Complications after Surgical Procedures in Patients with Cardiac Implantable Electronic Devices: Results of a Prospective Registry

Background: Complications after surgical procedures in patients with cardiac implantable electronic devices (CIED) are an emerging problem due to an increasing number of such procedures and aging of the population, which consequently increases the frequency of comorbidities. Objective: To identify the rates of postoperative complications, mortality, and hospital readmissions, and evaluate the risk factors for the occurrence of these events. Methods: Prospective and unicentric study that included all individuals undergoing CIED surgical procedures from February to August 2011. The patients were distributed by type of procedure into the following groups: initial implantations (cohort 1), generator exchange (cohort 2), and lead-related procedures (cohort 3). The outcomes were evaluated by an independent committee. Univariate and multivariate analyses assessed the risk factors, and the Kaplan-Meier method was used for survival analysis. Results: A total of 713 patients were included in the study and distributed as follows: 333 in cohort 1, 304 in cohort 2, and 76 in cohort 3. Postoperative complications were detected in 7.5%, 1.6%, and 11.8% of the patients in cohorts 1, 2, and 3, respectively (p = 0.014). During a 6-month follow-up, there were 58 (8.1%) deaths and 75 (10.5%) hospital readmissions. Predictors of hospital readmission included the use of implantable cardioverter-defibrillators (odds ratio [OR] = 4.2), functional class III-IV (OR = 1.8), and warfarin administration (OR = 1.9). Predictors of mortality included age over 80 years (OR = 2.4), ventricular dysfunction (OR = 2.2), functional class III-IV (OR = 3.3), and warfarin administration (OR = 2.3). Conclusions: Postoperative complications, hospital readmissions, and deaths occurred frequently and were strongly related to the type of procedure performed, type of CIED, and severity of the patient's underlying heart disease.


Introduction
Cardiac implantable electronic devices (CIED), including pacemakers (PM), implantable cardioverter-defibrillators (ICD), and cardiac resynchronization therapy (CRT) without (CRT-P) or with defibrillator (CRT-D) are the main innovations in cardiology in the last decades. 1 More than 737,000 procedures to implant these devices are performed every year worldwide, [2][3][4] with an estimated annual average in Brazil of 35,000 new implants and 15,000 reoperations devices are patients with severe left ventricular dysfunction often refractory to pharmacological treatment for heart failure. [13][14][15][16] Other factors also justifying the increasing number of complications include procedures to extract old leads, which carry a high surgical risk, and treatment of patients with CIED-related infections, who are often severely septicemic. 6,7,17 In this study, we implemented a prospective registry gathering data from clinical practice with the purpose of (1) identifying the rates of complications, hospital readmissions, and perioperative mortality within the first 6 months of clinical follow-up, and (2) evaluate the risk factors associated with the occurrence of these events. These data are intended to modify routine protocols in order to prevent and treat these events at an early stage.

Study design and population
The CIED Registry was a single-center prospective study conducted in a hospital providing advanced care. The study was approved by our institution's Research Ethics Committee, and the study participants signed a free and informed consent form.
We included all consecutive patients undergoing any type of surgical procedure involving artificial and permanent cardiac pacing between February and August 2011. The surgical procedures were performed by attending physicians, residents in cardiovascular surgery, and cardiologists undergoing training in artificial cardiac pacing.
All patients were followed up for 6 months after surgery through routine outpatient visits or, when attending other services, through telephone contact.

Study outcomes
The outcomes evaluated in the study included (1) intraoperative and immediate postoperative complications, or complications within the first 6 months of clinical follow-up; (2) the need for hospital readmissions; and (3) mortality from any cause.
The complications were characterized as (1) major, when life-threatening or requiring surgical reintervention for correction; and (2) minor, when suitable for treatment on an outpatient basis, involving device reprogramming, or requiring exclusive clinical observation. All major complications, hospital readmissions, and deaths were evaluated by an independent expert committee.

Study dynamics
We collected data at four distinct moments: immediately before surgery (immediate preoperative), at hospital discharge, and at 30 days and 6 months after surgery. The figure 1 shows the main phases of the study and the composition of the studied population.
In the immediate preoperative period, we collected demographic and clinical data prior to the CIED implantation, as well as information related to the clinical conditions of the patients upon collection of the data. When available, echocardiographic data were collected to determine the patients' ventricular function. We estimated the patients' left ventricular ejection fraction (LVEF) with the Teicholz method or, preferably, the Simpson method, considering as normal those values above 0.55.
In the assessments performed in the postoperative period and upon hospital discharge, we prioritized the evaluation of complications related to the surgical procedure, clinical complications arising from deterioration of the existing heart disease, and problems directly related to the CIED.

Electronic collection and management of the data
The data were stored in a database developed in the REDCap (Research Electronic Data Capture) software, 18 which is hosted in our institution's server. 19

Studied variables
We analyzed the following independent variables potentially associated with a risk of occurrence of the studied outcomes: demographic data, preoperative baseline clinical data, type of CIED, and type of procedure performed.
To improve our understanding of the severity of the procedures performed, we grouped the patients into three distinct cohorts: (1) initial implantation of conventional PM, ICD, CRT-P, or CRT-D; (2) change of pulse generators or procedures limited to the pulse generator pocket, characterized in this study as low-risk reoperations; and (3) reoperations involving previously implanted leads, such as lead extraction or upgrade procedures, characterized as high-risk reoperations.

Statistical analysis
The data were electronically exported to Excel (Microsoft Excel) spreadsheets and analyzed with SAS (Statistical Analysis System), SPSS (Statistical Package for the Social Sciences), and RStudio.
Quantitative variables are described as mean and standard deviation and qualitative variables as absolute and relative frequencies.
The association of independent variables with the occurrence of the evaluated outcomes was analyzed with chi-square or Fisher exact test. Differences in distribution of quantitative numerical variables according to the occurrence of outcomes (group with and without complications) were evaluated with Student's t test. We used multivariate logistic regression with the stepwise variable selection to evaluate independent risk factors, including those variables with associations with a p value ≤ 0.10 in the univariate analysis. Based on the logistic regression model, we estimated the magnitude of the effect of the variables included in the final model by calculating the odds ratios (OR) and their respective 95% confidence intervals (CI). The probability of survival and hospital readmission-free survival were estimated by the Kaplan-Meier method. We adopted a significance level of 5% in the statistical tests.
The patients were aged 4 days to 98.6 years with a median of 67.9 years. There was a slight predominance of males (51.5% of the cases). Most (66.4%) patients had no other heart disease apart from the underlying heart rate disturbance. Cardiomyopathy was diagnosed in 31.2% of the patients and was attributed to Chagas disease, or to idiopathic or ischemic causes. Only 1.1% of the patients presented a structural congenital heart disease.
The baseline assessment showed that most patients were oligosymptomatic in terms of manifestations of heart failure: 51.6% were in New York Heart Association (NYHA) functional class (FC) I, 33.2% in FC II, 14.0% in FC III, and 1.1% in FC IV.
Most patients presented with one or more comorbidities: 25.8% of the patients had one comorbidity, while 24.0% and 44.6% had two and three comorbidities, respectively. Only 5.6% of the patients had no other associated disease.
A total of 87.5% of the patients underwent echocardiographic studies. Among these patients, 49.8% had a normal LVEF, while 14.4% had LVEF estimated between 0.40 and 0.55, and 23.3% below 0.40.
Major complications were significantly more frequent (p = 0.014) in the cohort of patients undergoing high-risk reoperations (11.8%) when compared with those undergoing initial implantations (7.5%), and low-risk reoperations (1.6%). There were no significant differences in rates of minor complications among the three cohorts. The various types of complications observed are listed in Table 3. On univariate analysis, only administration of warfarin (p = 0.030) was identified as a risk factor for major complications, while no risk factors for minor complications were observed.

Discussion
Complications in surgical procedures for implantation or maintenance of CIEDs occur frequently. These complications may result from skin punctures during venous access procedures, handling of vein and cardiac catheters, contamination by infectious agents, anesthetic procedures, or other situations that occur less frequently. [6][7][8][9][10][11][12]20 Despite the fact that complications may occur at random, factors related to their increasing incidence have been described. For example, the experience of the hospital and the surgical team performing the procedure are strongly associated with the number of complications. 21,22 The type of implanted device and surgery performed also influence the outcome of the procedure. [8][9][10][11][12][13][14][15][16][17] Traditionally, surgeries for implantation of complex devices with a larger number of leads, as well as reoperations involving intravascular handling of the leads, particularly procedures to extract old leads, show a higher risk of complications. 8,9,16,17 The rates of perioperative and postoperative complications in procedures related to CIED have increased considerably and in disproportion to the number of initial device implantation. Several factors may be related to this fact, including aging of the population, as well as increasing number of comorbidities and prescription of anticoagulants and antiplatelet agents. [6][7][8][9][10][11] Another key factor is the incorporation into artificial cardiac pacing of cardioverter-defibrillators and CRT devices, which are mostly used to treat patients with severe left ventricular dysfunction. 13-16, 23,24 The present study identified a high rate of intraoperative and postoperative complications, although these complications were mostly minor in nature and not life-threatening or requiring intervention or hospital readmission for their management. These minor complications occurred at random and were unrelated to the type of procedure performed. On the other hand, major complications that were life-threatening or required reintervention or hospital readmission were more frequent in initial implantations (7.5%), and significantly more frequently in high-risk reoperations (11.8%). These rates, although consistent, were lower than those of major complications reported in the REPLACE Registry, which ranged from 4.0% to 15.3% in patients undergoing generator exchange and upgrade procedures, respectively. 8 Despite the high rate (10.5%) of hospital readmissions within 6 months from the surgical procedure, this rate was higher in patients undergoing high-risk reoperations, followed by those undergoing initial implantation. We also detected risk factors for this occurrence, mostly related to the severity of the heart disease, such as the requirement of any type of ICD or oral anticoagulant therapy, and preoperative NYHA FC III or IV. Data from the Danish Registry 9 and the Medicare program 21 have confirmed a higher morbidity rate with ICD alone or associated with CRT when compared with that with other devices.
Despite the high mortality rate from all causes observed in the same period (8.1%), this event was rarely related to the surgical procedure, but rather to the severity of the disease itself. We observed a higher risk of mortality among patients   who were either octogenarians, had severely decreased ventricular function or symptomatic heart failure, or received oral anticoagulant therapy. These rates are consistent with the mortality rates for heart failure reported in the Framingham Heart Study (10% in 30 days and 20-30% in 1 year), 24 as well as the annual mortality rates of 9% and 12% described in the CARE-HF 25 and COMPANION 26 studies, respectively.
On the other hand, patients who underwent procedures to exchange pulse generators alone or other procedures that did not involve intravascular handling had significantly lower risks of death, hospital readmission, or complications than the patients in the other two cohorts. The fact that the majority of these patients had their procedures scheduled electively may have been crucial to their better outcomes. Literature studies about complications and mortality in patients with CIED are mainly based on secondary analyses of randomized clinical trials or observational studies with limited sample sizes. As far as we know, the sample of this prospective registry is the largest to assess postoperative outcomes in patients with CIED in a single cardiology center in Brazil. Another aspect to be noted is that the data presented in this study reflect a picture of real-world clinical practice, since the analysis included all patients seen during a limited period of time, regardless of age, medical condition or surgical procedure, thus avoiding selection biases that could have invalidated a generalization of the results.

Limitations of the study
This study presents some limitations that must be considered in the interpretation of the results. Although the study included a representative sample, it reflects the care practices of a single cardiology hospital in the country, which is considered a reference center providing advanced artificial cardiac pacing therapies and a cardiology training center. Since this study was not designed to assess the effects of each surgeon's experience level and/or the volume of procedures performed individually, we are unable to claim that the surgeons' positions on the learning curve influenced the higher risk of intraoperative complications. The possibility of such association will be assessed in future studies conducted at our institution. Finally, a long-term follow-up of this population  is especially important to provide more robust evidence about possible adverse events that occur at later stages of care of patients with CIED, which are often underreported.

Conclusions
We conclude that adverse perioperative and postoperative events were frequent in the studied population. These events were strongly related to the type of procedure performed, type of device implanted, and, mainly, to the severity of the patient's underlying heart disease. We identified risk factors for mortality and hospital readmission, confirming that serious events occur in older patients and in those with more advanced cardiomyopathy.
The findings of this study confirm a need for specific care protocols to follow-up patients at a higher risk of presenting serious events.

Author contributions
Conception and design of the research: Silva KR, Costa R; Acquisition of data: Silva KR, Albertini CMM, Crevelari ES, Carvalho EIJ, Fiorelli AI; Analysis and interpretation of the data: Silva KR, Albertini CMM, Crevelari ES, Fiorelli AI, Costa R; Writing of the manuscript: Silva KR, Costa R; Critical

Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.

Sources of Funding
There were no external funding sources for this study.

Study Association
This study is not associated with any thesis or dissertation work.