Long-Term Outcomes of Percutaneous Coronary Intervention in Transplant Coronary Artery Disease in Pediatric Heart Transplant Recipients

Abstract: Objective. The purpose of this study was to assess the safety and efficacy of percutaneous coronary intervention (PCI) with bare-metal and drug-eluting stent (DES) use in pediatric orthotopic heart transplantation (OHT) recipients who developed transplant coronary artery disease (TCAD). Background. The short- and long-term outcomes in pediatric OHT patients with TCAD who underwent PCI are not well known. Methods. A retrospective review of medical records from two centers of pediatric OHT recipients who underwent PCI for TCAD was performed. From 1994 to 2011, twelve patients underwent PCI for TCAD at the two centers. Results. The mean age at PCI was 15.1 ± 3.5 years, and the time since transplant was 7.0 ± 4.8 years. Procedural success was attained in all patients. Seven patients (58.3%) received DESs. All patients were free from major adverse cardiac events (MACE) at 3 months. At a mean follow-up of 7.1 ± 4.9 years, 6 patients (50%) experienced MACE: 4 patients (33%) died (2 with rejection, 1 with possible stent thrombosis, and 1 had sudden death), 1 patient (8.3%) had myocardial infarction, and 1 patient (8.3%) underwent target vessel revascularization. Five patients (41.2%) underwent repeat OHT. Surveillance angiography was performed in 6 patients (50%), and binary restenosis was observed in 2 patients (33.3%), both of whom received DESs. Conclusions. Even though TCAD is a progressive disease, PCI is a feasible and effective palliative measure in pediatric OHT recipients. Noncompliance to immunosuppressive and antiplatelet therapy can contribute to MACE in these patients.

J INVASIVE CARDIOL 2012;24(6):278-281

Key words: orthotopic heart transplantation (OHT); TCAD

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Transplant coronary artery disease (TCAD), which is characterized by intimal proliferation and diffuse coronary narrowing, leads to graft dysfunction, and is a major cause of morbidity and mortality after the first year following orthotopic heart transplantation (OHT).^1-3 Percutaneous coronary intervention (PCI) has been performed as a palliative treatment for TCAD as medical therapy does not prevent intimal hyperplasia. Due to the paucity of organs, repeat OHT is not always a viable option and it is associated with increased mortality.⁴ Long-term data evaluating PCI in pediatric patients with TCAD are lacking, with most studies being small and limited to case reports.^3,5-7 The purpose of this study was to assess the short- and long-term outcomes of pediatric OHT patients with TCAD who underwent PCI with bare-metal (BMS) and drug-eluting stent (DES) implantation.

Methods

Between 1994 and 2010, twelve pediatric patients (age ≤19 years) who underwent PCI for TCAD at the University of California, Los Angeles Medical Center in Los Angeles, California (8 patients) and University of Arkansas for Medical Sciences, Arkansas Children’s Hospital in Little Rock, Arkansas (4 patients) were included in the study. The study was approved by the Institutional Review Board at both institutions. Medical records were reviewed to obtain information regarding patient demographic, angiographic, and clinical outcomes data.

Patients underwent PCI with standard techniques via the transfemoral approach. BMSs were used prior to 2003. Following that, DESs were used at the discretion of the operator. The DESs available to the operator included sirolimus-eluting stents (Cypher; Cordis, Johnson and Johnson Corporation), paclitaxel-eluting stents (Taxus; Boston Scientific Corporation) and everolimus-eluting stents (Xience V; Abbott Vascular). All patients received intravenous heparin during the PCI. Dual-antiplatelet therapy with aspirin and a thienopyridine (ticlopidine or clopidogrel) were recommended for a minimum of 1 month if BMSs were used and a minimum of 6 months if DESs were used before 2008 and a minimum of 1 year after 2008 if DESs were used. Intracoronary nitroglycerin was administered to prevent vasospasm. Immunosuppressive therapy was managed by the transplant cardiologists based upon their institutional protocols. Follow-up angiography was performed within the first 6 to 12 months or sooner if clinically indicated. Thereafter, angiography was performed at least annually or more frequently if PCI was performed. Reasons for failure to perform follow-up angiography included early death, repeat OHT, or noncompliance.

Major adverse cardiac events were defined as a composite of all-cause death, myocardial infarction, and target vessel revascularization. Cardiac death was defined as any death without clear non-cardiac cause. Myocardial infarction was diagnosed when serum creatine kinase levels increased to more than twice the upper limit of normal range with an elevated creatine kinase MB or troponin I. Target vessel revascularization was defined as a repeat revascularization of the treated vessel. Angiographic success was defined as a residual stenosis <10% and thrombolysis in myocardial infarction (TIMI) grade 3 flow at the end of the procedure. Binary restenosis was defined as a >50% diameter stenosis at follow-up. Definite/confirmed stent thrombosis was defined as acute coronary syndrome and evidence of stent thrombus or occlusion based upon coronary angiography or stent thrombosis confirmed by autopsy. Probable stent thrombosis was defined as any unexplained death within 30 days after PCI or myocardial infarction involving the target vessel territory without angiographic confirmation. Possible stent thrombosis was defined as unexplained death after 30 days of the index procedure.

Patient data were collected from medical records as well as telephone interviews with the patients’ physicians if they had experienced an adverse clinical event and recorded into a dedicated PCI database. The Social Security Death Index, which is a reliable indicator of mortality in the United States, was used to determine vital status if hospital source documentation was not available.

Continuous variables are presented as mean ± standard deviation and categorical variables are presented as percentages. Survival curves were generated using the Kaplan-Meier method. Statistical analysis was performed with SAS software (version 9.1; SAS Institute, Inc.).

Results

Demographic and clinical characteristics of the 12 patients are shown in Table 1. The mean age was 15.1 ± 3.5 years (range, 10 to 19 years), and 8 of 12 patients (75%) were females. Ten patients (83.3%) underwent elective PCI while 2 patients (16.7%) underwent PCI for non-ST elevation myocardial infarction. The mean ejection fraction was 62.6 ± 10.9%. The mean duration of time from OHT to PCI was 7.0 ± 4.8 years. BMS were used in 5 patients (41.7%), and DESs were used in 7 patients (58.3%). Only 1 patient received a BMS during the DES era. Dissection of the left main coronary artery occurred in a 14-year-old patient during diagnostic coronary angiography and was treated emergently with a 3.0 x 8 mm BMS. The mean stent diameter was 2.9 ± 0.3 mm, and mean stent length was 17.1 ± 11 mm.

All patients had angiographic success. At 3-month follow-up, all patients were free from major adverse cardiac events, stent thrombosis, and repeat OHT.

At a mean follow-up of 7.1 ± 4.9 years, 4 patients (33%) died (Figure 1). Two patients who received sirolimus-eluting stents died at 1.5 and 2.7 years, respectively, due to rejection from noncompliance with immunosuppressive therapy. Possible stent thrombosis occurred in a patient who was noncompliant with dual-antiplatelet therapy and died suddenly 5.2 months after PCI with a paclitaxel-eluting stent. One patient died suddenly 11.2 years after PCI with a BMS. Total survival at 7 years was 71.3%.

Non-ST elevation myocardial infarction occurred in one patient (8.3%) 5.4 years after PCI. Repeat coronary angiography did not demonstrate an infarct-related artery, and the patient was treated medically. Follow-up angiography was performed in 6 patients (50%). Binary restenosis occurred in 2 patients (16.7%) who underwent PCI with DES, of which 1 patient (8.3%) underwent target vessel revascularization and 1 patient underwent repeat OHT. Repeat OHT was performed in 5 patients (41.7%) at a mean follow-up of 2.3 years (range, 0.4 to 6.6 years). MACE-free survival at 7 years was 52.1%.

Discussion

TCAD is characterized by diffuse disease in the distal vessels and focal segmental disease in the proximal and mid-coronary arteries. The exact mechanism of TCAD is unknown, but appears to be related to both immune and non-immune causes. Other presumed mechanisms for the development of TCAD include frequent rejection episodes, co-existent hypertension and/or diabetes in the donor or recipient, as well as local and systemic effects of immunosuppressive agents.^8,9 The expected 4-year graft survival once TCAD occurs is 45%-50%.¹⁰

Pediatric patients have a lower prevalence of TCAD compared with adult OHT recipients. Freedom from TCAD at 6 years was 73% in infants younger than 1 year old at the time of OHT, 73% in children ages 1 to 10 years, and 53% in OHT recipients older than 11 years.¹¹ Overall, freedom from TCAD at 10 years was 66%. The lower prevalence of TCAD in pediatric OHT recipients may be explained by the plasticity of an immature immune system in infants and fewer cardiovascular risk factors for atherosclerosis in younger donors and recipients.¹²

This is the largest and longest study of pediatric patients who underwent PCI for TCAD. PCI is feasible and can serve as a palliative treatment until repeat OHT. Mortality is high once pediatric OHT patients develop with TCAD and noncompliance may compound the problem.

The development of TCAD portends a poor prognosis. It is the most common cause of death and graft loss in pediatric patients after OHT.¹⁰ The Pediatric Heart Transplant Study reported a graft survival rate of 50% at 2.8 years and freedom from death or graft loss within 4 years of less than 30% after the diagnosis of severe TCAD.¹² However, fewer than 50% of pediatric patients underwent routine surveillance angiography after OHT. This may be explained by the technical challenges of younger, smaller patients and the need for general anesthesia.

Treatment options for TCAD are limited. Medical therapy is ineffective in preventing and reversing TCAD. Surgical revascularization is infrequently performed in the pediatric population. TCAD is characterized by diffuse intimal thickening, which commonly involves the distal vessels and may render coronary artery bypass surgery infeasible. Furthermore, the lack of long-term data demonstrating efficacy and high perioperative mortality rates (40%-80%) make bypass surgery an unattractive option.^13,14 Repeat OHT is an option for suitable pediatric patients, but is associated with worse 1- and 5-year outcomes.¹¹ Repeat sternotomy makes repeat OHT technically more challenging and puts patients at increased risk for complications such as infection.

The data on PCI for TCAD, which predominantly includes adult patients, are associated with worse outcomes compared with PCI in native coronary arteries.^15,16 The higher rates of death, myocardial infarction, and target vessel revascularization after PCI for TCAD may be explained by the heightened inflammatory state of the transplanted coronary arteries, which provides a prothrombotic environment and perturbation of endothelial function with subsequent intimal hyperplasia.^17-20 However, in selected patients, the limited data suggest that PCI in TCAD is a viable treatment strategy.¹⁵

The safety and efficacy of PCI in pediatric patients less than 18 years in age is largely unknown since randomized trials with stents excluded these patients.²¹ The PCI data in pediatric patients are mainly limited to those with TCAD. In addition to providing definitive care for mainly focal TCAD, PCI may serve as a palliative bridge for more definitive therapy like repeat OHT. However, the data with pediatric OHT recipients are less robust and are limited to single-center studies with a small series of patients or case reports with limited follow-up. Tham et al reported that in 7 pediatric OHT recipients who underwent PCI, 2 patients had cardiac arrest and 1 died immediately after PCI.⁶ Five of the 6 surviving patients developed moderate to severe restenosis. Furthermore, PCI in the pediatric population is technically challenging given that the coronary arteries are smaller and therefore require smaller stents, femoral arteries are smaller and may be more difficult to cannulate, and the aortic root is smaller thus requiring smaller guiding catheters. The stent thrombosis rate is unknown, but may be higher because of smaller stent diameters. Although second-generation DESs have not been specifically studied in TCAD, they were safer and more efficacious compared with first-generation DESs and may provide better clinical outcomes in pediatric patients with TCAD.^22,23

Non-compliance is associated with late rejection and may limit the long-term success after OHT. It may be more commonly observed in the pediatric population, who may not fully comprehend the ramifications of non-compliance and the absolute necessity to adhere to their immunosuppressive therapy to prevent allograft rejection. Non-compliance may also be a manifestation of immaturity, “acting out,” and rebelling, which can occur in the adolescent years. Ringewald et al reported 49 episodes of late rejection in 15 patients with 37 episodes (76%) associated with non-compliance.²⁴ Two patients died from rejection secondary to non-compliance of immunosuppressive therapy in our study. Another patient was non-compliant with dual-antiplatelet therapy and died suddenly. Therefore, prior to PCI, it is imperative to discuss with the patient and family members the importance of compliance with dual-antiplatelet therapy, especially if DESs are used.

Treatment including various pharmacotherapies evolved over the course of the 16 years in our analysis. The typical immunosuppressive regimen after OHT has included calcineurin inhibitors like cyclosporine or tacrolimus, mycophenolate mofetil or azathioprine, and steroids.¹ However, the nephrotoxicity of cyclosporines may limit their long-term use. Mycophenolate mofetil has largely replaced azathioprine because of its better efficacy and safety profile. Proliferation signal inhibitors like sirolimus and everolimus may be used as an alternative to calcineurin inhibitors because of less nephrotoxicity.

Study limitations. The limitations of this study are that it is a small retrospective observational study, but it is the largest registry to date of pediatric OHT recipients. The restenosis rates are unknown because follow-up angiography was not performed on all patients. Some patients underwent repeat OHT after PCI, making it difficult to draw any conclusions regarding the impact of percutaneous revascularization on clinical outcomes. Comparison with medical therapy and surgical revascularization in pediatric patients with TCAD was not available.

Conclusion

PCI is a feasible and effective palliative measure in pediatric OHT recipients. Non-compliance with immunosuppressive and antiplatelet therapy can contribute to MACE in this pediatric population.

References

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From the ¹Division of Cardiology, UCLA Medical Center, Los Angeles, California, ²the Division of Pediatric Cardiology, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Arkansas, ³the Division of Cardiology, Dong-A University Medical Center, Busan, South Korea, and ⁴the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lee discloses Speaker’s Bureau fees from Boston Scientific Corporation, Abbott Vascular, St Jude Medical, and Medtronic. Dr Rajesh Sachdeva discloses Speaker’s Bureau fees from Volcano Corporation and St Jude Medical. Dr Ritu Sachdeva and Dr Kim report no disclosures.
Manuscript submitted November 29, 2011, provisional acceptance given January 23, 2012, final version accepted February 13, 2012.
Address for correspondence: Michael S. Lee, MD, UCLA Medical Center, Adult Cardiac Catheterization Laboratory, 10833 Le Conte Avenue, Room A2-237 CHS, Los Angeles, CA 90095-171715. Email: mslee@mednet.ucla.edu