Risk Factors for Prosthetic Pulmonary Valve Failure in Patients With Congenital Heart Disease

Accepted Manuscript Risk Factors for Prosthetic Pulmonary Valve Failure in Patients with Congenital Heart Disease Jose Maria Oliver, MD, PhD, Diego Garcia-Hamilton, MD, Ana Elvira Gonzalez, MD, Jose Ruiz-Cantador, MD, Angel Sanchez-Recalde, MD, Maria Luz Polo, MD, PhD, Angel Aroca, MD PII:

S0002-9149(15)01703-8

DOI:

10.1016/j.amjcard.2015.07.043

Reference:

AJC 21316

To appear in:

The American Journal of Cardiology

Received Date: 24 April 2015 Revised Date:

6 July 2015

Accepted Date: 9 July 2015

Please cite this article as: Oliver JM, Garcia-Hamilton D, Gonzalez AE, Ruiz-Cantador J, SanchezRecalde A, Polo ML, Aroca A, Risk Factors for Prosthetic Pulmonary Valve Failure in Patients with Congenital Heart Disease, The American Journal of Cardiology (2015), doi: 10.1016/ j.amjcard.2015.07.043. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT

Risk Factors for Prosthetic Pulmonary Valve Failure in Patients with Congenital Heart Disease

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Jose Maria Oliver MD PhDa,b,* Diego Garcia-Hamilton MDa,c Ana Elvira Gonzalez MDa,c

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Jose Ruiz-Cantador MDa,c Angel Sanchez-Recalde MDa,c

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Maria Luz Polo MD PhDa,d Angel Aroca MDa,d. Author Affiliations: a

Unidad de Cardiopatías Congénitas del Adulto. La Paz University Hospital, Madrid,

b

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Spain.

Instituto de Investigacion Sanitaria. Gregorio Marañon University Hospital, Madrid,

Spain.

Servicio de Cardiología. La Paz University Hospital, Madrid, Spain.

d

Servicio de Cirugía Cardiovascular Pediátrica y cardiopatías Congénitas. La Paz

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c

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University Hospital, Madrid, Spain. *Corresponding Author: Jose Maria Oliver Ruiz, Avenida Las Mimbreras 6, Majadahonda, 28221 Madrid. Telephone number: 0034-619067336. E-mail: [email protected]. Running Head: Risk factors for prosthetic pulmonary valve failure

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ACCEPTED MANUSCRIPT Abstract The incidence and risk factors for prosthetic pulmonary valve failure (PPVF) should be considered when determining optimal timing for pulmonary valve replacement (PVR) in asymptomatic patients with congenital heart disease (CHD). The cumulative freedom

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for re-intervention due to PPVF after 146 PVR in 114 CHD patients was analyzed. Six potential risk factors (underlying cardiac defect, history of palliative procedures,

number of previous cardiac interventions, hemodynamic indication for PVR, type of

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intervention, and age at intervention) were analyzed using Cox proportional hazard modeling. Receiving operating characteristics (ROC) curves were used for

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discrimination. Internal validation in patients with tetralogy of Fallot was also performed. Median age at intervention was 23 years. There were 60 re-interventions due to PPVF (41%). Median event-free survival was 14 years (95% confidence interval [CI] 12-16 years). The only independent risk factor was the age at intervention (HR 0.93;

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95% CI 0.90-0.97; p=0.001; Area under the ROC curve 0.95; 95% CI 0.92-0.98; p <0.001). The best cutoff point was 20.5 years old. Freedom from re-intervention for PPVF 15 years after surgery was 70% when it was performed at age > 20.5 years

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compared with 33% when age at intervention was < 20.5 years (p=0.004). Internal validation in 102 PVR in patient cohort with tetralogy of Fallot (ROC area 0.98; 95%

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CI 0.96-1.0; p<0.001) was excellent. In conclusion, age at intervention is the main risk factor of re-intervention for PPVF. The risk of re-intervention is two-fold when PVR is performed before the age of 20.5 years. Key words: Congenital heart disease. Tetralogy of Fallot. Valvular prosthesis (pulmonary). Prosthetic valve failure.

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ACCEPTED MANUSCRIPT Introduction In order to relief right ventricular (RV) outflow tract obstruction in patients with tetralogy of Fallot and other congenital heart diseases (CHD) it is often necessary to disrupt pulmonary valve integrity, which results in significant pulmonary regurgitation

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(PR) and RV volume overload1. Chronic severe PR is well tolerated for years but

eventually triggers a cascade of pathophysiological alterations, leading to RV dilation

and dysfunction2, atrial and ventricular arrhythmias3, exercise intolerance, heart failure

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and early mortality4,5. Pulmonary valve replacement (PVR) usually results in

disappearance or reduction of PR, improvement of functional class and reduction of

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diastolic and systolic RV volumes6. However, changes in RV systolic function7, burden of arrhytmias8, objective parameters of functional capacity9, and improved survival10,11 have not been demonstrated. The PVR can be surgically or percutaneously performed, usually using a biological valvular prosthesis. The mortality and morbidity of both

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procedures are low12 but the functional integrity of all available tissue valves deteriorates with time leading to prosthetic pulmonary valve failure (PPVF) and need for re-intervention. As the number of interventions is an independent predictor of death

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at long-term follow-up13, knowledge of the risk for PPVF is crucial for optimal timing of PVR. However, the rate of prosthesis degeneration can be highly variable and the

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risk factors for PPVF are not well established14,15. The main purpose of this study was to analyze the incidence and factors associated with PPVF in a large series of patients followed at a single center. Methods We conducted a retrospective cohort analysis of all patients who had undergone surgical PVR by a biological prosthesis or valved conduit, treated in the adult CHD unit at La Paz University Hospital, between January 1990 and December 2013. Patients in

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ACCEPTED MANUSCRIPT which PVR was due to a non-CHD cause were excluded. All available medical records, including echocardiograms, magnetic resonance or computed tomography imaging, hemodynamic studies and surgical protocols were revised. Follow-up was obtained from medical records supplemented of telephonic contact with patients themselves or

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their families. Complete follow-up was considered when a contact was available in the last year, a re-intervention due to PPVF was performed or the patient had died during follow-up. The study was approved by the local research Ethic Committee.

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The PPVF was defined as the need for pulmonary valve re-intervention,

including either surgical or transcatheter PVR. Six potential risk factors for PPVF were

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determined after literature revision: 1) underlying cardiac defect; 2) previous palliative procedure; 3) number of previous intracardiac interventions; 4) hemodynamic cause of PVR; 5) age at intervention; and 6) type of PVR. The underlying cardiac defect was classified as a) tetralogy of Fallot (including double outlet RV and pulmonary atresia

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with non-restrictive ventricular septal defect); b) pulmonary stenosis or atresia with intact ventricular septum; c) transposition complexes (including complete transposition and congenitally corrected transposition); and d) left ventricular outflow-tract

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abnormalities repaired by Ross or Ross-Konno techniques. The hemodynamic cause of PVR was classified as predominant stenosis or regurgitation. The type of PVR was

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classified as porcine heterograft, pulmonary or aortic homograft, or valved conduit. SPSS 15.0 for Windows (SPSS, Inc., Chicago, Illinois) was used for analysis.

Quantitative values are presented as mean ± SD or median and interquartile range (IQR) when appropriate. Discrete data are presented as percentage of total number of patients or total number of pulmonary prostheses. The event-free-time was analyzed by KaplanMeier method with 95% confidence intervals (CI), using as time scale the follow-up time between prosthetic valve insertion and date of re-intervention or censoring. For

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ACCEPTED MANUSCRIPT determining risk-factors of PPVF a Cox proportional model was used, and Hazard ratios (HR) with 95% CI were generated. As some patients had undergone two or more PVRs, the same patient could provide data for more than one time-interval and each new intervention was considered as an independent case. To analize the effect of age at

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intervention on the incidence of PPVF the series was subdivided by decades in four

groups, and event-free-times were compared using log rank test. In order to discriminate the value of age at intervention on the incidence of PPVF, statistical C index was used,

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determining the area under the ROC (receiving operating characteristics) curve with 95% CI and chi squared test. The best cut-point for age at intervention in the ROC

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curve was used for comparing actuarial curves of event-free-time, using Kaplan Meier method and the log rank test. Internal validation in the tetralogy of Fallot cohort was also performed. A bilateral p value < 0,05 was considered statistically significant in each analysis.

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Results

The study included 146 interventions of PVR in 114 patients with CHD. Table 1 shows demographic data, underlying CHD, number of previous cardiac interventions,

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palliative procedures, hemodynamic indication for PVR, and type of intervention in the whole cohort. Median postoperative follow-up was 7 years (IQR 13-34). The follow-up

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was complete in 94% of cases. Twelve patients died (11.5%) during the adult follow-up. Patients who died had transposition complex more often as underlying CHD (p=0.001) and more valved conduits (p=0.008), however there were not significant differences in age at PVR (p=0.45), palliative procedures (p=0.56), number of previous cardiac interventions (p=0.18) or hemodynamic indication for PVR (p=0.20). The cause of death was congestive heart failure in 4 cases, sudden death in 3, surgical re-intervention

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ACCEPTED MANUSCRIPT in 3 and endocarditis in 2. There were a total of 13 episodes of infective endocarditis after PVR in 13 patients. There were 60 cases of PPVF (41%) in 28 patients. Median event-free-time was 14 years (95% CI 12-16 years). Cumulative survival free from PPVF at 10, 15 and 20

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years since intervention was 71%, 41% and 25%, respectively (figure 1). Table 2 shows that there was no significant relationship between time to PPVF and underlying CHD, prior palliative procedure, number of previous intracardiac interventions, hemodynamic

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indication for PVR, or type of PVR. The only independent risk factor for PPVF was age at intervention (p=0.002). Figure 2 shows the event-free-time curves in patients grouped

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by decade of age at intervention (p=0.014 inter-groups). The area under ROC curve of the interrelation between age at intervention and PPVF was 0.95 (CI 0.92-0.98; p<0.001). The cut point for age at intervention with the best discriminative value for PPVF was 20.5 years old (figure 3A). Freedom from re-intervention due to PPVF 15

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years after PVR was 70% when intervention was performed at age > 20.5 years compared to 33% when PVR was undergone at age < 20.5 years (p=0.004) (figure 4A). Internal validation in 102 PVR in the cohort with tetralogy of Fallot showed an area

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under ROC curve of 0.98 (CI 96.5-1.0; p<0.001) (figure 3B). The best cut point was also 20.5 years old, and freedom from re-intervention due to PPVF 15 years after PVR

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was 64% when intervention was performed at age > 20.5 years as compared to 24% when PVR was undergone at age < 20.5 years (p=0.001) (figure 4B). Discussion

This study confirms the high incidence of PPVF in patients with CHD repaired by pulmonary valve prosthesis or RV-to-pulmonary artery valved conduit, showing a median survival free of re-intervention time for PPVF of 14 years. However, the incidence of PPVF was highly dependent on age at intervention. As shown in figure 2,

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ACCEPTED MANUSCRIPT there were no cases of PPVF among 47 patients whose surgery was performed after the age of 30 years, but there were 6 PPVF among 33 patients operated between 21 and 30 years (18%), 27 out of the 39 operated between 11 and 20 years (69%) and all of the 27 cases operated on before the age of 10 years.

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Different studies have shown that the incidence of PPVF may be related to the

underlying CHD, type of valve dysfunction (stenosis vs. insufficiency), type and size of prosthetic substitute, number of previous cardiac interventions and age at PVR16-20.

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Results of these studies are divergent, and while some show that the use of homografts has a higher incidence of prosthetic dysfunction18, others point out that the outcome of

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homografts is excellent19,20. Most of these studies did not take into account that the relation between age at surgery and the incidence of PPVF is so consistent that the effect of any predictor may be obscured by age factor15. In agreement with this concept, we found no significant relationship between underlying CHD, hemodynamic

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disturbance, prior palliative procedures, number of interventions or type of valvular substitute with the incidence of PPVF. Only age at the time of the intervention was an independent predictor.

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Previous studies conducted in pediatric population have highlighted the relationship between age at surgery and the incidence of PPVF 14,15,21,22. This study

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extends these findings to the adult population, showing that the effect of age at intervention on the incidence of PPVF is a continuous, at least during the first three decades of life. Despite this continuous variation in the incidence, the discriminative analysis showed a cutoff point between two groups with very different incidence of PPVF. While 70% of patients operated on at an age > 20.5 years remained free from reintervention due to PPVF 15 years after surgery, this percentage was only 33% when the procedure was performed at an age < 20.5 years (p=0,004). Internal validation of

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ACCEPTED MANUSCRIPT this cutoff was confirmed in 102 cases with tetralogy de Fallot. Sabaté-Rotés et al13, have recently showed similar findings in a large population of patients with tetralogy of Fallot who underwent PVR at a mean age of 31.4 ± 16.4 years. Only older age at intervention remained as an independent protective factor for re-intervention in the

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multivariate analysis. Comparing groups with high and low incidence of PPVF, they used a cutoff age of 18 years at intervention but no discriminative analysis for this relationship was obtained.

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The mechanisms for the interrelation between young age at intervention and early PPVF are not clear. They may be related with prosthetic size or with patient’s

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growth. This concept has led to the use of oversized conduits and prostheses in children not resulting in a reduction of PPVF incidence23. Also, this does not explain why this relationship is maintained in adolescents and young adults in whom sizing of PVR is not related to the age. The immunological response that results in degeneration of

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biological prosthetic valves is heightened during childhood24, and age-dependent histological changes have been noted in homografts or heterografts25. Moreover, the wide experience with valve prosthesis in adults with acquired heart diseases has shown

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that structural failure of biological prosthesis is also age dependent. The process of intrinsic degeneration and valve calcification is more pronounced in adolescents and

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young adults than in older patients, and it typically begins after the fifth year of valve replacement. In this sense, it is remarkable that actuarial curves depicted in figure 4 are identical during the first five years after intervention but the incidence of PPVF in both groups of patients progressively diverge after that time. These features are compatible with an accelerated process of prosthetic valve degeneration and calcification in younger ages.

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ACCEPTED MANUSCRIPT Several studies have shown that mortality related to PVR is low17,26,27 but morbidity is not negligible. Moreover, there is recent evidence that the incidence of infectious endocarditis after PVR may be high28,29 and 13 patients in this series (11,4%) presented infectious endocarditis on long-term postoperative follow-up. Thus, our

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findings advise caution in the current tendency on early timing for PVR in

asymptomatic young patients with repaired tetralogy of Fallot and severe right

ventricular outflow tract dysfunction. Current guidelines30 highlight symptomatic status

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together with functional class improvement as the main objectives of PVR in these

patients. In asymptomatic young patients, hypothetical benefits of early re-intervention

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should be counterbalanced with short and long term issues related to prosthetic valve disease. While improving survival or arrhythmic burden after PVR has not been demonstrated, surgical re-intervention should be postponed, if possible, until the third decade of life.

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This is a retrospective observational study in a cohort of patients followed in an adult CHD unit, in which complete follow-up was obtainable in 94% of cases. Referral bias was unavoidable because patients who died, or were lost on follow-up before adult

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age could not be included. Actually, death was not included as an event in actuarial analysis because late deaths were commonly due to causes other than PPVF but there

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was no significant difference in age at intervention between patients who died and survivors. The use of re-intervention due to PPVF as the endpoint may be imprecise because surgical indication could vary from one patient to another or from one era to other. However, it would be difficult to establish a clinical or hemodynamic cut point for defining the degree and the timing of prosthetic valve dysfunction.

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ACCEPTED MANUSCRIPT 1. Bashore TM. Adult Congenital Heart Disease: Right Ventricular Outflow Tract Lesions. Circulation 2007;115;1933-1947. 2. Geva T. Tetralogy of Fallot repair: ready for a new paradigm. J Thorac Cardiovasc Surg 2012;143:1305–1306.

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3. Khairy P, Aboulhosn J, Gurvitz MZ, Opotowsky AR, Mongeon FP, Kay J, Valente AM, Earing MG, Lui G, Gersony DR, Cook S, Ting JG, Nickolaus MJ, Webb G,

Landzberg MJ, Broberg CS; Alliance for Adult Research in Congenital Cardiology

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4. Murphy JG, Gersh BJ, Mair DD, Fuster V, McGoon MD, Ilstrup DM, McGoon DC, Kirklin JW, Danielson GK. Long-term outcome in patients undergoing surgical repair of tetralogy of Fallot. N Engl J Med 1993;329:593-599. 5. Nollert G, Fischlein T, Bouterwek S, Böhmer C, Klinner W, Reichart B. Long-term

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survival in patients with repair of tetralogy of Fallot: 36-year follow-up of 490 survivors of the first year after surgical repair. J Am Coll Cardiol 1997;30:1374– 1383.

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6. Ferraz Cavalcanti PE, Sá MP, Santos CA, Esmeraldo IM, de Escobar RR, de Menezes AM, de Azevedo OM Jr, de Vasconcelos Silva FP, Lins RF, Lima Rde C.

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Pulmonary valve replacement after operative repair of tetralogy of Fallot: metaanalysis and meta-regression of 3,118 patients from 48 studies. J Am Coll Cardiol 2013;62:2227-2243.

7. Tobler D, Crean AM, Redington AN, Van Arsdell GS, Caldarone CA, Nanthakumar K, Stambach D, Dos L, Wintersperger BJ, Oechslin EN, Silversides CK, Wald RM. The left heart after pulmonary valve replacement in adults late after tetralogy of Fallot repair. Int J Cardiol 2012;160:165-170.

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ACCEPTED MANUSCRIPT 8. Therrien J, Siu SC, Harris L, Dore A, Niwa K, Janousek J, Williams WG, Webb G, Gatzoulis MA. Impact of pulmonary valve replacement on arrhythmia propensity late after repair of tetralogy of Fallot. Circulation 2001;103:2489–2494. 9. Geva T, Gauvreau K, Powell AJ, Cecchin F, Rhodes J, Geva J, del Nido P.

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Randomized Trial of Pulmonary Valve Replacement With and Without Right

Ventricular Remodeling Surgery. Circulation 2010;122(11 Suppl):S201-S208. 10. Harrild DM, Berul CI, Cecchin F, Geva T, Gauvreau K, Pigula F, Walsh EP.

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Pulmonary valve replacement in tetralogy of Fallot: impact on survival and ventricular tachycardia. Circulation 2009;119:445-451.

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11. Lee C, Kim YM, Lee CH, Kwak JG, Park CS, Song JY, Shim WS, Choi EY, Lee SY, Baek JS. Outcomes of pulmonary valve replacement in 170 patients with chronic pulmonary regurgitation after relief of right ventricular outflow tract obstruction: implications for optimal timing of pulmonary valve replacement. J Am

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Coll Cardiol 2012;60:1005–1014.

12. Babu-Narayan SV, Diller GP, Gheta RR, Bastin AJ, Karonis T, Li W, Pennell DJ, Uemura H, Sethia B, Gatzoulis MA, Shore DF. Clinical Outcomes of Surgical

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Pulmonary Valve Replacement After Repair of Tetralogy of Fallot and Potential Prognostic Value of Preoperative ardiopulmonary Exercise Testing. Circulation

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2014;129:18-27.

13. Sabate Rotes A, Eidem BW, Connolly HM, Bonnichsen CR, Rosedahl JK, Schaff HV, Dearani JA, Burkhart HM. Long-term follow-up after pulmonary valve replacement in repaired tetralogy of Fallot. Am J Cardiol 2014;114:901-908. 14. Zubairi R, Malik S, Jaquiss RD, Imamura M, Gossett J, Morrow WR. Risk Factors for Prosthesis Failure in Pulmonary Valve Replacement. Ann Thorac Surg 2011;91:561-565.

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ACCEPTED MANUSCRIPT 15. Caldarone CA, McCrindle BW, Van Arsdell GS, Coles JG, Webb G, Freedom RM, Williams WG. Independent factors associated with longevity of prosthetic pulmonary valves and valved conduits. J Thorac Cardiovasc Surg 2000;120:10221030.

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16. Razzouk AJ, Williams WG, Cleveland DC, Coles JG, Rebeyka IM, Trusler GA,

Freedom RM. Surgical connections from ventricle to pulmonary artery. Comparison of four types of valved implants. Circulation 1992;86(5 Suppl):II154-II158.

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17. Danielson GK, Anderson BJ, Schleck CD, Ilstrup DM. Late results of pulmonary

ventricle to pulmonary artery conduits. Semin Thorac Cardiovasc Surg 1995;7:162-

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167.

18. Cleveland DC, Williams WG, Razzouk AJ, Trusler GA, Rebeyka IM, Duffy L, Kan Z, Coles JG, Freedom RM. Failure of cryopreserved homograft valved conduits in the pulmonary circulation. Circulation 1992;86(5 Suppl):II150-II153.

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19. Hazekamp MG, Kurvers MM, Schoof PH, Vliegen HW, Mulder BM, Roest AA, Ottenkamp J, Dion RA. Pulmonary valve insertion late after repair of Fallot's tetralogy. Eur J Cardiothorac Surg 2001;19:667-670.

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20. Niwaya K, Knott-Craig CJ, Lane MM, Chandrasekaren K, Overholt ED, Elkins RC. Cryopreserved homograft valves in the pulmonary position: risk analysis for

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intermediate-term failure. J Thorac Cardiovasc Surg 1999;117:141-146.

21. Discigil B, Dearani JA, Puga FJ, Schaff HV, Hagler DJ, Warnes CA, Danielson GK. Late pulmonary valve replacement after repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 2001;121:344-351. 22. Kanter KR, Budde JM, Parks WJ, Tam VK, Sharma S, Williams WH, Fyfe DA. One hundred pulmonary valve replacements in children after relief of right ventricular outflow tract obstruction. Ann Thorac Surg 2002;73:1801-1806.

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ACCEPTED MANUSCRIPT 23. Karamlou T, Ungerleider RM, Alsoufi B, Burch G, Silberbach M, Reller M, Shen I. Oversizing pulmonary homograft conduits does not significantly decrease allograft failure in children. Eur J Cardiothorac Surg 2005;27:548-553. 24. Baskett RJ, Ross DB, Nanton MA, Murphy DA. Factors in the early failure of

J Thorac Cardiovasc Surg 1996;112:1170-1179.

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cryopreserved homograft pulmonary valves in children: preserved immunogenicity.

25. Rajani B, Mee RB, Ratliff NB. Evidence for rejection of homograft cardiac valves

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in infants. J Thorac Cardiovasc Surg 1998;115:111-117.

26. Danielson GK, Anderson BJ, Schlek CD, Ilstrup DM. Late results of pulmonary

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ventricle to pulmonary artery conduits. Sem Cardiovasc Surg 1995;7:162-167. 27. Graham TP Jr, Bernard Y, Arbogast P, Thapa S, Cetta F, Child J, Chugh R, Davidson W, Hurwitz R, Kay J, Sanders S, Schaufelberger M. Outcome of pulmonary valve replacements in adults after tetralogy repair: a multi-institutional

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study. Congenit Heart Dis 2008;3:162-167.

28. Malekzadeh-Milani S, Ladouceur M, Iserin L, Bonnet D, Boudjemline Y. Incidence and outcomes of right-sided endocarditis in patients with congenital heart disease

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after surgical or transcatheter pulmonary valve implantation, J Thorac Cardiovasc Surg 2014;148:2253-2259.

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29. Albanesi F, Sekarski N, Lambrou D, Von Segesser LK, Berdajs DA. Incidence and risk factors for Contegra graft infection following right ventricular outflow tract reconstruction: long-term results. Eur J Cardiothorac Surg 2014;45:1070-1074.

30. Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H, Kilner P, Meijboom F, Mulder BJ, Oechslin E, Oliver JM, Serraf A, Szatmari A, Thaulow E, Vouhe PR, Walma E.

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ACCEPTED MANUSCRIPT ESC Guidelines for the management of grown-up congenital heart disease (new

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version 2010). Eur Heart J 2010;31:2915-2957.

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ACCEPTED MANUSCRIPT Figure legends Figure 1. Cumulative freedom from re-intervention for prosthetic valve failure after 146 pulmonary valve replacements in patients with congenital heart disease and right ventricular outflow tract dysfunction using Kaplan-Meier actuarial analysis.

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Figure 2. Kaplan- Meier cumulative freedom from re-intervention for prosthetic valve failure after 146 pulmonary valve replacements in patients with congenital heart disease classified by decade of age at intervention.

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Figure 3. Discriminative value of age at intervention on the prevalence of prosthetic pulmonary valve failure using area under receiving operating characteristics (ROC)

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curves in the whole series (A) and in patients with tetralogy of Fallot (B). Figure 4. Comparison between Kaplan- Meier cumulative freedom from re-intervention for prosthetic valve failure curves in patients operated on before and after the age of

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20.5 years. A) overall series. B) patients with tetralogy of Fallot.

ACCEPTED MANUSCRIPT Table 1. General characteristics of 114 patients with congenital heart disease repaired by prosthetic replacement of the pulmonary valve.

146

Male

68 (60%)

Age at intervention (years)

23 (13-34)

Age at end of the study

36±11

Underlying congenital heart disease 81 (71%)

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Tetralogy of Fallot

12 (10.5%)

Transposition complexes

12 (10.5%)

Others

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Pulmonary stenosis or atresia

Ross/Ross-Konno procedures

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Number of pulmonary valve replacements

8 (7%) 1 (1%)

Prior palliative procedures

Number of previous cardiac interventions Hemodynamic indication

49 (43%) 1 (1-2)

81 (55%)

Pulmonary valve regurgitation

57 (39%)

Others

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Type of intervention

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Pulmonary valve stenosis

8 (6%)

85 (58%)

Valved conduits

48 (33%)

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Porcine heterograft

Aortic or pulmonary homografts

21 (14%)*

Postoperative follow-up (years)

7 (3-12)

Reintervention by prosthetic failure

60 (41%)

Infective endocarditis

13 (11.5%)

Death

12 (10.5%)

Continuous variables are presented as mean ± SD or median with interquartile range. *Including 9 patients with homograft conduit

ACCEPTED MANUSCRIPT Table 2. Cox proportional modeling analysis of risk factors for pulmonary valve prosthetic failure in patients with congenital heart disease.

IC 95%

p

0.95

0.92-0.98

0.002

Tetralogy of Fallot

0.83

0.28-2.1

0.51

Pulmonary stenosis/atresia

0.77

0.45-3.6

0.61

Transposition complexes

1.08

0.55-2.1

0.82

Ross procedures

1.44

0.52-4.0

0.48

0.79-2.7

0.22

0.81

0.41-1.61

0.55

0.96

0.53-1.7

0.88

1.10

0.65-1.9

0.73

1.95

0.73-4.8

0.20

Prior palliative procedures

1.39

0.83-2.3

0.21

Number of previous interventions

1.13

0.80-1.6

0.49

Underlying heart defect

Hemodynamic indication 1.47

Regurgitation Type of valve replacement

Porcine heterografts Valved conduits

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Homografts

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Stenosis

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Abbreviations: CI, confidence interval

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Age at intervention (years)

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Hazard ratio

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1.0 1.0

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SC

0.8 0.8

0.6 0.6

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0.2 0.2

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0.4 0.4

0.0 0.0

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Cumulative Freedom from Reintervention for Prosthetic Valve Failure

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Postoperative Follow-up (years)

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1.0 1.0

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0.8 0.8

0.4 0.4

≤

EP

0.2 0.2

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0.6 0.6

0.0 0.0

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Cumulative Freedom from Reintervention for Prosthetic Valve Failure

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Postoperative Follow-up (years)

B

A

SC

1.0

0.8

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0.8

20.5 yrs

20.5 yrs

0.6 0.4

0.6

0.2

0.2

0.4

0.6

0.8

1 - Specificity

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0.0

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ROC area: 0.95 95% CI: 0.92-0.98 p<0.001

Overall (N:146)

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Sensitivity

1.0

0.0

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1.0

0.4

ROC area: 0.98 95% CI: 0.96-1.0 p<0.001

0.2

0.0 0.0

0.2

0.4

0.6

0.8

1.0

1 - Specificity

Tetralogy of Fallot (N:102)

ACCEPTED MANUSCRIPT

Overall (N=146) 1.0

(70%)

RI PT

0.8

Age at intervention: >20.5 years <20.5 years

0.4

(33%)

SC

0.6

p log-rank= 0.004 0.2

0.0

No at risk: 80 48 66

61

0

3

M AN U

Cumulative freedom from reintervention

A

29

17

7

4

54

41

31

16

6

9

12

15

Tetralogy of Fallot (N=102) (64%)

EP

1.0

0.8

Age at intervention: >20.5 years <20.5 years

AC C

Cumulative freedom from reintervention

B

TE D

Postoperative follow-up (years)

0.6

(24%)

0.4

0.2

0.0

p log-rank= 0.001

No at risk: 59 36

22

13

4

2

43

40

38

28

19

9

0

3

6

9

12

15

Postoperative follow-up (years)