Prognosis of pacing-dependent patients with cardiovascular implantable electronic devices

Background Data on the prognostic significance of pacing dependency in patients with cardiovascular implantable electronic devices (CIEDs) are sparse. Methods The prognostic significance of pacing dependency defined as absence of an intrinsic rhythm ≥ 30 bpm was determined in 786 patients with CIEDs at the authors’ institution using univariate and multivariate regression analysis to identify predictors of all-cause mortality. Results During 49 months median follow-up, death occurred in 63 of 130 patients with pacing dependency compared to 241 of 656 patients without pacing dependency (48% versus 37%, hazard ratio [HR] 1.34; 95% confidence interval [CI]: 1.02–1.78, P = 0.04). Using multivariate regression analysis, predictors of all-cause mortality included age (HR 1.07; 95% CI: 1.05–1.08, P < 0.01), history of atrial fibrillation (HR 1.32, 95% CI: 1.03–1.69, P < 0.01), chronic kidney disease (HR 1.28; 95% CI: 1.00–1.63, P = 0.048) and New York Heart Association (NYHA) class ≥ III (HR 2.00; 95% CI: 1.52–2.62, P < 0.01), but not pacing dependency (HR 1.15; 95% CI: 0.86–1.54, P = 0.35). Conclusions In contrast to age, atrial fibrillation, chronic kidney disease and heart failure severity as indexed by NYHA functional class III or IV, pacing dependency does not appear to be an independent predictor of all-cause mortality in patients with CIEDs.


Study population
The study population consisted of 786 patients with a permanent pacemaker or with an implantable defibrillator who were enrolled in the authors' pacemaker and defibrillator outpatient clinic between January 2018 and December 2018 and who were followed until January 2023 (.Fig. 1).Definitions used in this study and baseline characteristics of the study population stratified for patients with and without pacing dependency have been previously published [2].Briefly, pacemaker dependency was defined as absence of an  intrinsic rhythm ≥ 30 bpm after lowering the pacing rate to 30 bpm for at least 10 s or after transient inhibition of pacemaker therapy [2].Chronic kidney disease of at least stage 3 was diagnosed in the presence of at least two estimated glomerular filtration rates (eGFR) using the Modification of Diet in Renal Disease formula below 60 ml/min per 1.73 m 2 with an interval of at least 3 months.The study protocol was reviewed and approved by the ethics committee of the Philipps-University of Marburg, Germany.

Discussion
The main finding of the present study is that in the authors' cohort of 786 patients with CIEDs, independent predictors of allcause mortality include age, history of atrial fibrillation, chronic kidney disease and heart failure severity as indexed by NYHA functional class III or IV, but not pacing dependency.Their findings suggest that pacing dependency is merely a marker, but not a predictor for all-cause mortality in patients with CIEDs.Several previous investigators [1-14], including the authors' previous report [2], found a significant association between pacemaker dependency in patients with CIED and second or third degree AV block at implant, age, male gender and heart failure severity as by a higher NYHA functional class, reduced left ventricular ejection fraction and elevated brain natriuretic peptide.In addition, a twofold risk for pacemaker dependency in patients with CIED and chronic kidney disease compared to patients without chronic kidney disease was found [2].Due to the lack of follow-up data, however, most previous studies [2-8, 10, 12-14] investigating the prevalence of pacing dependency in patients with CIEDs did not provide information on whether pacing dependency is an independent prognostic predictor in patients with CIEDs or merely a marker for more advanced heart disease and comorbidities including heart failure and chronic kidney disease.
More than two decades ago, the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial [15] showed that in selected patients with no indication for cardiac pacing and a reduced left ventricular ejection fraction of 40% or less, frequent right ventricular pacing had a detrimental prognostic effect by increasing the combined endpoint of death or hospitalization for heart failure.Furthermore, Kiehl et al.
[16] described an increased rate of pacinginduced cardiomyopathy also in patients with preserved left ventricular ejection fraction at pacemaker implant in the pres-Herzschrittmachertherapie + Elektrophysiologie 1 • 2024 43  60) 133 (28) < 0.01 2.00 (1.52-2.62)Values are given as mean ± SD for continuous variables, and numbers and percentages for categorical variables HR (95% CI) hazard ratio (95% confidence interval), NYHA New York Heart Association ence of a right ventricular pacing burden of at least 20% [16].Subsequently,Khurshid et al. [17] demonstrated that pacing induced-cardiomyopathy could be reversed inthemajorityof patients byupgrading the pacingsystem to cardiac resynchronization therapy.In the present study, pacing-dependent patients had a mean amount of ventricular pacing of 98% compared to 36% ventricular pacing in patients without pacing dependency.Despite this high amount of ventricular pacing in pacingdependent patients, pacing dependency failed to predict all-cause mortality using multivariate analysis in the present study.Razaetal.[9] observed theneed for permanent pacemaker implantation for high-de-greeAV block(55%) or bradycardia(45%) in 141 of 6268 patients after cardiac surgery with a prevalence of pacemaker dependency of 40% in paced patients.Similar to the present study, the mean amount of ventricular pacing was much higher in pacing-dependent patients (91%) compared to nondependent patients (51%).During 5.6-year mean follow-up, Raza et al. [9] found a significant association between permanent pacemaker requirement after surgery and subsequent mortality by univariate analysis but not by multivariate analysis.Of note, Raza et al. [9] compared only the outcomes of patients with and without the need for a permanent pacemaker after surgery.In contrast to the present study, Raza et al. [9] did not perform a subgroup analysis of pacemaker patients with versus without pacing dependency.Sood et al. [11] investigated the prevalence and prognostic significance of pacing dependency in 1058 patients who received an implantable cardioverter-defibrillator for primary or secondary prevention of sudden cardiac death during 4.2 years mean follow-up.
Similar to the findings of the authors' study, Sood et al. [11] found pacing dependency to be associated with older age and a history of atrial fibrillation during followup.In contrast to the present study, Sood et al. [11] found pacing dependency to also be associated with a 48% increased risk for all-cause mortality using multivariate analysis, whereas pacing dependency was associated with a 35% increased mortality only by univariate analysis but not by multivariate analysis in the present study.This discrepancy between the study by Sood et al. [11] and this study may in part be explained by differences in study protocol and patient population.First, Sood et al.
[11] defined pacemaker dependency as an intrinsic rhythm < 40 beats per minute after inhibiting the pacemaker or an intrinsic rhythm < 50 bpm with transient symptoms of dizziness, whereas pacemaker dependency in the present study was defined as absence of an intrinsic rhythm ≥ 30 bpm after lowering the pacing rate to 30 bpm for at least 10 s or after transient inhibition of pacemaker therapy.Secondly,Sood et al. [11] exclusively investigated patients with implantable defibrillators with a mean left ventricular ejection fraction of 30%, whereas the majority of patients in the present study received permanent antibradycardia pacemakers with a significantly higher mean left ventricular ejection fraction of 43%.Finally, multivariate analysis in this study also included comorbidities like arterial hypertension, diabetes mellitus, chronic kidney disease and previous cardiac surgery or transcatheter aortic valve replacement.In the authors' previous report [2] describing the baseline characteristics of pacing-dependent versus nondependent patients, they already found a twofold risk for pacing dependency in patients with CIEDs and chronic kidney disease.Their present follow-up report demonstrates that chronic kidney disease but not pacing dependency is an independent predictor of all-cause mortality in patients with CIEDs in addition to older age, history of atrial fibrillation and NYHA functional heart failure class III or IV.

Conclusions
In contrast to age, history of atrial fibrillation, chronic kidney disease and heart failure severity as indexed by NYHA functional class III or IV, pacing dependency does not appear to be an independent predictor of all-cause mortality in patients with CIEDs.
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Fig. 2 8
Fig. 2 8 Kaplan-Meier curves for all-cause mortality stratified for: a pacing-dependent patients versus nondependent patients; b patients with a history of atrial fibrillation (AF) versus patients without a history of atrial fibrillation; c patients with New York Heart Association (NYHA) class III or IV versus patients with NYHA class I or II; d patients with chronic kidney disease (CKD) versus patients without chronic kidney disease

Table 1
Clinical characteristics of 786 patients with and without pacing dependency

All patients Pacing dependency Clinical variable n = 786 Yes (n = 130) No (n = 656) P value
Values are given as mean ± SD for continuous variables, and numbers and percentages for categorical variables, unless specified otherwise a Other cardiac diseases include hypertrophic cardiomyopathy, cardiac sarcoidosis, cardiac amyloidosis, and tricuspid valve replacement b Implantable defibrillator without symptomatic bradyarrhythmia at implant ACE angiotensin converting enzyme, ARB angiotensin receptor blocker, AV atrioventricular, CIED cardiovascular implantable electronic device, NYHA New York Heart Association Herzschrittmachertherapie + Elektrophysiologie 1 • 2024 41

Table 2
Univariate predictors of mortality in 786 patients with and without pacing dependency Values are given as mean ± SD for continuous variables, and numbers and percentages for categorical variables a Implantable defibrillator without symptomatic bradyarrhythmia at implant ACE angiotensin converting enzyme, ARB angiotensin receptor blocker, AV atrioventricular, CIED cardiovascular implantable electronic device, NYHA New York Heart Association