- Email: [email protected]
Outcomes after percutaneous coronary artery revascularization procedures for cardiac allograft vasculopathy in pediatric heart transplant recipients: A multi-institutional study
http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Outcomes after percutaneous coronary artery revascularization procedures for cardiac allograft vasculopathy in pediatric heart transplant recipients: A multi-institutional study Aamir Jeewa, MD,a Clifford Chin, MD,b Elfriede Pahl, MD,c Andrew M. Atz, MD,d Michael P. Carboni, MD,e Elizabeth Pruitt, MSPH,f David C. Naftel, PhD,f Rose Rodriguez, PNP,g Anne I. Dipchand, MDh for the Pediatric Heart Transplant Study (PHTS) Investigators From the aTexas Children’s Hospital, Baylor College of Medicine, Houston, Texas; bCincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; cAnn & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois; dMedical University of South Carolina, Charleston, South Carolina; e Duke Children’s Hospital & Health Center, Durham, North Carolina; fThe University of Alabama at Birmingham, Birmingham, Alabama; gMorgan Stanley Children’s Hospital of New York–Presbyterian, Columbia University Medical Center, New York, New York; and the hThe Hospital for Sick Children, Toronto, Ontario, Canada.
KEYWORDS: heart transplant; pediatric; cardiac; allograft; vasculopathy
BACKGROUND: Cardiac allograft vasculopathy is an important cause of long-term graft loss. In adults, percutaneous revascularization procedures (PRPs) have variable success with high restenosis rates and little impact on graft survival. Limited data exist in pediatric recipients of transplants. METHODS: Data from the Pediatric Heart Transplant Study (PHTS) were used to explore associations between PRPs and outcomes after heart transplant in patients listed r18 years old who received a first heart transplant between 1993 and 2009. RESULTS: Revascularization procedures were done in 28 of 3,156 (0.9%) patients; 13 patients had multiple PRPs giving a total of 51 PRPs performed across 15 centers. Mean recipient age at time of transplant was 7.7 ⫾ 6.7 years; mean donor age was 15.9 ⫾ 15.4 years. The mean time to first PRP was 5.7 ⫾ 3.2 years. Vessels involved were left anterior descending artery (41%), right coronary artery (25%), circumflex artery (18%), other coronary branches/unknown (16%). PRPs consisted of 38 (75%) stent implantations and 13 (25%) balloon angioplasties with an overall procedural success rate of 73%. Freedom from graft loss after PRPs was 89%, 75%, and 61% at 1, 3, and 12 months. In addition, patients with transplants from donors 430 years old were found to have less freedom from the need for a revascularization procedure than patients with transplants from younger donors (p o 0.0001). CONCLUSIONS: In this large pediatric heart transplant cohort, use of PRPs for cardiac allograft vasculopathy was rare, likely related to procedural feasibility of the interventions. Despite technically successful interventions, graft loss occurred in 39% within 1 year post-procedure; relisting for heart transplant should be considered. J Heart Lung Transplant 2015;34:1163–1168 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Aamir Jeewa, MD, 6621 Fannin Street, Suite 19345C, West Tower, Houston, TX 77030. Telephone: þ832-826-5682. E-mail address: [email protected]
Cardiac allograft vasculopathy (CAV) is an important cause of long-term morbidity and mortality after pediatric and adult heart transplantation.1–4 The prevalence of CAV is
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.11.011
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7.0%, 32.3%, and 45.7% among adult recipients at 1, 5, and 8 years post-transplantation.5 Therapies targeted to prevent the development of CAV include using statins and modifying immunosuppression regimens.6,7 However, after CAV has developed, the therapeutic interventions are limited and have variable success rates. These interventions include percutaneous revascularization procedures (PRPs) such as balloon angioplasty, coronary artery stent implantation, and coronary artery bypass grafting. Percutaneous interventions in adult patients with CAV have reported high angiographic success and low complication rates. However, restenosis rates were high, and overall incidence of graft loss was increased, highlighting the progressive nature of CAV post–heart transplant.8–10 Limited data exist on the true incidence of CAV in pediatric patients. A study by Pahl et al3 from the Pediatric Heart Transplant Study (PHTS) database between 1993 and 2001 revealed that 751 of 1,221 (62%) patients with transplants underwent 2,049 coronary angiography procedures. In this cohort, 30 patients (4%) had moderate to severe CAV showing that the incidence of moderate to severe CAV was less than in the adult population; however, the prognosis with moderate to severe disease was poor. There are fewer data with respect to coronary artery revascularization procedures in pediatric patients. Shaddy et al11 reported their experience with 3 pediatric patients requiring a revascularization procedure. All 3 patients had severe stenosis on angiography with a normal ejection fraction, lipid profile, and blood pressure. These patients also had successful procedures by angiography; however, all patients subsequently underwent retransplantation. Tham et al12 reported on a single-center pediatric experience with percutaneous coronary interventions in which 7 patients underwent a revascularization procedure. Major procedural complications in this study included death (n ¼ 1) and a resuscitated cardiac arrest (n ¼ 1). Of the 7 patients, 3 underwent retransplantation, and 3 died. The aforementioned single-center studies reveal an alarming amount of graft loss among patients who develop CAV and undergo revascularization procedures. The purpose of our study was to conduct a multiinstitutional review, from the PHTS participating centers, of the procedural and clinical outcomes of all children who underwent a PRP for CAV from 1993 to 2009. This study composes the largest review to date of coronary revascularization in pediatric patients with transplants.
Methods All participating centers had approval from their institutional review boards to participate in this study.
Data collection The PHTS database includes patient demographic, medical, and procedural data that were collected and submitted by operating centers at the time of the procedure. Data collection forms described the location and degree of stenosis in the diseased vessel, the type of coronary artery intervention—either balloon angioplasty or stent placement—and procedural success identified by
angiographic improvement of the percent stenosis. Clinical outcomes were also measured with regard to the development of a complication during the procedure and long-term graft and/or patient survival. Patients who had not undergone angiography prior were excluded from the study.
Design This was a retrospective review of the PHTS database of all patients listed r18 years old with an orthotopic heart transplant who have moderate or severe CAV as defined by angiography. Moderate stenosis was defined as major epicardial coronary vessel narrowing between 51% and 70% and severe stenosis Z71% as defined by the published Cardiac Transplant Registry Database criteria.13 The type of coronary revascularization procedures, location, and lesion characteristics were described. Recipient and donor risk factors were analyzed for predictors of the need for coronary revascularization. Outcomes of the revascularization procedure were divided into 2 categories: short-term and longterm outcomes. Short-term outcomes include procedural success and complication rates. Procedural success was defined as r20% residual stenosis after the intervention. Long-term outcomes include survival after intervention and/or graft loss secondary to death or retransplantation. Additional comparisons were made within recipient and donor age groups as potential risk factors for survival or the need for a PRP.
Data analysis Data were described using frequencies, means with SDs, and medians with ranges. The time-related freedom from revascularization for all patients and for patients with CAV were analyzed using Kaplan-Meier estimates, and associated factors were sought using Cox’s proportionate hazard models. Confidence limits of ⫾1 SE were used for comparison of means and survival proportions. A similar analysis was performed for the time-related events of restenosis and graft loss.
Results Baseline characteristics From January 1, 1993, to December 31, 2009, 3,156 pediatric heart transplants were performed in 35 PHTS participating institutions on patients ranging in age from birth to 21 years. During that time period, 11,430 angiograms were performed and 51 revascularization procedures in 28 patients with a first heart transplant were conducted at 15 of the 35 participating institutions. Baseline patient demographic data and characteristics for the study group are presented in Table 1. The mean age of patients at the time of PRP was 13.4 ⫾ 5.95 years, and the mean donor age was 15.9 years (range, 0.7–48.7 years).
Angiographic and procedural data The mean time to first coronary intervention was 5.7 ⫾ 3.2 years with 38 (75%) patients undergoing stent implantation and 13 (25%) undergoing balloon angioplasty. The left anterior descending coronary artery was the most common vessel requiring intervention (n ¼ 21; 41%)
Jeewa et al. Table 1
Outcomes After Revascularization in Children With CAV
1165
Patient Demographic Data and Characteristics
Male White BSA Age at transplant (years) Donor age at transplant ECMO Status at transplant 1 2 Induction therapy
Patients with revascularization procedure after first transplant n ¼ 28 Moderate/severe CAV n ¼ 11
None/mild CAV n ¼ 17
Moderate to severe CAV and no PRP vs all PRP patients
28 (53.85%) 35 (67.31%) 0.78 ⫾ 0.54 5.69 ⫾ 5.87
8 (72.73%) 7 (63.64%) 1.23 ⫾ 0.72 9.13 ⫾ 6.70
8 (47.06%) 10 (58.82%) 0.87 ⫾ 0.62 6.82 ⫾ 6.71
0.8479 0.4781 0.0994 0.1648
8.51 ⫾ 9.86 208 (6.59%)
8.67 ⫾ 11.08 0 (0.00%)
22.85 ⫾ 16.65 2 (18.18%)
11.35 ⫾ 13.02 2 (11.76%)
0.0344 0.0056 0.0032
2,578 (81.69%) 535 (16.95%) 1,796 (56.91%)
40 (76.92%) 11 (21.15%) 26 (50.00%)
9 (81.81%) 2 (18.18%) 4 (36.36%)
13 (76.47%) 4 (23.53%) 6 (35.29%)
All transplanted patients N ¼ 3,156
Patients with moderate to severe CAV without PRP n ¼ 52
1,758 (55.70%) 2,262 (71.67%) 0.80 ⫾ 0.54 6.11 ⫾ 6.15
0.2978
BSA, body surface area; CAV, cardiac allograft vasculopathy; ECMO, extracorporeal membrane oxygenation; PRP, percutaneous revascularization procedure.
followed by the right coronary artery (n ¼ 13; 25%), circumflex artery (n ¼ 9; 18%), and other coronary branches (n ¼ 7; 14%); the vessel was not identified in 1 patient. The overall procedural success rate was 73%. All patients survived the PRP, and no significant complications were noted.
Clinical outcomes The freedom from receiving the first revascularization procedure was 99% and 98% at 5 and 10 years, respectively (Figure 1). Freedom from graft death post-PRP was 89%, 75%, and 61% at 1, 3, and 12 months (Figure 2). Of the 28 patients who underwent a PRP after their first heart transplant, 13 (46.4%) were retransplanted, and 8 died (28.6%). Figure 2 also shows the freedom from graft death in children with transplants and moderate to severe CAV who did not undergo a PRP compared with children who did undergo a PRP (dashed line). When we looked at the freedom from graft death stratified by recipient age at the time of transplant, we found that younger recipients (r10 years old) were not statistically different from older recipients. However, the age of the organ donor significantly affected a child’s freedom from requiring a PRP (p o 0.0001). We found that recipients with transplants from older donors (i.e., 430 years old) had less freedom from requiring a coronary artery intervention compared with recipients with transplants from younger donors (Figure 3).
Discussion This study represents the largest pediatric dataset collected on patients requiring PRP for CAV. Although PRPs in pediatric patients with CAV have reasonable procedural success rates and a low degree of complications, the survival outcome is quite poor 1 year after revascularization. The development of CAV is multifactorial, involving risk factors such as immunosuppression regimens, cytomegalovirus
exposure, rejection history, donor age, and recipient hypertension.14,15 The pathogenesis of CAV is different from native coronary artery atherosclerosis, the most common cause for a coronary intervention in adults.2,16 CAV is a progressive disease with an often indolent course and does not manifest with discrete lesions but with irregular and microvascular infiltrative narrowing of the coronary artery vasculature. This particular characteristic of CAV makes it understandable why there is a lack of clinical outcome improvement despite a successful interventional procedure. Our findings of significant mortality for patients after a PRP are consistent with the adult transplant literature. The University of Alabama at Birmingham group looked at their data over 10 years and showed that the procedural success rate in 151 interventions was 97% with an associated mortality of 2.6%. However, freedom from restenosis was 57% at 6 months, and freedom from graft loss or death was 34% at 5 years after intervention.9 Simpson et al8 showed in their experience of 97 percutaneous interventions that shortterm restenosis rates were initially higher in patients who underwent balloon angioplasty vs stent placement; however, this benefit was negated by 6 months with similar restenosis rates between the 2 interventions. Additionally, 39.3% of patients died or underwent retransplantation almost 2 years after their first intervention. Our multicenter study did not show the high complication rates seen in the previous single-center pediatric studies detailing the results of PRPs. However, the procedural success rate was not as high as that reported in the adult transplant literature; this may be a reflection of the infrequency of coronary artery interventions in children and the increased technical difficulty in performing these procedures in this patient population. In addition, although there has been some evidence of the potential benefits of drug-eluting stents vs bare metal stents in adult patients with CAV, no such evidence exists in pediatric patients, and owing to limitations of the formbased data, no comment could be made on the outcomes using different PRP techniques.2
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Figure 1
Freedom of transplant recipients from first revascularization procedure.
Graft loss after diagnosis of and intervention for CAV is the major clinical finding of the present multi-institutional study. Death or retransplantation occurs in nearly 40% of patients 1 year after a PRP. Children who did undergo a PRP had worse early graft survival after the procedure compared with children with moderate to severe CAV who did not undergo PRP, with more comparable graft survival beyond 6 years. Consistent with adult literature, older donors seem to pose an additional risk for worsening CAV because there was lower freedom from revascularization procedures for patients who received transplants from older
donors, although the sample size was small.17 Conway et al18 performed an extensive review of the donor characteristics from the PHTS database and found that a greater age gap between recipient and donor was a risk factor for early mortality in recipients 410 years old. In addition, this study found that organs of older donors with longer ischemic times in recipients 410 years old was a significant risk factor for mortality within the first year. Although further research is warranted, transplant physicians may want to consider caution regarding organs of older donors in young recipients because this group has a
Figure 2 Freedom of transplant recipients from graft death after percutaneous revascularization procedure (PRP). Dashed line indicates the freedom from graft death in transplant recipients with moderate to severe CAV who did not undergo a PRP compared with patients who did undergo a PRP.
Jeewa et al.
Outcomes After Revascularization in Children With CAV
Figure 3
1167
Freedom of transplant recipients with older aged donors requiring revascularization.
higher propensity for coronary artery interventions secondary to CAV or death. An earlier review of the PHTS database by Pahl et al3 showed that although the incidence of moderate to severe CAV was overall low (1%, 2%, and 5% at 1, 3, and 5 years post-transplant), there was a higher incidence in patients with transplants from donors 430 years old, especially 2 years after transplant. This study also found a significant mortality risk for children with moderate to severe CAV with a 50% mortality within 2 years. Retransplantation may be the only viable option for longer term survival given the poor clinical outcome after CAV diagnosis, especially among patients in whom intervention is considered or performed. Recognizing that retransplantation is not without risk and despite an environment of donor shortages, it may still confer superior survival benefit compared with revascularization for CAV.19 The major limitation of this study is the small sample size because coronary artery interventions are done infrequently in pediatric patients. Form-based data are subject to potential errors in documentation as well as limiting the granularity of the data available. PRPs are a heterogeneous group of procedures and encompass many technical variances that may have affected procedural outcomes. Additionally, the success of a PRP was dependent on the operator’s subjective impressions of the lesion and classification according to Cardiac Transplant Registry Database standards and the resultant improvement after the procedure. Angiographic follow-up was not reported on, and intermediate procedural outcomes were unknown. In conclusion, in pediatric patients with CAV, the relative safety of PRPs was established in this study with reasonable angiographic short-term success rates. However, the long-term outcomes of PRPs do not have a positive impact on graft survival among patients 1 year after intervention, and early listing for retransplantation should be strongly considered in this cohort.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Boucek MM, Edwards LB, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: Fifth Official Pediatric Report—2001 to 2002. J Heart Lung Transplant 2002;21: 827-40. 2. Lee MS, Kobashigawa J, Tobis J. Comparison of percutaneous coronary intervention with bare-metal and drug-eluting stents for cardiac allograft vasculopathy. JACC Cardiovasc Interv 2008;1:710-5. 3. Pahl E, Naftel DC, Kuhn MA, et al. The impact and outcome of transplant coronary artery disease in a pediatric population: a 9-year multi-institutional study. J Heart Lung Transplant 2005;24:645-51. 4. Pahl E, Zales VR, Fricker FJ, Addonizio LJ. Posttransplant coronary artery disease in children. A multicenter national survey. Circulation 1994;90:II56-60. 5. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twentythird official adult heart transplantation report—2006. J Heart Lung Transplant 2006;25:869-79. 6. Mahle WT, Vincent RN, Berg AM, Kanter KR. Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation. J Heart Lung Transplant 2005;24:63-6. 7. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003;108:48-53. 8. Simpson L, Lee EK, Hott BJ, Vega DJ, Book WM. Long-term results of angioplasty vs stenting in cardiac transplant recipients with allograft vasculopathy. J Heart Lung Transplant 2005;24:1211-7. 9. Benza RL, Zoghbi GJ, Tallaj J, et al. Palliation of allograft vasculopathy with transluminal angioplasty: a decade of experience. J Am Coll Cardiol 2004;43:1973-81. 10. Lee MS, Yang T, Kandzari D, Mahmud E, Liao H, Kirtane A. Longterm clinical outcomes in patients treated with drug-eluting compared to bare-metal stents for the treatment of transplant coronary artery disease. Catheter Cardiovasc Interv 2012;80:533-8.
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11. Shaddy RE, Revenaugh JA, Orsmond GS, Tani LY. Coronary interventional procedures in pediatric heart transplant recipients with cardiac allograft vasculopathy. Am J Cardiol 2000;85:1370-2. 12. Tham EB, Yeung AC, Cheng CW, Bernstein D, Chin C, Feinstein JA. Experience of percutaneous coronary intervention in the management of pediatric cardiac allograft vasculopathy. J Heart Lung Transplant 2005;24:769-73. 13. Costanzo MR, Naftel DC, Pritzker MR, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998;17: 744-53. 14. Kobashigawa J. What is the optimal prophylaxis for treatment of cardiac allograft vasculopathy? Curr Control Trials Cardiovasc Med 2000;1:166-71.
15. Jeewa A, Dreyer WJ, Kearney DL, Denfield SW. The presentation and diagnosis of coronary allograft vasculopathy in pediatric heart transplant recipients. Congenit Heart Dis 2012;7:302-11. 16. Segovia J, Gomez-Bueno M, Alonso-Pulpon L. Treatment of allograft vasculopathy in heart transplantation. Expert Opin Pharmacother 2006;7:2369-83. 17. Nagji AS, Hranjec T, Swenson BR, et al. Donor age is associated with chronic allograft vasculopathy after adult heart transplantation: implications for donor allocation. Ann Thorac Surg 2010;90:168-75. 18. Conway J, Chin C, Kemna M, et al. Donorsʼ characteristics and impact on outcomes in pediatric heart transplant recipients. Pediatr Transplant 2013;17:774-81. 19. John R, Chen JM, Weinberg A, et al. Long-term survival after cardiac retransplantation: a twenty-year single-center experience. J Thorac Cardiovasc Surg 1999;117:543-55.
ORIGINAL CLINICAL SCIENCE
Outcomes after percutaneous coronary artery revascularization procedures for cardiac allograft vasculopathy in pediatric heart transplant recipients: A multi-institutional study Aamir Jeewa, MD,a Clifford Chin, MD,b Elfriede Pahl, MD,c Andrew M. Atz, MD,d Michael P. Carboni, MD,e Elizabeth Pruitt, MSPH,f David C. Naftel, PhD,f Rose Rodriguez, PNP,g Anne I. Dipchand, MDh for the Pediatric Heart Transplant Study (PHTS) Investigators From the aTexas Children’s Hospital, Baylor College of Medicine, Houston, Texas; bCincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; cAnn & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois; dMedical University of South Carolina, Charleston, South Carolina; e Duke Children’s Hospital & Health Center, Durham, North Carolina; fThe University of Alabama at Birmingham, Birmingham, Alabama; gMorgan Stanley Children’s Hospital of New York–Presbyterian, Columbia University Medical Center, New York, New York; and the hThe Hospital for Sick Children, Toronto, Ontario, Canada.
KEYWORDS: heart transplant; pediatric; cardiac; allograft; vasculopathy
BACKGROUND: Cardiac allograft vasculopathy is an important cause of long-term graft loss. In adults, percutaneous revascularization procedures (PRPs) have variable success with high restenosis rates and little impact on graft survival. Limited data exist in pediatric recipients of transplants. METHODS: Data from the Pediatric Heart Transplant Study (PHTS) were used to explore associations between PRPs and outcomes after heart transplant in patients listed r18 years old who received a first heart transplant between 1993 and 2009. RESULTS: Revascularization procedures were done in 28 of 3,156 (0.9%) patients; 13 patients had multiple PRPs giving a total of 51 PRPs performed across 15 centers. Mean recipient age at time of transplant was 7.7 ⫾ 6.7 years; mean donor age was 15.9 ⫾ 15.4 years. The mean time to first PRP was 5.7 ⫾ 3.2 years. Vessels involved were left anterior descending artery (41%), right coronary artery (25%), circumflex artery (18%), other coronary branches/unknown (16%). PRPs consisted of 38 (75%) stent implantations and 13 (25%) balloon angioplasties with an overall procedural success rate of 73%. Freedom from graft loss after PRPs was 89%, 75%, and 61% at 1, 3, and 12 months. In addition, patients with transplants from donors 430 years old were found to have less freedom from the need for a revascularization procedure than patients with transplants from younger donors (p o 0.0001). CONCLUSIONS: In this large pediatric heart transplant cohort, use of PRPs for cardiac allograft vasculopathy was rare, likely related to procedural feasibility of the interventions. Despite technically successful interventions, graft loss occurred in 39% within 1 year post-procedure; relisting for heart transplant should be considered. J Heart Lung Transplant 2015;34:1163–1168 r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Aamir Jeewa, MD, 6621 Fannin Street, Suite 19345C, West Tower, Houston, TX 77030. Telephone: þ832-826-5682. E-mail address: [email protected]
Cardiac allograft vasculopathy (CAV) is an important cause of long-term morbidity and mortality after pediatric and adult heart transplantation.1–4 The prevalence of CAV is
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.11.011
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7.0%, 32.3%, and 45.7% among adult recipients at 1, 5, and 8 years post-transplantation.5 Therapies targeted to prevent the development of CAV include using statins and modifying immunosuppression regimens.6,7 However, after CAV has developed, the therapeutic interventions are limited and have variable success rates. These interventions include percutaneous revascularization procedures (PRPs) such as balloon angioplasty, coronary artery stent implantation, and coronary artery bypass grafting. Percutaneous interventions in adult patients with CAV have reported high angiographic success and low complication rates. However, restenosis rates were high, and overall incidence of graft loss was increased, highlighting the progressive nature of CAV post–heart transplant.8–10 Limited data exist on the true incidence of CAV in pediatric patients. A study by Pahl et al3 from the Pediatric Heart Transplant Study (PHTS) database between 1993 and 2001 revealed that 751 of 1,221 (62%) patients with transplants underwent 2,049 coronary angiography procedures. In this cohort, 30 patients (4%) had moderate to severe CAV showing that the incidence of moderate to severe CAV was less than in the adult population; however, the prognosis with moderate to severe disease was poor. There are fewer data with respect to coronary artery revascularization procedures in pediatric patients. Shaddy et al11 reported their experience with 3 pediatric patients requiring a revascularization procedure. All 3 patients had severe stenosis on angiography with a normal ejection fraction, lipid profile, and blood pressure. These patients also had successful procedures by angiography; however, all patients subsequently underwent retransplantation. Tham et al12 reported on a single-center pediatric experience with percutaneous coronary interventions in which 7 patients underwent a revascularization procedure. Major procedural complications in this study included death (n ¼ 1) and a resuscitated cardiac arrest (n ¼ 1). Of the 7 patients, 3 underwent retransplantation, and 3 died. The aforementioned single-center studies reveal an alarming amount of graft loss among patients who develop CAV and undergo revascularization procedures. The purpose of our study was to conduct a multiinstitutional review, from the PHTS participating centers, of the procedural and clinical outcomes of all children who underwent a PRP for CAV from 1993 to 2009. This study composes the largest review to date of coronary revascularization in pediatric patients with transplants.
Methods All participating centers had approval from their institutional review boards to participate in this study.
Data collection The PHTS database includes patient demographic, medical, and procedural data that were collected and submitted by operating centers at the time of the procedure. Data collection forms described the location and degree of stenosis in the diseased vessel, the type of coronary artery intervention—either balloon angioplasty or stent placement—and procedural success identified by
angiographic improvement of the percent stenosis. Clinical outcomes were also measured with regard to the development of a complication during the procedure and long-term graft and/or patient survival. Patients who had not undergone angiography prior were excluded from the study.
Design This was a retrospective review of the PHTS database of all patients listed r18 years old with an orthotopic heart transplant who have moderate or severe CAV as defined by angiography. Moderate stenosis was defined as major epicardial coronary vessel narrowing between 51% and 70% and severe stenosis Z71% as defined by the published Cardiac Transplant Registry Database criteria.13 The type of coronary revascularization procedures, location, and lesion characteristics were described. Recipient and donor risk factors were analyzed for predictors of the need for coronary revascularization. Outcomes of the revascularization procedure were divided into 2 categories: short-term and longterm outcomes. Short-term outcomes include procedural success and complication rates. Procedural success was defined as r20% residual stenosis after the intervention. Long-term outcomes include survival after intervention and/or graft loss secondary to death or retransplantation. Additional comparisons were made within recipient and donor age groups as potential risk factors for survival or the need for a PRP.
Data analysis Data were described using frequencies, means with SDs, and medians with ranges. The time-related freedom from revascularization for all patients and for patients with CAV were analyzed using Kaplan-Meier estimates, and associated factors were sought using Cox’s proportionate hazard models. Confidence limits of ⫾1 SE were used for comparison of means and survival proportions. A similar analysis was performed for the time-related events of restenosis and graft loss.
Results Baseline characteristics From January 1, 1993, to December 31, 2009, 3,156 pediatric heart transplants were performed in 35 PHTS participating institutions on patients ranging in age from birth to 21 years. During that time period, 11,430 angiograms were performed and 51 revascularization procedures in 28 patients with a first heart transplant were conducted at 15 of the 35 participating institutions. Baseline patient demographic data and characteristics for the study group are presented in Table 1. The mean age of patients at the time of PRP was 13.4 ⫾ 5.95 years, and the mean donor age was 15.9 years (range, 0.7–48.7 years).
Angiographic and procedural data The mean time to first coronary intervention was 5.7 ⫾ 3.2 years with 38 (75%) patients undergoing stent implantation and 13 (25%) undergoing balloon angioplasty. The left anterior descending coronary artery was the most common vessel requiring intervention (n ¼ 21; 41%)
Jeewa et al. Table 1
Outcomes After Revascularization in Children With CAV
1165
Patient Demographic Data and Characteristics
Male White BSA Age at transplant (years) Donor age at transplant ECMO Status at transplant 1 2 Induction therapy
Patients with revascularization procedure after first transplant n ¼ 28 Moderate/severe CAV n ¼ 11
None/mild CAV n ¼ 17
Moderate to severe CAV and no PRP vs all PRP patients
28 (53.85%) 35 (67.31%) 0.78 ⫾ 0.54 5.69 ⫾ 5.87
8 (72.73%) 7 (63.64%) 1.23 ⫾ 0.72 9.13 ⫾ 6.70
8 (47.06%) 10 (58.82%) 0.87 ⫾ 0.62 6.82 ⫾ 6.71
0.8479 0.4781 0.0994 0.1648
8.51 ⫾ 9.86 208 (6.59%)
8.67 ⫾ 11.08 0 (0.00%)
22.85 ⫾ 16.65 2 (18.18%)
11.35 ⫾ 13.02 2 (11.76%)
0.0344 0.0056 0.0032
2,578 (81.69%) 535 (16.95%) 1,796 (56.91%)
40 (76.92%) 11 (21.15%) 26 (50.00%)
9 (81.81%) 2 (18.18%) 4 (36.36%)
13 (76.47%) 4 (23.53%) 6 (35.29%)
All transplanted patients N ¼ 3,156
Patients with moderate to severe CAV without PRP n ¼ 52
1,758 (55.70%) 2,262 (71.67%) 0.80 ⫾ 0.54 6.11 ⫾ 6.15
0.2978
BSA, body surface area; CAV, cardiac allograft vasculopathy; ECMO, extracorporeal membrane oxygenation; PRP, percutaneous revascularization procedure.
followed by the right coronary artery (n ¼ 13; 25%), circumflex artery (n ¼ 9; 18%), and other coronary branches (n ¼ 7; 14%); the vessel was not identified in 1 patient. The overall procedural success rate was 73%. All patients survived the PRP, and no significant complications were noted.
Clinical outcomes The freedom from receiving the first revascularization procedure was 99% and 98% at 5 and 10 years, respectively (Figure 1). Freedom from graft death post-PRP was 89%, 75%, and 61% at 1, 3, and 12 months (Figure 2). Of the 28 patients who underwent a PRP after their first heart transplant, 13 (46.4%) were retransplanted, and 8 died (28.6%). Figure 2 also shows the freedom from graft death in children with transplants and moderate to severe CAV who did not undergo a PRP compared with children who did undergo a PRP (dashed line). When we looked at the freedom from graft death stratified by recipient age at the time of transplant, we found that younger recipients (r10 years old) were not statistically different from older recipients. However, the age of the organ donor significantly affected a child’s freedom from requiring a PRP (p o 0.0001). We found that recipients with transplants from older donors (i.e., 430 years old) had less freedom from requiring a coronary artery intervention compared with recipients with transplants from younger donors (Figure 3).
Discussion This study represents the largest pediatric dataset collected on patients requiring PRP for CAV. Although PRPs in pediatric patients with CAV have reasonable procedural success rates and a low degree of complications, the survival outcome is quite poor 1 year after revascularization. The development of CAV is multifactorial, involving risk factors such as immunosuppression regimens, cytomegalovirus
exposure, rejection history, donor age, and recipient hypertension.14,15 The pathogenesis of CAV is different from native coronary artery atherosclerosis, the most common cause for a coronary intervention in adults.2,16 CAV is a progressive disease with an often indolent course and does not manifest with discrete lesions but with irregular and microvascular infiltrative narrowing of the coronary artery vasculature. This particular characteristic of CAV makes it understandable why there is a lack of clinical outcome improvement despite a successful interventional procedure. Our findings of significant mortality for patients after a PRP are consistent with the adult transplant literature. The University of Alabama at Birmingham group looked at their data over 10 years and showed that the procedural success rate in 151 interventions was 97% with an associated mortality of 2.6%. However, freedom from restenosis was 57% at 6 months, and freedom from graft loss or death was 34% at 5 years after intervention.9 Simpson et al8 showed in their experience of 97 percutaneous interventions that shortterm restenosis rates were initially higher in patients who underwent balloon angioplasty vs stent placement; however, this benefit was negated by 6 months with similar restenosis rates between the 2 interventions. Additionally, 39.3% of patients died or underwent retransplantation almost 2 years after their first intervention. Our multicenter study did not show the high complication rates seen in the previous single-center pediatric studies detailing the results of PRPs. However, the procedural success rate was not as high as that reported in the adult transplant literature; this may be a reflection of the infrequency of coronary artery interventions in children and the increased technical difficulty in performing these procedures in this patient population. In addition, although there has been some evidence of the potential benefits of drug-eluting stents vs bare metal stents in adult patients with CAV, no such evidence exists in pediatric patients, and owing to limitations of the formbased data, no comment could be made on the outcomes using different PRP techniques.2
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Figure 1
Freedom of transplant recipients from first revascularization procedure.
Graft loss after diagnosis of and intervention for CAV is the major clinical finding of the present multi-institutional study. Death or retransplantation occurs in nearly 40% of patients 1 year after a PRP. Children who did undergo a PRP had worse early graft survival after the procedure compared with children with moderate to severe CAV who did not undergo PRP, with more comparable graft survival beyond 6 years. Consistent with adult literature, older donors seem to pose an additional risk for worsening CAV because there was lower freedom from revascularization procedures for patients who received transplants from older
donors, although the sample size was small.17 Conway et al18 performed an extensive review of the donor characteristics from the PHTS database and found that a greater age gap between recipient and donor was a risk factor for early mortality in recipients 410 years old. In addition, this study found that organs of older donors with longer ischemic times in recipients 410 years old was a significant risk factor for mortality within the first year. Although further research is warranted, transplant physicians may want to consider caution regarding organs of older donors in young recipients because this group has a
Figure 2 Freedom of transplant recipients from graft death after percutaneous revascularization procedure (PRP). Dashed line indicates the freedom from graft death in transplant recipients with moderate to severe CAV who did not undergo a PRP compared with patients who did undergo a PRP.
Jeewa et al.
Outcomes After Revascularization in Children With CAV
Figure 3
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Freedom of transplant recipients with older aged donors requiring revascularization.
higher propensity for coronary artery interventions secondary to CAV or death. An earlier review of the PHTS database by Pahl et al3 showed that although the incidence of moderate to severe CAV was overall low (1%, 2%, and 5% at 1, 3, and 5 years post-transplant), there was a higher incidence in patients with transplants from donors 430 years old, especially 2 years after transplant. This study also found a significant mortality risk for children with moderate to severe CAV with a 50% mortality within 2 years. Retransplantation may be the only viable option for longer term survival given the poor clinical outcome after CAV diagnosis, especially among patients in whom intervention is considered or performed. Recognizing that retransplantation is not without risk and despite an environment of donor shortages, it may still confer superior survival benefit compared with revascularization for CAV.19 The major limitation of this study is the small sample size because coronary artery interventions are done infrequently in pediatric patients. Form-based data are subject to potential errors in documentation as well as limiting the granularity of the data available. PRPs are a heterogeneous group of procedures and encompass many technical variances that may have affected procedural outcomes. Additionally, the success of a PRP was dependent on the operator’s subjective impressions of the lesion and classification according to Cardiac Transplant Registry Database standards and the resultant improvement after the procedure. Angiographic follow-up was not reported on, and intermediate procedural outcomes were unknown. In conclusion, in pediatric patients with CAV, the relative safety of PRPs was established in this study with reasonable angiographic short-term success rates. However, the long-term outcomes of PRPs do not have a positive impact on graft survival among patients 1 year after intervention, and early listing for retransplantation should be strongly considered in this cohort.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
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