Author + information
- Received September 26, 2017
- Revision received November 27, 2017
- Accepted December 19, 2017
- Published online February 26, 2018.
- Mark Dennis, MBBS Honsa,b,
- Diana Zannino, MScc,
- Karin du Plessis, PhDc,
- Andrew Bullock, MBBSd,
- Patrick J.S. Disney, MBBSe,
- Dorothy J. Radford, MBBS, MDf,
- Tim Hornung, MDg,
- Leeanne Grigg, MBBSh,
- Rachael Cordina, MBBS, PhDa,b,
- Yves d’Udekem, MD, PhDc,i and
- David S. Celermajer, MBBS, PhD, DSca,b,∗ ()
- aSydney Medical School, University of Sydney, Camperdown, Sydney, Australia
- bDepartment of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Sydney, Australia
- cMurdoch Children’s Research Institute, Melbourne, Australia
- dChildren’s Cardiac Centre, Princess Margaret Hospital for Children, Perth, Australia
- eDepartment of Cardiovascular Services, Royal Adelaide Hospital, Adelaide, Australia
- fAdult Congenital Heart Unit, The Prince Charles Hospital, Brisbane, Australia
- gGreen Lane Paediatric and Congenital Cardiac Service, Starship Children’s Hospital Auckland, Auckland, New Zealand
- hDepartment of Cardiology, The Royal Melbourne Hospital, Melbourne, Australia
- iDepartments of Cardiac Surgery and Cardiology, Royal Children’s Hospital, Melbourne, Australia
- ↵∗Address for correspondence:
Dr. David S. Celermajer, Cardiology Department, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia.
Background Long-term outcomes of Fontan patients who survive to age ≥16 years have not been well characterized. The Australian and New Zealand Fontan Registry (ANZFR) provides a unique opportunity to understand survival and complication rates in Fontan patients who transition to adult congenital heart disease centers.
Objectives This study sought to describe the survival and complications of adult patients who have had a Fontan procedure.
Methods The study analyzed outcomes in patients ≥16 years of age who were prospectively enrolled in the ANZFR.
Results Data from all 683 adult survivors from the ANZFR were analyzed. Mortality status was confirmed from the National Death Index. There were 201 atriopulmonary (AP) connections and 482 total cavopulmonary connections (249 lateral tunnels and 233 extracardiac conduits). For these subjects, the survival rate at age 30 years was 90% (95% CI: 87% to 93%), and it was 80% (95% CI: 75% to 87%) at 40 years of age. Survival at age 30 years was significantly worse for the patients with AP connections (p = 0.03). At latest follow-up, only 53% of patients were in New York Heart Association functional class I. After the age of 16 years, 136 (20%) had experienced at least 1 new arrhythmia, 42 (6%) required a permanent pacemaker, 45 (7%) had a thromboembolic event, and 135 (21%) required a surgical reintervention. Only 41% (95% CI: 33% to 51%) of Fontan patients were free of serious adverse events at 40 years of age.
Conclusions This comprehensively followed cohort showed that a variety of morbid complications is common in Fontan adults, and that there is a substantial incidence of premature death, particularly in patients with AP connections.
The Fontan procedure, a palliative operation for children born with effectively “single-ventricle” hearts, has undergone multiple modifications since the first such procedure was reported >40 years ago, for tricuspid atresia (1). Long-term survival and morbidity data on Fontan-treated children are emerging, with several intermediate-sized (2–5) and, more recently, large registry studies describing very good survival into adolescence and young adulthood (6,7). Increasingly, adult survivors of the Fontan operation are being “transitioned” from care by pediatric cardiologists to care in specialized centers for adults with congenital heart disease (ACHDs). Studies on the clinical course of young adult Fontan survivors are important to inform patients, families, and clinicians. Particularly, information is required regarding survival and complication rates, including premature death, ventricular failure, thromboembolism, arrhythmias, and protein-losing enteropathy (PLE); such data are currently lacking, especially for patients entering middle age. We therefore sought to review young adult patients who have undergone the Fontan operation in Australia and New Zealand and who are comprehensively followed through the Australian and New Zealand Fontan Registry (ANZFR).
The ANZFR has been described in detail previously (6). In brief, since 2008 when the registry was commenced, all patients who had a Fontan procedure in Australia or New Zealand, or who had had their procedure overseas but are followed in our region, were included. A retrospective audit was then completed to capture all Fontan procedures completed in the region. Follow-up data were gained from all hospital databases and private cardiology practices. Patients are reminded to contact their physicians after 18 months have elapsed without a visit. Ethics approval exists nationally and at participating local institutions in both Australia and New Zealand. All pediatric and ACHD centers within Australia and New Zealand participate in the ANZFR. Of a total current 1,366 patients (of all ages) in the registry, 683 patients at or over the age of 16 years who had undergone Fontan procedures (excluding Björk procedures) were included in this study. Of these, all Australian patients had vital status follow-up from the National Death Registry completed in April 2017. Survival data for the entire registry cohort were reported in 2014 (6). The current report updated and expanded this information 3 years later and concentrated exclusively on adult Fontan patients (≥16 years), thereby aiming to provide the most relevant contemporary information for ACHD patients, families, and caregivers.
The following terms were prospectively defined:
Fontan failure: death, heart transplantation, Fontan takedown or conversion, PLE, plastic bronchitis, or New York Heart Association functional class III or IV at follow-up.
Thromboembolic events: thrombus within the Fontan circuit, pulmonary embolism, transient ischemic attack, or persistent stroke.
Serious adverse events (other than death or transplant): Fontan failure, sustained supraventricular tachycardia (SVT), stroke, thromboembolism, and requirement for permanent pacemaker after hospital discharge following the Fontan procedure.
Pre-existing complications and morbidity: serious adverse events or reinterventions occurring before the age of 16 years.
“New complications and morbidity”: those occurring after age 16 years.
Descriptive statistics for categorical variables were reported as frequency and percentage, and continuous variables were reported as mean ± SD or median (range), as appropriate. Survival and freedom from endpoints not subjected to competing risks were examined using Kaplan-Meier analysis, and risk factors were examined using Cox regression analysis. Time-to-event endpoints subjected to competing risks were examined using cumulative incidence curves, and risk factors were examined using cause-specific Cox regression (8). Patients who underwent a Fontan procedure over the age of 16 years (n = 44; 6.6%) were entered into the risk set at the age when the Fontan procedure was performed. All factors with moderate evidence against the null hypothesis (p < 0.1) were included in the multivariable analyses. Statistical tests were 2 sided, with an alpha level of 0.05 for statistical significance. Surgical “eras” were defined and analyzed by decade from 1973 to 1982, 1983 to 1992, 1993 to 2002, and 2003 to 2016. Analyses were carried out using R version 3.2.3 software (R Foundation, Vienna, Austria).
We report on 683 patients who met the inclusion criteria, at age 26 ± 8 years (median 24 years; range 16 to 67.6 years; 55% male). The median age at Fontan procedure had been 5.0 years (range 0.3 to 40.9 years). Baseline characteristics of the cohort are shown in Table 1 and in full detail in Online Table 1. A total of 201 patients had an atriopulmonary connection (AP) Fontan, and 482 had had 1 of 2 types of total cavopulmonary connection (TCPC); 249 had a lateral tunnel (LT), and 233 had an extracardiac conduit (ECC). Regarding New York Heart Association functional class, 78% of patients reported class I or II symptoms at latest follow-up.
Existing complications and morbidity (before age 16 years)
Complications and morbidities occurring before the age of 16 years are shown in Table 2. A total of 104 patients (15%) had experienced an arrhythmic event. SVT, atrial flutter, and atrial fibrillation had occurred in 53%, 38%, and 18% of these patients, respectively. Of those patients with atrial fibrillation, incidences were 15 (30%) in the AP Fontan group versus 1 (3%) in the LT group and 3 (12%) in the ECC group (p = 0.008). Sick sinus syndrome had been diagnosed in 19% of patients and complete heart block in 13%. The median age of pacemaker insertion in childhood was 8.6 years (range 4.2 to 15.9 years) (n = 37).
Of the 37 (5%) patients with a history of a thromboembolic event, 15 patients (41%) had a stroke, 6 (16%) had a transient ischemic attack, and 3 patients (8%) had a pulmonary embolism. Only 1 patient had multiple thromboembolic events.
The median age at reintervention was 8 years (range 1.7 to 15.9 years), and 51 (7%) patients required a second reintervention (median age 9.8 years [range 3.1 to 15.7 years]). PLE occurred in 11 patients (2%) at a median age of 12 years (range 3.4 to 15.3 years).
Survival from age 16 years onward
Median follow-up from 16 years of age was 8.6 years (range 6 days to 51.6 years), and overall survival is depicted in Central Illustration, Part A. Survival at 30 years of age was 86% for AP versus 93% for TCPC (p = 0.03); at 40 years, survival was 78% for AP versus 81% for TCPC (log-rank test for AP vs. TCPC; p = 0.08) (Central Illustration, Part B). At 50 years of age, survival in the AP group was 61% (95% CI: 46% to 81%); too few TCPC patients had survived to that age to allow meaningful survival statistics. Of those 62 patients who died after the age of 16 years, 18 (29%) died of heart failure, 4 (6%) deaths were caused by confirmed arrhythmias, other rarer causes were identified in 15, and cause of death was unknown in 18 patients (Table 3). Seventeen patients underwent heart transplantation, with a cumulative freedom from death or heart transplantation of 87% (95% CI: 84% to 91%) at age 30 years.
On univariable analysis, atrioventricular (AV) valve repair or replacement and/or moderate or severe pre-operative AV valve regurgitation (p = 0.02), presence of systemic-pulmonary or venovenous collateral vessels (p = 0.05), and male sex (p = 0.02) were associated with death or heart transplantation. For full univariable analysis, see Online Tables 2 to 5. Only male sex, AV valve repair or replacement, and/or moderate or severe pre-operative AV valve regurgitation remained statistically significant predictors on multivariable analysis (Table 4).
Complications and morbidity in adult survivors
New complications and/or morbidities occurring at or after 16 years of age are summarized in Table 5.
After the age of 16 years, arrhythmic events occurred in 136 (20%) patients at a median age of 21 years (range 16.1 to 46 years); 69 patients had experienced atrial flutter, 81 SVT, and 43 atrial fibrillation. The cumulative incidence of supraventricular arrhythmia is depicted in Figure 1. Pre-Fontan pulmonary artery pressure (p = 0.02), type of Fontan repair (p < 0.001), presence of fenestration (p = 0.01), and bidirectional cavopulmonary shunt (p = 0.001) were univariable predictors of SVT. On multivariable analysis, the presence of AP was associated with more atrial arrhythmias. Incidence of SVT before 16 years of age was also predictive of subsequent SVT as an adult (Table 4). Permanent pacemakers were required in a total of 41 (6%) adult patients at a median age of 24.3 years (range 16 to 45.7 years), and defibrillators were inserted in 2 patients, at ages 29 and 40 years. One patient had a pacemaker implanted inserted before the Fontan procedure at 17.8 years (age at Fontan 18.2 years).
Thromboembolic events and reoperations
A total of 45 (7%) patients experienced a thromboembolic event at a median age of 22.6 years (range 16.1 to 41.2 years). A total of 23 patients experienced a stroke or transient ischemic attack, and 13 had a pulmonary embolism. There was no significant difference on log-rank test among AP, LT, and ECC Fontan patients (p = 0.8).
A total of 135 patients (22%) required a reoperation (Table 6) since turning 16 years of age, at a median age of 21.7 years (range 16 to 50.7 years). A total of 31 (23%) patients required more than 1 separate intervention, 77% of these in the AP group. At 30 years of age, the cumulative incidence of reoperation across procedures was 25% (95% CI: 21% to 30%); it was 30% (95% CI: 24% to 37%) for AP and 22% (95% CI: 14% to 32%) for LT Fontan types (p = 0.02). Given the relatively recent introduction of the ECC procedure, only 3 patients with ECC Fontan had reached 30 years of age.
Fontan failure occurred in 115 patients, with a median age at failure of 22.5 years (range 16.4 to 50 years) (Figure 2A). PLE occurred in 10 patients (1%); 6 AP and 4 LT. No adult patients experienced plastic bronchitis. Freedom from Fontan failure at or after age 16 years was higher in both the LT and ECC groups versus the AP group (p < 0.001) (Figure 2B). Fontan type (p < 0.001), era of Fontan repair from 1973 to 1982 (p = 0.04), length of hospital stay (p = 0.02), pre-operative moderate to severe or greater AV valve regurgitation, and AV repair or replacement and/or AV valve regurgitation (both p = 0.02) were all associated with failure on univariable analysis. On multivariable analysis, SVT before 16 years of age predicted Fontan failure, whereas the presence of an LT Fontan type reduced the risk of failure (Table 4).
Prevalence of serious adverse events
A total of 190 patients experienced a serious adverse event at a median age of 21 years. At 30 years of age, 52% (95% CI: 45% to 59%) of patients with an AP Fontan procedure were free from serious adverse events, as opposed to 74% (95% CI: 66% to 83%) and 61% (95% CI: 46% to 80%) of LT and ECC patients, respectively (p < 0.001).
The number of patients who have undergone a Fontan procedure and have survived to young adulthood and into middle age is increasing substantially (9). Our large study focuses on morbidities and mortality in adult Fontan patients, by using the comprehensive data collected over the last 10 years in the ANZFR. By assessing patients ≥16 years old, a unique perspective concerning such patients transitioning to ACHD centers and their expectations is possible.
Survival and transplantation
Medium-term survival of Fontan patients has increased over time (6,10); our data suggest that this trend (at least in part) reflects the transition from AP to TCPC-type repairs, from the mid-1980s onward. Most recently published “long-term” follow-up studies (to at least 20 years after the Fontan procedure) report survival rates from 61% to 83%, but have only few patients over 30 years of age (4,6,7). Even these studies have reported significant mortality, especially in the AP cohort, occurring toward 30 years of age. Our updated long-term survival rate at 90% at 30 years of age compares favorably with other reports to this age (7,11).
In our study, the most common identified cause of death was cardiac failure (n = 18). Further, 17 patients received cardiac transplantation. Transplantation rates remain low; this is likely a result of several factors, including a paucity of donors, the complex timing and decision making with regard to Fontan takedown or conversion versus cardiac transplantation, and the noncardiac morbidities that are common in long-term Fontan patients (12). In our study 13% of deaths were sudden and were presumed to be caused by arrhythmia, consistent with previous reports (4,13).
Of interest, only male sex and the presence of AV replacement or at least moderate regurgitation at the time of the Fontan operation were predictive of death or heart transplantation. Higher mortality rates in male patients with congenital heart disease (including Fontan patients) have been previously described, and the cause of this is not known. The lack of cardioprotective estrogen in male patients has been postulated. Men with congenital heart disease are also reported to be admitted with cardiovascular disease more often than women (14). Male sex is also associated with a higher incidence of arrhythmias, endocarditis, and surgery in patients with ACHD; this may also contribute to their apparently higher mortality rates (15).
Our data support previous studies (7,16,17) that the presence of significant AV regurgitation and/or the need for AV valve repair or replacement is associated with worse outcomes in the adult Fontan patients. The optimal timing of AV valve intervention, in terms severity of regurgitation and characterization of ventricular function, is not clear, and in the absence of clear guidelines, management differs among surgical units.
The absence of a subpulmonary ventricle and the obligate systemic venous hypertension in the Fontan circulation contribute to the development of significant late complications (18). At 40 years of age, only 41% of all adult patients were free from a serious adverse event. Further, 22% of patients required reoperation or intervention, with significantly more reinterventions in the AP group. Although a significant number of patients in the LT and ECC groups experienced adverse events, age-adjusted morbidity remains significantly lower than in the AP group. Within the next 10 years a substantial rise in the number of ECC patients reaching 30 years of age will occur. It will be instructive to see whether this repair continues to be associated with lower complication rates in the future.
The onset of tachyarrhythmias has been considered both a cause and a consequence of clinical decline (19), and in the long term it is associated with Fontan failure (20), sudden cardiac death (4), and all-cause mortality (21). Atrial tachyarrhythmias have been reported in up to 57% of patients (4,22–25), albeit in younger, predominantly AP Fontan cohorts. Sinus node dysfunction is reported in 40% of patients with AP connections and in up to 25% of LT and extracardiac cavopulmonary connections (26). In our cohort, 20% experienced an atrial arrhythmic event; the incidence was substantially lower in LT (11%) and ECC (6%) groups versus the AP group (46%). This finding supports other previous data (27), and it suggests that the lesser degree of atrial manipulation, suturing, and distention in these operations results in reduced arrhythmia and thus may contribute to improved overall survival. Whether the ECC procedure has significant benefit in terms of tachyarrhythmias versus the LT group is not clear, and comparison thus far has been limited by smaller cohorts with shorter follow-up in the ECC group. A recent systematic review and meta-analysis (28), however, suggests that ECC may provide a benefit in the development of late (>30 days) arrhythmias.
As expected, the presence of SVT in childhood was significantly associated with an increased hazard of developing such arrhythmias subsequently, after age 16 years. It is known that atrial arrhythmias, including SVT, not only represent an acute hemodynamic risk to the Fontan patient, but also may compromise hemodynamics and quality of life and lead to early death (26). Thus, studies are required to understand optimal management strategies for SVT in these patients, with possibilities including medications, ablation, arrhythmia surgery, and/or TCPC conversions in AP patients. We have previously demonstrated improved results when Fontan conversion is undertaken earlier, after onset of arrhythmias (29).
Although the study is large and comprises almost all Fontan survivors from Australia and New Zealand (to the best of our knowledge), it has the limitations inherent in any registry; certain data are collected retrospectively, and several data fields are incomplete for certain centers and patients. There are several complications of potential interest that have not been sufficiently well characterized across the cohort, such as liver and renal complications, although these have been reported recently in a subset of 150 of our Fontan patients from Australia and New Zealand (30). Detailed imaging data and exercise measurements were not available for the majority of our patients in the registry. Treatment strategies are at physicians’ discretion, rather than uniform. Not all factors taken into account in the selection of patients for their initial Fontan operation were available. Cause of death data were not available in a substantial minority, and deaths occurring overseas may have not been reported to the registry, although vital status was known with certainty for all the Australian patients through the National Death Registry. In addition, there are significant differences among definitions of Fontan failure in published reports, thus making direct comparison with other studies difficult.
Given that the AP was a procedure performed in an earlier era than TCPC, units transitioned to alternate Fontan procedures at different time points across Australia and New Zealand. Even though the surgical era was not significant on multivariable analysis, it is difficult to rule out the possibility completely that significantly worse outcomes in our AP patients are, at least in part, the result of an “era” effect. In practical terms, however, our data are still informative in terms of providing prognostic data, for AP and TCPC Fontan patients.
Survival of children with a single-ventricle–type heart has been enhanced by the development of the Fontan procedure, resulting in a large and increasing number of Fontan-treated adults. Nevertheless, this report from patients in the comprehensive ANZFR highlights novel and important information for adults with a Fontan circulation, their families, and their careers; premature death and several morbidities are common and increase substantially with older age. In particular, the AP-type Fontan procedure, male sex, and moderate or severe AV valve regurgitation portend a poorer prognosis in this group.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Adults who underwent the Fontan procedure early in life face considerable late morbidity and premature death. The onset of SVT may signal the need to assess the Fontan circulation.
TRANSLATIONAL OUTLOOK: More long-term studies are needed to identify differences in outcomes between the various methods used to establish Fontan conduits and reduce late complications and mortality rates.
The authors acknowledge support provided by the National Health and Medical Research Council of Australia to the Australian and New Zealand Fontan Registry and the support provided to the Murdoch Children’s Research Institute by the Victorian Government’s Operational Infrastructure Support Program. They also acknowledge assistance provided through the National Death Index linkage and Australian Institute of Health and Welfare in compiling data.
This work was supported by a National Health and Medical Research Council (NHMRC) Partnership Grant (1076849). Dr. d’Udekem is a Clinician Practitioner Fellow of the National Health and Medical Research Council (NHMRC) (1082186); and has received consulting fees from Merck Sharp & Dohme and Actelion. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- adult congenital heart disease
- Australian and New Zealand Fontan Registry
- extracardiac conduit
- lateral tunnel
- protein-losing enteropathy
- supraventricular tachycardia
- total cavopulmonary connection
- Received September 26, 2017.
- Revision received November 27, 2017.
- Accepted December 19, 2017.
- 2018 American College of Cardiology Foundation
- Gewillig M.
- Khairy P.,
- Fernandes S.M.,
- Mayer J.E. Jr..,
- et al.
- Giannico S.,
- Hammad F.,
- Amodeo A.,
- et al.
- d’Udekem Y.,
- Iyengar A.J.,
- Galati J.C.,
- et al.
- Pundi K.N.,
- Johnson J.N.,
- Dearani J.A.,
- et al.
- Coats L.,
- O’Connor S.,
- Wren C.,
- O’Sullivan J.
- Shi W.Y.,
- Yong M.S.,
- McGiffin D.C.,
- et al.
- Pundi K.N.,
- Pundi K.N.,
- Johnson J.N.,
- et al.
- Zomer A.C.,
- Ionescu-Ittu R.,
- Vaartjes I.,
- et al.
- Verheugt C.L.,
- Uiterwaal C.S.,
- van der Velde E.T.,
- et al.
- Clift P.,
- Celermajer D.
- Carins T.A.,
- Shi W.Y.,
- Iyengar A.J.,
- et al.
- Gewillig M.,
- Wyse R.K.,
- de Leval M.R.,
- Deanfield J.E.
- Durongpisitkul K.,
- Porter C.J.,
- Cetta F.,
- et al.
- Deal B.J.,
- Jacobs M.L.
- Li D.,
- Fan Q.,
- Hirata Y.,
- Ono M.,
- An Q.
- Wilson T.G.,
- d’Udekem Y.,
- Winlaw D.S.,
- et al.