Novel two‐lead cardiac resynchronization therapy system provides equivalent CRT responses with less complications than a conventional three‐lead system: Results from the QP ExCELs lead registry

Abstract Introduction The novel two‐lead cardiac resynchronization therapy (CRT)‐DX system utilizes a floating atrial dipole on the implantable cardioverter‐defibrillator lead, and when implanted with a left ventricular (LV) lead, offers a two‐lead CRT system with AV synchrony. This study compared complication rates and CRT response among subjects implanted with a two‐lead CRT‐DX system to those subjects implanted with a standard three‐lead CRT‐D system. Methods and Results A total of 240 subjects from the Sentus QP—Extended CRT Evaluation with Quadripolar Left Ventricular Leads postapproval study were selected to identify 120 matched pairs based on similar demographic characteristics using a Greedy algorithm. The complication‐free rate was evaluated as the primary endpoint. All‐cause mortality, heart failure hospitalizations, device diagnostic data, New York Heart Association (NYHA) class improvement, and defibrillator therapy were evaluated from clinical data, in‐office interrogations, and remote monitoring throughout the follow‐up period. Complication‐free survival favored the CRT‐DX group with 92.5% without a major complication compared to 85.0% in the CRT‐D cohort (P = .0495; 95% confidence interval: 0.1%‐14.9%) over a mean follow‐up of 1.3 and 1.4 years, respectively. Incidence of all‐cause mortality, heart failure hospitalizations, NYHA changes at 6 months postimplant, and percent of LV pacing during CRT therapy were similar in both device cohorts. Inappropriate shocks were more frequent in the CRT‐D cohort with 5.8% of subjects receiving an inappropriate shock vs 0.8% in the CRT‐DX cohort. Conclusion The results of this subanalysis demonstrate that the CRT‐DX system can provide similar CRT responses and significantly fewer complications when compared to a similar cohort with a conventional three‐lead CRT‐D system.


| INTRODUCTION
Cardiac resynchronization therapy (CRT) is a proven treatment to reduce morbidity and mortality in patients with heart failure. [1][2][3] Compared to single or dual-chamber implantable cardioverter-defibrillator (ICD) therapy, risks associated with CRT can include increased complication rates. [4][5][6][7] The DX system can deliver CRT utilizing a novel two-lead system that incorporates atrial sensing on the ICD lead for SVT discrimination and AV synchronization, thus allowing for CRT delivery with fewer leads. The twolead CRT-DX systems are considered for subjects without a need for atrial pacing, including those with permanent atrial fibrillation (AF).
Prior studies have demonstrated the accuracy and utility of atrial sensing with an ICD lead with a floating atrial dipole. [8][9][10][11][12] Additionally, several studies have compared the complication rates in conventional three-lead CRT-D systems to those rates seen in dual and single chamber ICD systems. [4][5][6][7] However, no studies have evaluated the complication rates in a population of heart failure patients implanted with a two-lead CRT-DX system, and only one prior study exists to compare two-lead CRT-DX and three-lead CRT-D system performance. 13 This subanalysis of the Sentus QP-Extended CRT Evaluation with Quadripolar Left Ventricular Leads (QP ExCELs) study compares the complication rates and CRT response of subjects implanted with two-lead CRT-DX systems to those subjects implanted with conventional three-lead CRT-D systems.

| METHODS
We retrospectively analyzed complication rates and CRT responses from subjects who were enrolled in the QP ExCELs study at US sites. QP ExCELs is a prospective, multicenter, international, nonrandomized, com- CRT-DX systems consist of a CRT-DX pulse generator and a DX ICD lead. The DX ICD lead is a 7.8 French, bipolar, single coil, active fixation ICD lead. Two electrodes spaced 15 mm apart and mounted 15 to 17 cm proximal to the lead tip comprise a larger atrial sensing dipole to provide atrial diagnostics and, therefore, eliminate the need for an atrial lead for effective atrial sensing. The atrial signal is amplified up to four times and bandpass-filtered to enable P-wave detection while excluding signal frequencies outside of the atrial range. 14,15 The SMART detection algorithm available in the DX system utilizes the atrial signal to provide SVT discrimination. 8,14 The goal of this subanalysis is to compare the overall complication rates and CRT responses in matched cohorts implanted with a two-lead CRT-DX and three-lead CRT-D ICD system (each CRT-DX subject paired with a CRT-D control). All subjects in this subanalysis were de novo implants (CRT-DX: Intica 7 HF-T QP; CRT-D: Ilivia 7 HF-T QP; BIOTRONIK SE & Co KG) and selected from the QP ExCELs general patient population with a minimum of 6 months of possible follow-up time. In total, 120 matched pairs were identified using a 1 to 1 Greedy algorithm matched for gender, NYHA class, and heart failure etiology, plus an allowable age difference of ±8 years. These subjects were enrolled at 50 US study sites.
A study flow diagram for this study population is provided in Figure 1.
Device diagnostic data, CRT responses, and complications were collected at required visits and via remote follow-up utilizing daily transmissions from the Home Monitoring system (BIOTRONIK SE & Co KG) throughout the follow-up period. NYHA class was collected at baseline and at the 6-month follow-up visit. A minimum of 10 daily transmissions were required to be included for analysis of device data.
All device data was assessed by taking an average of all per subject means obtained for daily transmissions throughout follow-up. LV pacing during CRT therapy is defined as the percentage of cardiac cycles that the LV is paced simultaneously with the RV, whether RV is paced or intrinsic. Subclinical AF in the form of device-detected atrial high rate episode (AHRE) is nominally programmed as a counter of 36/48 atrial events more than 200 bpm, whereas AHRE burden is defined as the % of time the device has detected an atrial tachyarrhythmia. Each device is equipped with an accelerometer to measure subject activity % as a percentage of time the subject is physically active in a day.
Device tachyarrhythmia settings and programming were determined per investigator discretion. All available shock therapies were adjudicated by two independent physicians. SHAIK ET AL. | 1785

| Study primary endpoint
The primary endpoint was defined as the freedom from implanted system and implant-related major complications. Major complications were defined as events related or possibly related to the implanted system or the implant procedure and requiring invasive intervention to resolve. All major complications were adjudicated by an independent Clinical Events Committee (CEC) comprised of physicians blinded to device cohort.
In addition, minor complications were evaluated for each cohort.
Minor complications were defined as events related or possibly related to the implanted system or the implant procedure and not requiring invasive intervention to resolve.

| Statistical analysis
Continuous variables were reported as means with standard deviation (SD) or as median with interquartile range (IQR) when normality was not met. Categorical variables were presented as frequencies with percentages. The cohorts were compared using a two-tailed paired t test or Wilcoxon signed-rank test for continuous variables, while McNemar's test, or Bowker's test were used for categorical variables. A Yates correction of 0.5 was used for continuity when zero cell counts were present. The 95% confidence intervals (CI) were calculated for the difference in continuous variables, as well as, for paired proportion differences. The major complication rates for the endpoint were evaluated using the Kaplan-Meier curve with 95% CI based on the Peto SD.
All statistical analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC) with a significance level of 0.05.

| RESULTS
Clinical characteristics of the study population at the time of enrollment are provided in Table 1

| Primary endpoint analysis
To evaluate the incidence of major complications over follow-up exposure postimplant, the calculated Kaplan-Meier curve is provided in Figure 2. Among both cohorts, a total of 33 major complication events were adjudicated as related or possibly related to the implanted system or implant procedure over the follow-up period. The percentage of subjects in each cohort with a major or minor complication related or possibly related to a specific system component (implant procedure, ICD device, RA lead, RV lead, LV lead) is provided in Table 2. To characterize the distribution of AF in each cohort over the follow-up period, median daily AHRE burden and maximum daily AHRE burden episode duration grouped using cut-offs of 6 minutes, 5.5 hours, and 24 hours are provided in Table 3.

| Clinical health status parameters
The total incidence of all-cause mortality was 1.3%. Two subject deaths (1.7%) occurred in the CRT-D cohort, and one subject death (0.8%) occurred in the CRT-DX cohort over the follow-up period. No cardiovascular deaths were noted. In addition, three subjects (2.5%) in the CRT-DX cohort had a total of four heart failure (HF) hospitalization events, and three subjects (2.5%) in the CRT-D group had a total of three HF hospitalization events. Two subjects in the CRT-D cohort required a heart transplant procedure, compared to none in the CRT-DX cohort.
When NYHA changes at 6 months were evaluated, improve-  Clinical variables with a P value of "-----" represent an exact match between the cohorts. *P values of less than .05 are in bold.

| Defibrillator therapy during follow-up
Throughout the follow-up, 24 appropriate shock therapy events oc-  Note: A major complication is defined as events related or possibly related to the implanted system or the implant procedure and requiring invasive intervention to resolve. A minor complication is defined as events related or possibly related to the implanted system or the implant procedure and not requiring invasive intervention to resolve. A major/minor complication in more than one system component is possible; therefore, the total in Table 2 may be more than the number of subjects with one or more major/minor complication. Abbreviation: CRT, cardiac resynchronization therapy.
variables difficult; however, the increased variation in the ventricular pacing percentage seen in the CRT-DX cohort reflects the higher daily median AHRE burden in this cohort (Table 3).
One previous study prospectively compared CRT performance and physiologic responses in a group of heart failure subjects implanted with a CRT-DX and CRT-D system and found no differences in LV reverse modeling, cardiopulmonary exercise performance, and NYHA class improvement. 13 In addition, several studies have demonstrated the utility of the DX lead. 11,12,26 Specifically, it was shown in a cohort of 249 subjects that P-wave amplitudes in the DX ICD system cohort were comparable and stable (~3.5 mV), and that SVT discrimination was equivalent when compared to a dual-chamber ICD system over 12 months of follow-up. 15 Moreover, the SENSE trial showed comparable rates of subclinical AF in the DX system compared to a dualchamber ICD system, with no incidence of inappropriate therapies delivered in the DX ICD system cohort over 1 year of follow-up. 10  F I G U R E 3 NYHA changes at 6 months follow-up. An NYHA was not obtained at baseline and/or 6 months for 25 and 33 subjects in the CRT-DX and CRT-D cohorts. All percentages are displayed as absolute percentages (out of 120 subjects). CRT, cardiac resynchronization therapy; NYHA, New York Heart Association

| Limitations
Our study has several limitations. While the data were collected from a large, prospective study, this subanalysis was conducted retrospectively and endpoints were not predefined. In contrast to many large, national registry-based studies that rely only on site identification and reporting of events, this study utilized frequent monitoring and careful review of source documentation plus independent adjudication to ensure accuracy and limit underreporting. This may have resulted in a higher rate of reported complications. Device programming, including pacing modes, ventricular tracking rates, and tachyarrhythmia settings, were not controlled for in this study and were determined per physician discretion.
Last, diagnosis of AF history at enrollment was not collected as part of the QP ExCELs study.

| CONCLUSIONS
Our subanalysis results show the CRT-DX system can provide similar CRT responses and significantly fewer complications, indicating that the CRT-DX system is a capable alternative in patients without an atrial pacing indication.