Need for pacing in patients who qualify for an implantable cardioverter‐defibrillator: Clinical implications for the subcutaneous ICD

Abstract Background Implantation of the subcutaneous implantable cardioverter‐defibrillator (S‐ICD) is spreading and has been shown to be safe and effective; however, it does not provide brady‐pacing. Currently, data on the need for brady‐pacing and cardiac resynchronization therapy (CRT) implantation in patients with ICD indication are limited. Methods The Multicenter Automatic Defibrillator Implantation Trial (MADIT)‐II enrolled post‐MI patients with reduced ejection fraction (EF ≤ 35%), randomized to either an implantable cardioverter‐defibrillator (ICD) or conventional medical therapy. Kaplan–Meier analyses and multivariate Cox models were performed to assess the incidence and predictors of pacemaker (PM), or CRT implantation in the conventional arm of MADIT‐II, after excluding 32 patients (6.5%) with a previously implanted PM. Results During the median follow‐up of 20 months, 24 of 458 patients (5.2%) were implanted with a PM or a CRT (19 PM, 5 CRT). Symptomatic sinus bradycardia was the primary indication for PM implantation (n = 9, 37%), followed by AV block (n = 5, 21%), tachy‐brady syndrome (n = 4, 17%), and carotid sinus hypersensitivity (n = 1, 4%). Baseline PR interval >200 ms (HR = 3.07, 95% CI: 1.24–7.57, p = .02), and CABG before enrollment (HR = 6.88, 95% CI: 1.58–29.84, p = .01) predicted subsequent PM/CRT implantation. Patients with PM/CRT implantation had a significantly higher risk for heart failure (HR = 2.67, 95% CI = 1.38–5.14, p = .003), but no increased mortality risk (HR = 1.06, 95% CI = 0.46–2.46, p = .89). Conclusion The short‐term need for ventricular pacing or CRT implantation in patients with MADIT‐II ICD indication was low, especially in those with a normal baseline PR interval, and such patients are appropriate candidates for the subcutaneous ICD.


| INTRODUC TI ON
The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) was a randomized clinical trial investigating the role of the implantable cardioverter-defibrillator (ICD) in postmyocardial infarction (MI) patients with severely reduced left ventricular ejection fraction (LVEF ≤ 35%). The primary results of MADIT-II showed ICD implantation to reduce all-cause mortality when compared to conventional medical treatment (Shah et al., 2010).
Today, thousands of patients are implanted with ICD based on the MADIT-II indication. More recently, the introduction of the subcutaneous implantable cardioverter-defibrillator (S-ICD) revolutionized the field by introducing a defibrillator system without an implanted lead in the heart (Sanghera, Sanders, Husby, & Bentsen, 2014).
Implantation of subcutaneous implantable cardioverter-defibrillator (S-ICD) is spreading worldwide and has been shown to be safe and effective to terminate life-threatening ventricular tachyarrhythmias (Burke et al., 2015;Gold et al., 2017). Recent propensity-matched studies also suggested that the S-ICD has similar complication rates as the transvenous ICD, but less lead-related complications, and a much lower cost of complications (Brouwer et al. (2016); Brouwer et al., 2018). However, the S-ICD does not currently provide brady-pacing. Currently, data on the need for brady-pacing and the need for cardiac resynchronization therapy (CRT) in patients with MADIT-II ICD indication are limited.
Therefore, the aim of the current MADIT-II substudy was (a) to evaluate the need for brady-pacing and the need for cardiac resynchronization therapy in patients in the conventional medical treatment arm in MADIT-II, (b) to identify baseline predictors of brady-pacing and indication for subsequent cardiac resynchronization therapy, and (c) to evaluate the risk of subsequent heart failure and mortality in patients undergoing PM/CRT implantation, enrolled in the conventional medical treatment arm in MADIT-II.

| Study population
The design and primary results of the MADIT-II trial were previously published (Moss et al., 2002). Briefly, the MADIT-II trial was designed to determine the effectiveness of the implantable cardioverter-defibrillators to reduce all-cause mortality in patients with reduced left ventricular function following a myocardial infarction.
Subjects over the age of 21 years who had a documented myocardial infarction 1 month or more before study enrollment and a low left ventricular ejection fraction of less than ≤35% were enrolled in MADIT-II. Patients were randomly assigned in a 3:2 ratio to either ICD or conventional medical therapy. The primary end point of MADIT-II was death from any cause. Clinical data and interrogation data from the ICD devices were sent to the study Coordination and Data Center (CDC) at the University of Rochester, Heart Research Follow-Up Program, Rochester, New York.
The current study included 458 patients (37%) randomized to the conventional medical treatment arm of MADIT-II, with no implanted ICDs. We excluded 32 patients (6.5%) from the analyses who had previously implanted pacemaker devices before enrollment in MADIT-II.

| End points and definitions
Subjects enrolled in MADIT-II were followed for an average of 20 months. A pacemaker or CRT implantation for any reason was the primary end point of the current analysis. Secondary end point was subsequent heart failure events and all-cause mortality following pacemaker or CRT implantation. Adverse event reports were individually reviewed for evidence of pacemaker or CRT implantation during the course of the trial by the primary author, Dr. Valentina Kutyifa. A p-value of < .05 was statistically significant and bolded.

| RE SULTS
During the median follow-up of 20 months in MADIT-II, there were a total of 24 out of 458 patients (5.2%) implanted with a PM or a CRT device. Five of these patients (21%) received a CRT device due to heart failure symptoms. The cumulative probability of PM/CRT implantation was 3% at 1 year, 5% at 2 years, and 7% at 3 years of follow-up ( Figure 1).

| Predictors of PM/CRT Implantation
When assessing baseline predictors for subsequent PM/CRT implantation in MADIT-II, we found that a prolonged baseline PR F I G U R E 1 Cumulative Probability of PM/CRT implantation in MADIT-II interval >200 ms was linked to a threefold increase in the risk of PM/CRT implantation (p = .02; Table 2). The cumulative probability of PM/CRT implantation in patients with a normal baseline PR interval ≤200 ms at baseline was 2% at 1 year, and 6% at 3 years, as compared to the cumulative probability of 9% at 1 year, and 12% at 3 years in patients with PR interval >200 ms ( Figure 2).
Interestingly, the majority of the PM/CRT implantations occurred in this group in the first year of follow-up (9% 1-year cumulative probability).
In addition, a prior history of CABG was associated with a significant, almost sevenfold increase in the likelihood of PM/CRT implantation during follow-up (p = .01; Table 2). The cumulative probability of PM/CRT implantation at 1 year was 8% versus 1%, and 12% versus 2% at 3 years with or without a prior CABG ( Figure 3).

| Risk of heart failure and all-cause mortality following PM/CRT implantation
Following a PM or CRT implantation, there was a significant, 2.67fold increased risk of subsequent HF events observed, following adjustments for relevant clinical covariates. However, the risk of allcause mortality was not significantly higher following the PM/CRT implantation (HR = 1.06, p = 089, Table 3).

| Sensitivity analyses
We have also performed sensitivity analysis predicting PM implantation while excluding patients with CRT indication during the follow-up, and we had consistent findings (Prior CABG: HR = 11.57, p = .018, and PR > 200 ms: HR = 2.40, p = .09).

| D ISCUSS I ON
In this substudy of MADIT-II, we show that the need for pacing or CRT implantation was ~2% per year, and it was predicted by a prolonged PR interval >200 ms at baseline, and by the history of prior CABG. Patients with a PM/CRT implantation in MADIT-II had a significantly higher risk of subsequent heart failure events, but the risk of all-cause mortality was not increased. Altogether our findings suggest a low rate for bradycardia pacing/CRT implantation in primary prevention ICD patients.  (Barold, Ilercil, Leonelli, & Herweg, 2006;Kwok & Rashid M et al., 2016;Magnani et al., 2013). In addition, a prolonged AV interval has been frequently reported in heart failure patients (~10%), and it was linked to an unfavorable outcome in cardiac resynchronization therapy candidates, unless they had non-LBBB (Cleland et al., 2008;Kutyifa et al., 2014;Olshansky et al., 2012;Salden, Kutyifa, Stockburger, Prinzen, & Vernooy, 2018).
Nevertheless, a study by Uhm et al. suggested that PR interval is associated not only with atrial fibrillation and left ventricular dysfunction, but also with an increased risk of advanced atrioventricular block (Uhm et al., 2014), explaining why patients in our cohort more frequently developed a need for pacing in the prolonged AVinterval subgroup. Importantly, in our study, a prolonged PR interval predicted not only the need for pacing but also the development of heart failure events and a need for CRT, suggesting that it is a marker for multiple outcomes.
We need to acknowledge, however, that at the time of the MADIT-II trial, beta-blockers were less frequently used as they are today. In MADIT-II, beta-blockers were administered in 61%-67% while in recent ICD trials, this rate is 90%-95% (Gasparini et al., 2013;Moss et al., 2012). Therefore, the need for pacing in MADIT-II might be underestimated. More contemporary databases of ICD patients could be potentially helpful to ascertain the need for pacing with optimal medical treatment for HF.

| CON CLUS IONS
The need for ventricular pacing or CRT implantation in MADIT-II patients was low, ~2% per year, especially in those with normal PR interval and no prior CABG, and in such patients, an S-ICD can be considered for primary prevention ICD indication.
However, a large proportion of these patients are currently indicated for CRT implantation, and the need for pacing might be underestimated in MADIT-II due to the low proportion of betablocker use.

CO N FLI C T O F I NTE R E S T
Dr. Kutyifa -use the text in the manuscript. Drs. Zareba and Goldenberg received research grants from Boston Scientific. The protocol was approved by the institutional review boards of the participating hospitals. All patients provided an informed consent. Note: Models were adjusted for blood urea nitrogen, and prior hospitalization.