Author + information
- Received March 5, 2013
- Revision received June 2, 2013
- Accepted July 8, 2013
- Published online December 3, 2013.
- Javariah Siddiqui, MBBS∗,
- Christian P. Brizard, MD†,‡,
- John C. Galati, PhD§,‖,
- Ajay J. Iyengar, MBBS∗,¶,
- Darren Hutchinson, MD#,
- Igor E. Konstantinov, MD, PhD†,‡,
- Gavin R. Wheaton, MD∗∗,
- James M. Ramsay, MD†† and
- Yves d'Udekem, MD, PhD†,‡,¶∗ ()
- ∗University of Melbourne, Melbourne, Australia
- †Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Australia
- ‡Department of Pediatrics of the University of Melbourne, Melbourne, Australia
- §Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Melbourne, Australia
- ‖Department of Mathematics and Statistics, La Trobe University, Melbourne, Australia
- ¶Murdoch Children's Research Institute, Melbourne, Australia
- #Department of Cardiology, Royal Children's Hospital, Melbourne, Australia
- ∗∗Department of Cardiology, Women's & Children's Hospital, Adelaide, Australia
- ††Department of Cardiology, Princess Margaret Hospital for Children, Perth, Australia
- ↵∗Reprint requests and correspondence:
Dr. Yves d'Udekem, Department of Cardiac Surgery, Royal Children’s Hospital, Flemington Road, Parkville, Melbourne, Victoria 3052, Australia
Objectives This study sought to compare outcomes after surgical valvuloplasty and balloon dilation of the aortic valve in neonates and infants.
Background Surgical techniques of aortic valve repair have improved and there is today controversy on the best approach to treat neonatal congenital aortic valve stenosis.
Methods Retrospective review of data and follow-up of 123 consecutive neonates and infants (35 females, 88 males) undergoing intervention for congenital aortic stenosis.
Results From 1977 to 2009, 123 consecutive neonates (<30 days) and infants (31 days to 1 year) underwent relief of congenital aortic stenosis. Median age at procedure was 27 days (6 to 76 days). Twenty-year survival was 80 ± 7%. Fifty-four patients required a re-intervention and freedom from re-intervention was 55 ± 6% at 10 years and 40 ± 6% at 20 years. By multivariate analysis, having the relief of stenosis by balloon valvuloplasty and undergoing initial treatment as a neonate were predictive of re-intervention. Freedom from re-intervention at 5 years was 27% after balloon valvuloplasty versus 65% after surgery. At latest follow-up, an additional 16 patients had moderate or severe stenosis and 8 had regurgitation. Freedom from re-intervention or stenosis was 39 ± 5% at 15 years. By multivariate analysis, balloon valvuloplasty (p < 0.001) and treatment as a neonate (p = 0.003) were again predictive of stenosis or re-intervention. Thirty-five patients ultimately needed a valve replacement. Significant predictor of the requirement of valve replacement was unicuspid aortic valve (p < 0.001). Freedom from valve replacement was 55 ± 7% at 20 years.
Conclusions Surgical valvuloplasty remains the best approach to treat neonates and infants with congenital aortic stenosis. After surgery, a higher proportion of patients remain free of re-intervention than after interventional catheterization and the relief of their stenosis lasts longer.
Critical aortic valve stenosis in infants and neonates can be treated either by surgery or balloon valvuloplasty. The current knowledge is that these 2 approaches yield equivalent results in terms of survival and rate of reoperation (1). Most centers have accordingly favored one or the other approaches following their own preferences and the type of expertise developed locally. This knowledge of equality of outcomes after both approaches has been based on large comparative trials dating from the mid-90s. It has been argued that the surgeries analyzed in this comparative study were limited in their vast majority to blade commissurotomies and that the subsequent evolution of surgical techniques made these comparisons obsolete (2–4). Recent data from surgical series indicate that surgery may achieve better outcomes than balloon valvuloplasty, but contemporary studies comparing outcomes after surgery and interventional catheterization are lacking (5). In our center, aortic valve disease has for many years been subjected to both forms of therapy. We decided to review our experience with balloon valvuloplasty and aortic valve surgery in order to delineate their respective outcomes in terms of survival and need for re-intervention and ultimate valve replacement.
This study was approved by the local Human Research Ethics Committee and the need for consent was waived because of the retrospective nature of the study. The files of all patients undergoing a procedure for aortic valve stenosis before the age of 1 year in the Royal Children’s Hospital, Melbourne, were reviewed. Between 1977 and 2009, there were 129 patients excluding the patients with hypoplastic left heart syndrome and borderline small left ventricles who underwent a Norwood procedure. Additionally, 3 overseas patients and 3 presenting with complex intra-cardiac malformations were excluded limiting the cohort of the study to 123 (35 females, 88 males).
Of these, 67 were neonates (<30 days) with a median age of 7 days (interquartile range [IQR]: 2 to 16 days) and 56 were infants (age >31 days and <365 days) with a median age of 81 days (IQR: 50 to 135 days). The median age at time of initial treatment was 27 days (IQR: 6 to 76 days). Of the 123 patients, 66 (53%) had isolated congenital aortic stenosis although 57 had associated cardiac lesions (Table 1). The morphology of the valve was described in the operative notes in 121 patients and was found to be unicuspid in 11 (9%), bicuspid in 90 (74%), and tricuspid in 20 (17%).
Nine patients had undergone a previous cardiac procedure: coarctation repair (n = 6), coarctation and mitral valve repair (n = 1), coarctation and aortic arch repair (n = 1), and resection of sub-aortic stenosis (n = 1).
The initial aortic valve procedure consisted in a balloon valvuloplasty in 37 patients and in a surgical procedure in 86 patients. The mean pre-procedural peak gradient was comparable in the patients undergoing balloon dilation (78 ± 22 mm Hg) and surgery (69 ± 29 mm Hg) (p = 0.097). The distribution of the procedures over the study period is displayed in Figure 1. The median balloon size to aortic annulus ratio was 0.95 (IQR: 0.83 to 1.07). Surgical techniques were limited to blade commissurotomy, resection of nodular dysplasia, and thinning of the leaflets in 75 patients (Fig. 2). Eleven patients had more complex procedures consisting in recreation of 1 commissure (n = 9) or 2 commissures (n = 1) and triangular resection of the leaflet free edge (n = 1). The commissures were recreated by adjunction of 2 separate patches of glutaraldehyde preserved autologous pericardium to the opened area of the valve (Fig. 2).
Seventeen of the 123 patients (15%) underwent the following concomitant 19 procedures: coarctation repair (n = 8), hypoplastic aortic arch repair (n = 1), ventricular septal defect repair (n = 6), atrial septal defect repair (n = 3), and a mitral valve repair and left atrial size reduction (n = 1).
Hospital mortality was defined as death prior to hospital discharge or within 30 days of the surgery. Late mortality was defined as death after discharge or more than 30 days from the first valve intervention. Early re-interventions were defined as any operation on a previous valve intervention or replacement before hospital discharge and were considered separate to late re-operations occurring after hospital discharge. Reporting of valve-related outcomes, such as valve thrombosis and bleeding events, were based on published guidelines (6). Follow-up information was gathered from the hospital database or collected from their referring cardiologists.
Statistical analysis was performed using Stata version 11.0 (StataCorp, College Station, Texas). Symmetric continuous variables were summarized as mean ± SD, and median (interquartile range) otherwise. Risk factors for the following time-related outcomes were examined using Cox regression analysis: mortality, re-intervention, valve replacement, moderate or greater restenosis or re-intervention, moderate or greater regurgitation, and failure of event-free long-term outcome. For all endpoints, time was measured starting from the day of the initial procedure. For the regurgitation endpoint, patient times were considered to have been censored in the event of a first re-intervention, and similarly, all non-mortality endpoints were considered to have been censored in the event of late death. The variables examined are listed in Table 2. Where feasible, variables identified by univariate analysis as the ones most likely to be associated with the given endpoint (hazard ratio [HR]: >2.0 or HR <0.5; p < 0.05) were included in a multivariable model.
There were 4 early deaths for a hospital mortality of 3%. Of these, 3 deaths occurred after surgery: one in the early 1980s in a 9-day-old patient who had a good post-operative result but who died from hyperkalemia, one in 2006 soon after extracorporeal circulation membrane oxygenation (ECMO) removal in an 11-day-old patient supported for 8 days, and multi-system organ failure led to the death of a 3-month-old patient on the 19th post-operative day. The fourth patient died after balloon dilation as a result of meconium aspiration and respiratory distress 31 days post-intervention. Three patients needed a chest exploration for hemopericardium and 3 patients developed a femoral artery thrombosis after a balloon dilation of the aortic valve. One patient was noted to have a right ventricular thrombus after surgery, which was treated conservatively.
The mean follow-up in hospital survivors was 10 ± 7 years. Only 1 patient was lost to follow-up. Concurrent completion of follow-up was 83% (102 of 123). There were 12 late deaths (10%). Eight late deaths occurred in patients who had initially a surgical procedure and 4 patients after an initial balloon dilation. Late mortality occurred between 43 days to 19 years, postoperatively. The causes of death were low output syndrome (n = 2), stroke (n = 1), arrhythmia (n = 1), sudden unexpected death (n = 2), noncardiac (n = 2), and unknown (n = 4). Survival of all patients from the time of intervention at 10 and 20 years were, respectively, 88% (95% CI: 81% to 93%) and 80% (95% CI: 61% to 90%) (Fig. 3). By univariable analysis, the factors most likely to be associated with late mortality were presence of endocardial fibroelastosis (HR: 10.3; 95% CI: 3.3 to 32.0; p < 0.001), concurrent diagnosis of heart failure (HR: 4.7; 95% CI: 1.4 to 16.0; p = 0.02), and aortic annulus size (HR: 0.6; 95% CI: 0.3 to 0.96; p = 0.035). A multivariable analysis to separate the effects of these factors was not feasible because of the small number of late deaths.
Freedom from re-intervention
Fifty-four of the 119 hospital survivors (45%) required a re-intervention. Five patients required early re-interventions during the initial hospital stay. From these, 4 patients were following an unsuccessful balloon valvuloplasty that failed to decrease the gradient and 1 patient was due to residual aortic stenosis post-valvotomy. Four of these 5 patients ultimately required a Ross procedure during the initial hospital stay. Forty-nine patients underwent a re-intervention after hospital discharge. Thirty-five patients had only 1 re-intervention, 11 had 2, and 3 had 3 re-interventions. Re-intervention procedures were balloon valvuloplasty (n = 12), blade commissurotomy with leaflet thinning and nodular resection (n = 8), complex aortic valve repair (n = 14), and Ross procedure (n = 31).
At the last follow-up, 14 (38%) of the 37 patients undergoing balloon valvuloplasty and 55 (64%) of the 86 patients undergoing surgery had not required re-intervention. Freedom from re-intervention at 5, 10, and 20 years, respectively, were 70% (95% CI: 60% to 78%), 55% (95% CI: 43% to 65%), and 40% (95% CI: 28% to 52%).
Of the factors examined (Table 2), univariable analysis identified having a balloon valvuloplasty (HR: 3.2; p < 0.001), undergoing an initial procedure as a neonate (HR: 2.5; p = 0.003) (or lower age at the time of initial procedure), unicuspid valve morphology (HR: 3.6; p = 0.011), the presence of endocardial fibroelastosis (HR: 2.4; p = 0.042), and the presence of an atrial septal defect (HR: 2.0; p = 0.046) as the factors most likely to be associated with re-intervention. The last 3 factors occurred, respectively, in 9, 11, and 12 patients only, and therefore were not included in a multivariable model. Of the remaining 2 factors, by multivariable analysis both having a balloon valvuloplasty as the primary procedure (HR: 4.0; 95% CI: 2.1 to 7.7; p < 0.001) and undergoing initial treatment as a neonate (HR: 3.0; 95% CI: 1.6 to 5.6; p = 0.001) were predictive of re-intervention.
The median time to re-intervention was 11 months (IQR: 2 months to 5 years) after an initial balloon valvuloplasty and 5 years (IQR: 11 months to 12 years) after a surgical procedure. Ten years after the initial procedure, freedom from re-intervention was 27% (95% CI: 10% to 47%) after balloon valvuloplasty and 65% (95% CI: 52% to 76%) after surgery (Fig. 4).
Freedom from valve replacement
Thirty-five patients underwent a valve replacement that consisted of the Ross procedure. Univariable analysis identified having a unicuspid valve at time of intervention (HR = 11.2; 95% CI: 3.8 to 33; p ≤ 0.001) as the most likely factor predicting the need for valve replacement. Thirteen of the 37 patients (35%) undergoing a balloon valvuloplasty and 22 of the 86 undergoing surgery (26%) ultimately needed a Ross procedure. Freedom from valve replacement was 83% (95% CI: 74% to 90%) at 5 years and 55% (95% CI: 39% to 68%) at 20 years.
The gradient through the aortic valve decreased from 78 ± 22 mm Hg to 40 ± 16 mm Hg after balloon valvuloplasty (p < 0.001) and from 69 ± 29 mm Hg to 30 ± 17 mm Hg after surgery (p < 0.001). The post-procedural decrease in the transvalvular gradient was similar after both procedures (38 mm Hg vs. 39 mm Hg).
Freedom from significant restenosis or re-intervention
At latest follow-up 16 of the 69 patients who did not undergo a re-intervention were considered by their cardiologist to suffer from at least moderate stenosis. Their mean peak gradient was 51 ± 14 mm Hg. Freedom from either re-intervention or more than moderate stenosis was 39% (95% CI: 28% to 49%) at 15 years. At latest follow-up the gradient of those who did not undergo a re-intervention and were considered to have less than moderate stenosis was 32 ± 16 mm Hg.
Of the factors examined, univariate analysis identified having a balloon valvuloplasty (HR: 2.9; p < 0.001), unicuspid valve morphology (HR: 3.9; p = 0.001), undergoing initial treatment as a neonate (HR: 1.8; p = 0.024) (or lower age at initial treatment), and the presence of endocardial fibroelastosis (HR: 2.3; p = 0.032) as the factors most likely to be associated with either restenosis or re-intervention. The second and fourth factors were omitted from the multivariable model because of the small number of patients having these factors. By multivariable analysis, both having a balloon valvuloplasty (HR: 3.6; 95% CI: 2.0 to 6.4; p < 0.001) and undergoing initial treatment as a neonate (HR: 2.2; 95% CI: 1.3 to 3.7; p = 0.003) were predictive of restenosis or re-intervention.
Six years after the initial procedure, freedom from re-intervention or more than moderate restenosis was 30% (95% CI: 14% to 47%) after balloon valvuloplasty and 66% (95% CI: 54% to 76%) after surgery (Fig. 5).
Freedom from regurgitation
At latest follow-up or just prior to first re-intervention, 32 patients had moderate or greater regurgitation. Of these 32 patients, 16 had moderate regurgitation, 8 had moderate to severe regurgitation, and 8 had severe regurgitation. Of the 69 patients who had not needed a re-intervention, 8 had moderate regurgitation.
By univariable analysis, having a unicuspid valve (HR: 8.1; 95% CI: 2.5 to 26; p < 0.001) was predictive of occurrence of regurgitation. Freedom from significant regurgitation was 84% (95% CI: 75% to 90%) at 5 years, 71% (95% CI: 59% to 80%) at 10 years and 57% (95% CI: 40% to 71%) at 20 years.
Event-free long-term outcome
Forty-four patients had an event-free long-term outcome defined as requiring no re-intervention and having less than moderate stenosis and regurgitation at latest follow-up. Ultimately, 9 of the 37 patients who underwent balloon valvuloplasty (24%) and 39 of the 86 who underwent surgery (45%) were susceptible to have long-lasting results with no re-intervention and less than moderate regurgitation and stenosis. The mean follow-up of these patients was 8 ± 7 years (median 6 years; IQR: 2 to 17 years). By univariable analysis, unicuspid valve morphology (HR = 4.6; p < 0.001), having balloon valvuloplasty as the initial procedure (HR: 2.7; p < 0.001) and undergoing initial treatment as a neonate (HR: 1.8; p = 0.018) (or lower age at initial treatment) were associated with not having an event-free long-term outcome. According to multivariable analysis, both having a balloon valvuloplasty (HR: 3.2; 95% CI: 1.8 to 5.7; p < 0.001) and being a neonate at time of initial intervention (HR: 2.2; 95% CI: 1.3 to 3.6; p = 0.002) were predictive of not having an event-free long-term outcome (with unicuspid valve morphology being excluded from the model because of the small number of patients with this factor).
Specific outcomes in neonates and infants
When analyzed separately in neonates and infants, patients undergoing balloon valvuloplasty had a higher risk of re-intervention than those undergoing surgery (respectively HR: 4; p = 0.001 and HR: 3.08; p = 0.047). After surgery, freedom from re-intervention at 10 years was 55% (95% CI: 37% to 70%) for neonates and 78% (95% CI: 57% to 89%) for infants. After balloon valvuloplasty, freedom from re-intervention at 8 years was 15% (95% CI: 1% to 44%) for neonates and 40% (95% CI: 12% to 68%) for infants (Figs. 6A and 6B).
In 2001, in 1 of the very few comparative multi-centric studies existing in the field of congenital heart disease, McCrindle et al. (1) compared the results of balloon valvuloplasty with surgery and found that both approaches achieved similar outcomes in terms of survival and re-intervention. Most centers are favoring only 1 of the 2 approaches, following the expertise developed locally and their personal bias. The vast majority of centers (7–9) are favoring balloon valvuloplasty at this age, likely because the initial decision is in the hands of the cardiologists who are the first physicians to care for the patient and because the expertise in balloon valvuloplasty has been easier to develop than advanced surgical techniques.
The last 2 decades have seen an improvement of the techniques of aortic valve repair, and the expansion of their use in the adult population and it is possible that the surgical procedures performed nowadays are superior than those practiced in the past (5,10). Until recently, neonatal surgery of the aortic valve was limited to blind transapical dilation of the valve or simple blade commissurotomy. A third of the patients undergoing surgery in the comparative study of 2001 underwent a transapical balloon dilation, a procedure closer to balloon valvuloplasty than contemporary surgery (11). Surgeons are now realizing that in order to achieve a more durable repair it is necessary to de-bulk the leaflets from all thickening and nodular dysplasia and to resuspend with patches the incised unsupported portion of the leaflets.
Knowledge gained by a single center retrospective study will always be limited by the fact that within 1 center, 1 approach will always be favored, and expertise will mainly be developed in that area. Our team over the course of the last 6 years has clearly favored the surgical treatment of aortic valve disease, but for 14 years, both approaches were offered. Because it has been unusual to offer both approaches to patients, it was worth reviewing our experience despite the lack of randomization in order to compare their long-term outcomes especially in terms of reoperation rate and mode of failure.
Survival of the entire group compares favorably to previous results with a hospital mortality of 2% and a late mortality close to 10%. As expected, the patients with the most extreme form of the disease and the patients requiring a procedure as neonates were at higher risk of mortality.
There was in our patients a striking difference between the 2 approaches in the risk of re-intervention. Clearly, patients necessitating an intervention earlier in life have a higher risk of requiring re-intervention. By the end of the second decade following the procedure, half of our patients required a second procedure, but half of those remaining free of re-intervention were still showing significant aortic valve stenosis, and were likely to require a re-intervention in the near future. In this review of our historical experience, patients undergoing balloon valvuloplasty required re-intervention more rapidly than those undergoing surgical valvuloplasty. One will argue that this observed difference is related to the poor results achieved with balloon valvuloplasty in our center because we were in our learning curve at that time. The re-intervention rate after catheter intervention in our center was inferior to those reported by Pedra (11). However, the 68% freedom from re-intervention at 10 years of neonates and infants undergoing surgery were still superior to the best results reported after balloon dilation of an entire pediatric population (8). In our center, where both approaches were concomitantly offered over the course of the years, and even before the present analysis was conducted, there was a gradual shift in decision-making favoring surgery over interventional catheterization.
We believe that benefits of both approaches should not only be weighed in terms of re-intervention rates, but more importantly, in terms of the proportion of patients who may have a subsequent surgery postponed for several decades. At the term of our follow-up close to half of the patients who underwent surgery were living with a non-stenotic, non-regurgitant native valve, a much higher proportion than if they had undergone an initial balloon valvuloplasty. We hope that a proportion of these patients may live with their native valve for more than 2 decades. Delaying by several years the re-intervention is a benefit that compensates for the invasiveness of surgery. We believe that the majority of the patients undergoing balloon valvuloplasty will ultimately end up with a valve replacement because of the destructive nature of balloon valvuloplasty. The majority of these patients will end with a Ross procedure. There has been evidence that up to a quarter of the patients may see these autografts fail in the 2 decades following the initial Ross procedure because of the observed dilation of the transplanted autograft roots (12). It is believed that root dilation may be prevented by favoring the inclusion technique over the root replacement or by including the autograft in a prosthetic graft (13). Inclusion technique can only be performed in larger roots and can only rarely be performed in the pediatric age. We hope that postponing the Ross procedure to the adult age will allow the use of techniques allowing better outcomes after the Ross procedure. We believe that after aortic valve repair, long-standing growth of the aortic root will be observed (14) and we hope that this growth will enable the surgeon to perform a higher proportion of inclusion technique at a later age.
The main limitation of the study is its retrospective nature. This design cannot eliminate potential selection bias in the distribution of the patients between the 2 approaches. Additionally, the comparison between both approaches may have been fraught by an era effect favoring the patients undergoing surgery as in the most recent years when progress may have still occurred with both approaches, the vast majority of patients underwent surgery.
In our one center’s experience, surgical valvuloplasty remained the best approach to treat neonates and infants with congenital aortic stenosis. After surgery, a higher proportion of patients remain free of re-intervention than after interventional catheterization and the relief of their stenosis lasts longer.
This research project was supported by the Victorian Government's Operational Infrastructure Support Program. Dr. d’Udekem is a Career Development Fellow of The National Heart Foundation of Australia (CR 10M 5339). Dr. Brizard is an adviser to Allied Health Care Group, Australia, and has received travel funds. Dr. d’Udekem is a consultant to Merck Sharp & Dohme; and receives consultancy fees. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviation and Acronym
- balloon valv.
- balloon valvuloplasty
- Received March 5, 2013.
- Revision received June 2, 2013.
- Accepted July 8, 2013.
- American College of Cardiology Foundation
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