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Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death
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Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 https://doi.org/10.1016/j.hlc.2017.11.007
REVIEW
Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death
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[TD$FIRSNAME]C.L.[TD$FIRSNAME.] [TD$SURNAME]Poh[TD$SURNAME.] a[1_TD$IF],b,c, [TD$FIRSNAME]Y.[TD$FIRSNAME.] [TD$SURNAME]d’Udekem[TD$SURNAME.], MD, PhD a,b,c* a
Department of Cardiac Surgery, The Royal Children’s Hospital, Melbourne, Vic, Australia Department of Paediatrics, University of Melbourne, Melbourne, Vic, Australia Heart Research, The Murdoch Childrens Research Institute, Melbourne, Vic, Australia
b c
Received 10 November 2016; accepted 18 November 2017; online published-ahead-of-print xxx
Aim
We now know that 20–40% of patients with a single ventricle will develop heart failure after the second decade post-Fontan surgery. However, we remain unable to risk-stratify the cohort to identify patients at highest risk of late failure and death. We conducted a systematic review of all reported late outcomes for patients with a Fontan circulation to identify predictors of late death.
Methods
We searched MEDLINE, Embase and PubMed with subject terms (‘‘single ventricle”, ‘‘Hypoplastic left heart syndrome”, ‘‘congenital heart defects” or ‘‘Fontan procedure”) AND (‘‘heart failure”, ‘‘post-operative complications”, ‘‘death”, ‘‘cause of death”, ‘‘transplantation” or ‘‘follow-up studies”) for relevant studies between January 1990 and December 2015. Variables identified as significant predictors of late death on multivariate analysis were collated for metaanalysis. Survival data was extrapolated from Kaplan-Meier survival curves to generate a distribution-free summary survival curve.
Results
Thirty-four relevant publications were identified, with a total of 7536 patients included in the analysis. Mean follow-up duration was 114 months (range 24–269 months). There were 688 (11%) late deaths. Predominant causes of death were late Fontan failure (34%), sudden death (19%) and perioperative death (16%). Estimated mean Kaplan-Meier survival at 5, 10 and 20 years post Fontan surgery were 95% (95%CI 93–96), 91% (95%CI 89–93) and 82% (95%CI 77–85). Significant predictors of late death include prolonged pleural effusions post Fontan surgery (HR1.18, 95%CI 1.09–1.29, p < 0.001), protein losing enteropathy (HR2.19, 95%CI 1.69–2.84, p < 0.001), increased ventricular end diastolic volume (HR1.03 per 10 ml/BSA increase, 95%CI 1.02–1.05, p < 0.001) and having a permanent pacemaker (HR12.63, 95% CI 6.17–25.86, p < 0.001).
[4_TD$IF]Conclusions
Over 80% of patients who survive Fontan surgery will be alive at 20 years. Developing late sequelae including protein losing enteropathy, ventricular dysfunction or requiring a pacemaker predict a higher risk of late death.
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Q5 *Corresponding[3_TD$IF] author at: Department of Cardiac Surgery, The Royal Children’s Hospital, 50 Flemington Road, Parkville, Vic 3052, Australia. Tel.: (03) 9345 5200, Fax: (03) 93456001. Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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Introduction
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C.L. Poh, Y. d’Udekem
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As we head towards the fifth decade of Fontan surgery, there is a new optimism towards the long-term survival of these patients. Late follow-up studies report survival rates between 60 and 80%, 20 years after Fontan surgery [1–3]. With population projections predicting this cohort to double in the next 20 years, we will soon face a large population of adult patients living with a Fontan circulation requiring longterm surveillance. However, till today, we still lack reliable criteria to risk-stratify this cohort, so as to identify those at highest risk of late failure and death. Improving our standard of care requires the identification of those most at risk of seeing the demise of their circulation. The small size of patients’ cohorts in existing studies limit the relevance of prognostic factors identified. Therefore, we conducted a systematic review of all reported outcomes of patients with a Fontan circulation to identify predictors of late death in this population.
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Methods
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MEDLINE, Embase and PubMed were searched with subject terms (‘‘single ventricle”, ‘‘Hypoplastic left heart syndrome”, ‘‘congenital heart defects” or ‘‘Fontan procedure”) AND (‘‘heart failure”, ‘‘post-operative complications”, ‘‘death”, ‘‘cause of death”, ‘‘transplantation” or ‘‘follow-up studies”) for relevant studies published from January 1990 to December 2015. Reference lists of eligible studies were also hand searched for additional articles. All relevant abstracts were screened. Selected reports were then appraised in the full text with consideration of the following inclusion criteria: 1) All patients included were beyond the stage of Fontan completion, 2) follow-up data was available beyond the immediate perioperative period (within 30 days post Fontan completion), 3) the incidence of late mortality was described. There were no limitations to the type of Fontan surgery. Serial studies with duplicate data from the same cohort were excluded from the survival analysis. However, all independent predictors of death were identified to ensure a comprehensive review.
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Data Extraction
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Relevant study data was extracted from the selected studies. This included publication-related details, baseline patient characteristics, Fontan surgery related details, morbidity and mortality at latest follow-up, and all significant predictors of late death identified on multivariate analysis. All selected studies were screened to identify Kaplan-Meier (KM) survival curves for the combined analysis of overall survival for the pooled cohort. Only survival curves from studies with follow-up longer than 5 years were included in the analysis to generate the final summary survival curve. For the systematic review of predictors of late death, only variables identified as statistically significant on multivariate analysis were included. Variables identified by three or more
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studies to be significant predictors of the endpoint were included in the final meta-regression analysis. Studies focussing on the review of single predictors of late death or failure were excluded from this review as they were limited by their methodology to overestimate their value of prediction [4]. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [5] and The Cochrane Collaboration and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [6].
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Data Analysis
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Continuous variables were reported as mean standard deviation. For the purpose of the meta- analysis of continuous data, medians and interquantile ranges reported in individual studies were converted to the form of mean standard deviation as per the methodology proposed by Wan et al. [7]. For the purpose of generating a distributionfree summary survival curve, all studies with follow-up data beyond a mean of 5 years were reviewed to identify KM survival curves. Conditional survival probabilities were re-constructed from published survival curves using the DigitizeIt software and the algorithm previously described [8]. The conditional survival probabilities extracted were then pooled at fixed time intervals (second yearly till final time-point on KM curve) with consideration for betweenstudy variance. The summary KM survival curve was generated with final time cut-off at 22 years post Fontan surgery, being the last time-point with at least two studies contributing to the meta-analysis. Summary survival probabilities were then derived via Stata, Version 14.0 (Metacorp package) using the product-limit estimator, as the product of the pooled estimates [9]. Confidence intervals of the summary survival probabilities were derived using the log-log transformation. Independent predictors of late mortality were identified as described above, and analysed using Review Manager (RevMan), Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
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Results
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The search strategy identified 1570 journal articles. Additional hand searches of reference lists found nine additional reports, resulting in a total of 1579 citations. All articles were screened via review of their abstracts. A total of 64 relevant manuscripts for late mortality were identified. For late mortality, eight studies reported on duplicate patient cohorts without additional relevant survival analysis and were excluded [10–17]. An additional 15 studies were excluded on further review: follow-up of all single ventricle patients of different stages of surgical palliation (7) [18–24]; late outcomes not clearly described (2) [25,26]; and subject cohort not representative of actual cohort (6) [27–32]. Forty-one studies satisfied inclusion criteria. Of these, seven studies reported on duplicate cohorts [33–39]. These were excluded from
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Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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survival analysis but included for risk factor analysis. The remaining 34 studies were reviewed [1–3,40–70]. The selected studies reported on a total of 7536 patients. Median study cohort size was 133 (IQR 56–260) patients from median of one surgical unit (range 1–15). Approximately 60% (3217/5578) were male. Hypoplastic left heart syndrome was the dominant diagnosis for 13% (785/6017). Of the total cohort, 33% (1280/3910) were right ventricular dominant, 16% (224/1400) had dextrocardia and 14% (529/ 3658) had heterotaxy. Significant atrio-ventricular regurgitation was present pre-Fontan operation in 9% (259/2855). The majority of patients received surgical staging preFontan. Systemic pulmonary arterial shunts, pulmonary artery banding and bidirectional cavopulmonary shunts were performed in 51% (1489/2914), 19% (701/3611) and 55% (2596/4692) of the cohort. Mean age at Fontan completion was 7.95 6.56 years. Type of Fontan operation received was atrio-pulmonary for 28% (2025/7149), Bjorktype for 2% (198/7149), lateral tunnel for 34% (2461/7149) and 36% (2610/7149) with an extra-cardiac conduits. Only 36% of the Fontan procedures were fenestrated. Mean cardiopulmonary bypass time was 90.3 47.4 minutes and mean aortic cross-clamp time was 40.7 27.4 minutes. Overall hospital mortality was 8% (550/6777). Mean follow-up duration was 114.2 94.7 months. There were 688 (11%) late deaths within the total cohort. Median
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late mortality was 5% (mean 7%, IQR 2–9%, range 0-33%). In studies with follow-up longer than 10 years median follow-up, late mortality was 18% (391/2225). Duration between Fontan surgery and late death was reported for only 19% of patients who faced late death, at mean 14.1 8.2 years post Fontan completion. The main cause of late death was described for 246 patients: late Fontan failure (90) sudden death (46) perioperative (39) of which 11 were post-Fontan conversion and seven were post-transplant, thrombo-embolism (10), sepsis (7), respiratory failure (6), neurological (6), multi-organ failure (5), bleeding (5), cancer (3), PLE (2), liver failure (2) and others/unknown (25). A summary survival curve was derived from the extrapolation of survival data from nine studies [1,2,40,45,49,54,55,60,70] (Figure 1). Estimated mean Kaplan-Meier survival at 5, 10 and 20 years post Fontan surgery were 95% (95%CI: 93–96), 91% (95%CI: 89–93) and 82% (95%CI: 77–85). All variables identified as significant predictors of late death on multivariate analysis are listed in Table 1. The most significant predictors of late death identified on metaanalysis were prolonged chest tube duration during Fontan surgery (HR 1.18, 95%CI 1.09–1.29, p < 0.001), protein losing enteropathy (HR 2.19, 95%CI 1.69–2.84, p [5_TD$IF]< 0.001), increased ventricular end diastolic volume (HR 1.03 per 10 ml/BSA increase, 95%CI1.02–1.05, p < 0.001) and having a permanent pacemaker (HR 12.63, 95%CI 6.17–25.86, p < 0.001).
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Figure 1 Summary survival curve from the extrapolation of Kaplan-Meier survival data of 9 included studies (n = 2660).
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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Table 1 Summary table of predictors of late death identified as significant on multivariate analysis in studies included. Bando d’Udekem Dabal Diller Driscoll Elder Fontan Gaynor Gentle Ghelani Khairy Mitchell O’Brien *Ohuchi Pundi Rathod Stamm et al
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Predictors of late mortality (Baseline characteristics)
[2_TD$IF]Male Down syndrome
HLHS
Complex single ventricle
Heterotaxy (only lateral tunnel pts) Common AV valve
AV valve dysfunction Right ventricular dominance
(Perioperative factors) AP Fontan (type)
Older age at Fontan
Earlier surgical era Longer cross-clamp time
Longer bypass time
Concurrent AV valve replacement Prolonged pleural effusions
Post-op renal insufficiency
Post-op ventricular arrhythmia
Elevated LA pressure
Elevated RA pressure Elevated mean PA pressure
(Late follow-up factors)
Protein losing enteropathy Pacemaker
Lower resting O2 saturations
Diuretic therapy
High VAS score Raised RA pressure
Increased ventricular end diastolic volume
Lower peak systolic circumferential strain
Lower heart rate reserve
Elevated serum noradrenaline
Reduced FEV1
Elevated BNP
C.L. Poh, Y. d’Udekem
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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Of the patients who were alive with adequate follow-up, 4% (138/3207) developed protein losing enteropathy and 10% (103/1068) had significant atrio-ventricular valve regurgitation. Twenty-three per cent of surviving patients required further surgical re-interventions (1412/6138) post Fontan completion. This consisted of transplantation (n = 132), late Fontan takedown (n = 44) and Fontan conversion (n = 216). Late arrhythmia was noted in 15% of the cohort (722/4667) over the course of follow-up. At latest follow-up, only 6% (262/4367) had a New York Heart
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Association (NYHA) score of more than or equal to 3 (Figures 2–5).
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Discussion
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Reports of late outcomes over the past years now support a more optimistic outlook for patients with a Fontan circulation [2,43,48]. However, the relevance of these reviews is limited by the small patient cohorts. Through this review, we hoped to provide an overview of their long-term
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Figure 2 Forest plot of hazard ratios for prolonged pleural effusions post Fontan surgery and late death.
Figure 3 Forest plot of hazard ratios for Protein Losing Enteropathy and late death.
Figure 4 Forest plot of hazard ratios for having a permanent pacemaker and late death.
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Figure 5 Forest plot of hazard ratios for increased ventricular end diastolic volume and late death.
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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outcomes, and identify risk factors that may be associated with late prognosis.
Late Outcomes of Patients [6_TD$IF]with Fontan Circulation
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Overall predicted 20-year survival was 82%. To accurately interpret the significance of this result, it is important to first delineate the population from which this is captured. The current study cohort reflected a population where 13% had hypoplastic left heart syndrome, one third had rightventricle dominance, with an equal distribution of patients between atrio-pulmonary, lateral tunnel and extra-cardiac Fontan circulation. However, in the most recent report from the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database, 65% of patients received extra-cardiac conduits while 20% have lateral tunnels [71]. Hypoplastic left heart syndrome is becoming more prevalent in all recent series, with more patients surviving the initial stages of palliation. In our study, it is striking that the risk factors predicting poor outcomes were different from those identified at the time Choussat’s ‘‘Ten Commandments” of the ideal Fontan candidate was described 40 years ago [72]. This proves that we now understand the importance of patient selection, and the need for aggressive management of critical lesions such as atrio-ventricular valve regurgitation.
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Mechanisms of Late Death
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The primary cause of late death in patients in this review was Fontan failure. This review was unable to capture the underlying mechanisms leading to late failure and death. It does not establish to what extent the degradation of the pulmonary circulation and end-organ dysfunction contribute to their progressive decline. It does, however, recognise that the onset of myocardial dysfunction is closely related to late Fontan failure. The role of Fontan failure in the setting of preserved ventricular function is also increasingly recognised, further complicating management [53].
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Predictors of Late Mortality
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This review was not designed to establish a relationship of causality between the identified predictors and late death. However, it assists us to identify the patient subpopulation at greatest risk of failure and death. Protein losing enteropathy represents the worst end of end-organ sequelae in a Fontan circulation. As such, it naturally remains a major predictor of poor prognosis. It was not surprising to identify that an increase in end-diastolic ventricular volume, undoubtedly a marker of systolic ventricular dysfunction, would signal the start of a rapid deterioration of the Fontan circulation. However, the deleterious impact of having a pacemaker on late survival was the most surprising finding. This may have been selected for a higher risk cohort facing the sequelae of intractable arrhythmias, or patients who have undergone Fontan conversion. A causative relationship between having a pacemaker and increased mortality has yet to be established. Nonetheless, we believe the development of atrial
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tachyarrhythmias may be an early sign of decline in the Fontan circulation [73]. Suboptimal pacing may cause the loss of atrio-ventricular synchrony that patients with a Fontan circulation heavily depend on, increasing pulmonary pressures and ultimately leading to Fontan failure. Some have explored the use of cardiac resynchronisation therapy with multi-site pacing to improve cardiac function in the setting of Fontan failure, and may be an avenue that should be further explored [74]. It is likely that some prognostic factors, such as the presence of elevated B-type natriuretic peptide (BNP), peak oxygen uptake (VO2) and functional markers of liver dysfunction may have been under-represented in this review, due to their inconsistent use in patient monitoring. We are now facing a growing population of patients with a Fontan circulation. In conclusion, we need to identify those most at risk of failure of their circulation today, in order to provide them with more intensive care. Patients with prolonged effusions at the time of the Fontan completion, those developing protein-losing enteropathy and ventricular dysfunction are at highest risk of having failure of their circulation. Pacemaker implantation is the most important predictor of late death after Fontan. The causality of this relationship warrants urgent investigation, to guide the long-term management of these challenging patients.
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Acknowledgement
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Dr CL Poh is supported by the Health Professional Scholarship from the National Heart Foundation of Australia Prof Yves d’Udekem is a consultant for MSD and Actelion. He is an NHMRC Clinician Practitioner Fellow (1082186). The Victorian Government’s Operational Infrastructure Support Program supported this research project.
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Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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influencing early and late outcome. J Thorac Cardiovasc Surg 1997;114:376–91. Gaynor J, Bridges N, Cohen M, Mahle W, DeCampli W, Steven J, et al. Predictors of outcome after the Fontan operation: is hypoplastic left heart syndrome still a risk factor. J Thorac Cardiovasc Surg 2002;123:237–45. Driscoll D, Offord K, Feldt R, Schaff H, Puga F, Danielson G. Five- to fifteen- year follow-up after Fontan operation. Circulation 1992;85:469– 96. Ghelani S, Harrild D, Gauvreau K, Geva T, Rathod R. Comparison between echocardiograph and cardiac magnetic resonance imaging in predicting transplant-free survival after the Fontan operation. Am J Cardiol 2015;116:1132–8. Ohuchi H, Yasuda K, Miyazaki A, Iwasa T, Sakaguchi H, Shin O, et al. Comparison of prognostic variables in children and adults with Fontan circulation. Int J Cardiol 2014;173:277–83. Rathod R, Prakash A, Kim Y, Germanakis I, Powell A, Gauvreau K, et al. Cardiac magnetic resonance paramaters predict transplantation-free survival in patients with Fontan circulation. Circ Cardiovasc Imaging 2014;7. Stamm C, Friehs I, Mayer Jr J, Zurakowski D, Triedman J, Moran A, et al. Long-term results of the lateral tunnel Fontan operation. J Thorac Cardiovasc Surg 2001;121:28–41. Alphonso N, Baghai M, Sundar P, Tulloh R, Austin C, Anderson D. Intermediate-term outcome following the fontan operation: a survival, functional and risk-factor analysis. Eur J Cardiothorac Surg 2005;28: 529–35. Amodeo A, Galletti L, Marianeschi S, Picardo S, Giannico S, Renzi P, et al. Extracardiac Fontan operation for complex cardiac anomalies: seven years’ experience. J Thorac Cardiovasc Surg 1997;114:1020–31. Atik E, Ikari N, Martins T, Barbero-Marcial M. Fontan operation and the cavopulmonary technique. immediate and late results according to the presence of atrial fenestration. Arq Bras Cardiol 2002;78:162–6. Atz A, Zak V, Mahony L, Uzark K, Shrader P, Gallagher D, et al. Survival data and predictors of functional outcome an average of 15 years after the Fontan procedure: the Pediatric Heart Network Fontan Cohort. Congenit Heart Dis 2015;10:E30–42. Bando K, Turrentine M, Park H, Sharp T, Scavo V, Brown J. Evolution of the Fontan procedure in a single center. Ann Thorac Surg 2000;69:1837–9. Dabal R, Kirklin J, Kukreja M, Brown R, Cleveland D, Eddins M, et al. The modern Fontan operation shows no increase in mortality out to 20 years: a new paradigm. J Thorac Cardiovasc Surg 2014;148:2517–24. De Vadder K, Van De Bruaene A, Gewillig M, Meyns B, Troost E, Budts W. Predicting outcome after Fontan palliation: a single-centre experience, using simple clinical variables. Acta Cardiol 2014;69:7–14. Diller G, Giardini A, Dimopoulos K, Gargiulo G, Muller J, Derrick G, et al. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonyar exercise testing in 321 patients. Eur Heart J 2010;31:3073–80. Elder R, McCabe N, Veledar E, Kogon B, Jokhadar M, Rodriguez III F, et al. Risk factors for major adverse events late after Fontan palliation. Congenit Heart Dis 2015;10:159–68. Fontan F, Kirklin J, Fernandez G, Costa F, Naftel D, Tritto F, et al. Outcome after a ‘‘perfect” Fontan operation. Circulation 1990;81:1520–36. Fujii Y, Sano S, Kotani Y, Yoshizumi K, Kasahara S, Ishino K, et al. Midterm to long-term outcome of total cavopulmonary connection in high-risk adult candidates. Ann Thorac Surg 2009;87:562–70. Giannico S, Hammad F, Amodeo A, Michelon G, Drago F, Turchetta A, et al. Clinical outcomes of 193 extracardiac Fontan patients. J Am Coll Cardiol 2006;47:2065–73. Giannakoulos G, Dimopoulos K, Yuksel S, Inuzuka R, Pijuan-Domenech A, Hussain W, et al. Atrial tachyarrhythmias late after Fontan operation are related to increase in mortality and hospitalization. Int J Cardiol 2012;157:221–6. Griffiths E, Kaza A, von Ballmoos Wyler W, Loyola H, Valente A, Blume E, et al. Evaluating failing Fontans for heart transplantation: predictors of death. Ann Thorac Surg 2009;88:558–64. Haas G, Hess H, Black M, Onnasch J, Mohr F, van Son J. Extracardiac conduit Fontan procedure: early and intermediate results. Eur J Cardiothorac Surg 2000;17:648–54. Hosein R, Clarke A, McGuirk S, Griselli M, Stumper O, De Giovanni J, et al. Factors influencing early and late outcome following the Fontan procedure in the current era. The ‘Two Commandments’? Eur J Cardiothorac Surg 2007;31:344–53. Kavarana M, Pagni S, Recto M, Sobczyk W, Yeh Y, Mitchell M, et al. Seven-year clinical experience with the extracardiac pedicled pericardial Fontan operation. Ann Thorac Surg 2005;80:37–43.
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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[57] Kim S, Kim W, Lim H, Lee J. Outcome of 200 patients after an extracardiac Fontan procedure. J Thorac Cardiovasc Surg 2008;136:108–16. [58] Laschinger J, Redmond J, Cameron D, Kan J, Richard R. Intermediate results of the extracardiac Fontan procedure. Ann Thorac Surg 1996;62:1261–7. [59] Lee J, Choi J, Kang C, Bae E, Kim Y, Rho J. Surgical results of patients with a functional single ventricle. Eur J Cardiothorac Surg 2003;24:716–22. [60] Mastalir E, Kalil R, Horowitz E, Wender O, Sant’Anna J, Prates P, et al. Late clinical outcomes of the Fontan operation in patients with tricuspid atresia. Arq Bras Cardiol 2002;79:56–60. [61] Mendoza A, Albert L, Ruiz E, Boni L, Ramos V, Velasco J, et al. Fontan operation: hemodynamic factors associated with postoperative outcomes. Rev Esp Cardiol 2012;65:356–62. [62] Mitchell M, Ittenbach R, Gaynor J, Wernovsky G, Nicolson S, Spray T. Intermediate outcomes after the Fontan procedure in the current era. J Thorac Cardiovasc Surg 2006;131:172–80. [63] Nakano T, Kado H, Tachibana T, Hinokiyama K, Shiose A, Kajimoto M, et al. Excellent midterm outcome of extracardiac conduit total cavopulmonary connection: results of 126 cases. Ann Thorac Surg 2007;84:1619– 26. [64] O’Brien J, Marshall J, Young A, Handley K, Lofland G. The nonfenestrated extracardiac Fontan procedure: a cohort of 145 patients. Ann Thorac Surg 2010;89:1815–20. [65] Ohuchi H, Kagisaki K, Miyazaki A, Kitano M, Yazaki S, Sakaguchi H, et al. Impact of the evolution of the Fontan operation on early and late mortality: a single-center experience of 405 patients over 3 decades. Ann Thorac Surg 2011;92:1457–67. [66] Ono M, Boethig D, Goerler H, Lange M, Westhoff-Bleck M, Breymann T. Clinical outcome of patients 20 years after Fontan operation —
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effect of fenestration on late morbidity. Eur J Cardiothorac Surg 2006;30:923–9. Petrossian E, Reddy V, McElhinney D, Akkersdijk G, Moore P, Parry A, et al. Early results of the extracardiac conduit Fontan operation. J Thorac Cardiovasc Surg 1999;117:688–96. Sharma R, Iyer K, Airan B, Saha K, Das B, Bhan A, et al. Univentricular repair — early and midterm results. J Thorac Cardiovasc Surg 1995;110:1692–701. Tweddell J, Nersesian M, Mussatto K, Nugent M, Simpson P, Mitchell M, et al. Fontan palliation in the modern era: factors impacting mortality and morbidity. Ann Thorac Surg 2009;88:1291–9. van de Bosch A, Roos-Hesselink J, van Domburg R, Bogers A, Simoons M, Mejiboom F. Long-term outcome and quality of life in adult patients after the Fontan Operation. Am J Cardiol 2004;93:1141–5. Jacobs J, Maruszewksi B. Functionally univentricular heart and the fontan operation: lessons learned about patterns of practice and outcomes from the congenital heart surgery databases of the European association for cardio-thoracic surgery and the society of thoracic surgeons. World J Pediatr Congenit Heart Surg 2013;4:349–55. Choussat A, Fontan F, Besse P. Selection criteria for the Fontan procedure. In: Anderson R, Shinebourne E, editors. Paediatric cardiology. Edinburgh, Scotland: Churchill Livingstone; 1977. p. 559–66. Carins T, Shi W, Iyengar A, Nisbet A, Forsdick V, Zannino D, et al. Longterm outcomes after first-onset arrhythmia in Fontan physiology. J Thorac Cardiovasc Surg 2016;152:1355–63. Sojak V, Mazic U, Cesen M, Schrader J, Danojevic N. Cardiac resynchronization therapy for the failing Fontan patient. Ann Thorac Surg 2008;85:2136–8.
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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REVIEW
Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death
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[TD$FIRSNAME]C.L.[TD$FIRSNAME.] [TD$SURNAME]Poh[TD$SURNAME.] a[1_TD$IF],b,c, [TD$FIRSNAME]Y.[TD$FIRSNAME.] [TD$SURNAME]d’Udekem[TD$SURNAME.], MD, PhD a,b,c* a
Department of Cardiac Surgery, The Royal Children’s Hospital, Melbourne, Vic, Australia Department of Paediatrics, University of Melbourne, Melbourne, Vic, Australia Heart Research, The Murdoch Childrens Research Institute, Melbourne, Vic, Australia
b c
Received 10 November 2016; accepted 18 November 2017; online published-ahead-of-print xxx
Aim
We now know that 20–40% of patients with a single ventricle will develop heart failure after the second decade post-Fontan surgery. However, we remain unable to risk-stratify the cohort to identify patients at highest risk of late failure and death. We conducted a systematic review of all reported late outcomes for patients with a Fontan circulation to identify predictors of late death.
Methods
We searched MEDLINE, Embase and PubMed with subject terms (‘‘single ventricle”, ‘‘Hypoplastic left heart syndrome”, ‘‘congenital heart defects” or ‘‘Fontan procedure”) AND (‘‘heart failure”, ‘‘post-operative complications”, ‘‘death”, ‘‘cause of death”, ‘‘transplantation” or ‘‘follow-up studies”) for relevant studies between January 1990 and December 2015. Variables identified as significant predictors of late death on multivariate analysis were collated for metaanalysis. Survival data was extrapolated from Kaplan-Meier survival curves to generate a distribution-free summary survival curve.
Results
Thirty-four relevant publications were identified, with a total of 7536 patients included in the analysis. Mean follow-up duration was 114 months (range 24–269 months). There were 688 (11%) late deaths. Predominant causes of death were late Fontan failure (34%), sudden death (19%) and perioperative death (16%). Estimated mean Kaplan-Meier survival at 5, 10 and 20 years post Fontan surgery were 95% (95%CI 93–96), 91% (95%CI 89–93) and 82% (95%CI 77–85). Significant predictors of late death include prolonged pleural effusions post Fontan surgery (HR1.18, 95%CI 1.09–1.29, p < 0.001), protein losing enteropathy (HR2.19, 95%CI 1.69–2.84, p < 0.001), increased ventricular end diastolic volume (HR1.03 per 10 ml/BSA increase, 95%CI 1.02–1.05, p < 0.001) and having a permanent pacemaker (HR12.63, 95% CI 6.17–25.86, p < 0.001).
[4_TD$IF]Conclusions
Over 80% of patients who survive Fontan surgery will be alive at 20 years. Developing late sequelae including protein losing enteropathy, ventricular dysfunction or requiring a pacemaker predict a higher risk of late death.
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Q5 *Corresponding[3_TD$IF] author at: Department of Cardiac Surgery, The Royal Children’s Hospital, 50 Flemington Road, Parkville, Vic 3052, Australia. Tel.: (03) 9345 5200, Fax: (03) 93456001. Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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Introduction
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As we head towards the fifth decade of Fontan surgery, there is a new optimism towards the long-term survival of these patients. Late follow-up studies report survival rates between 60 and 80%, 20 years after Fontan surgery [1–3]. With population projections predicting this cohort to double in the next 20 years, we will soon face a large population of adult patients living with a Fontan circulation requiring longterm surveillance. However, till today, we still lack reliable criteria to risk-stratify this cohort, so as to identify those at highest risk of late failure and death. Improving our standard of care requires the identification of those most at risk of seeing the demise of their circulation. The small size of patients’ cohorts in existing studies limit the relevance of prognostic factors identified. Therefore, we conducted a systematic review of all reported outcomes of patients with a Fontan circulation to identify predictors of late death in this population.
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Methods
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MEDLINE, Embase and PubMed were searched with subject terms (‘‘single ventricle”, ‘‘Hypoplastic left heart syndrome”, ‘‘congenital heart defects” or ‘‘Fontan procedure”) AND (‘‘heart failure”, ‘‘post-operative complications”, ‘‘death”, ‘‘cause of death”, ‘‘transplantation” or ‘‘follow-up studies”) for relevant studies published from January 1990 to December 2015. Reference lists of eligible studies were also hand searched for additional articles. All relevant abstracts were screened. Selected reports were then appraised in the full text with consideration of the following inclusion criteria: 1) All patients included were beyond the stage of Fontan completion, 2) follow-up data was available beyond the immediate perioperative period (within 30 days post Fontan completion), 3) the incidence of late mortality was described. There were no limitations to the type of Fontan surgery. Serial studies with duplicate data from the same cohort were excluded from the survival analysis. However, all independent predictors of death were identified to ensure a comprehensive review.
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Data Extraction
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Relevant study data was extracted from the selected studies. This included publication-related details, baseline patient characteristics, Fontan surgery related details, morbidity and mortality at latest follow-up, and all significant predictors of late death identified on multivariate analysis. All selected studies were screened to identify Kaplan-Meier (KM) survival curves for the combined analysis of overall survival for the pooled cohort. Only survival curves from studies with follow-up longer than 5 years were included in the analysis to generate the final summary survival curve. For the systematic review of predictors of late death, only variables identified as statistically significant on multivariate analysis were included. Variables identified by three or more
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studies to be significant predictors of the endpoint were included in the final meta-regression analysis. Studies focussing on the review of single predictors of late death or failure were excluded from this review as they were limited by their methodology to overestimate their value of prediction [4]. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [5] and The Cochrane Collaboration and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [6].
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Data Analysis
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Continuous variables were reported as mean standard deviation. For the purpose of the meta- analysis of continuous data, medians and interquantile ranges reported in individual studies were converted to the form of mean standard deviation as per the methodology proposed by Wan et al. [7]. For the purpose of generating a distributionfree summary survival curve, all studies with follow-up data beyond a mean of 5 years were reviewed to identify KM survival curves. Conditional survival probabilities were re-constructed from published survival curves using the DigitizeIt software and the algorithm previously described [8]. The conditional survival probabilities extracted were then pooled at fixed time intervals (second yearly till final time-point on KM curve) with consideration for betweenstudy variance. The summary KM survival curve was generated with final time cut-off at 22 years post Fontan surgery, being the last time-point with at least two studies contributing to the meta-analysis. Summary survival probabilities were then derived via Stata, Version 14.0 (Metacorp package) using the product-limit estimator, as the product of the pooled estimates [9]. Confidence intervals of the summary survival probabilities were derived using the log-log transformation. Independent predictors of late mortality were identified as described above, and analysed using Review Manager (RevMan), Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
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Results
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The search strategy identified 1570 journal articles. Additional hand searches of reference lists found nine additional reports, resulting in a total of 1579 citations. All articles were screened via review of their abstracts. A total of 64 relevant manuscripts for late mortality were identified. For late mortality, eight studies reported on duplicate patient cohorts without additional relevant survival analysis and were excluded [10–17]. An additional 15 studies were excluded on further review: follow-up of all single ventricle patients of different stages of surgical palliation (7) [18–24]; late outcomes not clearly described (2) [25,26]; and subject cohort not representative of actual cohort (6) [27–32]. Forty-one studies satisfied inclusion criteria. Of these, seven studies reported on duplicate cohorts [33–39]. These were excluded from
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Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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survival analysis but included for risk factor analysis. The remaining 34 studies were reviewed [1–3,40–70]. The selected studies reported on a total of 7536 patients. Median study cohort size was 133 (IQR 56–260) patients from median of one surgical unit (range 1–15). Approximately 60% (3217/5578) were male. Hypoplastic left heart syndrome was the dominant diagnosis for 13% (785/6017). Of the total cohort, 33% (1280/3910) were right ventricular dominant, 16% (224/1400) had dextrocardia and 14% (529/ 3658) had heterotaxy. Significant atrio-ventricular regurgitation was present pre-Fontan operation in 9% (259/2855). The majority of patients received surgical staging preFontan. Systemic pulmonary arterial shunts, pulmonary artery banding and bidirectional cavopulmonary shunts were performed in 51% (1489/2914), 19% (701/3611) and 55% (2596/4692) of the cohort. Mean age at Fontan completion was 7.95 6.56 years. Type of Fontan operation received was atrio-pulmonary for 28% (2025/7149), Bjorktype for 2% (198/7149), lateral tunnel for 34% (2461/7149) and 36% (2610/7149) with an extra-cardiac conduits. Only 36% of the Fontan procedures were fenestrated. Mean cardiopulmonary bypass time was 90.3 47.4 minutes and mean aortic cross-clamp time was 40.7 27.4 minutes. Overall hospital mortality was 8% (550/6777). Mean follow-up duration was 114.2 94.7 months. There were 688 (11%) late deaths within the total cohort. Median
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late mortality was 5% (mean 7%, IQR 2–9%, range 0-33%). In studies with follow-up longer than 10 years median follow-up, late mortality was 18% (391/2225). Duration between Fontan surgery and late death was reported for only 19% of patients who faced late death, at mean 14.1 8.2 years post Fontan completion. The main cause of late death was described for 246 patients: late Fontan failure (90) sudden death (46) perioperative (39) of which 11 were post-Fontan conversion and seven were post-transplant, thrombo-embolism (10), sepsis (7), respiratory failure (6), neurological (6), multi-organ failure (5), bleeding (5), cancer (3), PLE (2), liver failure (2) and others/unknown (25). A summary survival curve was derived from the extrapolation of survival data from nine studies [1,2,40,45,49,54,55,60,70] (Figure 1). Estimated mean Kaplan-Meier survival at 5, 10 and 20 years post Fontan surgery were 95% (95%CI: 93–96), 91% (95%CI: 89–93) and 82% (95%CI: 77–85). All variables identified as significant predictors of late death on multivariate analysis are listed in Table 1. The most significant predictors of late death identified on metaanalysis were prolonged chest tube duration during Fontan surgery (HR 1.18, 95%CI 1.09–1.29, p < 0.001), protein losing enteropathy (HR 2.19, 95%CI 1.69–2.84, p [5_TD$IF]< 0.001), increased ventricular end diastolic volume (HR 1.03 per 10 ml/BSA increase, 95%CI1.02–1.05, p < 0.001) and having a permanent pacemaker (HR 12.63, 95%CI 6.17–25.86, p < 0.001).
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Figure 1 Summary survival curve from the extrapolation of Kaplan-Meier survival data of 9 included studies (n = 2660).
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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Table 1 Summary table of predictors of late death identified as significant on multivariate analysis in studies included. Bando d’Udekem Dabal Diller Driscoll Elder Fontan Gaynor Gentle Ghelani Khairy Mitchell O’Brien *Ohuchi Pundi Rathod Stamm et al
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Predictors of late mortality (Baseline characteristics)
[2_TD$IF]Male Down syndrome
HLHS
Complex single ventricle
Heterotaxy (only lateral tunnel pts) Common AV valve
AV valve dysfunction Right ventricular dominance
(Perioperative factors) AP Fontan (type)
Older age at Fontan
Earlier surgical era Longer cross-clamp time
Longer bypass time
Concurrent AV valve replacement Prolonged pleural effusions
Post-op renal insufficiency
Post-op ventricular arrhythmia
Elevated LA pressure
Elevated RA pressure Elevated mean PA pressure
(Late follow-up factors)
Protein losing enteropathy Pacemaker
Lower resting O2 saturations
Diuretic therapy
High VAS score Raised RA pressure
Increased ventricular end diastolic volume
Lower peak systolic circumferential strain
Lower heart rate reserve
Elevated serum noradrenaline
Reduced FEV1
Elevated BNP
C.L. Poh, Y. d’Udekem
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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Of the patients who were alive with adequate follow-up, 4% (138/3207) developed protein losing enteropathy and 10% (103/1068) had significant atrio-ventricular valve regurgitation. Twenty-three per cent of surviving patients required further surgical re-interventions (1412/6138) post Fontan completion. This consisted of transplantation (n = 132), late Fontan takedown (n = 44) and Fontan conversion (n = 216). Late arrhythmia was noted in 15% of the cohort (722/4667) over the course of follow-up. At latest follow-up, only 6% (262/4367) had a New York Heart
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Association (NYHA) score of more than or equal to 3 (Figures 2–5).
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Discussion
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Reports of late outcomes over the past years now support a more optimistic outlook for patients with a Fontan circulation [2,43,48]. However, the relevance of these reviews is limited by the small patient cohorts. Through this review, we hoped to provide an overview of their long-term
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Figure 2 Forest plot of hazard ratios for prolonged pleural effusions post Fontan surgery and late death.
Figure 3 Forest plot of hazard ratios for Protein Losing Enteropathy and late death.
Figure 4 Forest plot of hazard ratios for having a permanent pacemaker and late death.
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Figure 5 Forest plot of hazard ratios for increased ventricular end diastolic volume and late death.
Please cite this article in press as: Poh CL, d’Udekem Y. Life After Surviving Fontan Surgery: A Meta-Analysis of the Incidence and Predictors of Late Death. Heart, Lung and Circulation (2017), https://doi.org/10.1016/j.hlc.2017.11.007
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outcomes, and identify risk factors that may be associated with late prognosis.
Late Outcomes of Patients [6_TD$IF]with Fontan Circulation
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Overall predicted 20-year survival was 82%. To accurately interpret the significance of this result, it is important to first delineate the population from which this is captured. The current study cohort reflected a population where 13% had hypoplastic left heart syndrome, one third had rightventricle dominance, with an equal distribution of patients between atrio-pulmonary, lateral tunnel and extra-cardiac Fontan circulation. However, in the most recent report from the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database, 65% of patients received extra-cardiac conduits while 20% have lateral tunnels [71]. Hypoplastic left heart syndrome is becoming more prevalent in all recent series, with more patients surviving the initial stages of palliation. In our study, it is striking that the risk factors predicting poor outcomes were different from those identified at the time Choussat’s ‘‘Ten Commandments” of the ideal Fontan candidate was described 40 years ago [72]. This proves that we now understand the importance of patient selection, and the need for aggressive management of critical lesions such as atrio-ventricular valve regurgitation.
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Mechanisms of Late Death
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The primary cause of late death in patients in this review was Fontan failure. This review was unable to capture the underlying mechanisms leading to late failure and death. It does not establish to what extent the degradation of the pulmonary circulation and end-organ dysfunction contribute to their progressive decline. It does, however, recognise that the onset of myocardial dysfunction is closely related to late Fontan failure. The role of Fontan failure in the setting of preserved ventricular function is also increasingly recognised, further complicating management [53].
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Predictors of Late Mortality
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This review was not designed to establish a relationship of causality between the identified predictors and late death. However, it assists us to identify the patient subpopulation at greatest risk of failure and death. Protein losing enteropathy represents the worst end of end-organ sequelae in a Fontan circulation. As such, it naturally remains a major predictor of poor prognosis. It was not surprising to identify that an increase in end-diastolic ventricular volume, undoubtedly a marker of systolic ventricular dysfunction, would signal the start of a rapid deterioration of the Fontan circulation. However, the deleterious impact of having a pacemaker on late survival was the most surprising finding. This may have been selected for a higher risk cohort facing the sequelae of intractable arrhythmias, or patients who have undergone Fontan conversion. A causative relationship between having a pacemaker and increased mortality has yet to be established. Nonetheless, we believe the development of atrial
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tachyarrhythmias may be an early sign of decline in the Fontan circulation [73]. Suboptimal pacing may cause the loss of atrio-ventricular synchrony that patients with a Fontan circulation heavily depend on, increasing pulmonary pressures and ultimately leading to Fontan failure. Some have explored the use of cardiac resynchronisation therapy with multi-site pacing to improve cardiac function in the setting of Fontan failure, and may be an avenue that should be further explored [74]. It is likely that some prognostic factors, such as the presence of elevated B-type natriuretic peptide (BNP), peak oxygen uptake (VO2) and functional markers of liver dysfunction may have been under-represented in this review, due to their inconsistent use in patient monitoring. We are now facing a growing population of patients with a Fontan circulation. In conclusion, we need to identify those most at risk of failure of their circulation today, in order to provide them with more intensive care. Patients with prolonged effusions at the time of the Fontan completion, those developing protein-losing enteropathy and ventricular dysfunction are at highest risk of having failure of their circulation. Pacemaker implantation is the most important predictor of late death after Fontan. The causality of this relationship warrants urgent investigation, to guide the long-term management of these challenging patients.
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Acknowledgement
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Dr CL Poh is supported by the Health Professional Scholarship from the National Heart Foundation of Australia Prof Yves d’Udekem is a consultant for MSD and Actelion. He is an NHMRC Clinician Practitioner Fellow (1082186). The Victorian Government’s Operational Infrastructure Support Program supported this research project.
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