Pacemaker implantation in pediatric heart transplant recipients: Predictors, outcomes, and impact on survival Iqbal El-Assaad, MD,* Sadeer G. Al-Kindi, MD,† Guilherme H. Oliveira, MD,† Penny Houghtaling, MS,‡ Bruce L. Wilkoff, MD, FHRS,§ Gerard J. Boyle, MD,¶ Peter F. Aziz, MD, FHRS¶ From the *Department of Pediatrics, Cleveland Clinic Children’s, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, †Advanced Heart Failure Center, Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, ‡Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland, Ohio, §Department of Cardiovascular Medicine, Section of Cardiac Pacemakers and Electrophysiology, Cleveland Clinic, Cleveland, Ohio, and ¶ Division of Pediatric Cardiology, Cleveland Clinic Children’s, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio. BACKGROUND Little is known about the incidence of permanent pacemaker (PPM) implantation after heart transplantation (HTx) in the pediatric population. OBJECTIVE The purpose of this study was to investigate the incidence, predictors, and outcomes of acute need for PPM implantation in pediatric HTx recipients. METHODS We queried the United Network for Organ Sharing (UNOS) database for all pediatric (age o18 years) patients who received HTx (1994–2014). Regression models are reported for prediction of PPM implantation. RESULTS A total of 6156 patients were analyzed, of whom 69 (1.1%) required posttransplant PPM implantation acutely. PPM use decreased over the study period (hazard ratio [HR] 0.95, P ¼ .01). Compared with the non-PPM group, PPM group was more likely to be older (10 vs 5.0 years, P o.001), used antiarrhythmics (35.6% vs 18.3%, P ¼ .006), required intraaortic balloon pump (2.9% vs 0.5%, P ¼ .049), and had undergone biatrial anastomosis (68.1% vs 48.2%, P ¼ .007). In a multivariable model, PPM implantation was predicted by higher donor age (HR 1.05, P ¼ .002), biatrial anastomosis (HR 2.53, P ¼ .04) and antiarrhythmic use (HR 2.12,
P ¼ .02). After adjusting for baseline characteristics, PPM recipients were at increased risk for posttransplant infection (47.8% vs 26.4%, P ¼ .001) and dialysis (15.9% vs 6.6%, P ¼ .003). Adjusted graft survival did not differ between the 2 groups (P ¼ .78). CONCLUSION Acute postoperative PPM implantation in pediatric HTx recipients is rare and has decreased over time. Acute PPM use is associated with biatrial anastomosis, antiarrhythmic use, and older donor age. Although PPM recipients had higher incidences of infections and dialysis, PPM implantation did not adversely impact survival. KEYWORDS Pediatric population; Bradyarrhythmia; Heart transplantation; Pacemaker; United Network for Organ Sharing database ABBREVIATIONS CI ¼ confidence interval; HR ¼ hazard ratio; HTx ¼ heart transplantation; IABP ¼ intraaortic balloon pump; IQR ¼ interquartile range; UNOS ¼ United Network for Organ Sharing; PPM ¼ permanent pacemaker (Heart Rhythm 2015;12:1776–1781) I 2015 Heart Rhythm Society. All rights reserved.
Introduction Drs. El-Assaad and Al-Kindi contributed equally to this work. This work was supported in part by Health Resources and Services Administration Contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Dr. Wilkoff has received consultant fees and honoraria from Boston Scientific, Medtronic, Spectranetics, and St. Jude Medical. Address reprint requests and correspondence: Dr. Peter F. Aziz, Division of Pediatric Cardiology, Cleveland Clinic Children’s, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Ave, Cleveland, OH 44195. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
Heart transplantation (HTx) has been increasingly performed in the pediatric population since 1967,1 with more than 500 pediatric transplants per year.2 Major advances in surgical techniques and immunosuppressive strategies have resulted in a 77% 10-year survival rate in pediatric HTx recipients.3 Bradyarrhythmias in the form of atrioventricular block or sinus node dysfunction after HTx is a major complication in the posttransplant period potentially requiring permanent pacing.4 Most data on pacemaker use are derived from adult literature and thus may not apply to the pediatric population. A few studies have reported the use of a permanent pacemaker (PPM) in pediatric patients but are limited by http://dx.doi.org/10.1016/j.hrthm.2015.04.045
El-Assaad et al
Pacemakers After Pediatric Heart Transplant
small sample size in single-center analyses.5,6 he incidence of bradyarrhythmias requiring pacemaker placement in the pediatric population has been variably reported at 2.8% to 6.6%.5,6 Given the lack of reliable data in the pediatric population, we sought to investigate the incidence, predictors, and outcomes associated with acute need for PPM placement after pediatric HTx using a large national registry.
Methods Study population This study included all pediatric patients age younger than 18 years who received single-organ HTx from 1994 to 2014. Patients were identified from the United Network for Organ Sharing(UNOS)/Organ Procurement and Transplantation Network database (Health Resources and Services Administration). UNOS records recipient and donor information in all centers across the United States. Data used in this study were collected from the transplant candidate registration form and the transplant recipient registration form, which typically are filed at listing and at the time of discharge from the hospital after transplantation, respectively. Thus, pacemaker implantation is defined as that performed during index hospitalization for transplantation. Information about survival and need for PPM implantation was retrieved. HTx recipients were divided into 2 groups: those who received pacemakers postoperatively and before discharge, and those who did not. Patients with unknown pacemaker status were excluded from the study (n = 218). The study was approved by the Institutional Review Board at the Cleveland Clinic Foundation. We compared baseline demographics and clinical characteristics between the PPM group and controls. Variables studied included recipient/donor age, recipient/donor gender, recipient/donor ethnicity, underlying cardiac cause, human leukocyte antigen mismatching status, UNOS listing status, surgical technique (bicaval vs biatrial anastomosis), ischemic time, and treatment therapies including extracorporeal membrane oxygenation, intraaortic balloon pump (IABP), ventricular assist device, ionotropes, antiarrhythmic and amiodarone use before transplant. Data on antiarrhythmics and amiodarone were available only for patients transplanted before 2007. Variables that were significantly different in the univariate analysis were studied in a multivariable model. In order to rule out an era effect on rates of PPM implantation, we analyzed PPM use as a continuous variable from 1994 to 2014.
Statistical analysis Categorical variables are expressed as percentage of available data and compared using χ2 Pearson test. Continuous variables are reported as median and interquartile range (IQR) and compared using independent t test. Variables that were significant in univariate analysis were used to evaluate the association between a patient variable and PPM placement in a multivariable logistic regression model. A similar
1777 logistic regression model was also used to adjust for other posttransplant outcomes. The association was expressed as hazard ratio (HR) and 95% confidence interval (CI). Survival was described using the Kaplan–Meier method (tested with log-rank test). Cox proportional hazard model was used to adjust for significant baseline characteristics and transplant year. No assumptions were made for missing data. The final multivariable logistic regression model uses a listwise deletion for the studied variables. Follow-up time was calculated using a previously published method.7 All statistical analyses were performed using SPSS software (version 19.0, IBM SPSS Statistics, IBM Corp, Chicago, IL). P o.05 was considered significant.
Results Over the study period, 6156 pediatric patients (median age 5.0 years, IQR 0–13.0 years) with a known pacemaker status underwent HTx. The majority were male (n ¼ 3390 [55.1%]) and Caucasian (n ¼ 3600 [58.5%]). Sixty-nine patients (1.1%) required PPM implantation after transplant. There was a decrease in utilization of pacemakers over the study period (HR 0.95, 95% CI 0.91–0.99, P ¼ .01). Compared with controls, the PPM group was older at the time of transplant (median age 10 years vs 5 years, P o.001), more likely at listing to require IABP (2.9% vs 0.5%, P ¼ .049), use antiarrhythmic medications (35.6% vs 18.3%, P ¼ .006), and have biatrial anastomoses (68.1% vs 48.2%, P ¼ .007). There was no difference with regard to gender, ethnicity, underlying cause, human leukocyte antigen mismatching status, initial UNOS status, graft ischemic time, and need for other therapies, including extracorporeal membrane oxygenation, ionotropes, ventricular assist device, or amiodarone use at listing (Table 1). In addition, PPM recipients were more likely to receive a heart from older donors (median age 12 years vs 6 years, P o.001). Other evaluated donor factors including gender, ethnicity, and left ventricular ejection fraction were not significantly different. Baseline demographics and clinical recipient for all patients are listed in Table 1.
Predictors of pacemaker implantation In univariate analyses, recipient age (P o.001), donor age (P o.001), biatrial anastomosis (P ¼ .007), antiarrhythmic use (P ¼ .006), and need for IABP at listing (P ¼ .049) predicted PPM implantation. In the multivariable regression model, the significant associations noted previously dissipated, and only donor age (HR 1.05, 95% CI 1.02–1.09, P ¼ .002), biatrial anastomosis (HR 2.53, 95% CI 1.02–6.25, P ¼ .04), and antiarrhythmic use (HR 2.12, 95% CI 1.12–4.00, P ¼ .02) remained significant predictors of pacemaker implantation (Table 2).
Posttransplant outcomes and graft survival Compared with controls, the PPM group had higher incidences of posttransplant infections (47.8% vs 26.4%,
1778 Table 1
Heart Rhythm, Vol 12, No 8, August 2015 Baseline demographic and clinical characteristics for heart transplant recipients PPM (n ¼ 69)
Median age (years) Male gender Ethnicity Caucasian African American Hispanics Asian Other Underlying cause Congenital heart disease Cardiomyopathy Retransplant Human leukocyte antigen mismatching 0–2 3–4 5–6 Antiarrhythmics at listing* Amiodarone at listing* Extracorporeal membrane oxygenation Ionotropes Ventricular assist device IABP Dialysis Initial UNOS status 1A 1B 2 Old status I Median ischemic time (hours) Biatrial anastomosis
No PPM (n ¼ 6087)
P value
10 (2.5–15) 37 (53.6)
5 (0–13) 3353 (55.1)
o.001 .809 .386
39 (56.5) 16 (23.2) 7 (10.1) 5 (7.2) 2 (2.9)
3561 (58.5) 1199 (19.7) 944 (15.5) 222 (3.6) 161 (2.6)
21 (30.4) 42 (60.9) 6 (8.7)
2506 (41.2) 3234 (53.1) 347 (5.7)
2 (4.2) 19 (39.6) 27 (56.3) 16 (35.6) 8 (18.2) 6 (8.7) 37 (53.6) 7 (20) 2 (2.9) 3 (4.5)
146 (3.0) 1778 (36.5) 2945 (60.5) 580 (18.3) 285 (8.9) 358 (5.9) 3069 (50.4) 595 (15.3) 30 (0.5) 196 (3.3)
.153
.878
38 (55.1) 6 (8.7) 10 (14.5) 15 (21.7) 3.33 (2.80–4.02) 47 (68.1)
.006 .055 .300 .630 .477 .049 .482 .483
3824 (68.2) 542 (8.9) 859 (14.1) 860 (14.1) 3.55 (2.83–4.27) 2935 (48.2)
.492 .007
Bold P values represent significant P values (P o 0.05). Number of patients (%) and median age with interquartile range (IQR) are shown for categorical and continuous data, respectively. IABP ¼ intraaortic balloon pump; PPM ¼ permanent pacemaker; UNOS ¼ United Network for Organ Sharing. * Available data before 2007.
P ¼ .002), dialysis (15.9% vs 6.6%, P ¼ .006), rejection before discharge (29% vs 15.6%, P ¼ .049), and other surgical procedures (41.3% vs 14.3%, P o.001). There were no differences in stroke and length of hospitalization. After adjustment for baseline characteristics, only posttransplant infection (P ¼ .001), dialysis (P ¼ .003), and need for other surgical procedures (P o.001) remained significant. We found no significant difference in the risk of mortality after mean follow-up of 6.21 years (IQR 6.02–6.40) between those who required pacemakers and those who did not (logrank P ¼ .08). However, the overall crude mortality was significantly higher in the PPM group at 2 years posttransplant (log-rank P ¼ .006). There was no difference in mortality after adjustment for donor/recipient age, IABP, antiarrhythmic, biatrial anastomosis, and transplant year (HR 1.07, 95% CI 0.68–1.68, P ¼ .78; Figure 1).
Discussion To our knowledge, this is the first study to investigate the predictors of PPM requirement after HTx in the pediatric population. Increasing donor age, antiarrhythmic use, and biatrial anastomosis were the main predictors for pacemaker implantation in the postoperative period. Our study also shows that pediatric HTx recipients who require PPM placement in the
acute postoperative period have similar long-term prognosis compared to those who did not require pacemakers. Another finding is that the incidence of PPM implantation is very low at 1.1%. This is the first study to investigate the acute need for PPM implantation after orthotopic heart transplant. Previous studies have reported on the long-term need for PPM in the pediatric population. Cannon et al5 found that 2 of 106 pediatric patients (1.9%) required PPM placement within 3 months. Similarly, Chinnock et al6 reported that only 1 of 246 infants (0.41%) who underwent HTx during the study period required PPM implantation within 3 months, comparable to our finding. Interestingly, PPM implantation in our study also was Table 2 Multivariable regression model for prediction of permanent pacemaker implantation
List year Donor age (per year) Recipient age (per year) Biatrial anastomosis Intraaortic balloon pump use Antiarrhythmic at listing
Hazard ratio (95% confidence interval)
P value
0.996 (0.909–1.092) 1.052 (1.019–1.086) 0.971 (0.902–1.046) 2.529 (1.023 – 6.247) 1.469 (0.176–12.261) 2.118 (1.120–4.002)
.940 .002 .438 .044 .722 .021
Bold P values represent significant P values (P o 0.05).
El-Assaad et al
Figure 1
Pacemakers After Pediatric Heart Transplant
1779
Kaplan–Meier curve for crude (left) and adjusted (right) graft survival after heart transplant in permanent pacemaker recipients vs control subjects.
lower than that reported in adults, which has been about 10.9%.8 Because we showed that the risk of PPM implantation increases by 5.2% per year of donor age (HR 1.052, P ¼ .002), it is possible that the overall lower incidence of PPM in pediatric compared to adult patients could be attributed to younger pediatric donors. This is in accordance with UNOS rules and regulations that prioritize listed pediatric patients over adults for grafts collected from pediatric donors.9 Our PPM rate is strikingly lower than the 5.6% PPM rate reported by Cantillon et al8 because of the different patient population. This difference may be attributable to the fact that their analysis excluded patients who died before discharge from the index hospitalization, in addition to including pacemakers that were implanted later during follow-up, as opposed to the acute implantation of PPM during the index hospitalization reported in our study. It is important to note that UNOS does not provide data on the indications for PPM requirement (ie, sinus node dysfunction, atrioventricular block, symptomatic bradycardia) or the required modality of pacing. The 3 patients reported in previous pediatric studies all required acute pacemaker placement because of sinus node dysfunction5,6; however, data extrapolation to identify major PPM indications in the 69 patients in our study is invalid because of the small sample size. In addition, we demonstrated for the first time that pediatric recipients requiring pacemaker implantation in the immediate postoperative period have excellent long-term survival despite higher risk of infection and dialysis. The crude survival analysis showed that there was an early difference in mortality and a nonsignificant trend toward higher late mortality among patients who required PPM. This likely is due to the fact that this is an overall “sicker” population, as this difference dissipated after adjusting for baseline characteristics. Our cohort analysis confirms findings from previous adult studies that showed associations between PPM need and higher donor age8 and biatrial anastomosis.8,10,11 The lower
incidence with bicaval technique is likely the result of preservation of right atrial anatomy and function. It is also associated with less sinus node injury and lower rates of atrial dilatation.4,12 Although we show that donor age is a statistically significant predictor of acute PPM implantation, HR of 1.05 is small and may not be clinically meaningful. Similarly, the higher incidence of acute PPM implantation in association with biatrial anastomosis may not be clinically relevant in the current era given that most centers have moved away from this technique because of sinus node dysfunction.13 We observed an increased rate of infection in those who required pacemaker implantation. although device-related infections could explain the increased infection rate, it is possible that this population is generally sicker, with higher rates of rejection, and possibly have higher requirements for immunosuppressants, increasing the risk for infections.14 Because of inherent limitations of the UNOS database, we were unable to categorize the etiology of posttransplant infection, so our interpretation remains speculative. Similarly, the increased rate of dialysis could be attributed to the sicker population. In addition, we observed that antiarrhythmic use before transplantation was associated with a higher risk of PPM implantation. This may be due to the use of amiodarone, which had a nonsignificant trend to increased rates of PPM implantation in our cohort (P ¼ .055). In 2 retrospective series of adult HTx recipients, pretransplant amiodarone use was associated with lower heart rates and higher incidence of atrial pacing without an effect on mortality, rejection, or inotropic support.15,16 This is largely attributed to the long half-life of amiodarone, which can linger for months after its discontinuation. In addition to amiodarone, other antiarrhythmics could have contributed to the increase in PPM implantation. Anecdotal reports have suggested that sotalol
1780 and procainamide may alter the electrophysiologic properties of the transplanted heart and cause bradycardia in the postoperative period.17,18 Thus, it is imperative that clinicians seek history of pretransplant use of antiarrhythmics, especially amiodarone, and factor it into the decision to implant a PPM because some of those patients will have reversible bradycardia.
Study limitations This retrospective study is based on a large database that was collected over 3 decades. Details of quality control of data collection are not available; however, UNOS conducts site audits to ensure quality control of the collected information,19 and reports from the UNOS registry have contributed significantly to our understanding of transplantation outcomes. The outcomes of transplant, PPM placement techniques, and immunosuppression have evolved over the years, so data early in the study might not be representative of current practice. Some essential data about implantation date, indications, specific antiarrhythmic medications, posttransplant infection types, medication compliance, and immunosuppression regimen are unavailable and thus limit adjustment for confounding factors and our ability to explain major differences in the 2 groups. Furthermore, the database does not include information beyond discharge from the hospital after transplantation, which limits our ability to study later need for pacing. Nonetheless, this large cohort provides statistical power that is unlikely to be found in single-center or multicenter studies.
Conclusion Acute postoperative pacemaker implantation in pediatric HTx recipients is rare and has decreased over time. PPM use is associated with biatrial anastomosis, antiarrhythmic use, and older donor age. Although PPM recipients had higher incidences of infections and dialysis, it did not adversely impact survival.
Acknowledgment We thank Mrs. Patricia Agatisa, research coordinator in the Department of Human Resources, Cleveland Clinic, Cleveland, Ohio, for statistical contributions essential to this study and final manuscript editing.
Heart Rhythm, Vol 12, No 8, August 2015
References 1. Kantrowitz A, Haller JD, Joos H, Cerruti MM, Carstensen HE. Transplantation of the heart in an infant and an adult. Am J Cardiol 1968;22:782–790. 2. Dipchand AI, Kirk R, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dobbels F, Lund LH, Rahmel AO, Yusen RD, Stehlik J. The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Heart Transplantation Report—2013; focus theme: age. J Heart Lung Transplant 2013;32:979–988. 3. Ross M, Kouretas P, Gamberg P, Miller J, Burge M, Reitz B, Robbins R, Chin C, Bernstein D. Ten-and 20-year survivors of pediatric orthotopic heart transplantation. J Heart Lung Transplant 2006;25:261–270. 4. Thajudeen A, Stecker EC, Shehata M, Patel J, Wang X, McAnulty JR JH, Kobashigawa J, Chugh SS. Arrhythmias after heart transplantation: mechanisms and management. J Am Heart Assoc 2012;1:e001461. 5. Cannon BC, Denfield SW, Friedman RA, Fenrich AL, Dreyer WJ, Towbin JA, Kertesz NJ. Late pacemaker requirement after pediatric orthotopic heart transplantation may predict the presence of transplant coronary artery disease. J Heart Lung Transplant 2004;23:67–71. 6. Chinnock RE, Torres VI, Jutzy RV, Johnston JK, Larsen RL, Razzouk AJ, Baum MF, Janner DL. Cardiac pacemakers in pediatric heart transplant recipients: incidence, indications, and associated factors. Pediatric Heart Transplant GroupLoma Linda. Pacing Clin Electrophysiol 1996;19:26–30. 7. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Contr Clin Trials 1996;17:343–346. 8. Cantillon DJ, Tarakji KG, Hu T, Hsu A, Smedira NG, Starling RC, Wilkoff BL, Saliba WI. Long-term outcomes and clinical predictors for pacemaker-requiring bradyarrhythmias after cardiac transplantation: analysis of the UNOS/OPTN cardiac transplant database. Heart Rhythm 2010;7:1567–1571. 9. Alkhaldi A, Chin C, Bernstein D. Pediatric cardiac transplantation. Semin Pediatr Surg 2006;15:188–198. 10. Weiss ES, Nwakanma LU, Russell SB, Conte JV, Shah AS. Outcomes in bicaval versus biatrial techniques in heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant 2008;27:178–183. 11. Meyer SR, Modry DL, Bainey K, Koshal A, Mullen JC, Rebeyka IM, Ross DB, Bowker S, Wang S. Declining need for permanent pacemaker insertion with the bicaval technique of orthotopic heart transplantation. Can J Cardiol 2005;21: 159–163. 12. Hunt SA, Haddad F. The changing face of heart transplantation. J Am Coll Cardiol 2008;52:587–598. 13. Weiss ES, Nwakanma LU, Russell SB, Conte JV, Shah AS. Outcomes in bicaval versus biatrial techniques in heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant 2008;27:178–183. 14. Walsh EP, Cecchin F. Recent advances in pacemaker and implantable defibrillator therapy for young patients. Curr Opin Cardiol 2004;19:91–96. 15. Macdonald P, Hackworthy R, Keogh A, Sivathasan C, Chang V, Spratt P. The effect of chronic amiodarone therapy before transplantation on early cardiac allograft function. J Heart Lung Transplant 1991;10:743–748. 16. Chelimsky-Fallick C, Middlekauff HR, Stevenson WG, Kobashigawa J, Saxon LA, Moriguchi J, Brownfield ED, Hamilton MA, Drinkwater D, Laks H. Amiodarone therapy does not compromise subsequent heart transplantation. J Am Coll Cardiol 1992;20:1556–1561. 17. Alvarez L, Escudero C, Torralba A, Millan I. Electrophysiologic effects of procainamide, mexiletine, and amiodarone on the transplanted heart: experimental study. J Thorac Cardiovasc Surg 1995;109:899–904. 18. Zimmerman H, Nolan PE, Copeland JG, Sethi G. A rare cause of graft dysfunction after a heart transplant. Interact Cardiovasc Thorac Surg 2010;11: 719–720. 19. Daily OP, Kauffman HM. Quality control of the OPTN/UNOS Transplant Registry. Transplantation 2004;77:1309; author reply 1309–1310.
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CLINICAL PERSPECTIVES With major advances in surgical techniques and immunosuppressive therapy, pediatric heart transplant procedures continue to rise, which necessitates the need to improve our understanding of major complications encountered in the immediate postoperative period. One of these major complications is bradyarrhythmias requiring permanent pacemaker (PPM) implantation. This is the first and the largest study to investigate the incidence, outcomes, and predictors of acute need for PPM placement after heart transplantation in the pediatric population using a national heart transplant registry. Acute need for posttransplant PPM implantation has decreased over the past 2 decades because of changes in the surgical transplantation technique (ie, bicaval anastomosis). The long-term survival rate in patients requiring pacemaker placement in the immediate postoperative period is comparable to those who do not despite them being at higher risk for having posttransplant infection and dialysis rates. Donor age, biatrial anastomosis technique, and antiarrhythmic use were associated with a higher rate of PPM implantation. The decision to treat preoperative arrhythmias should be carefully considered, and clinicians should explore the history of antiarrhythmic use (especially amiodarone) before transplant in order to exclude reversible bradycardia.
P ¼ .02). After adjusting for baseline characteristics, PPM recipients were at increased risk for posttransplant infection (47.8% vs 26.4%, P ¼ .001) and dialysis (15.9% vs 6.6%, P ¼ .003). Adjusted graft survival did not differ between the 2 groups (P ¼ .78). CONCLUSION Acute postoperative PPM implantation in pediatric HTx recipients is rare and has decreased over time. Acute PPM use is associated with biatrial anastomosis, antiarrhythmic use, and older donor age. Although PPM recipients had higher incidences of infections and dialysis, PPM implantation did not adversely impact survival. KEYWORDS Pediatric population; Bradyarrhythmia; Heart transplantation; Pacemaker; United Network for Organ Sharing database ABBREVIATIONS CI ¼ confidence interval; HR ¼ hazard ratio; HTx ¼ heart transplantation; IABP ¼ intraaortic balloon pump; IQR ¼ interquartile range; UNOS ¼ United Network for Organ Sharing; PPM ¼ permanent pacemaker (Heart Rhythm 2015;12:1776–1781) I 2015 Heart Rhythm Society. All rights reserved.
Introduction Drs. El-Assaad and Al-Kindi contributed equally to this work. This work was supported in part by Health Resources and Services Administration Contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Dr. Wilkoff has received consultant fees and honoraria from Boston Scientific, Medtronic, Spectranetics, and St. Jude Medical. Address reprint requests and correspondence: Dr. Peter F. Aziz, Division of Pediatric Cardiology, Cleveland Clinic Children’s, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Ave, Cleveland, OH 44195. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
Heart transplantation (HTx) has been increasingly performed in the pediatric population since 1967,1 with more than 500 pediatric transplants per year.2 Major advances in surgical techniques and immunosuppressive strategies have resulted in a 77% 10-year survival rate in pediatric HTx recipients.3 Bradyarrhythmias in the form of atrioventricular block or sinus node dysfunction after HTx is a major complication in the posttransplant period potentially requiring permanent pacing.4 Most data on pacemaker use are derived from adult literature and thus may not apply to the pediatric population. A few studies have reported the use of a permanent pacemaker (PPM) in pediatric patients but are limited by http://dx.doi.org/10.1016/j.hrthm.2015.04.045
El-Assaad et al
Pacemakers After Pediatric Heart Transplant
small sample size in single-center analyses.5,6 he incidence of bradyarrhythmias requiring pacemaker placement in the pediatric population has been variably reported at 2.8% to 6.6%.5,6 Given the lack of reliable data in the pediatric population, we sought to investigate the incidence, predictors, and outcomes associated with acute need for PPM placement after pediatric HTx using a large national registry.
Methods Study population This study included all pediatric patients age younger than 18 years who received single-organ HTx from 1994 to 2014. Patients were identified from the United Network for Organ Sharing(UNOS)/Organ Procurement and Transplantation Network database (Health Resources and Services Administration). UNOS records recipient and donor information in all centers across the United States. Data used in this study were collected from the transplant candidate registration form and the transplant recipient registration form, which typically are filed at listing and at the time of discharge from the hospital after transplantation, respectively. Thus, pacemaker implantation is defined as that performed during index hospitalization for transplantation. Information about survival and need for PPM implantation was retrieved. HTx recipients were divided into 2 groups: those who received pacemakers postoperatively and before discharge, and those who did not. Patients with unknown pacemaker status were excluded from the study (n = 218). The study was approved by the Institutional Review Board at the Cleveland Clinic Foundation. We compared baseline demographics and clinical characteristics between the PPM group and controls. Variables studied included recipient/donor age, recipient/donor gender, recipient/donor ethnicity, underlying cardiac cause, human leukocyte antigen mismatching status, UNOS listing status, surgical technique (bicaval vs biatrial anastomosis), ischemic time, and treatment therapies including extracorporeal membrane oxygenation, intraaortic balloon pump (IABP), ventricular assist device, ionotropes, antiarrhythmic and amiodarone use before transplant. Data on antiarrhythmics and amiodarone were available only for patients transplanted before 2007. Variables that were significantly different in the univariate analysis were studied in a multivariable model. In order to rule out an era effect on rates of PPM implantation, we analyzed PPM use as a continuous variable from 1994 to 2014.
Statistical analysis Categorical variables are expressed as percentage of available data and compared using χ2 Pearson test. Continuous variables are reported as median and interquartile range (IQR) and compared using independent t test. Variables that were significant in univariate analysis were used to evaluate the association between a patient variable and PPM placement in a multivariable logistic regression model. A similar
1777 logistic regression model was also used to adjust for other posttransplant outcomes. The association was expressed as hazard ratio (HR) and 95% confidence interval (CI). Survival was described using the Kaplan–Meier method (tested with log-rank test). Cox proportional hazard model was used to adjust for significant baseline characteristics and transplant year. No assumptions were made for missing data. The final multivariable logistic regression model uses a listwise deletion for the studied variables. Follow-up time was calculated using a previously published method.7 All statistical analyses were performed using SPSS software (version 19.0, IBM SPSS Statistics, IBM Corp, Chicago, IL). P o.05 was considered significant.
Results Over the study period, 6156 pediatric patients (median age 5.0 years, IQR 0–13.0 years) with a known pacemaker status underwent HTx. The majority were male (n ¼ 3390 [55.1%]) and Caucasian (n ¼ 3600 [58.5%]). Sixty-nine patients (1.1%) required PPM implantation after transplant. There was a decrease in utilization of pacemakers over the study period (HR 0.95, 95% CI 0.91–0.99, P ¼ .01). Compared with controls, the PPM group was older at the time of transplant (median age 10 years vs 5 years, P o.001), more likely at listing to require IABP (2.9% vs 0.5%, P ¼ .049), use antiarrhythmic medications (35.6% vs 18.3%, P ¼ .006), and have biatrial anastomoses (68.1% vs 48.2%, P ¼ .007). There was no difference with regard to gender, ethnicity, underlying cause, human leukocyte antigen mismatching status, initial UNOS status, graft ischemic time, and need for other therapies, including extracorporeal membrane oxygenation, ionotropes, ventricular assist device, or amiodarone use at listing (Table 1). In addition, PPM recipients were more likely to receive a heart from older donors (median age 12 years vs 6 years, P o.001). Other evaluated donor factors including gender, ethnicity, and left ventricular ejection fraction were not significantly different. Baseline demographics and clinical recipient for all patients are listed in Table 1.
Predictors of pacemaker implantation In univariate analyses, recipient age (P o.001), donor age (P o.001), biatrial anastomosis (P ¼ .007), antiarrhythmic use (P ¼ .006), and need for IABP at listing (P ¼ .049) predicted PPM implantation. In the multivariable regression model, the significant associations noted previously dissipated, and only donor age (HR 1.05, 95% CI 1.02–1.09, P ¼ .002), biatrial anastomosis (HR 2.53, 95% CI 1.02–6.25, P ¼ .04), and antiarrhythmic use (HR 2.12, 95% CI 1.12–4.00, P ¼ .02) remained significant predictors of pacemaker implantation (Table 2).
Posttransplant outcomes and graft survival Compared with controls, the PPM group had higher incidences of posttransplant infections (47.8% vs 26.4%,
1778 Table 1
Heart Rhythm, Vol 12, No 8, August 2015 Baseline demographic and clinical characteristics for heart transplant recipients PPM (n ¼ 69)
Median age (years) Male gender Ethnicity Caucasian African American Hispanics Asian Other Underlying cause Congenital heart disease Cardiomyopathy Retransplant Human leukocyte antigen mismatching 0–2 3–4 5–6 Antiarrhythmics at listing* Amiodarone at listing* Extracorporeal membrane oxygenation Ionotropes Ventricular assist device IABP Dialysis Initial UNOS status 1A 1B 2 Old status I Median ischemic time (hours) Biatrial anastomosis
No PPM (n ¼ 6087)
P value
10 (2.5–15) 37 (53.6)
5 (0–13) 3353 (55.1)
o.001 .809 .386
39 (56.5) 16 (23.2) 7 (10.1) 5 (7.2) 2 (2.9)
3561 (58.5) 1199 (19.7) 944 (15.5) 222 (3.6) 161 (2.6)
21 (30.4) 42 (60.9) 6 (8.7)
2506 (41.2) 3234 (53.1) 347 (5.7)
2 (4.2) 19 (39.6) 27 (56.3) 16 (35.6) 8 (18.2) 6 (8.7) 37 (53.6) 7 (20) 2 (2.9) 3 (4.5)
146 (3.0) 1778 (36.5) 2945 (60.5) 580 (18.3) 285 (8.9) 358 (5.9) 3069 (50.4) 595 (15.3) 30 (0.5) 196 (3.3)
.153
.878
38 (55.1) 6 (8.7) 10 (14.5) 15 (21.7) 3.33 (2.80–4.02) 47 (68.1)
.006 .055 .300 .630 .477 .049 .482 .483
3824 (68.2) 542 (8.9) 859 (14.1) 860 (14.1) 3.55 (2.83–4.27) 2935 (48.2)
.492 .007
Bold P values represent significant P values (P o 0.05). Number of patients (%) and median age with interquartile range (IQR) are shown for categorical and continuous data, respectively. IABP ¼ intraaortic balloon pump; PPM ¼ permanent pacemaker; UNOS ¼ United Network for Organ Sharing. * Available data before 2007.
P ¼ .002), dialysis (15.9% vs 6.6%, P ¼ .006), rejection before discharge (29% vs 15.6%, P ¼ .049), and other surgical procedures (41.3% vs 14.3%, P o.001). There were no differences in stroke and length of hospitalization. After adjustment for baseline characteristics, only posttransplant infection (P ¼ .001), dialysis (P ¼ .003), and need for other surgical procedures (P o.001) remained significant. We found no significant difference in the risk of mortality after mean follow-up of 6.21 years (IQR 6.02–6.40) between those who required pacemakers and those who did not (logrank P ¼ .08). However, the overall crude mortality was significantly higher in the PPM group at 2 years posttransplant (log-rank P ¼ .006). There was no difference in mortality after adjustment for donor/recipient age, IABP, antiarrhythmic, biatrial anastomosis, and transplant year (HR 1.07, 95% CI 0.68–1.68, P ¼ .78; Figure 1).
Discussion To our knowledge, this is the first study to investigate the predictors of PPM requirement after HTx in the pediatric population. Increasing donor age, antiarrhythmic use, and biatrial anastomosis were the main predictors for pacemaker implantation in the postoperative period. Our study also shows that pediatric HTx recipients who require PPM placement in the
acute postoperative period have similar long-term prognosis compared to those who did not require pacemakers. Another finding is that the incidence of PPM implantation is very low at 1.1%. This is the first study to investigate the acute need for PPM implantation after orthotopic heart transplant. Previous studies have reported on the long-term need for PPM in the pediatric population. Cannon et al5 found that 2 of 106 pediatric patients (1.9%) required PPM placement within 3 months. Similarly, Chinnock et al6 reported that only 1 of 246 infants (0.41%) who underwent HTx during the study period required PPM implantation within 3 months, comparable to our finding. Interestingly, PPM implantation in our study also was Table 2 Multivariable regression model for prediction of permanent pacemaker implantation
List year Donor age (per year) Recipient age (per year) Biatrial anastomosis Intraaortic balloon pump use Antiarrhythmic at listing
Hazard ratio (95% confidence interval)
P value
0.996 (0.909–1.092) 1.052 (1.019–1.086) 0.971 (0.902–1.046) 2.529 (1.023 – 6.247) 1.469 (0.176–12.261) 2.118 (1.120–4.002)
.940 .002 .438 .044 .722 .021
Bold P values represent significant P values (P o 0.05).
El-Assaad et al
Figure 1
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Kaplan–Meier curve for crude (left) and adjusted (right) graft survival after heart transplant in permanent pacemaker recipients vs control subjects.
lower than that reported in adults, which has been about 10.9%.8 Because we showed that the risk of PPM implantation increases by 5.2% per year of donor age (HR 1.052, P ¼ .002), it is possible that the overall lower incidence of PPM in pediatric compared to adult patients could be attributed to younger pediatric donors. This is in accordance with UNOS rules and regulations that prioritize listed pediatric patients over adults for grafts collected from pediatric donors.9 Our PPM rate is strikingly lower than the 5.6% PPM rate reported by Cantillon et al8 because of the different patient population. This difference may be attributable to the fact that their analysis excluded patients who died before discharge from the index hospitalization, in addition to including pacemakers that were implanted later during follow-up, as opposed to the acute implantation of PPM during the index hospitalization reported in our study. It is important to note that UNOS does not provide data on the indications for PPM requirement (ie, sinus node dysfunction, atrioventricular block, symptomatic bradycardia) or the required modality of pacing. The 3 patients reported in previous pediatric studies all required acute pacemaker placement because of sinus node dysfunction5,6; however, data extrapolation to identify major PPM indications in the 69 patients in our study is invalid because of the small sample size. In addition, we demonstrated for the first time that pediatric recipients requiring pacemaker implantation in the immediate postoperative period have excellent long-term survival despite higher risk of infection and dialysis. The crude survival analysis showed that there was an early difference in mortality and a nonsignificant trend toward higher late mortality among patients who required PPM. This likely is due to the fact that this is an overall “sicker” population, as this difference dissipated after adjusting for baseline characteristics. Our cohort analysis confirms findings from previous adult studies that showed associations between PPM need and higher donor age8 and biatrial anastomosis.8,10,11 The lower
incidence with bicaval technique is likely the result of preservation of right atrial anatomy and function. It is also associated with less sinus node injury and lower rates of atrial dilatation.4,12 Although we show that donor age is a statistically significant predictor of acute PPM implantation, HR of 1.05 is small and may not be clinically meaningful. Similarly, the higher incidence of acute PPM implantation in association with biatrial anastomosis may not be clinically relevant in the current era given that most centers have moved away from this technique because of sinus node dysfunction.13 We observed an increased rate of infection in those who required pacemaker implantation. although device-related infections could explain the increased infection rate, it is possible that this population is generally sicker, with higher rates of rejection, and possibly have higher requirements for immunosuppressants, increasing the risk for infections.14 Because of inherent limitations of the UNOS database, we were unable to categorize the etiology of posttransplant infection, so our interpretation remains speculative. Similarly, the increased rate of dialysis could be attributed to the sicker population. In addition, we observed that antiarrhythmic use before transplantation was associated with a higher risk of PPM implantation. This may be due to the use of amiodarone, which had a nonsignificant trend to increased rates of PPM implantation in our cohort (P ¼ .055). In 2 retrospective series of adult HTx recipients, pretransplant amiodarone use was associated with lower heart rates and higher incidence of atrial pacing without an effect on mortality, rejection, or inotropic support.15,16 This is largely attributed to the long half-life of amiodarone, which can linger for months after its discontinuation. In addition to amiodarone, other antiarrhythmics could have contributed to the increase in PPM implantation. Anecdotal reports have suggested that sotalol
1780 and procainamide may alter the electrophysiologic properties of the transplanted heart and cause bradycardia in the postoperative period.17,18 Thus, it is imperative that clinicians seek history of pretransplant use of antiarrhythmics, especially amiodarone, and factor it into the decision to implant a PPM because some of those patients will have reversible bradycardia.
Study limitations This retrospective study is based on a large database that was collected over 3 decades. Details of quality control of data collection are not available; however, UNOS conducts site audits to ensure quality control of the collected information,19 and reports from the UNOS registry have contributed significantly to our understanding of transplantation outcomes. The outcomes of transplant, PPM placement techniques, and immunosuppression have evolved over the years, so data early in the study might not be representative of current practice. Some essential data about implantation date, indications, specific antiarrhythmic medications, posttransplant infection types, medication compliance, and immunosuppression regimen are unavailable and thus limit adjustment for confounding factors and our ability to explain major differences in the 2 groups. Furthermore, the database does not include information beyond discharge from the hospital after transplantation, which limits our ability to study later need for pacing. Nonetheless, this large cohort provides statistical power that is unlikely to be found in single-center or multicenter studies.
Conclusion Acute postoperative pacemaker implantation in pediatric HTx recipients is rare and has decreased over time. PPM use is associated with biatrial anastomosis, antiarrhythmic use, and older donor age. Although PPM recipients had higher incidences of infections and dialysis, it did not adversely impact survival.
Acknowledgment We thank Mrs. Patricia Agatisa, research coordinator in the Department of Human Resources, Cleveland Clinic, Cleveland, Ohio, for statistical contributions essential to this study and final manuscript editing.
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References 1. Kantrowitz A, Haller JD, Joos H, Cerruti MM, Carstensen HE. Transplantation of the heart in an infant and an adult. Am J Cardiol 1968;22:782–790. 2. Dipchand AI, Kirk R, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dobbels F, Lund LH, Rahmel AO, Yusen RD, Stehlik J. The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Heart Transplantation Report—2013; focus theme: age. J Heart Lung Transplant 2013;32:979–988. 3. Ross M, Kouretas P, Gamberg P, Miller J, Burge M, Reitz B, Robbins R, Chin C, Bernstein D. Ten-and 20-year survivors of pediatric orthotopic heart transplantation. J Heart Lung Transplant 2006;25:261–270. 4. Thajudeen A, Stecker EC, Shehata M, Patel J, Wang X, McAnulty JR JH, Kobashigawa J, Chugh SS. Arrhythmias after heart transplantation: mechanisms and management. J Am Heart Assoc 2012;1:e001461. 5. Cannon BC, Denfield SW, Friedman RA, Fenrich AL, Dreyer WJ, Towbin JA, Kertesz NJ. Late pacemaker requirement after pediatric orthotopic heart transplantation may predict the presence of transplant coronary artery disease. J Heart Lung Transplant 2004;23:67–71. 6. Chinnock RE, Torres VI, Jutzy RV, Johnston JK, Larsen RL, Razzouk AJ, Baum MF, Janner DL. Cardiac pacemakers in pediatric heart transplant recipients: incidence, indications, and associated factors. Pediatric Heart Transplant GroupLoma Linda. Pacing Clin Electrophysiol 1996;19:26–30. 7. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Contr Clin Trials 1996;17:343–346. 8. Cantillon DJ, Tarakji KG, Hu T, Hsu A, Smedira NG, Starling RC, Wilkoff BL, Saliba WI. Long-term outcomes and clinical predictors for pacemaker-requiring bradyarrhythmias after cardiac transplantation: analysis of the UNOS/OPTN cardiac transplant database. Heart Rhythm 2010;7:1567–1571. 9. Alkhaldi A, Chin C, Bernstein D. Pediatric cardiac transplantation. Semin Pediatr Surg 2006;15:188–198. 10. Weiss ES, Nwakanma LU, Russell SB, Conte JV, Shah AS. Outcomes in bicaval versus biatrial techniques in heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant 2008;27:178–183. 11. Meyer SR, Modry DL, Bainey K, Koshal A, Mullen JC, Rebeyka IM, Ross DB, Bowker S, Wang S. Declining need for permanent pacemaker insertion with the bicaval technique of orthotopic heart transplantation. Can J Cardiol 2005;21: 159–163. 12. Hunt SA, Haddad F. The changing face of heart transplantation. J Am Coll Cardiol 2008;52:587–598. 13. Weiss ES, Nwakanma LU, Russell SB, Conte JV, Shah AS. Outcomes in bicaval versus biatrial techniques in heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant 2008;27:178–183. 14. Walsh EP, Cecchin F. Recent advances in pacemaker and implantable defibrillator therapy for young patients. Curr Opin Cardiol 2004;19:91–96. 15. Macdonald P, Hackworthy R, Keogh A, Sivathasan C, Chang V, Spratt P. The effect of chronic amiodarone therapy before transplantation on early cardiac allograft function. J Heart Lung Transplant 1991;10:743–748. 16. Chelimsky-Fallick C, Middlekauff HR, Stevenson WG, Kobashigawa J, Saxon LA, Moriguchi J, Brownfield ED, Hamilton MA, Drinkwater D, Laks H. Amiodarone therapy does not compromise subsequent heart transplantation. J Am Coll Cardiol 1992;20:1556–1561. 17. Alvarez L, Escudero C, Torralba A, Millan I. Electrophysiologic effects of procainamide, mexiletine, and amiodarone on the transplanted heart: experimental study. J Thorac Cardiovasc Surg 1995;109:899–904. 18. Zimmerman H, Nolan PE, Copeland JG, Sethi G. A rare cause of graft dysfunction after a heart transplant. Interact Cardiovasc Thorac Surg 2010;11: 719–720. 19. Daily OP, Kauffman HM. Quality control of the OPTN/UNOS Transplant Registry. Transplantation 2004;77:1309; author reply 1309–1310.
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CLINICAL PERSPECTIVES With major advances in surgical techniques and immunosuppressive therapy, pediatric heart transplant procedures continue to rise, which necessitates the need to improve our understanding of major complications encountered in the immediate postoperative period. One of these major complications is bradyarrhythmias requiring permanent pacemaker (PPM) implantation. This is the first and the largest study to investigate the incidence, outcomes, and predictors of acute need for PPM placement after heart transplantation in the pediatric population using a national heart transplant registry. Acute need for posttransplant PPM implantation has decreased over the past 2 decades because of changes in the surgical transplantation technique (ie, bicaval anastomosis). The long-term survival rate in patients requiring pacemaker placement in the immediate postoperative period is comparable to those who do not despite them being at higher risk for having posttransplant infection and dialysis rates. Donor age, biatrial anastomosis technique, and antiarrhythmic use were associated with a higher rate of PPM implantation. The decision to treat preoperative arrhythmias should be carefully considered, and clinicians should explore the history of antiarrhythmic use (especially amiodarone) before transplant in order to exclude reversible bradycardia.
