. Methods and results The EFFORTLESS S-ICD Registry is a non-randomized, standard of care, multicentre Registry designed to collect long-term, system-related, clinical, and patient reported outcome data from S-ICD implanted patients since June 2009. Follow-up data are systematically collected over 60-month post-implant including Quality of Life. The study population of 472 patients of which 241 (51%) were enrolled prospectively has a mean follow-up duration of 558 days (range 13–1342 days, median 498 days), 72% male, mean age of 49 ± 18 years (range 9–88 years), 42% mean left ventricular ejection fraction. Complication-free rates were 97 and 94%, at 30 and 360 days, respectively. Three hundred and seventeen spontaneous episodes were recorded in 85 patients during the follow-up period. Of these episodes, 169 (53%) received therapy, 93 being for Ventricular Tachycardia/Fibrillation (VT/VF). One patient died of recurrent VF and severe bradycardia. Regarding discrete VT/VF episodes, first shock conversion efficacy was 88% with 100% overall successful clinical conversion after a maximum of five shocks. The 360-day inappropriate shock rate was 7% with the vast majority occurring for oversensing (62/73 episodes), primarily of cardiac signals (94% of oversensed episodes). Conclusion The first large cohort of real-world data from an International patient S-ICD population demonstrates appropriate system performance with clinical event rates and inappropriate shock rates comparable with those reported for conventional ICDs. Clinical trial registration URL: http://www.clinicaltrials.gov. Unique identifier NCT01085435.

Safety and Efficacy of the Totally Subcutaneous Implantable Defibrillator: 2-Year Results From a Pooled Analysis of the IDE Study and EFFORTLESS Registry

BACKGROUND The entirely subcutaneous implantable cardioverter-defibrillator (S-ICD) is the first implantable defibrillator that avoids placing electrodes in or around the heart. Two large prospective studies (IDE [S-ICD System IDE Clinical Investigation] and EFFORTLESS [Boston Scientific Post Market S-ICD Registry]) have reported 6-month to 1-year data on the S-ICD. OBJECTIVES The objective of this study was to evaluate the safety and efficacy of the S-ICD in a large diverse population. METHODS Data from the IDE and EFFORTLESS studies were pooled. Shocks were independently adjudicated, and complications were measured with a standardized classification scheme. Enrollment date quartiles were used to assess event rates over time. RESULTS Eight hundred eighty-two patients who underwent implantation were followed for 651±345 days. Spontaneous ventricular tachyarrhythmia (VT)/ventricular fibrillation (VF) events (n=111) were treated in 59 patients; 100 (90.1%) events were terminated with 1 shock, and 109 events (98.2%) were terminated within the 5 available shocks. The estimated 3-year inappropriate shock rate was 13.1%. Estimated 3-year, all-cause mortality was 4.7% (95% confidence interval: 0.9% to 8.5%), with 26 deaths (2.9%). Device-related complications occurred in 11.1% of patients at 3 years. There were no electrode failures, and no S-ICD-related endocarditis or bacteremia occurred. Three devices (0.3%) were replaced for right ventricular pacing. The 6-month complication rate decreased by quartile of enrollment (Q1: 8.9%; Q4: 5.5%), and there was a trend toward a reduction in inappropriate shocks (Q1: 6.9% Q4: 4.5%). CONCLUSIONS The S-ICD demonstrated high efficacy for VT/VF. Complications and inappropriate shock rates were reduced consistently with strategic programming and as operator experience increased. These data provide further evidence for the safety and efficacy of the S-ICD. (Boston Scientific Post Market S-ICD Registry [EFFORTLESS]; NCT01085435; S-ICD® System IDE Clinical Study; NCT01064076).

A Leadless Intracardiac Transcatheter Pacing System

BACKGROUND A leadless intracardiac transcatheter pacing system has been designed to avoid the need for a pacemaker pocket and transvenous lead. METHODS In a prospective multicenter study without controls, a transcatheter pacemaker was implanted in patients who had guideline-based indications for ventricular pacing. The analysis of the primary end points began when 300 patients reached 6 months of follow-up. The primary safety end point was freedom from system-related or procedure-related major complications. The primary efficacy end point was the percentage of patients with low and stable pacing capture thresholds at 6 months (≤2.0 V at a pulse width of 0.24 msec and an increase of ≤1.5 V from the time of implantation). The safety and efficacy end points were evaluated against performance goals (based on historical data) of 83% and 80%, respectively. We also performed a post hoc analysis in which the rates of major complications were compared with those in a control cohort of 2667 patients with transvenous pacemakers from six previously published studies. RESULTS The device was successfully implanted in 719 of 725 patients (99.2%). The Kaplan-Meier estimate of the rate of the primary safety end point was 96.0% (95% confidence interval [CI], 93.9 to 97.3; P<0.001 for the comparison with the safety performance goal of 83%); there were 28 major complications in 25 of 725 patients, and no dislodgements. The rate of the primary efficacy end point was 98.3% (95% CI, 96.1 to 99.5; P<0.001 for the comparison with the efficacy performance goal of 80%) among 292 of 297 patients with paired 6-month data. Although there were 28 major complications in 25 patients, patients with transcatheter pacemakers had significantly fewer major complications than did the control patients (hazard ratio, 0.49; 95% CI, 0.33 to 0.75; P=0.001). CONCLUSIONS In this historical comparison study, the transcatheter pacemaker met the prespecified safety and efficacy goals; it had a safety profile similar to that of a transvenous system while providing low and stable pacing thresholds. (Funded by Medtronic; Micra Transcatheter Pacing Study ClinicalTrials.gov number, NCT02004873.).

Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: Data from the European Long-QT syndrome implantable cardioverter-defibrillator (LQTS ICD) registry

Background— A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. Methods and Results— The study population included 233 patients. Beginning in 2002, data were collected prospectively. Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516±65 milliseconds; mean age at implantation was 30±17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow-up, 4.6±3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age 500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. Conclusions— Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary. # Clinical Perspective {#article-title-18}Background— A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. Methods and Results— The study population included 233 patients. Beginning in 2002, data were collected prospectively. Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516±65 milliseconds; mean age at implantation was 30±17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow-up, 4.6±3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age <20 years at implantation, a QTc >500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. Conclusions— Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary.

The entirely subcutaneous implantable cardioverter-defibrillator: initial clinical experience in a large Dutch cohort.

OBJECTIVES The purpose of the study was to evaluate the efficacy and safety of the entirely subcutaneous implantable cardioverter-defibrillator (S-ICD). BACKGROUND A new entirely S-ICD has been introduced, that does not require lead placement in or on the heart. The authors report the largest multicenter experience to date with the S-ICD with a minimum of 1-year follow-up in the first 118 Dutch patients who were implanted with this device. METHODS Patients were selected if they had a class I or IIa indication for primary or secondary prevention of sudden cardiac death. All consecutive patients from 4 high-volume centers in the Netherlands with an S-ICD implanted between December 2008 and April 2011 were included. RESULTS A total of 118 patients (75% males, mean age 50 years) received the S-ICD. After 18 months of follow-up, 8 patients experienced 45 successful appropriate shocks (98% first shock conversion efficacy). No sudden deaths occurred. Fifteen patients (13%) received inappropriate shocks, mainly due to T-wave oversensing, which was mostly solved by a software upgrade and changing the sensing vector of the S-ICD. Sixteen patients (14%) experienced complications. Adverse events were more frequent in the first 15 implantations per center compared with subsequent implantations (inappropriate shocks 19% vs. 6.7%, p = 0.03; complications 17% vs. 10%, p = 0.10). CONCLUSIONS This study demonstrates that the S-ICD is effective in terminating ventricular arrhythmias. There is, however, a considerable percentage of ICD related adverse events, which decreases as the therapy evolves and experience increases.

Permanent Leadless Cardiac Pacing: Results of the LEADLESS Trial

Background— Conventional cardiac pacemakers are associated with several potential short- and long-term complications related to either the transvenous lead or subcutaneous pulse generator. We tested the safety and clinical performance of a novel, completely self-contained leadless cardiac pacemaker. Methods and Results— The primary safety end point was freedom from complications at 90 days. Secondary performance end points included implant success rate, implant time, and measures of device performance (pacing/sensing thresholds and rate-responsive performance). The mean age of the patient cohort (n=33) was 77±8 years, and 67% of the patients were male (n=22/33). The most common indication for cardiac pacing was permanent atrial fibrillation with atrioventricular block (n=22, 67%). The implant success rate was 97% (n=32). Five patients (15%) required the use of >1 leadless cardiac pacemaker during the procedure. One patient developed right ventricular perforation and cardiac tamponade during the implant procedure, and eventually died as the result of a stroke. The overall complication-free rate was 94% (31/33). After 3 months of follow-up, the measures of pacing performance (sensing, impedance, and pacing threshold) either improved or were stable within the accepted range. Conclusions— In a prospective nonrandomized study, a completely self-contained, single-chamber leadless cardiac pacemaker has shown to be safe and feasible. The absence of a transvenous lead and subcutaneous pulse generator could represent a paradigm shift in cardiac pacing. Clinical Trial Registration— URL: . Unique identifier: [NCT01700244][1]. # CLINICAL PERSPECTIVE {#article-title-26} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01700244&atom=%2Fcirculationaha%2F129%2F14%2F1466.atomBackground— Conventional cardiac pacemakers are associated with several potential short- and long-term complications related to either the transvenous lead or subcutaneous pulse generator. We tested the safety and clinical performance of a novel, completely self-contained leadless cardiac pacemaker. Methods and Results— The primary safety end point was freedom from complications at 90 days. Secondary performance end points included implant success rate, implant time, and measures of device performance (pacing/sensing thresholds and rate-responsive performance). The mean age of the patient cohort (n=33) was 77±8 years, and 67% of the patients were male (n=22/33). The most common indication for cardiac pacing was permanent atrial fibrillation with atrioventricular block (n=22, 67%). The implant success rate was 97% (n=32). Five patients (15%) required the use of >1 leadless cardiac pacemaker during the procedure. One patient developed right ventricular perforation and cardiac tamponade during the implant procedure, and eventually died as the result of a stroke. The overall complication-free rate was 94% (31/33). After 3 months of follow-up, the measures of pacing performance (sensing, impedance, and pacing threshold) either improved or were stable within the accepted range. Conclusions— In a prospective nonrandomized study, a completely self-contained, single-chamber leadless cardiac pacemaker has shown to be safe and feasible. The absence of a transvenous lead and subcutaneous pulse generator could represent a paradigm shift in cardiac pacing. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT01700244.

Rationale and design of the PRAETORIAN trial: A Prospective, RAndomizEd comparison of subcuTaneOus and tRansvenous ImplANtable cardioverter-defibrillator therapy

BACKGROUND Implantable cardioverter-defibrillators (ICDs) are widely used to prevent fatal outcomes associated with life-threatening arrhythmic episodes in a variety of cardiac diseases. These ICDs rely on transvenous leads for cardiac sensing and defibrillation. A new entirely subcutaneous ICD overcomes problems associated with transvenous leads. However, the role of the subcutaneous ICD as an adjunctive or primary therapy in patients at risk for sudden cardiac death is unclear. STUDY DESIGN The PRAETORIAN trial is an investigator-initiated, randomized, controlled, multicenter, prospective 2-arm trial that outlines the advantages and disadvantages of the subcutaneous ICD. Patients with a class I or IIa indication for ICD therapy without an indication for bradypacing or tachypacing are included. A total of 700 patients are randomized to either the subcutaneous or transvenous ICD (1:1). The study is powered to claim noninferiority of the subcutaneous ICD with respect to the composite primary endpoint of inappropriate shocks and ICD-related complications. After noninferiority is established, statistical analysis is done for potential superiority. Secondary endpoint comparisons of shock efficacy and patient mortality are also made. CONCLUSION The PRAETORIAN trial is a randomized trial that aims to gain scientific evidence for the use of the subcutaneous ICD compared with the transvenous ICD in a population of patients with conventional ICD with respect to major ICD-related adverse events. This trial is registered at ClinicalTrials.gov with trial ID NCT01296022.

Early performance of a miniaturized leadless cardiac pacemaker: the Micra Transcatheter Pacing Study

Aims Permanent cardiac pacing is the only effective treatment for symptomatic bradycardia, but complications associated with conventional transvenous pacing systems are commonly related to the pacing lead and pocket. We describe the early performance of a novel self-contained miniaturized pacemaker. Methods and results Patients having Class I or II indication for VVI pacing underwent implantation of a Micra transcatheter pacing system, from the femoral vein and fixated in the right ventricle using four protractible nitinol tines. Prespecified objectives were >85% freedom from unanticipated serious adverse device events (safety) and <2 V 3-month mean pacing capture threshold at 0.24 ms pulse width (efficacy). Patients were implanted (n = 140) from 23 centres in 11 countries (61% male, age 77.0 ± 10.2 years) for atrioventricular block (66%) or sinus node dysfunction (29%) indications. During mean follow-up of 1.9 ± 1.8 months, the safety endpoint was met with no unanticipated serious adverse device events. Thirty adverse events related to the system or procedure occurred, mostly due to transient dysrhythmias or femoral access complications. One pericardial effusion without tamponade occurred after 18 device deployments. In 60 patients followed to 3 months, mean pacing threshold was 0.51 ± 0.22 V, and no threshold was ≥2 V, meeting the efficacy endpoint (P < 0.001). Average R-wave was 16.1 ± 5.2 mV and impedance was 650.7 ± 130 ohms. Conclusion Early assessment shows the transcatheter pacemaker can safely and effectively be applied. Long-term safety and benefit of the pacemaker will further be evaluated in the trial. Clinical Trial Registration ClinicalTrials.gov ID NCT02004873.

Implantable cardioverter-defibrillator harm in young patients with inherited arrhythmia syndromes: A systematic review and meta-analysis of inappropriate shocks and complications

BACKGROUND Implantable cardioverter-defibrillators (ICDs) are implanted with the intention to prolong life in selected patients with inherited arrhythmia syndromes, but ICD implantation is also associated with inappropriate shocks and complications. OBJECTIVE We aimed to quantify the rate of inappropriate shocks and other ICD-related complications to be able to weigh benefit and harm in these patients. METHODS We performed a systematic review and meta-analysis of inappropriate shock and/or other ICD-related complication rates, including ICD-related mortality, in patients with inherited arrhythmia syndromes, that is, arrhythmogenic right ventricular cardiomyopathy/dysplasia, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, dilated cardiomyopathy due to a mutation in the lamin A/C gene, long QT syndrome, and short QT syndrome. We searched MEDLINE and EMBASE from inception to May 30, 2014. RESULTS Of 2471 unique citations, 63 studies comprising 4916 patients with inherited arrhythmia syndromes (mean age of 39 ± 15 years) were included. Inappropriate shocks occurred in 20% of patients (crude annual rate of 4.7% per year), with a significantly higher rate in studies published before 2008 (6.1% per year vs 4.1% per year). Moreover, 22% experienced ICD-related complications (4.4% per year) and there was a 0.5% ICD-related mortality (0.08% per year). CONCLUSION ICD implantation carries a significant risk of inappropriate shocks and inhospital and postdischarge complications in relatively young patients with inherited arrhythmia syndromes. These data can be used to better inform patients and physicians about the expected risk of adverse ICD events and thereby facilitate shared decision making.