Relation of Prolonged Pacemaker Dependency After Cardiac Surgery to Mortality

Abstract

•In a retrospective multicenter study, around 1% of the patients require PPI after cardiac surgery.•More than 30% of these patients recover A/V conduction property within months.•Pacemaker dependency is associated with higher mortality.•SR before surgery seems to have a protective effect on pacemaker dependency. Permanent pacemaker implantation (PPI) represents a rare complication after cardiac surgery, with no uniform agreement on timing and no information on follow-up. A multicenter retrospective study was designed to assess pacemaker dependency (PMD) and long-term mortality after cardiac surgery procedures. Between 2004 and 2016, PPI-patients from 18 centers were followed. Time-to-event data were evaluated with semiparametric regression Cox models and semiparametric Fine and Gray model for competing risk framework. Of 859 (0.90%) PPI-patients, 30% were pacemaker independent (PMI) at 6 months. PMD showed higher mortality compared with PMI (10-year survival 80.1% ± 2.6% and 92.2% +2.4%, respectively, log-rank p-value < 0.001) with an unadjusted hazard ratio for death of 0.36 (95% CI 0.20 to 0.65, p< 0.001 favoring PMI) and an adjusted hazard ratio of 0.19 (95% CI 0.08 to 0.45, p< 0.001 with PMD as reference). Crude cumulative incidence function of restored PMI rhythm at follow-up at 6 months, 1 year and 12 years were 30.5% (95% CI 27.3% to 33.7%), 33.7% (95% CI 30.4% to 36.9%) and 37.2% (95% CI 33.8% to 40.6%) respectively. PMI was favored by preoperative sinus rhythm with normal conduction (SR) (HR 2.37, 95% CI 1.65 to 3.40, p< 0.001), whereas coronary artery bypass grafting and aortic valve replacement were independently associated with PMD (HR 0.63, 95% CI 0.45 to 0.88, p = 0.006 and HR 0.807, 95% CI 0.65 to 0.99, p = 0.047 respectively). Time-to-implantation was not associated with increased rate of PMI. Although 30% of PPI-patients are PMI after 6 months, PMD is associated with higher mortality at long term. Permanent pacemaker implantation (PPI) represents a rare complication after cardiac surgery, with no uniform agreement on timing and no information on follow-up. A multicenter retrospective study was designed to assess pacemaker dependency (PMD) and long-term mortality after cardiac surgery procedures. Between 2004 and 2016, PPI-patients from 18 centers were followed. Time-to-event data were evaluated with semiparametric regression Cox models and semiparametric Fine and Gray model for competing risk framework. Of 859 (0.90%) PPI-patients, 30% were pacemaker independent (PMI) at 6 months. PMD showed higher mortality compared with PMI (10-year survival 80.1% ± 2.6% and 92.2% +2.4%, respectively, log-rank p-value < 0.001) with an unadjusted hazard ratio for death of 0.36 (95% CI 0.20 to 0.65, p< 0.001 favoring PMI) and an adjusted hazard ratio of 0.19 (95% CI 0.08 to 0.45, p< 0.001 with PMD as reference). Crude cumulative incidence function of restored PMI rhythm at follow-up at 6 months, 1 year and 12 years were 30.5% (95% CI 27.3% to 33.7%), 33.7% (95% CI 30.4% to 36.9%) and 37.2% (95% CI 33.8% to 40.6%) respectively. PMI was favored by preoperative sinus rhythm with normal conduction (SR) (HR 2.37, 95% CI 1.65 to 3.40, p< 0.001), whereas coronary artery bypass grafting and aortic valve replacement were independently associated with PMD (HR 0.63, 95% CI 0.45 to 0.88, p = 0.006 and HR 0.807, 95% CI 0.65 to 0.99, p = 0.047 respectively). Time-to-implantation was not associated with increased rate of PMI. Although 30% of PPI-patients are PMI after 6 months, PMD is associated with higher mortality at long term. Permanent pacemaker implantation (PPI) after cardiac surgery for brady-arrhythmia's and/or atrio-ventricular (A/V) conduction defects occurs in up to 1%to 3% of patients after coronary artery bypass graft (CABG), 5% after mitral valve replacement (MVR), and reportedly up to 12% after aortic valve replacement (AVR).1Matthews IG Fazal IA Bates MG Turley AJ In patients undergoing aortic valve replacement, what factors predict the requirement for permanent pacemaker implantation?.Interact Cardiovasc Thorac Surg. 2011; 12: 475-479Crossref PubMed Scopus (61) Google Scholar, 2Onalan O Crystal A Lashevsky I Khalameizer V Lau C Goldman B Fremes S Newman D Lukomsky M Crystal E Determinants of pacemaker dependency after coronary and/or mitral or aortic valve surgery with long-term follow-up.Am J Cardiol. 2008; 101: 203-208Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 3Steyers 3rd, CM Khera R Bhave P Pacemaker dependency after cardiac surgery: a systematic review of current evidence.PLoS One. 2015; 10e0140340Crossref PubMed Scopus (28) Google Scholar. Brady-arrhythmia's requiring pacemaker implant include sick sinus syndrome, atrial fibrillation with slow ventricular response, and several degrees of A/V block.3Steyers 3rd, CM Khera R Bhave P Pacemaker dependency after cardiac surgery: a systematic review of current evidence.PLoS One. 2015; 10e0140340Crossref PubMed Scopus (28) Google Scholar Although pacemaker dependency decays with time, depending on the type of indication, new or recurrent conduction disturbances may develop at variable time points after hospital discharge.2Onalan O Crystal A Lashevsky I Khalameizer V Lau C Goldman B Fremes S Newman D Lukomsky M Crystal E Determinants of pacemaker dependency after coronary and/or mitral or aortic valve surgery with long-term follow-up.Am J Cardiol. 2008; 101: 203-208Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,4Raza SS Li JM John R Chen LY Tholakanahalli VN Mbai M Adabag AS Long-term mortality and pacing outcomes of patients with permanent pacemaker implantation after cardiac surgery.Pacing Clin Electrophysiol. 2011; 34: 331-338Crossref PubMed Scopus (51) Google Scholar,5Rene AG Sastry A Horowitz JM Cheung J Liu CF Thomas G Ip JE Lerman BB Markowitz SM Recovery of atrioventricular conduction after pacemaker placement following cardiac valvular surgery.J Cardiovasc Electrophysiol. 2013; 24: 1383-1387Crossref PubMed Scopus (21) Google Scholar However, data addressing this topic are heterogeneous, dependent on local protocols, and, therefore, poorly informative.3Steyers 3rd, CM Khera R Bhave P Pacemaker dependency after cardiac surgery: a systematic review of current evidence.PLoS One. 2015; 10e0140340Crossref PubMed Scopus (28) Google Scholar Current guidelines consider advanced second or third degree A/V block lasting at least 7 days after cardiac surgery as a class I indication for PPI, but the evidence is based on relatively small studies ranging between 150 and 250 patients, with short-term follow up.6Epstein AE DiMarco JP Ellenbogen KA Estes 3rd, NA Freedman RA Gettes LS Gillinov AM Gregoratos G Hammill SC Hayes DL Hlatky MA Newby LK Page RL Schoenfeld MH Silka MJ Stevenson LW Sweeney MO Tracy CM Epstein AE Darbar D DiMarco JP Dunbar SB Estes 3rd, NAM Ferguson TB Hammill SC Karasik PE Link MS Marine JE Schoenfeld MH Shanker AJ Silka MJ Stevenson LW Stevenson WG Varosy PD American College Cardiology FoundationAmerican Heart Association Task Force on Practice GuidelinesHeart Rhythm Society2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.J Am Coll Cardiol. 2013; 61: e6-75PubMed Google Scholar,7Kusumoto FM Schoenfeld MH Barrett C Edgerton JR Ellenbogen KA Gold MR Goldschlager NF Hamilton RM Joglar JA Kim RJ Lee R Marine JE McLeod CJ Oken KR Patton KK Pellegrini CN Selzman KA Thompson A Varosy PD 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.J Am Coll Cardiol. 2019; 74: 932-987Crossref PubMed Scopus (88) Google Scholar Also, the impact of a PPI after cardiac surgery on survival is not known. Based on these premises we developed a multicenter working group to thoroughly investigate the actual incidence of PPI after cardiac surgery procedures in a large population. The purposes of this study were to evaluate the pacemaker dependency after PPI, to describe the influence of pre-operative sinus rhythm with normal conduction (SR) on pacemaker dependency and to assess the long-term mortality after PPI. The study population was retrospectively extracted, analyzing the institutional databases of 18 cardiac surgery units that are part of the G.I.R.O.C. (Italian Group for Research Outcome in Cardiac Surgery) and adhered to the study protocol. The requirement for PPI was determined by the cardiologist, the cardiac surgeon and the electrophysiologist of each center. All datasets analyzed were collected and responded to the requirements of a minimum dataset of predefined variables. Patients who underwent cardiac surgery from January 2004 to December 2016 requiring postoperative PPI during the hospitalization related to cardiac surgery procedures were included in the study. Patients with preoperative indication to PPI, who underwent implantable cardioverter defibrillator or cardiac resynchronization therapy treatment, were excluded. Preoperative and demographic information, operative data, and perioperative mortality and complications for all patients were retrieved from the institutional databases. The primary outcomes included pacemaker dependency at follow-up and long-term mortality. The secondary outcome described the influence of pre-operative SR on pacemaker dependency. Pacemaker dependency was defined as the absence of intrinsic rhythm on a postdischarge assessment performed by reducing the pacemaker frequency below 40 beats per minute (bpm) during 15 seconds. The presence of SR with associated conduction status and the presence of supraventricular arrhythmia were also recorded. Patients were considered pacemaker independent (PMI) if they had SR or atrial fibrillation with an adequate ventricular response at 40 bpm. Follow-up information was obtained by direct patient visit and electrophysiology analysis on simple EKG tracings. Patient data collection was truncated on December 31, 2016; patients who did not experience the events were considered as rightly censored. The study was conducted after approval of the individual Ethical Committees at each institution (Principal Investigator Ethical Committee approval nr.1467, date March 4, 2014). Normally distributed variables (by Kolmogorov-Smirnov test) are reported as mean and standard deviation, non-normally distributed variables are reported as median and quartiles. Pairwise comparison was performed with student's t test or Mann-Whitney U-test in case of continuous variables and chi-square with Fisher's exact test in case of categorical variables. Following discharge, the primary events were managed as time-to-event data and analyzed with nonparametric and semiparametric methods. Discharge from hospital after surgery was defined as beginning of follow-up and all intraoperative deaths and in-hospital were excluded from time-to-event analysis. Time-to-event distributions were separately analyzed according to primary event-type (death, cardiac death and freedom from pacemaker dependency), using Kaplan-Meier estimates and Cox regression for the time-to-death analysis and Fine & Gray models in competing risk framework for time-to-cardiac death (with no-cardiac death as competing risk) and time-to-freedom from pacemaker dependency (with death as competing risk). The variables selection for the Cox models was performed by a forward stepwise regression (probability of stay = 0.10, probability of entry = 0.05). For time-to-cardiac death and time-to-freedom from pacemaker dependency, nonparametric analyses of the outcome variables of interest were computed with the cumulative incidence function (CIF), and subdistribution hazards and comparisons were computed by means of Fine and Gray test. Direct regression modeling of the effect of covariates on CIF was performed through the semi-parametric proportional hazard model for the subdistribution hazards proposed by Fine and Gray, allowing for time-varying effect of the covariates. The variables selection for the Fine & Gray models was performed by a forward stepwise regression with the Bayesian Information Criterion as selection criteria. Hazards proportionality and time-dependent effects were checked with the analysis of Shoenfeld residuals, Kolmogorov-Smirnov test, and Cramer von Mises test. Missing values occurred for variables with a max of 3%. The center effect was evaluated with mixed effect model with center as random effect. Missing values were substituted by means of multiple imputation, as described in order to reduce bias and increase statistical power. For all analyses, we used R 3.3.1 (R Development Core Team (2016), R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org/) Patient population included 94.693 cardiac surgery procedures from January 2004 to December 2016. During this period, 859 patients (0.90%) underwent PPI within 30 days after surgery. Table 1 shows the baseline characteristics of the study groups. Median time from cardiac surgery to PPI was 8 days (ranging from 2 to 10 days).Table 1Baseline characteristics of patients (n = 859)Pre-operative Data and Co-morbities VariablesStudy Group (n = 859)Age, mean (SD) (years)68,7 (12,4)Women443 (51,6%)Hypertension537 (62,5%)Active endocarditis45 (5,2%)Diabetes mellitus (requiring drug treatment)184 (21,4%)Previous stroke47 (5,5%)Chronic renal failure48 (5,6%)Dialysis9 (1,1%)Chronic pulmonary disease123 (14,3%)Pulmonary hypertension (systolic PA pressure >55 mm Hg172 (20,0%)Extracardiac arteriopathy*any one or more of the following: claudication, carotid occlusion or >50% stenosis, previous or planned intervention on the abdominal aorta, limb arteries or carotids.124 (14,4%)Previous myocardial infarction81 (9,4%)Recent myocardial infarction36 (4,2%)Left ventricular ejection fraction, mean (SD), %54,2 (11,4)NYHA Class III/IV410 (47,7%)Previous cardiac surgery105 (12,2%)Urgent status of operation27 (3,1%)ECG Sinus rhythm640 (74,5%) Left bundle branch block87 bundle branch Left Left atrioventricular atrioventricular artery bypass valve valve valve for atrial one or more of the following: claudication, carotid occlusion or >50% stenosis, previous or planned intervention on the abdominal aorta, limb arteries or in a new patients who underwent PPI during primary hospitalization and no death was PPI patients after rate at and 12 years were (95% to (95% to and (95% to respectively. Cardiac mortality at and 12 years were (95% to (95% CI to and (95% CI to respectively. A shows the Kaplan-Meier estimates for the long-term survival of patients with PMD at follow-up and who restored A/V conduction (PMI) p-value < 0.001), based on follow-up and a median follow-up of months. B shows the of the cardiac death between PMD and with death as a competing risk and test p-value = and respectively). The unadjusted hazard ratio for mortality was (95% CI to p-value = 0.001), in of PMI. The adjusted hazard ratio was (95% CI to p-value < 0.001) with PMD as of PMD with increased long-term mortality center effect was in the regression The long-term survival with 95% are in 1 The of hazards proportionality for the Cox model was by the analysis of Schoenfeld test p-value for all PMI as an independent protective for long-term mortality after surgery and of the adjusted Cox semiparametric model for long-term CI of renal in a new Table of the adjusted Fine and Gray model for restored CI of artery bypass valve in a new A the of restored rhythm at follow-up. Crude CIF at 6 months, 1 and 12 years were 30.5% (95% CI 27.3% to 33.7%), 33.7% (95% CI 30.4% to and 37.2% (95% CI 33.8% to 40.6%) respectively. in more than 30% of patients with postoperative PPI to a Direct regression modeling of the effect of covariates on CIF of PMI that PMI was favored by preoperative SR (HR 95% CI to p < whereas (HR 95% CI to and (HR 95% CI to were independently associated to dependency test and Cramer von Mises test and was not (HR 95% CI to p = center effect was in the regression Preoperative SR as an independent favoring PMI after PPI. 2 B shows the adjusted CIF of PMI in patients with preoperative SR and this is the study on patients who underwent PPI after cardiac surgery with an long-term follow incidence of PPI was in with SS Li JM John R Chen LY Tholakanahalli VN Mbai M Adabag AS Long-term mortality and pacing outcomes of patients with permanent pacemaker implantation after cardiac surgery.Pacing Clin Electrophysiol. 2011; 34: 331-338Crossref PubMed Scopus (51) Google O M A D M D S Permanent pacemaker implantation following cardiac surgery: and long-term Clin Electrophysiol. PubMed Scopus Google S Lau C J Goldman Cardiac pacing following surgery for Surg. PubMed Scopus Google Scholar O M A D M D S Permanent pacemaker implantation following cardiac surgery: and long-term Clin Electrophysiol. PubMed Scopus Google Scholar PPI incidence of in cardiac surgery whereas S Lau C J Goldman Cardiac pacing following surgery for Surg. PubMed Scopus Google Scholar this in of the rate of PPI is also described in of SS Li JM John R Chen LY Tholakanahalli VN Mbai M Adabag AS Long-term mortality and pacing outcomes of patients with permanent pacemaker implantation after cardiac surgery.Pacing Clin Electrophysiol. 2011; 34: 331-338Crossref PubMed Scopus (51) Google Scholar. PPI occurs more after valvular surgery to the of the conduction to the cardiac A S S B A I Pacemaker dependency after aortic valve recover Cardiovasc Thorac Surg. 2013; PubMed Scopus Google Scholar and is reported in up to in A D S G S valve replacement in mitral valve a J Surg. 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In the current more than 30% of patients were PMI after 6 follow-up. at an of patients were independent from pacemaker that the rhythm occurs in the 6 than during the following of PMI in patients with A/V block of at years and 30% at 10 years are also a regression of PMD at long-term follow-up after O Crystal A Lashevsky I Khalameizer V Lau C Goldman B Fremes S Newman D Lukomsky M Crystal E Determinants of pacemaker dependency after coronary and/or mitral or aortic valve surgery with long-term follow-up.Am J Cardiol. 2008; 101: 203-208Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar In PPI occurred within the in of data that to reduce of PPI by patient selection and by of In study, of PMD in the long were and Although may have higher incidence of PPI in the postoperative SR at the long is more in these groups. PMI in up to of PPI patients after cardiac surgery at time AG Sastry A Horowitz JM Cheung J Liu CF Thomas G Ip JE Lerman BB Markowitz SM Recovery of atrioventricular conduction after pacemaker placement following cardiac valvular surgery.J Cardiovasc Electrophysiol. 2013; 24: 1383-1387Crossref PubMed Scopus (21) Google O M A D M D S Permanent pacemaker implantation following cardiac surgery: and long-term Clin Electrophysiol. PubMed Scopus Google Scholar The of A/V conduction disturbances after cardiac surgery may with direct of the conduction as the J R A G and of atrioventricular block after coronary artery bypass J Cardiol. 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A in this study is the impact of PMD on Although previous studies to higher mortality in PPI patients, we a survival of restored rhythm in patients with PMI at follow-up. in PPI patients with mortality during follow-up compared with PPI patients JR M S Long-term survival after permanent pacemaker analysis of for increased PubMed Scopus Google Scholar Also, as by the as the pacing increase and mortality at absence of ventricular pacing a for the protective effect of the restored sinus rhythm in this JR Epstein AE A and and PubMed Scopus Google Scholar of long-term mortality in PPI patients in population are and valvular JR M S Long-term survival after permanent pacemaker analysis of for increased PubMed Scopus Google Scholar In renal and were of long-term mortality in PPI D M Long-term requirement for pacemaker implantation after cardiac valve replacement Full Text Full Text PDF PubMed Scopus Google Scholar higher of PPI after valve surgery in patients with renal and PPI patients with sick sinus survival than with degree A/V A Hammill SC CM Hayes DL between of pacing and long-term survival in the Am Coll Cardiol. 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