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J Thorac Cardiovasc Surg 2007;134:1429-1437
© 2007 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease |
a The Congenital Heart Surgeon’s Society Data Center, Toronto, Ontario, Canada
b The Hospital for Sick Children, Toronto, Ontario, Canada
c The Cleveland Clinic Foundation, Cleveland, Ohio
d Children’s Mercy Hospital, Kansas City, Mo
e University of Texas Southwestern Medical Center, Dallas, Tex
f Alfred duPont Hospital for Children, Wilmington, Del
g Montreal Childrens Hospital, Montreal, Quebec, Canada
h Boston Children’s Hospital, Boston, Mass
i Children’s Heart Clinic, Minneapolis, Minn
j St Christopher Hospital for Children, Philadelphia, Penn.
Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-9, 2007.
Received for publication May 17, 2007; revisions received July 19, 2007; accepted for publication July 24, 2007. * Address for reprints: Edward J. Hickey, MD, the Congenital Heart Surgeons’ Society, Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. (Email: hickeydoc{at}yahoo.com).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Methods: Between 1994 and 2001, 362 neonates with critical left ventricular outflow tract obstruction were prospectively enrolled by 26 institutions. Initial procedure indicated intended univentricular repair (n = 223; 84 deaths) or biventricular repair (n = 139; 39 deaths). Parametric risk–hazard analysis identified predictors of death for univentricular and for biventricular repair, which allowed prediction of the 5-year univentricular survival advantage for every infant. Survival was scrutinized for children managed discordantly to univentricular survival advantage predictions.
Results: Incremental factors for death after univentricular repair were as follows: tricuspid regurgitation, smaller mitral annulus z-score, smaller indexed dominant ventricular length, and presence of a large ventricular septal defect; risk factors after biventricular repair were as follows: minimum left ventricular outflow tract diameter, endocardial fibroelastosis, left ventricular dysfunction, and smaller mid-aortic arch. These variables formed the univentricular survival advantage tool (all P < .0001, R 2 = 0.92). Discordant management was more common with biventricular than with univentricular repair (56% vs 21%; P < .01). Discordant pursuit of biventricular repair was associated with significantly more observed versus expected deaths (biventricular repair 30 vs 14; P < .001; univentricular repair 20 vs 13; P = .02). Survival after biventricular repair is sensitive to changes in univentricular survival advantage values, especially in borderline candidates. In contrast, univentricular repair survival is insensitive to changes in univentricular survival advantage values.
Conclusions: Inappropriate pursuit of biventricular repair in borderline candidates is more frequent and more consequential in survival terms than is inappropriate pursuit of univentricular repair. Use of the univentricular survival advantage tool will help identify infants for whom univentricular repair may be a better choice than attempting biventricular repair.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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In treating the spectrum of critical left ventricular outflow tract (LVOT) obstruction, making the wrong initial choice between biventricular (BVR) versus univentricular repair (UVR) can prove fatal. The common perception that biventricular physiology is inherently superior to univentricular physiology has led to a bias favoring BVR.1
We hypothesized that pursuit of BVR in borderline candidates increases mortality.
The Congenital Heart Surgeons’ Society (CHSS) has previously published a prediction model to aid in optimal decision-making for neonates with critical LVOT obstruction.1 We subsequently discovered that the decision logic was overly sensitive to age at admission. In addition, the increasing occurrence of antenatal diagnosis complicates the determination of precise age at admission. Therefore, we have refined the model by expanding the cohort, extending follow-up duration, and using more robust analytic methods. Using the new model, we categorized actual management strategies as concordant or discordant with respect to the model’s prediction for optimal survival. The survival impact of discordant decisions was evaluated.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Critical neonatal LVOT obstruction was defined as stenosis occurring at any level from the subvalvular region to the innominate artery with or without left ventricular hypoplasia, such that the systemic circulation was ductus dependent. Of the 410 neonates, 366 met inclusion criteria of atrioventricular and ventriculoarterial concordant connections, aortic and mitral valve patency, and aortic arch continuity and underwent an intervention to relieve obstruction within 30 days of birth. We excluded 4 patients referred for cardiac transplantation from subsequent analysis, leaving a study cohort of 362 neonates (Figure E1).
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Echocardiograms (n = 214 patients) were requested and reviewed by a blinded examiner. If echocardiograms were not available, functional and morphologic indices (Table E1) were extracted from reports. Patients’ families were contacted annually by the CHSS Data Center staff, and completeness of this follow-up was 88% in 2006.
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n = 5), and Yasui procedure3,4 (n = 2) (Figures E3 and E4).
Of these, 1 underwent transplantation and 11 were converted to UVR. All are included in the BVR analysis.
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UVR-SA decision tool
Development of the UVR-SA tool included the following: (1) separate risk factor analyses for death after intended UVR and BVR management, (2) prediction of 5-year survival for each patient with either strategy using these analyses, and (3) identification of predictors for the survival difference between strategies.
Separate parametric models for time-related survival after intended UVR and BVR were generated as previously described.1,5 However, covariates representing age or surrogates thereof were suppressed in the current multivariable analyses (see below). One new covariate investigated was minimal LVOT diameter (regardless of level). Variable selection used bagging.6 One thousand bootstrap samples were analyzed automatically with P =.1 for retention of variables. Those appearing in 50% or more of bootstrap models or clusters were considered reliable for inclusion in the final models.
Age at admission and age at first intervention were suppressed in both UVR and BVR models. We tested this decision by exploring correlation of age with morphologic and functional variables, its colinearity with other variables and survival, goodness of fit of the model with and without age, and its relation to decision management.
Using the UVR and BVR multivariable equations, we estimated 5-year survival for each patient, first as if the patient had undergone UVR and second as if the patient had undergone BVR. Differences between predictions for UVR 5-year survival and BVR 5-year survival were analyzed by bagging and linear regression to generate the UVR-SA tool.
Use of UVR-SA tool to classify discordant management decisions
For each patient, the UVR-SA values were calculated and used to predict the "optimal management decision" for that patient.
A positive value favors UVR management and a negative value favors BVR management. For a given patient, if predicted 5-year survival for UVR is 75% and for BVR is 60%, the UVR-SA value would be +15, indicating a 15-point survival difference favoring UVR. Alternatively, if predicted survival for UVR is 52% and for BVR is 60%, the UVR-SA value would be –8, indicating an 8-point survival difference favoring BVR. A UVR-SA value of zero indicates that predicted survival is equal with either approach, and therefore neither is favored over the other.
When the UVR-SA prediction was in accordance with clinical intent to treat, management was labeled as "concordant." When the UVR-SA prediction was not in accordance with clinical intent to treat, management was labeled as "discordant."
Survival consequences of discordant management
Three methods were used to compare actual survival with best predicted 5-year survival according to the UVR-SA value. For each group (UVR concordant, UVR discordant, BVR concordant, BVR discordant), Kaplan–Meier survival estimates were generated. In addition, for each patient, cumulative hazard was estimated at the time of follow-up by the multivariable equation for the management pathway associated with the best predicted 5-year survival. Expected number of deaths was the sum of these cumulative hazard estimates. This was compared with actual deaths by the 
2 test. Finally, for each patient a survival curve was generated by the multivariable equation for the management pathway with the best predicted 5-year survival. Survival curves for infants within each of the 4 groups were aggregated and the mean was compared with corresponding Kaplan–Meier estimates.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Five-year unadjusted survival after UVR was 62% ± 3% (Figure E5). Incremental risk factors for death included moderate or severe tricuspid regurgitation (P < .01), large ventricular septal defect (VSD, P = .01), smaller mitral valve z-score (P < .01), and smaller indexed length of the dominant (apex-forming) ventricle (P = .02). Moderate or severe tricuspid regurgitation or a large VSD were associated with especially poor survival (Figure E6).
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Use of UVR-SA Tool to Classify Discordant Management Decisions
The distribution of UVR-SA values in the 362 study patients ranged from +78 (strongly favoring UVR) to –81 (strongly favoring BVR) with a median of +15. For a neonate with the mean UVR-SA value of +15, predicted 5-year survival is 15% better with UVR than with BVR. UVR-SA value was negative in 30% of patients (favoring BVR) and positive in 70% (favoring UVR).
The median UVR-SA value within the UVR group was +29 (range –81 to +78, Figure 2, dashed line). A positive value (79% of this group) indicated that the actual strategy pursued was concordant with the predicted strategy of the UVR-SA value ("UVR concordant"). A negative score (21% of this group) indicated that the strategy pursued was discordant with the predicted strategy ("UVR discordant").
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Survival Consequences of Discordant Management
Five-year survival with UVR management was similar with concordant and discordant management, 63% versus 56%, respectively. If BVR had been pursued for discordant UVR patients, the predicted 5-year survival would have been 70% (Figure 3) and 7 deaths may have been prevented (20 actual vs 13 expected with BVR management; P =. 02, Table 2).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Determinants of survival after UVR
Tricuspid regurgitation is associated with increasing mortality after UVR and was also identified in the previous CHSS prediction model1 and this revision. It contributes to volume overload, right ventricular failure, and compromised cardiac output. Attempts to repair established or new-onset tricuspid regurgitation are increasingly being made to reduce attrition after the Norwood palliation and improve the chances of successful Fontan repair.7
Mitral annular size correlates highly with left heart structural dimensions and also with mortality after UVR, and it likely represents a robust surrogate for overall left-sided structural hypoplasia. A small annulus did not correlate with mitral stenosis or regurgitation. Although UVR largely neutralizes the inadequacy of the left ventricle, others have demonstrated improved survival after Norwood palliation in situations in which the left heart is not hypoplastic.8,9
Larger indexed length of the dominant ventricle was associated with improved survival in UVR. Because the dominant ventricle was almost exclusively the right ventricle, this variable may reflect the functional adequacy of the right ventricle in assuming the systemic role. Right-sided functional variables were sparse in our UVR-SA model development and those of others.10,11 The identification of this unusual variable therefore reinforces the need to more closely quantify the influence of right ventricular features on outcome in critical LVOT obstruction.
Although we have found the presence of a large VSD to be associated with increased mortality after UVR, we cannot offer an explanation for this.
Determinants of survival after BVR
Both here and previously,1,11,12 EFE has been identified as an important predictor of death after BVR, even when left ventricular function is adequate. Although the reliability of diagnosing EFE by echocardiography has been questioned, we1 have previously demonstrated correlation between preintervention evaluation and findings at autopsy. Furthermore, we and others11 have found that thickened echo-bright endocardium is a robust prognostic determinant, regardless of true correlation with pathologic specimens.
A newly considered variable, the minimum LVOT dimension (regardless of level), was a more reliable risk factor than any single level of LVOT obstruction, including the aortic valve. A small aortic valve z-score is, however, a feature associated with early BVR intervention (particularly BAV) and death,1,11,13 especially in very young children.1 Inclusion of the broader concept of minimum LVOT dimension allows identification of additional neonates with more diffuse LVOT hypoplasia who also respond poorly to aortic valvotomy. An indexed LVOT diameter smaller than 16 mm/m2 (equivalent to 4 mm for a body surface area of 0.25 m2) confers disproportionately poor predicted survival after BVR (Figure E7, a).
The importance of diffuse LVOT hypoplasia is emphasized by the impact of distal arch dimensions on survival after BVR. More diffuse phenotypic disease is likely to be less amenable to either surgical or balloon valvotomy alone. In some infants, distal arch hypoplasia and coarctation may predominate, a condition recently termed hypoplastic left heart complex.14 This latter circumstance requires intervention directed primarily toward the arch and we therefore consider it a separate entity.
Age
Suppression of age in this revision of the UVR-SA prediction model does not undermine its clinical importance. Other informative variables have instead been incorporated without compromising goodness of fit. Age variables are problematic, first because of imprecision (age at admission) and second because they may be prone to manipulation (age at intervention). Variables that may be manipulated by the user are inherently undesirable for a predictive model based on patient-specific characteristics. For example, no inference can be made that delaying the date of intervention will alter outcome, yet the inclusion of age provides the potential for this erroneous decision logic. In addition, the increasing advent of fetal diagnosis further confounds the use of admission age as a variable.15 Because young age is an especially strong determinant of poor outcome after BVR, small inadvertent variations will result in large predictive differences.
Interestingly, young age is a risk factor for BVR16 but not for UVR (where it may even be protective.17) We therefore explored functional and anatomic features for which young age at BVR is a surrogate. Only a smaller aortic valve z-score was identified, and this was only within those BVR infants discordantly managed (the majority by BAV). The inference is that tight, discrete aortic valve stenosis requiring very early intervention is often managed by BAV, with high resulting mortality. The UVR-SA tool identifies 80% of these high-risk infants as being better served by UVR. The impact of BVR (especially BAV) in extremely young neonates needs to be further explored.
Alternative models for critical LVOT obstruction
Other prediction models have been devised for critical LVOT obstruction, including the Rhodes score,10 which has been recently tested against the previous CHSS model.11 However, the Rhodes score was generated in a homogeneous subset of infants with discrete valvular stenosis (not necessarily ductus-dependent), all of whom had BVR. It is therefore applicable only to the most favorable cases, ideally suited to BAV. Furthermore, it provides no survival comparison with an alternative strategy. Colan and associates11 have nevertheless reported the revalidation of the Rhodes score, although in a population of infants preselected for BVR on the basis of favorable features.
UVR-SA tool to improve decision management
In the clinical arena, we recognize that the UVR-SA tool should be seen as an aid to decision making, not a rule. The UVR-SA tool must be applied to an individual patient in the context of local expertise and family preference. However, larger UVR-SA values should prompt greater caution when pursuing discordant management than more modest (borderline) values. Furthermore, the sensitivity of BVR survival to changes in UVR-SA indicates that discordant pursuit of BVR is more costly in survival terms than discordant pursuit of UVR. In fact, infants receiving discordant BVR display the best predicted UVR survival (80% at 5 years).
Limitations
Several limitations are inherent in the use of our prediction model. Although the tool integrates complex information, it does not include all patient characteristics or factors specific to an individual institution. Also, the UVR-SA tool uses survival as the end point, without considering functional performance, reintervention, or quality of life, which are all important considerations. This present analysis identified only early hazard phases. It is likely that late hazard phases exist for both strategies, particularly after UVR.18 Similarly, the impact on survival of unplanned reintervention after BVR is not clearly understood.
The use of death as the primary end point has not included "crossovers" to opposite strategies as "events." However, crossover from BVR to UVR (n = 12, 9%) was considerably more frequent than the converse (n = 7, 3%). Therefore, an analytical strategy incorporating crossovers as events further biases against BVR in borderline cases and would strengthen our message further.
As practice evolves with the more widespread use of modalities such as the Ross–Konno procedure, hybrid palliation,19 and modifications of the Yasui procedure,4 the UVR-SA will require recalibration with new cohorts and continued follow-up. The CHSS is presently enrolling a contemporary cohort for the purposes of model revalidation and refinement while exploring modern treatment modalities and investigating functional outcomes.
The advantage of studying a multi-institutional cohort is that the full spectrum of management strategies (and outcomes) is incorporated. However, a disadvantage is that institution-specific factors may influence the development and application of a predictive model. For example, institution-specific differences in outcome may have biased the risk factors associated with one strategy or the other. Similarly, the applicability of the model’s predictions may be jeopardized by differences in local technical expertise.
Finally, this analysis has been undertaken on a cohort between 1994 and 2001. Although outcomes of all procedures are likely to have improved since then, we would contend that outcomes after UVR have enjoyed a more pronounced relative improvement. For example, several groups are reporting operative mortality below 20%20 and even approaching 10%21,22 after stage I Norwood palliation. Relatively greater improvements in UVR survival would further strengthen our conclusions.
Implicit in the use of prediction models is that heeding their advice will translate into improved clinical outcomes. The ideal revalidation of our model would involve a prospective trial in which infants managed in accordance with the UVR-SA tool are compared with infants managed according to current clinical practice. Such a trial seems unlikely. However, a cohort of neonates with LVOT obstruction that the CHSS is presently enrolling will serve as an ideal substrate for comparing the overall predictive accuracy of survival.
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Conclusions |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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Footnotes |
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionsReferences |
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