CONGENITAL: TRUNCUS ARTERIOSUS

Long-term outcomes of truncus arteriosus repair: A

modulated renewal competing risks analysis
Alvise Guariento, MD,a Ilias P. Doulamis, MD, PhD,a Steven J. Staffa, MS,b Laura Gellis, MD,c
Nicholas A. Oh, MD,a Takashi Kido, MD, PhD,a John E. Mayer, MD,a Christopher W. Baird, MD,a
Sitaram M. Emani, MD,a David Zurakowski, MS, PhD,b Pedro J. del Nido, MD,a and
Meena Nathan, MD, FRCS, MPHa
CONG

ABSTRACT A smaller RV-PA conduit size and TV insufficiency at

diagnosis are risk factors associated with increased
overall mortality

Objective: In this study, we sought to identify independent risk factors for mortality Truncal valve (TV) reoperation
1. Number of TV cusps

and reintervention after early surgical correction of truncus arteriosus using a novel 2. Moderate/severe TV insufficiency
or TV stenosis at diagnosis
3. Need for concomitant TV
statistical method. operation at index operation

Earlier RV-PA conduit reintervention

Methods: Patients undergoing neonatal/infant truncus arteriosus repair between 1. Conduit size d 11 mm at index
operation

January 1984 and December 2018 were reviewed retrospectively. An innovative sta-
A novel analysis for risks of mortality and reinter-
tistical strategy was applied integrating competing risks analysis with modulated
vention after TA repair.
renewal for time-to-event modeling.
Results: A total of 204 patients were included in the study. Mortality occurred in 32 CENTRAL MESSAGE
patients (15%). Smaller right ventricle to pulmonary artery conduit size and truncal Despite improved survival with
valve insufficiency at birth were significantly associated with overall mortality (right
truncus arteriosus repair, rein-
ventricle to pulmonary artery conduit size: hazard ratio, 1.34; 95% confidence inter-
val, 1.08-1.66, P ¼ .008; truncal valve insufficiency: hazard ratio, 2.5; 95% confidence terventions are common and
interval, 1.13-5.53, P ¼ .024). truncal valve insufficiency at birth, truncal valve inter- related to truncal valve anatomy
vention at index repair, and number of cusps (4 vs 3) were associated with truncal
and initial conduit size.
valve reoperations (truncal valve insufficiency: hazard ratio, 2.38; 95%, confidence
interval, 1.13-5.01, P ¼ .02; cusp number: hazard ratio, 6.62; 95% confidence interval,
PERSPECTIVE
2.54-17.3, P < .001). Right ventricle to pulmonary artery conduit size 11 mm or less
Many factors determine long-term outcomes af-
was associated with a higher risk of early catheter-based reintervention (hazard ra- ter complete repair of truncus arteriosus.
tio, 1.54; 95% confidence interval, 1.04-2.28, P ¼ .03) and reoperation (hazard ratio, Competing risks regression model with a modu-
1.96; 95% confidence interval, 1.33-2.89, P ¼ .001) on the right ventricle to pulmo- lated renewal approach identified conduit size
nary artery conduit. and truncal valve insufficiency at index operation
as risk factors for mortality, and truncal valve char-
Conclusions: Smaller right ventricle to pulmonary artery conduit size and truncal
acteristics and initial conduit size as risk factors
valve insufficiency at birth were associated with overall mortality after truncus ar-
for earlier than usual reintervention.
teriosus repair. Quadricuspid truncal valve, the presence of truncal valve insuffi-
ciency at the time of diagnosis, and truncal valve intervention at index repair See Commentaries on pages 237, 238, and 239.
were associated with an increased risk of reoperation. The size of the right ventricle
to pulmonary artery conduit at index surgery is the single most important factor for
early reoperation and catheter-based reintervention on the conduit. (J Thorac Car-
diovasc Surg 2022;163:224-36) Truncus arteriosus (TA) is a rare congenital heart defect,
occurring in 6 to 10 per 100,000 live births.1 Embryologi-
cally, this lesion is thought to arise from the malseptation
of the conotruncus and is frequently associated with other
From the Departments of aCardiac Surgery, bAnesthesiology and Surgery, and cCardi-
ology, Boston Children’s Hospital, Harvard Medical School, Boston, Mass. anatomic features, such as a truncal valve (TV) with a
A.G. and I.P.D. contributed equally.
Read at the 100th Annual Meeting of The American Association for Thoracic Sur-
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Received for publication May 30, 2020; revisions received Jan 27, 2021; accepted for take you to the table of con-
publication Jan 27, 2021; available ahead of print Feb 12, 2021.
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300 Longwood Ave, Boston, MA 02115 (E-mail: meena.nathan@cardio.chboston. AATS Annual Meeting Web-
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224 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Guariento et al
Abbreviations and Acronyms
AIC ¼ Akaike’s Information Criterion
CAA ¼ coronary artery anomaly
CI ¼ confidence interval
HR ¼ hazard ratio
PA ¼ pulmonary artery
P25-P75 ¼ 25th-75th percentiles
RV-PA ¼ right ventricle to pulmonary artery
TA ¼ truncus arteriosus
TV ¼ truncal valve
VSD ¼ ventricular septal defect
variable number of leaflets (1 to 4), subarterial ventricular
septal defect (VSD), coronary artery anomalies (CAAs),
and variations of pulmonary artery (PA) origins.2
Although medical management is often necessary to
initially stabilize patients, the recommended strategy is a
single-staged surgical correction of the truncal defect
and its associated pathologies in the first few days of
life. With improvements in surgical technique, several
studies have found that neonatal surgical repair portends
excellent short- and long-term survival when compared
with delayed repair.3,4 Although neonatal complete repair
has been found to be effective, reinterventions are not
uncommon and related to the durability of conduits and
presence of TV disease. These factors play an important
role during surgical decision-making on the choice of
conduits and repair techniques for the TV (if needed
during neonatal surgery). Thus, surgical management of
TA remains challenging.
Many single-center studies are limited by the number of
cases for this rare pathology, whereas multicenter studies,
which use varying analytic methods, have provided mixed
results for outcomes and risk factors for mortality and
reintervention.5-9 The objective of our study was to review a
35-year experience of patients with TA with respect to surgical
techniques used and in-hospital and long-term outcomes. In
particular, we sought to identify independent factors that lead
to mortality, reoperations on the TV, and reinterventions on
the right ventricle to pulmonary artery (RV-PA) conduit using
a novel statistical analytic technique. Unlike standard
approaches, our analysis allowed us to include repeated events
in the model and avoid censoring of information due to early
mortality. This was performed with a competing risks regres-
sion model in conjunction with a modulated renewal approach.
MATERIALS AND METHODS
Study Design and Definitions
A single-center retrospective review of consecutive patients who under-
went complete repair of TA between January 1984 and December 2018 was
approved by Boston Children’s Hospital Institutional Review Board on
clinical investigations, with waiver of consent (Protocol Number IRB-
P00030403).
The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1
Congenital: Truncus Arteriosus
Patients who died before complete repair (N ¼ 11), cases of hemitrun-
cus or pseudotruncus (N ¼ 16), and patients who survived to hospital
discharge but had no documented follow-up after surgery (N ¼ 24) were
excluded from the current study (Figure E1).
A modified Van Praagh classification for TA was used: type 1 with an
aorticopulmonary septum partly formed, resulting in a partially separate
main PA; type 2, with an aorticopulmonary septum entirely absent, result-
ing in an absent main PA, with both PA branches arising directly from the
common trunk; type 3, with absence of 1 pulmonary arterial branch
CONG
(either), this lung being supplied by collateral vessels; and type 4, with
an hypoplastic, atretic, or absent aortic isthmus associated with a large pat-
ent ductus arteriosus.2
Data collected included patient demographic characteristics, presence
of syndromes, associated cardiac anomalies, prior interventions, operative
details, and postoperative complications (Table 1). Because a VSD is a part
of the TA complex, only the presence of multiple VSDs was considered as
an associated cardiac anomaly. A CAA was defined as an anomaly of the
origin or course of the coronaries. Preoperative or postoperative TV insuf-
ficiency and stenosis were recorded. TV stenosis was estimated by Doppler
evaluation from multiple views, and the highest maximum instantaneous
gradient was used to categorize as moderate or greater (gradient
>50 mm Hg) or less than moderate (<50 mm Hg). TV regurgitation was
graded by echocardiography according to a composite assessment scale
as none/mild (no retrograde flow in the descending aorta, vena contracta
width <4 mm), moderate/severe (retrograde flow in the descending aorta,
vena contracta >4 mm).
Outcomes
Primary study end points were early mortality, late mortality, overall
mortality, reinterventions on the TV, and reinterventions on the RV-PA
conduit. Early mortality was defined as death occurring within 30 days
of surgery if discharged home before 30 days or before hospital discharge.
Late mortality was defined as mortality after hospital discharge or beyond
30 days of the initial surgical repair, whichever occurred later. Overall mor-
tality was defined as death occurring at any time during or after surgery.
Reintervention was defined as any interventional catheterization or cardiac
reoperation after discharge. Data on mortality and reoperation or catheter-
based intervention after initial surgery were collected on all patients from
the time of the index procedure to last documented follow-up.
Prior studies focusing specifically on the types of valved homograft im-
planted for RV-PA connection during primary repair have demonstrated
that time to reoperation on the RV-PA conduit was shorter for smaller
conduit sizes. Specifically, conduit size was 11 mm or less were associated
with shorter time to conduit replacement.10 We divided our cohort into 2
groups based on this threshold.
Statistical Analysis
Continuous data are summarized as medians and 25th-75th percentiles
(P25-P75), and categorical data are presented using frequencies and per-
centages. Overall survival was analyzed using Kaplan–Meier curves with
95% confidence intervals (CIs) estimated using Greenwood’s formula.
Kaplan–Meier curves are presented with the number of patients at risk
over the course of follow-up truncated at the time point when less than
10 patients were at risk. Univariable and multivariable Cox proportional
hazards regression modeling analyses were used to analyze risk factors
of mortality while adjusting for baseline covariates with results presented
as hazard ratios (HRs) with 95% CI and P values. Separate Cox regression
analyses were performed for early mortality, late mortality, and overall
mortality. A sensitivity analysis for late mortality was performed using
competing risks regression analysis with early mortality considered as a
competing event. Time zero for all analyses of early and overall mortality
was defined as the date of initial truncus repair and for late mortality as date
of discharge after initial truncus repair. For analyses of the risk factors
225
 Congenital: Truncus Arteriosus Guariento et al

TABLE 1. Patient demographics, operative data, and outcomes TABLE 1. Continued

Median (P25-P75) Median (P25-P75)
or N (%) or N (%)
Demographics Pulmonary hypertensive crisis 12 (6)
Male gender 100 (49) Sepsis 12 (6)
Age at surgery (d) 13 (6-48) ECMO support 11 (5)
BSA (m2) 0.21 (0.18-0.22) Days on ECMO support 7 (3-8)
CONG

Prematurity 16 (8) Other 24 (11)

Neonates 133 (65) Postoperative TV insufficiency moderate or 14 (7)
Type of TA greater
Type A1 79 (39) Postoperative TV stenosis moderate or greater 2 (1)
Type A2 72 (36) Overall mortality 32 (15)
Type A3 20 (10) 30-d mortality 11 (5)
Type A4* 29 (14) Late mortality 21 (10)
Unknowny 4 (1) Age at death in case of late mortality (y) 0.5 (0.2-1.3)
Type of TV P25-P75, 25th-75th percentiles: interquartile range; BSA, body surface area; TA, trun-
Bicuspid 23 (11) cus arteriosus; TV, truncal valve; ASD, atrial septal defect; PDA, patent ductus arterio-
sus; CAA, coronary artery anomaly; RV-PA, right ventricle to pulmonary artery; PFO,
Tricuspid 113 (55)
patent foramen ovale; ICU, intensive care unit; LOS, length of stay; ECMO, extracor-
Quadricuspid 52 (25) poreal membrane oxygenation; . *TA with interrupted aortic arch. ySome of the older
Unknowny 16 (9) cases lacked this information. zSee Table E1.
Preoperative TV insufficiency moderate or greater 38 (19)
Preoperative TV stenosis moderate or greater 12 (6)
DiGeorge syndrome 44 (22) associated with reoperation and catheter-based reintervention on RV-PA
Total associated cardiac anomalies N ¼ 142 conduit as well as the analysis of reoperation on the TV, we used an inno-
ASD 63 (31) vative statistical methodology that incorporated a time-to-event analysis
framework with repeated events within the same patient while accounting
PDA 37 (18)
for mortality as a competing outcome via informative censoring, namely, a
CAA 28 (14)
modulated renewal analysis with competing-risks regression. The Fine-
Single right coronary artery 8 (4) Gray model11 was used to incorporate early mortality as competing risk
Anomalous origin of the left coronary artery 6 (3) with the Nelson-Aalen estimator12 applied to handle multiple events per
Single left coronary artery 5 (2) patient as a cumulative sum. In the competing risks regression, the 3 end
Intramural left coronary artery 5 (2) states analyzed were (1) the event of interest (reoperation on RV-PA
Dual left anterior descending coronary artery 3 (1) conduit, catheter-based reintervention on RV-PA conduit, or reoperation
Anomalous origin of the right coronary artery 1 (1) on TV); (2) mortality (the competing event as informative censoring);
Otherz 42 (19) and (3) loss to follow-up (noninformative censoring).13 Cumulative inci-
dence functions were presented to estimate the cause-specific probability
Operative data
of the event of interest occurring up to a particular follow-up time point,
RV-PA conduit type while allowing for repeated reoperations or catheter-based reinterven-
Aortic homograft 109 (53) tions14 (Figure E2).
Pulmonary homograft 74 (36) The results of univariable and multivariable competing risks regression
Other 21 (11) models are presented using sub-distribution HR (crude and adjusted,
Size of conduit (mm) 10 (9-11) respectively) with corresponding 95% CI and P values. A priori selected
Size of conduit 11 mm 115 (56) preoperative and intraoperative variables were included in the models.
Total associated procedures N ¼ 143 Akaike’s Information Criterion (AIC) was calculated to assess model fit
ASD/PFO closure 55 (27) and parsimony for multivariable models, with a minimized AIC represent-
ing a parsimonious and robust multivariable model. Variables with P less
Aortic arch reconstruction 29 (14)
than .1 on univariable analysis were included in the multivariable
Concomitant TV surgery 22 (11)
competing risks regression modeling, while incorporating multiple events
Repair 22 (11) per patient in a modulated renewal framework. Time to event was used as
Replacement 0 (0) predictor variable for patients who had more than 1 reintervention to assess
Othery 37 (18) the association between time interval from previous renewal and the risk of
Outcomes each outcome. Cox-Snell residuals were visually assessed to evaluate the
Postoperative ICU stay (d) 8 (5-11) proportional hazards assumption while analyzing multiple measurements
per patient (Figure E3). Cox-Snell residual plots that were close to the
Postoperative-hospital LOS (d) 16 (12-26)
45-degree line were considered as supporting the proportional hazards
Patients w/t postoperative complications 90 (44)
assumption. Sensitivity analysis for patients who were excluded for lack
No. of postoperative complications N ¼ 118 of documented follow-up and subgroup analysis of neonates only was
Arrhythmia 26 (13) also performed. Stata software version 16.0 (StataCorp LLC, College Sta-
Bleeding 20 (10) tion, Tex) was used for statistical analyses with modeling done using the
Cardiac failure 17 (8) stcrreg command. Appendix E1 includes the Stata code and syntax written
(Continued) to perform competing risks regression with modulated renewal as well as
the data structure.

226 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Guariento et al Congenital: Truncus Arteriosus

TABLE 2. Follow-up data TABLE 2. Continued

Median (P25-P75) or N (%) Median (P25-P75) or N (%)
Total patients at follow-up on survivors 180/193 (93) Interval between each reoperation (y) 7.4 (5.9-10.3)
Total No. of reoperations on TV N ¼ 51
Length of follow-up (y) 11.6 (5.1-21.6)
Type of reoperations on TV
Patients with any reoperation/catheter- 149 (83) Repair 35/51 (68)
based reintervention Replacement 16/51 (32)
Freedom from above (y) 1.6 (0.5-4.5)

CONG
Patients with reoperation on aorta/LVOT 18 (10)
Patients with reoperations/catheter-based 141 (78) Freedom from above (y) 11.4 (4.9-19.7)
reintervention on RV-PA conduit No. of reoperations/patient 1.0 (1, 1)
Freedom from above (y) 2.4 (0.9-5.2) Total No. of reoperations on aorta/ N ¼ 18
Patients with catheter-based 117 (65) LVOT
reintervention on RV-PA conduit Type of reoperations on aorta/LVOT
Freedom from above (y) 3.8 (0.9-9.5) Ascending aorta replacement 7/18 (40)
No. of catheter-based reinterventions/ 1 (1-2) Valve-sparing aortic root 5/18 (30)
patient replacement
Interval between each catheter-based 3.0 (1.7-4.7) Ascending aorta plasty reduction 4/18 (20)
reintervention (y) Subaortic enlargement 2/18 (10)
Total No. of catheter-based N ¼ 222 Patients with other type of reoperations 14/18 (80)
reinterventions on RV-PA conduit Freedom from other type of 10.9 (5.2-20.1)
Type of catheter-based reintervention reoperations
on RV-PA conduit No. of other types of reoperations/ 1 (1-1)
Balloon dilatation 94/222 (42) patient
Stenting 91/222 (41) Total No. of reoperations on LVOT/ N ¼ 14
Biological valve 37/222 (17) aorta
Patients with reoperation on RV-PA 119 (66) PM/ICD implantation 5/14 (30)
conduit Tricuspid valve plasty 4/14 (20)
Freedom from above (y) 4.0 (1.7-7.9) Unroofing of AAOCA 2/14 (10)
No. of reoperations/patient 1 (1-2) Mitral valve plasty 2/14 (10)
Interval between each reoperation (y) 7.2 (5.2-10.6) Pulmonary vein stenosis repair 1/14 (10)
Total No. of reoperations on RV-PA N ¼ 176 P25-P75, 25th-75th percentiles: interquartile ranges; RV-PA, right ventricle to pulmo-
conduit nary artery; PA, pulmonary artery; TV, truncal valve; LVOT, left ventricle outflow
Type of reoperation on RV-PA conduit tract; PM, pacemaker; ICD, implantable cardioverter defibrillator; AAOCA, anoma-
lous aortic origin of coronary artery.
Aortic homograft 64/176 (36)
Biological valve 43/176 (24)
RESULTS
Pulmonary homograft 32/176 (18)
Patch enlargement 31/176 (17)
Study Population
Contegra 5/176 (3) During a 35-year period (1984-2018), 204 consecutive
Gore-Tex tube (WL Gore & 1/176 (1) patients (100 male and 104 female) underwent complete repair
Associates, Flagstaff, Ariz) of TA (Figure E1). The median age was 13 days (P25-P75:
Patients with catheter-based 86 (48) 6-48 days). A total of 133 patients (65%) were neonates and
reintervention on PAs 16 patients (8%) were born prematurely. According to Van
Freedom from above (y) 2.9 (0.7-10.6) Praagh classification, A1-2 type of TA was diagnosed in 151
No. of catheter-based reinterventions/ 2 (1-3) patients (75%), A3 type in 20 patients (10%), and 29 patients
patient (14%) had type A4. The TV was tricuspid in just more than
Interval between each catheter-based 2.8 (1.4-5.5) half of the patients (N ¼ 113; 55%), bicuspid in 23 patients
reintervention (y) (11%), and quadricuspid in 52 patients (25%). The TV had
Total No. of catheter-based N ¼ 220
moderate/severe insufficiency or stenosis in 38 (19%) and
reinterventions on PAs
12 (6%) of the cases, respectively. DiGeorge syndrome was
Type of catheter-based reintervention
on PA
present in 44 patients (22%). More than half of the patients
Balloon dilatation 144/220 (64) (N ¼ 106; 52%) had other associated cardiac anomalies
Stenting 76/220 (36) (Tables 1 and E1).
Patients with reoperation on TV 36 (20)
Freedom from above (y) 9.1 (4.3-18.4)
Perioperative Data
No. of reoperations/patient 1 (1-2)
In all patients, the surgical technique was as follows: con-
(Continued)
trol of 1 or both pulmonary arteries, cardiopulmonary

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 227
 Congenital: Truncus Arteriosus
bypass, dissection of the PAs, detachment of PAs from the
great vessels (most often the truncal root), direct or patch
closure of the remaining defect in the great vessels, and
VSD patch closure. The continuity between the right
ventricle and the PA was established by a conduit connect-
ing the main PA to the right ventricular outflow tract in all
cases. In case of moderate/severe TV stenosis or insuffi-
CONG
ciency, specific techniques were used according to the anat-
omy of the TVand the cause of valvular disease as described
in Table E1.15
The median cardiopulmonary bypass and aortic cross-
clamp times were 149 minutes (P25-P75: 127-175 minutes)
and 89 minutes (P25-P75: 72-112 minutes), respectively.
For the RV-PA conduit, an aortic homograft was used in
109 (53%) cases and a pulmonary homograft in 74
(36%) cases. Conduit size was 11 mm or less in 115 patients
(56%). The most common concomitantly performed pro-
cedures were atrial septal defect or patent foramen ovale
closure (N ¼ 55; 27%), aortic arch reconstruction
(N ¼ 29; 14%), and TV repair (N ¼ 22; 11%) (Tables 1
and E1).
Median postoperative intensive care unit stay and post-
operative hospital stay were 8 days (P25-P75: 5-11 days)
and 16 days (P25-P75: 12-26 days), respectively.
Arrhythmia was the most common postoperative compli-
cation (N ¼ 26; 13%), followed by postoperative
bleeding (N ¼ 20; 10%). Other complications, such as
cardiac failure, pulmonary hypertensive crisis, sepsis,
and need for extracorporeal membrane oxygenation sup-
port, had an incidence less than10%. A total of 14 pa-
tients (7%) and 2 patients (1%) had moderate/severe
100%
75%
Overall Survival
50%
25%
0%
0 5
Number at risk
191
FIGURE 1. Kaplan–Meier 1-, 5-, 10-, and 20-year survivals. Shaded area depicts 95% CIs. The numbers at risk in each group are shown at the bottom. The
curve has been truncated for time points at which patients at risk were less than 10. CI, Confidence interval.
228 The Journal of Thoracic and Cardiovascular Surgery c January 2022
Guariento et al
postoperative TV insufficiency and stenosis, respectively
(Table 1).
Postoperative Outcomes: A Novel Multivariable
Renewal Modulated Competing Risks Model
There were 193 (95%) early survivors. Follow-up was
complete for 180 (93%) survivors with a median duration
of 11.6 years (P25-P75: 5.1-21.6 years). Of the survivors,
149 (83%) underwent reoperation or catheter-based reinter-
vention at a median interval of 1.6 years (Table 2).
Mortality. Overall mortality was 15% at median follow-
up of 11.6 years (Table 2). One-year mortality was 14%
(95% CI, 9-19) and increased to a predicted 19% at 20 years
(95% CI, 13-26) (Figure 1). Multiorgan failure was the
most common cause of death (16/204; 8%), followed by
arrhythmia (5/204; 2%) (Table E1). Median age at death
postdischarge was 6 months. Initial RV-PA conduit size
less than 10 mm was associated with 22% mortality
(n ¼ 17/77) (Table E1).
Univariable regression analysis of 12 variables (models
included the following covariates: size of RV-PA conduit
as a continuous variable, gender, weight, prematurity, type
of TA, DiGeorge syndrome, other syndromes, TV insuffi-
ciency, TV stenosis, number of TV cusps, CAA, and year
of surgery) identified small RV-PA conduit size and prema-
turity as risk factors for overall postoperative mortality (HR,
1.29; 95% CI, 1.05-1.58, P ¼ .02 and HR, 2.64; 95% CI,
1.01-6.91, P ¼ .04, respectively), whereas moderate or
greater TV insufficiency and moderate or greater TV steno-
sis equal or higher than moderate were marginally associ-
ated with overall mortality (HR, 2.04; 95% CI, 0.97-4.32,
Overall Survival:
1-year: 86% (95% CI: 81%-91%)
5-year: 85% (95% CI: 79%-89%)
10-year: 84% (95% CI: 78%-89%)
20-year: 81% (95% CI: 74%-87%)
10 15 20 25
Follow-up time (years)
135 99 75 51 29
Guariento et al Congenital: Truncus Arteriosus

P ¼ .06 and HR, 2.62; 95% CI, 0.92-7.48, P ¼ .07, respec- TABLE 3. Univariable modulated renewal competing risk analysis of
tively). In the multivariable analysis, small RV-PA conduit reoperation on truncal valve
size and moderate or greater TV insufficiency were signifi- Variable HR 95% CI P value
cant risk factors for overall mortality (adjusted HR, 1.34; RV-PA 11 mm 0.78 (0.38-1.60) .497
95% CI, 1.08-1.66, P ¼ .01 and HR, 2.5; 95% CI, 1.13- Gender
5.53, P ¼ .02, respectively) (Table E2). The univariable Female Reference . .
Cox regression model for early mortality identified moder- Male 0.57 (0.28-1.18) .129

CONG
ate or greater TV insufficiency or stenosis as significant and Weight (kg) 0.94 (0.78-1.13) .495
marginally significant risk factors (HR, 3.47; 95% CI, 1.06-
Prematurity Cannot estimate . .
11.36, P ¼ .04 and HR, 3.64; 95% CI, 0.79-16.83, P ¼ .09,
respectively); however, none reached statistical significance DiGeorge syndrome 1.22 (0.56-2.66) .623
in the multivariable analysis (Table E3). TV insufficiency 4.78 (2.43-9.39) <.001*
A sensitivity analysis for late mortality was performed TV stenosis 3.28 (1.19-9.03) .022*
using a Cox regression model in which early mortality CAA 2.09 (0.91-4.80) .082
was treated as a competing event. Small RV-PA conduit
Type
size was the only identifiable risk factor for late mortality
1 Reference . .
(HR, 1.39; 95% CI, 1.06-1.81, P ¼ .02) (Table E4).
2 0.71 (0.31-1.58) .397
Reoperation on truncal valve. Overall freedom from re- 3 0.48 (0.06-3.86) .492
operation on the TV was 80% with a median time to inter- 4y 1.52 (0.65-3.53) .332
vention of 9.1 years at median follow-up of 11.6 years Other syndromes 0.66 (0.11-4.21) .684
(Table 3). Multivariable composite/integrated analysis re-
No. of cusps
vealed that TV regurgitation and number of TV cusps
2 1.99 (0.66-6.05) .224
(quadricuspid vs tricuspid) were significant risk factors
3 Reference . .
for reoperation on the TV (adjusted HR, 2.38; 95% CI, 4 9.24 (3.91-21.8) <.001*
1.13-5.01, P ¼ .02; and adjusted HR, 6.62; 95% CI, 2.54-
Year of surgeryz 1.11 (0.92-1.33) .281
17.3, P < .001, respectively) (Figure 2 and Table 3). A
shorter duration of the interval from previous reoperation Multivariable modulated renewal competing risk analysis of
on the TV was associated with increase hazard risk (HR, reoperation on truncal valve
0.92; 95% CI, 0.89, 0.95; P <.001). Subgroup analysis of Variable HR 95% CI P value
neonates showed that only TV regurgitation was a signifi- TV insufficiency 2.38 (1.13-5.01) .023*
cant independent predictor of reoperation on the TV (HR, TV stenosis 2.42 (0.82-7.18) .111
6.48; 95% CI, 2.2-19.5; P ¼ .001). No. of cusps
Catheter-based reintervention on right ventricle to pul- 2 1.67 (0.53-5.14) .375
monary artery conduit. Overall freedom from catheter- 3 Reference . .
based reintervention on the RV-PA conduit was 35% with 4 6.62 (2.54-17.3) <.001*
a median time to intervention of 3.8 years at median Variables with P <.10 on univariable analysis were included in the multivariable
follow-up of 11.6 years. Univariable composite/integrated model. Competing risks regression was used to incorporate mortality as a competing
event, and modulated renewal analysis to account for repeated events within the same
analysis of 12 variables revealed that RV-PA conduit patient. Statistically significant values are in bold. HR, Hazard ratio; CI, confidence
11 mm or less was the only significant risk factor for interval; RV-PA, right ventricle to pulmonary artery, TV, truncal valve; CAA, coronary
catheter-based reintervention on the RV-PA conduit (unad- artery anomaly. *Statistically significant. yTA with interrupted aortic arch. zEstimates
shown for 5-year increments.
justed HR, 1.54; 95% CI, 1.04-2.28, P ¼ .03) (Figure 2 and
Table 4). A shorter duration of the interval from previous
catheter-based reintervention on RV-PA conduit was associ- P ¼ .04, respectively) (Figure 2 and Table 5). A shorter
ated with increase hazard risk (HR, 0.92, 95% CI, 0.89- duration of the interval from previous reoperation on RV-
0.95; P <.001). PA conduit was associated with increase hazard risk (HR,
Reoperation on right ventricle to pulmonary artery 0.90; 95% CI, 0.86, 0.94; P<.001). Pulmonary homografts
conduit. Overall freedom from reoperation on the RV-PA as RV-PA conduit were associated with lower risk for
conduit was 34% with a median time to intervention of conduit reoperation (HR, 0.59; 95% CI, 0.39-0.89,
4 years at median follow-up of 11.6 years. The compos- P ¼ .011) while adjusting for size of conduit (Video 1).
ite/integrated analysis revealed that RV-PA conduit
11 mm or less and year of surgery 2011 or earlier were DISCUSSION
significantly associated with need for reoperation on the In our study, we demonstrated that neonatal TA repair can
RV-PA conduit (adjusted HR, 1.96; 95% CI, 1.33-2.89, be achieved with acceptable mortality. Initial RV-PA
P ¼ .001 and adjusted HR, 1.50; 95% CI, 1.01-2.22, conduit size less than 10 mm was associated with 22%

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 229
 Congenital: Truncus Arteriosus Guariento et al

Reoperation on Truncal Valve Reoperation on Truncal Valve

100 100
HR (bicuspid vs. tricuspid) = 1.99 HR = 4.78
90 90
Cumulative Incidence (%)

Cumulative Incidence (%)

95% CI: 0.66 - 6.05 95% CI: 2.43 - 9.40
P = .224 Quadricuspid P < .001
80 80
HR (quadricuspid vs. tricuspid) = 9.24 Truncal Valve Insufficiency
70 95% CI: 3.91 - 21.8 70
P < .001
60 60
50 50
CONG

40 40
Bicuspid
30 30 No Truncal Valve Insufficiency
20 Tricuspid 20
10 10
0 0
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
A Years B Years

Multivariable Competing Risks Regression for

Re-operation on Truncal Valve

Truncal valve
*
insufficiency

Truncal valve
stenosis

Number of cusps
(3 vs 1)

Number of cusps
(4 vs 3) *

0.5 0.75 1 2 3 5 10 20
C Adjusted Hazard Ratio (95% CI)

FIGURE 2. Cumulative incidence for reoperation on TVover 30 years of follow-up according to number of TV cusps (A) and TV insufficiency (B). Forest
plots indicating adjusted HR and 95% CI of the statistically significant risk factors identified by multivariable modulated renewal competing risks regression
analysis for reoperation on TV (C). Covariates included in the model for reoperation on RV-PA conduit were TV insufficiency, TV stenosis, and number of
TV cusps. HR, Hazard ratio; CI, confidence interval. *P<.05 (confidence limits for cumulative incidence estimates and number of patients at risk are shown
in Table E5).

mortality compared with 13% for 10 to 13 mm size and
12% for 14 mm or greater conduits (Table E1). Adjusted
analysis using conduit size as a continuous variable (rather
than the a priori selected categories of 11 mm vs larger
conduits, which was not associated with any of our mortal-
ity outcomes) revealed that smaller size of initial RV-PA
conduit and TV regurgitation were associated with overall
mortality (Figure 3). Reinterventions on the TV were
needed in approximately 20% at 10 years and were pre-
dominantly predicted by abnormal TV morphology (quad-
ricuspid TV) and presence of moderate or greater TV
regurgitation at birth. As expected, conduit reinterventions
both surgical and catheter based were not uncommon and
were required in approximately one-third of patients by
10 years. We were able to identify smaller conduit size
(11 mm) as a risk factor for earlier than usual interven-
tions on the RV-PA conduit. Of note, our center
predominantly used homografts as RV-PA conduits, and
we were able to demonstrate that pulmonary homografts
had superior longevity even after adjusting for size of
conduit. Reported risk factors for mortality, TV, and conduit
reinterventions after early TA repair vary considerably in
the literature.4-6,9,16,17 This is likely due to small sample
size and possible era effect in single-center studies, given
the time required to accrue sufficient numbers for analysis.
This has been partly mitigated by recent multicenter
studies.7-9
As mortality after neonatal TA repair predominantly oc-
curs in the first year after surgery,16 the main long-term
challenge in managing these patients is related to reinter-
ventions, often multiple, on the TV or RV-PA conduit.8 In-
dividual centers vary in the approach to and timing of
these interventions, making risk prediction based on
single-center studies less generalizable. Multicenter

230 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Guariento et al Congenital: Truncus Arteriosus

TABLE 4. Univariable modulated renewal competing risk analysis of TABLE 5. Univariable modulated renewal competing risk analysis of
catheter-based reintervention on right ventricle to pulmonary artery reoperation on right ventricle to pulmonary artery conduit
conduit Variable HR 95% CI P value
Variable HR 95% CI P value RV-PA 11 mm 1.74 (1.19-2.55) .004*
RV-PA 11 mm 1.54 (1.04-2.28) .031* Gender
Gender Female Reference . .
Female Reference . . Male 1.02 (0.71-1.46) .921

CONG
Male 0.97 (0.68-1.39) .872 Weight (kg) 0.99 (0.75-1.03) .106
Weight (kg) 0.94 (0.82-1.07) .313 Prematurity 0.46 (0.15-1.41) .174
Prematurity 0.69 (0.24-1.99) .491 DiGeorge syndrome 1.28 (0.85-1.94) .242
DiGeorge syndrome 1.39 (0.91-2.12) .131 TV insufficiency 0.95 (0.59-1.53) .839
TV insufficiency 0.74 (0.44-1.26) .267 TV stenosis 0.75 (0.38-1.50) .421
TV stenosis 1.18 (0.43-3.23) .750 CAA 0.99 (0.58-1.68) .965
CAA 1.25 (0.77-2.03) .360 Type
Type 1 Reference . .
1 1.2 (0.51-2.81) .677 2 1.02 (0.68-1.54) .910
2 1.17 (0.51-2.73) .708 3 1.39 (0.68-2.82) .364
3 Reference . . 4y 1.36 (0.79-2.33) .269
4y 1.85 (0.73-4.66) .194 Other syndromes 0.41 (0.15-1.12) .082
Other syndromes 0.89 (0.34-2.37) .818 No. of cusps
No. of cusps 2 Reference . .
2 Reference . . 3 1.1 (0.64-1.89) .719
3 1.72 (0.99-2.98) .054 4 1.23 (0.69-2.21) .481
4 1.34 (0.72-2.49) .358 Year of surgeryz 0.86 (0.78-0.96) .006*
Year of surgeryz 1 (0.92-1.11) .927
Multivariable modulated renewal competing risk analysis of
Multivariable modulated renewal competing risk analysis of reoperation on RV-PA conduit
catheter-based reintervention on RV-PA conduit Variable HR 95% CI P value
Variable HR 95% CI P value RV-PA 11 mm 1.96 (1.33-2.89) .001*
RV-PA 11 mm 1.54 (1.04-2.28) .031* Year of surgery 2001z 1.50 (1.01-2.22) .043*
Variables with P <.10 on univariable analysis were included in the multivariable Variables with P <.10 on univariable analysis were included in the multivariable
model along with conduit size. Competing risks regression was used to incorporate model. Competing risks regression was used to incorporate mortality as a competing
mortality as a competing event, and modulated renewal analysis was used to take
event, and modulated renewal analysis was used to take into account repeated events
into account repeated events within the same patient. AIC ¼ 975. Statistically signif-
within the same patient. AIC ¼ 989. Statistically significant values are in bold. HR,
icant values are in bold. HR, Hazard ratio; CI, confidence interval; RV-PA, right
Hazard ratio; CI, confidence interval; RV-PA, right ventricle to pulmonary artery; TV,
ventricle to pulmonary artery, TV, truncal valve; CAA, coronary artery anomaly. *Sta-
truncal valve; CAA, coronary artery anomaly. *Statistically significant. yTA with in-
tistically significant. yTA with interrupted aortic arch. zEstimates shown for 5-year terrupted aortic arch. zEstimates shown for 5-year increments.
increments.

Furthermore, using the Kaplan–Meier estimator for time

studies, on the other hand, often do not include reinterven-
tions over time, and limit their risk modeling to the first
occurrence of any event.7-9
In the current study, we propose a novel statistical model
for the analysis of risk factors for reintervention on the
RV-PA conduit and TVafter neonatal/infant TA repair while
accounting for mortality. We were able to estimate
cumulative incidence of important end points while
accounting for multiple events per patient and accounting
for mortality as a competing event. This novel combined
approach is valuable in providing insight into the data on
multiple or repeated events while handling informative
censoring from mortality.13 Standard Kaplan–Meier curve
analysis is a single event methodology and does not permit
multiple repeated events within the same patients.
to the first catheter-based reintervention or reoperation
would fail to use all the data available on each patient.
Over the course of long-term follow-up, early informative
censoring due to mortality may bias the results if traditional
Cox regression and Kaplan–Meier curves were
implemented instead of competing risk regression. In fact,
patients who died early may be at an elevated risk for
reoperation or catheter-based reintervention had they
continued to be followed. The value of using both
multivariable competing risks regression and modulated
renewal analysis as a combined methodology provides
greater insight and a better understanding of these
time-to-event outcomes after TA repair.
With this modeling, our data revealed low early mor-
tality and relatively good long-term survival, compared

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 231
 Congenital: Truncus Arteriosus
CONG
VIDEO 1. Dr Meena Nathan, MD, FRCS, MPH, presents the rationale and
importance of the study. Dr David Zurakowski, MS, PhD, describes the
innovation of the statistical model used. Video available at: https://www.
jtcvs.org/article/S0022-5223(21)00252-X/fulltext.
with other groups.8,18 One-year mortality confirmed that
most deaths occurred in the short term after surgery. In
our cohort, on adjusted analysis, overall mortality was
associated with moderate or greater TV insufficiency
and smaller conduit size, while early mortality had no
identified risk factors. A competing-risk analysis was
also performed with early mortality as a competing event
for late mortality and again smaller conduit was the only
factor that was significant (Figure 4). This differed
somewhat from other groups that demonstrated
associations with spectrum complexity (ie, Van Praagh
Type A4) or CAA with early mortality,7,9,19,20 and with
TV disease and DiGeorge syndrome with late
Long-term Outcomes
of Truncus Arteriosus Repair
A NOVEL COMPETING RISKS ANALYSIS
A smaller RV-PA conduit size and TV insufficiency at diagnosis
are risk factors associated with increased overall mortality
FIGURE 3. A novel analysis for risks of mortality and reintervention after TA repair. RV-PA, Right ventricle to pulmonary artery; TV, truncal valve.
232 The Journal of Thoracic and Cardiovascular Surgery c January 2022
Guariento et al
mortality.6,8 We speculate that our novel analysis and
the single-center design of our study enabled a better
understanding of the competing events that contributed
to mortality in our cohort.
As reported in the literature, TV disease contributes
significantly to the morbidity of patients with TA, although
freedom from reoperation was approximately 80% at
10 years in our prior study.15 It is not surprising that risk fac-
tors for reoperation on TV were mainly associated with
morphology of the TV. Thus, dysplastic and incompetent
valves, or those that may have required surgical manipula-
tion during initial repair, were more prone to subsequent
surgery (Figure 4). However, patients who underwent TV
repair at index surgery had similar outcomes irrespective
of the repair strategies used, unlike in prior reports.15
Also, subsequent reintervention on the TV was not associ-
ated with increased late mortality.
As expected, most patients required RV-PA conduit
reinterventions, either catheter-based procedures or reoper-
ations. The value of accounting for multiple interventions
allows further understanding of the impact of important
risk factors. In our cohort, approximately 90% of patients
received a homograft at index surgery, thus reducing hetero-
geneity related to the type of conduit. The size of the
conduit was the single most important factor that deter-
mined the need for reintervention. In particular, a conduit
size 11 mm or less resulted in a 2-fold increase in risk
both for catheter-based reintervention and conduit reopera-
tion (Figure 4), not dissimilar to prior studies.6,7,21 Addi-
tionally, as expected, an era effect was noted. This was
INDEPENDENT FACTORS LEADING
TO REINTERVENTION ON:
TV reoperation
1. Number of TV cusps
2. Moderate/severe TV insufficiency
or TV stenosis at diagnosis
3. Need for concomitant TV
operation at index operation
Earlier RV-PA conduit reintervention
1. Conduit size d 11 mm at index
operation
Guariento et al Congenital: Truncus Arteriosus

Recatherization on RV-PA Conduit Reoperation on RV-PA Conduit

100 100
RV-PA d 11 mm
90 90 RV-PA d 11 mm
Cumulative Incidence (%)

Cumulative Incidence (%)

80 80
RV-PA > 11 mm
70 70
60 RV-PA > 11 mm 60
50 50

CONG
40 40
30 30
20 20 HR = 1.74
HR = 1.54
10 95% CI: 1.04 - 2.28 10 95% CI: 1.19 - 2.55
P = .031 P = .004
0 0
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30
A Years B Years

Reoperation on RV-PA Conduit Competing Risks Regression for

100 Re-catheterization on RV-PA Conduit
90
Cumulative Incidence (%)

2001 or before
80
After 2001 RV-PA < 11 mm *
70
60
50 0.5 0.75 1 1.5 2 2.5
40 Hazard Ratio (95% CI)
D
30
Multivariable Competing Risks Regression for
20 HR = 1.50 Re-operation on RV-PA Conduit
10 95% CI: 1.01 - 2.22
P = .043
0
RV-PA < 11 mm *
0 5 10 15 20 25 30
C Years
Year of Surgery
d 2001 *

0.5 0.75 1 1.5 2 2.5 3

Adjusted Hazard Ratio (95% CI)
E
FIGURE 4. Cumulative incidence for catheter-based reintervention on RV-PA conduit over 35 years of follow-up according to RV-PA conduit size (A).
Cumulative incidence for reoperation on RV-PA conduit over 30 years of follow-up according to RV-PA conduit size (B) and year of surgery (C). Forest
plots indicating adjusted HR and 95% CI of the statistically significant risk factors identified by multivariable modulated renewal competing risks regression
analysis for catheter-based reintervention (D) and reoperation on RV-PA conduit (E). Covariates included in the model for reoperation on RV-PA conduit
were RV-PA conduit size and year of surgery. Only RV-PA conduit size was included in the model for catheter-based reintervention on RV-PA conduit. RV-
PA, Right ventricle-pulmonary artery; HR, hazard ratio; CI, confidence interval. *P<.05 (confidence limits for Cumulative Incidence Estimates and number
of patients at risk are shown in Table E5).

probably related to the difference in the availability of small
size homografts in the past and to the different conduit pres-
ervation strategies available at that time.
Study Limitations
First, it is a retrospective examination of a cohort of pa-
tients that spans 4 decades and thus includes diverse periop-
erative care management and potentially an era effect.
Infants undergoing concomitant TA repair with an interrup-
ted aortic arch or an aortic arch obstruction (Van Praagh
Type A4) were included in the study to provide the full
spectrum of the disease. Although we recognize that Type
A4 is known to have a high early mortality,22 our study
showed no association between TA type and subsequent
mortality or need for reoperation. Body surface area was
not available for all patients (especially for patients oper-
ated in an earlier era) and therefore the indexed conduit
diameter could not be calculated for all patients in our
cohort. However, an analysis of the patient subgroups in
which body surface area was available did not show any dif-
ference, consistent with the results of other groups.8 Given
the retrospective nature of our dataset, we specifically
looked for interactions between conduit size and weight at
TA repair, and for the interaction between conduit size
and conduit type, and found no significant interactions.
The final model that excludes these nonsignificant

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 233
 Congenital: Truncus Arteriosus
interactions showed that a smaller conduit size remained an
independent risk factor for mortality. However, our model
does not include other factors that may contribute to conduit
size choice, such as the size of conduits available at the time
of the truncus repair or other patient- and procedure-specific
factors. Therefore, given the association between small
conduit size and mortality in our dataset, at this stage we
CONG
recommend choosing a larger conduit appropriate for
weight. One possible speculation is that a smaller conduit
at initial truncus repair is likely to result in restriction to
the right ventricular outflow at an earlier time point, result-
ing in hemodynamic disturbance, which could likely
contribute to mortality.
CONCLUSIONS
Complete repair of TA at our center was associated with
acceptable early and long-term outcomes. A novel
statistical approach that accounts for competing risks and
modulated renewal analysis identified small conduit size
and TV regurgitation at index operation as risk factors for
overall mortality after TA repair. The number of TV cusps,
the presence of TV insufficiency and the need for a
concomitant TV operation are associated with an increased
risk of reoperation on the TV. The size of the RV-PA conduit
is the single most important factor for reoperation and
catheter-based reintervention on the RV-PA conduit.
Although pulmonary homografts have better long-term
outcomes, the decision on the type of homograft used as
RV- PA conduit is primarily dependent on what is available
at time of intervention. A conduit that is capable of somatic
growth with minimal degeneration remains the Holy Grail
and will mitigate the need for repeated conduit
reintervention. As techniques for successful neonatal TV
repair develop, earlier successful TV repair may change
the trajectory of reinterventions in this patient population.
Webcast
You can watch a Webcast of this AATS meeting presenta-
tion by going to: https://aats.blob.core.windows.net/media/
20AM/Presentations/Long-Term%20Outcomes%20of%
20Truncus%20Arteri.mp4.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to
disclose conflicts of interest and to decline handling or re-
viewing manuscripts for which they may have a conflict
234 The Journal of Thoracic and Cardiovascular Surgery c January 2022
Guariento et al
of interest. The editors and reviewers of this article have
no conflicts of interest.
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Guariento et al
Key Words: competing risks, long-term outcomes, modu-
lated renewal, risk factors, statistical analysis, truncus arte-
riosus
Discussion
Presenter: Dr Alvise Guariento
Dr Victor O. Morell (Pittsburgh, Pa).
Dr Guariento and associates at Boston
Children’s Hospital describe their expe-
rience with TA repair in neonates and
infants using a competing risks regres-
sion model with modulated renewal
analysis. There were 204 patients be-
tween January 1984 and December
2018. The authors found an early mortality of 5%. At
20 years, the mortality was approximately 20% for the group.
On multivariate analysis, no risk factors for postoperative
mortality were identified. With a median follow-up of
approximately 12 years, the majority of patients had under-
gone reintervention. Multivariate, renewal, modulated,
competing risk regression analysis revealed that RV-PA
conduit less than 11 mm in diameter and year of surgery (pa-
tients operated on before 2011) were significantly associated
with the need for reoperation. Also, TV insufficiency and
quadricuspid TVs were risk factors for reoperation.
Multiple studies have shown an association among Di-
George syndrome, truncus type A4, TV insufficiency, and
coronary artery anomalies associated with mortality in this
group of patients.
Do you believe that these factors don’t play any role in mor-
tality in this TA? The risk factors for reoperation identifying
your studies are consistent with previous reports. Did you
look at pulmonary versus aortic homographs to see if there
was a difference between the type of homograft conduit and
the incidence of reoperations in your group, because most of
your patients had a pulmonary homograft or an aortic homo-
graft. Are you using conduits greater than 11 mm in diameter
now based on your current findings? Again, wonderful presen-
tation and thanks for the opportunity to comment on this.
Dr Alvise Guariento (Boston, Mass).
As for your first question: If we believe
in these results, I can say that I was sur-
prised, like you, probably. I think the
next step would be to understand why
we didn’t have what people have shown
in the past. The only strong risk factor
was a TV preoperative insufficiency.
So, I focused my attention on that particular group of patients
who had this disease, and, of course, the mortality was higher
for those patients. Of 38 patients, we had almost 16 deaths,
which is certainly a higher mortality than for the overall pop-
ulation.
The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1
Congenital: Truncus Arteriosus
I don’t have a full answer as to why this was not confirmed
by multivariable analysis. I believe Boston Children’s Hospi-
tal’s strategy of being fairly aggressive on TV repair could
certainly have played a role. In this regard, historically, at
Boston Children’s coronary anomalies have been addressed
surgically in the early period of a child’s life. This is a
possible answer that I have given myself. But again, I’m
CONG
happy to discuss with you whether it can be true or not.
Regarding the role of DiGeorge syndrome on RV-PA
conduit reinterventions, I think the beauty of this new anal-
ysis is to be able to control a little bit more the influence of
risk factors on the number of interventions and the freedom
from reinterventions.
We did look at the difference between a pulmonary homo-
graft and an aortic homograft. The number of homografts
was pretty much divided in half. Pulmonary homografts as
RV-PA conduits were associated with a lower risk for conduit
reoperation. Our study was particularly nice because we were
lucky to have at Boston Children’s more than 95% of the pa-
tients treated with homografts since the early era.
Unfortunately, as you probably read in our article, one lim-
itation of this study was that we were unable to obtain an in-
dex value for all the patients because the body surface area
was not available for patients back in the 1970s and 1980s.
There is an article from last year published in the Journal,
in which the authors were able to index these values. Their
results were similar to what we saw.
Dr Emile Bacha (New York, NY). Like
everybody else, I was disappointed
that you could not elicit risk factors.
It’s surprising because you would think
that a 2-kg baby with TA with a single
coronary and TV insufficiency would
be at higher risk than a 3.5-kg baby
without those risk factors. The common
problem that we have is a baby with TA and moderate-to-se-
vere TV insufficiency. Then the question becomes, do you
approach the valve during the first repair or do you simply
repair the truncus, ignore the valve, and say, “This is all vol-
ume load related”? I’m not sure there are good indicators as
to whether to operate early on the valve at the initial repair or
not. Does your study give you any indication regarding this
specific issue, how many patients had a primary TV repair
in your study, and how did they do?
Dr Guariento. I agree with you. I don’t think the final
answer to this study is: “There are no risk factors, and
we’re happy with it.” I think the large number of
patients who were treated for TV insufficiency in Boston
is a good indicator of the fact that we do need to intervene
on this.
Dr Bacha. How many cases do you have that have pri-
mary TV repair at the time of the initial surgery? Do you
know?
235
 Congenital: Truncus Arteriosus
Dr Guariento. I have almost 11% of the total population,
but in patients who had preoperative TV insufficiency, it is
more than 70%.
Dr Bacha. Quite aggressive.
Dr Guariento. Indeed. I believe that the reason why this
was not shown to be an indicator of risk for early mortality
was because the surgeons are aggressive at addressing the
CONG
truncal valve.
Dr Bacha. They neutralize the risk factor.
Dr Guariento. Yes. This is my belief. However, I can’t
be certain if this is true or not. This is just what we have
seen in our study. Perhaps Dr Emani can comment further.
Dr Sitaram Emani (Boston, Mass). I
agree. We are aggressive at addressing
the TV. I won’t go so far as to say that
we’ve figured out the best technique,
and this group has a significant reoper-
ation rate. Types of techniques that
we’ve used to manage the TV range
from resection of the nondominant
leaflet and tricuspidization to bicuspidization of the valve.
Each technique has its advantages and disadvantages, and
I think the reoperation rate we see in the late term is related
to ongoing risk of recurrent truncal insufficiency. However,
given the small number of overall events, it can be difficult
to establish with certainty true correlations for some of the
other risk factors. Nevertheless, some of the putative risk
factors such as DiGeorge do not play as important a role
as we once thought they did, perhaps because of better med-
ical management.
Dr Robert D.B. Jaquiss (Dallas, Tex).
Ram, can you or Dr Guariento
comment on the late loss? I was sur-
prised there was an additional 15% of
the original cohort lost by 20 years.
You think of somebody coming out of
a truncus repair as a neonate who’s
got pretty good left ventricular
236 The Journal of Thoracic and Cardiovascular Surgery c January 2022
Guariento et al
function, good right ventricular function, and yet 15% of
the original cohort had died by age 20 years. I was a little
surprised that the number is that high, but I can’t recall hav-
ing seen this large a long-term follow-up, so maybe that’s
happening everywhere and I just don’t know about it. Do
you have a sense of what those kids are dying of?
Dr Guariento. Indeed, first, we have shown that early
mortality is pretty high, as everyone showed in the past.
As a matter of fact, 14% was the overall mortality rate in
the early period (1-year mortality). However, late mortality
plays a role, and that is a good point. I think we should
divide our patients and do a subgroup analysis on the late
follow-up and see what the potential risk factors for mortal-
ity in the long term are.
Dr Jaquiss. Do you think they’re mostly cardiac deaths
or is this where the DiGeorge becomes a bigger player?
Dr Guariento. I think they’re cardiac. DiGeorge
did not seem to play a role in this particular study. Of
course, another factor in this study is that we included
type A4.
Dr Glenn S. Van Arsdell (Los An-
geles, Calif). This is potentially good
news. Does this mean that the 1200-
g/1500-g patient undergoes operation
right away and that is not a risk fac-
tor? What about severe ventricular
hypertrophy? Did you have any of
those, and was that also not a risk
factor?
Dr Guariento. This is a good point. However, few pa-
tients were identified as having ventricular hypertrophy.
But, again, this is a good point, and that’s probably the
most important risk factor.
Dr Emani. We must consider our selection bias for pa-
tients who undergo primary repair. We will perform branch
PA banding for some of the highest-risk patients. So the
extremely high-risk patients may not be included in the
risk factor analysis for primary repair.
Guariento et al Congenital: Truncus Arteriosus

APPENDIX E1. COMPETING RISKS REGRESSION
WITH MODULATED RENEWAL IN STATA
The table shows a subset of hypothetical data formatted
appropriately for competing risks regression with
modulated renewal using the Stata code that follows.
End state
 Stop time (y) represents the time point at the end of the
time interval relative to the time of initial procedure.
 End state represents the event that occurred at the end of
that time interval for the patient. The patient may have
undergone a reoperation, died, or been noninformatively
censored as lost to follow-up.
 Sex is coded as 1 for females and 0 for males

CONG
(1 ¼ reoperation;  Prematurity is coded as 1 for yes and 0 for no
Start Stop 2 ¼ mortality; Sex
Patient time time 3 ¼ noninformative (1 ¼ female;
Note that the same patient may experience multiple
ID (y) (y) censoring) 0 ¼ male) Prematurity events of interest (reoperations). For example, patient
number 1 experiences reoperations two times, and is fol-
1 0 0.19 1 1 0
lowed for an additional 32.22 years after the second
1 0.19 2.35 1 1 0
reoperation.
1 2.35 34.57 3 1 0 The Stata code below can be used to fit a competing risks
2 0 0.40 2 0 1 regression model for reoperation (the outcome of interest)
3 0 10.50 1 1 0 while considering mortality as a competing risk and ac-
3 10.5 13.20 1 1 0 counting for multiple events within the same patient. We
3 13.2 24.10 3 0 0 use sex and prematurity as model covariates. The third
4 0 9.55 3 1 0
line of code can be used to plot cumulative incidence func-
tions stratified by sex:
stset stoptimeyears, failure(endstate¼1) time0(starttime-
 Patient ID is the unique patient identifier. years) id(patientid)
 Start time (y) represents the time point at the start of the stcrreg ib0.sex ib0.prematurity, compete(endstate¼¼2)
time interval relative to the time of initial procedure. stcurve, cif at1(sex¼1) at2(sex¼0)

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 236.e1
 Congenital: Truncus Arteriosus Guariento et al

Enrollment
ASSESSED FOR ELIGIBILITY (N = 255)
Surgical repair of truncus arteriosus between 1984 and 2008
CONG

Excluded (N = 27)
Mortality before complete repair (N = 11)
Allocation

Hemitruncus or pseudotruncus (N = 16)

Eligible Patients (N = 228)

Follow-up

Excluded (N = 24)
Follow-up < 1 year (n = 20)
Incomplete post-operative data (n = 4)

Total Analyzed (n = 204)

Analysis

Early Mortality
Analyzed for Follow-up (n = 204)
Late Mortality
Re-interventions

FIGURE E1. Consort diagram of the study (early mortality, N ¼ 11; late mortality, N ¼ 21; reinterventions, N ¼ 149).

236.e2 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Guariento et al Congenital: Truncus Arteriosus

Re-Operation on Re-Catheterization
Re-operation on TV
RV-PA conduit on RV-PA conduit

Event #1 36 pts 119 pts 117 pts

Event #2 15 pts 45 pts 53 pts

CONG
Event #3 2 pts 12 pts 26 pts

Event #4 16 pts

Event #5 3 pts

Event #6 2 pts

FIGURE E2. Number of events in the cohort based on the number of repeated events to accompany the cumulative incidence function. TV, Truncal valve;
RV-PA, right ventricle to pulmonary artery.

Re-operation on Truncal Valve Re-catherization on RV-PA Conduit

2
3

1.5
2
1

1
.5

0 0
0 .5 1 1.5 2 0 1 2 3
A Partial Cox-Snell residual B Partial Cox-Snell residual

Re-operation on RV-PA Conduit

4

0
0 1 2 3 4
C Partial Cox-Snell residual

FIGURE E3. Visual assessment of partial Cox-Snell residuals for reoperation on TV (A), catheter-based reintervention on RV-PA conduit (B), and reop-
eration on RV-PA conduit (C). RV-PA, Right ventricle to pulmonary artery.

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 236.e3
 Congenital: Truncus Arteriosus Guariento et al

TABLE E1. Perioperative data TABLE E2. Univariable and multivariable Cox regression analysis of
Median (P25-P75) or N (%) mortality (overall mortality)

Previous palliation 4 (2%) Variable HR 95% CI P value

Main PA banding 2 (1%) RV-PA 11 mm 1.78 (0.68-4.65) .237
Bilateral PAs banding 2 (1%) RV-PA conduit size* 1.29 (1.05-1.58) .017y
CBP time (min) 149 (125; 175)
Gender
ACC time (min) 89 (72; 112) Female Reference . .
CONG

CA time (min) 5 (0; 14) Male 1.23 (0.62-2.47) .555

Patients w/t associated procedures 103 (50%) Weight (kg) 0.84 (0.58-1.2) .337

Total associated procedures N ¼ 143 Prematurity 2.64 (1.01-6.91) .047y

ASD/PFO closure 55 (27%) DiGeorge syndrome 0.59 (0.23-1.54) .285
Aortic arch reconstruction 29 (14%) TV insufficiency 2.04 (0.97-4.32) .061
Concomitant TV surgery 22 (11%)
Repair 22 (11%) TV stenosis 2.62 (0.92-7.48) .071
Replacement 0 (0%) CAA 1.42 (0.58-3.45) .440
PDA ligation 14 (7%) Type
PAs reconstruction 8 (4%) 1 Reference . .
MAPCAs unifocalization 6 (3%) 2 1.13 (0.5-2.57) 1.13
Multiple VSD closure 5 (2%) 3 1.2 (0.34-4.33) 1.2
Coarctation repair 4 (2%) 4k 1.02 (0.32-3.19) 1.02
No. of postoperative complications N ¼ 118 Other syndromes 2.07 (0.49-8.67) .319
Arrhythmia 26 (13%)
No. of cusps
Bleeding 20 (10%)
2 1.69 (0.53-5.41) .762
Cardiac failure 17 (8%)
3 Reference . .
Pulmonary hypertensive crisis 12 (6%)
4 1.95 (0.79-4.8) .146
Sepsis 12 (6%)
ECMO support 11 (5%) Year of surgeryz 0.97 (0.81-1.19) .830
Days on ECMO support 7 (3; 8) Multivariable Cox regression analysis of mortality
Pleural effusion 9 (4%) Variable HR 95% CI P value
Wound complications 6 (3%)
RV-PA conduit size* 1.34 (1.08-1.66) .008x
Renal failure 3 (1%)
Pneumothorax 2 (1%) TV insufficiency 2.5 (1.13-5.53) .024x
TV reoperation in the same hospitalization 4 (2%) Variables with P <.10 on univariable analysis were included in the multivariable
Cause of death model. Statistically significant values are in bold. CAA, Coronary artery anomaly;
CI, confidence interval; HR, hazard ratio; RV-PA, right ventricle to pulmonary artery;
Multiple organ failure 16 (8%)
TV, truncal valve. AIC ¼ 306. HR, Hazard ratio; CI, confidence interval; RV-PA, right
Arrhythmia 5 (2%) ventricle to pulmonary artery; TV, truncal valve; CAA, coronary artery anomaly. *Per
Cardiac failure 3 (1%) 1-mm decrease. yStatistically significant. zEstimates shown for 5-year increments.
Neurologic 2 (1%) xP <.05. kTA with interrupted aortic arch.
Sepsis 2 (1%)
Pulmonary hypertension 2 (1%)
Pulmonary vein stenosis 2 (1%)
Death according to conduit size
<10 mm 17/77 (22.1%)
10-13 mm 12/90 (13.3%)
14 mm 2/17 (11.8%)
P25-P75, 25th-75th percentiles; PA, pulmonary artery; CPB, cardiopulmonary
bypass; ACC, aortic crossclamp; CA, circulatory arrest; ASD, atrial septal defect;
PFO, patent foramen ovale; TV, truncal valve; PDA, patent ductus arteriosus;
MAPCA, major aorto-pulmonary collateral arteries; VSD, ventricular septal defect;
ECMO, extracorporeal membrane oxygenation.

236.e4 The Journal of Thoracic and Cardiovascular Surgery c January 2022

Guariento et al Congenital: Truncus Arteriosus

TABLE E3. Univariable and multivariable Cox regression analysis of TABLE E4. Univariable and multivariable Cox regression analysis of
mortality (early mortality) mortality late mortality)
Variable HR 95% CI P value Variable HR 95% CI P value
RV-PA 11 mm 1.26 (0.27-5.92) .772 RV-PA 11 mm 2.14 (0.63-7.27) .223
RV-PA conduit size* 1.13 (0.82-1.56) .445 RV-PA conduit size* 1.39 (1.06-1.81) .017y
Gender Gender
Female Reference . . Female Reference . .

CONG
Male 0.61 (0.18-2.1) .438 Male 1.78 (0.74-4.29) .201
Weight (kg) 0.44 (0.14-1.34) .150 Weight (kg) 0.92 (0.65-1.31) .655
Prematurity 2.61 (0.56-12.07) .220 Prematurity 2.67 (0.78-9.14) .118
DiGeorge syndrome 0.33 (0.04-2.61) .296 DiGeorge syndrome 0.74 (0.25-2.2) .587
TV insufficiency 3.47 (1.06-11.36) .04y TV insufficiency 1.47 (0.54-4) .456
TV stenosis 3.64 (0.79-16.83) .099 TV stenosis 2.06 (0.48-8.86) .330
CAA 1.35 (0.29-6.25) .701 CAA 1.46 (0.49-4.33) .499
Type Type
1 Reference . . 1 Reference . .
2 0.85 (0.23-3.15) .803 2 1.38 (0.48-3.97) .555
3 0.82 (0.09-7.04) .858 3 1.53 (0.31-7.6) .605
4x No early mortalities 4 1.84 (0.52-6.54) .343
Other syndromes No early mortalities Other syndromes 3.29 (0.76-14.1) .110
No. of cusps No. of cusps
2 No early mortalities 2 2.37 (0.69, 8.15)
3 Reference . . 3 Reference . .
4 2.08 (0.41-10.31) .370 4 1.88 (0.63-5.6) .255
Year of surgeryz 0.78 (0.55-1.1) .150 Year of surgeryz 1.11 (0.88-1.41) .383
Statistically significant values are in bold. HR, Hazard ratio; CI, confidence interval;
Multivariable Cox regression analysis of mortality
RV-PA, right ventricle to pulmonary artery; TV, truncal valve; CAA, coronary artery
Variable HR 95% CI P value anomaly. *TA with interrupted aortic arch. yStatistically significant. zEstimates
TV insufficiency 3.04 (0.89-10.34) .076 shown for 5-year increments.

TV stenosis 2.57 (0.53-12.51) .242

Variables with P <.10 on univariable analysis were included in the multivariable
model. AIC ¼ 115. Statistically significant values are in bold. HR, Hazard ratio;
CI, confidence interval; RV-PA, right ventricle to pulmonary artery; TV, truncal valve;
CAA, coronary artery anomaly. *Per 1-mm decrease. yStatistically significant.
zEstimates shown for 5-year increments. xTA with interrupted aortic arch.

The Journal of Thoracic and Cardiovascular Surgery c Volume 163, Number 1 236.e5
 Congenital: Truncus Arteriosus Guariento et al

TABLE E5. Numbers at risk and confidence limits for cumulative incidence estimates
Reoperation on TV by no. of cusps
Bicuspid Tricuspid Quadricuspid
Years No. at risk 95% CI No. at risk 95% CI No. at risk 95% CI
1 26 . 105 . 69 .
5 22 . 83 0.004-0.07 45 0.06-0.26
10 17 0.004-0.22 58 0.02-0.12 19 0.21-0.53
CONG

20 10 0.07-0.43 23 0.04-0.18 5 0.39-0.76

30 4 0.10-0.49 3 0.05-0.25 1 0.73-0.97
Reoperation on RV-PA conduit by year
2001 or before After 2001
Years No. at risk 95% CI No. at risk 95% CI
1 142 0.001-0.05 73 0.04-0.15
5 86 0.37-0.57 33 0.26-0.49
10 40 0.63-0.81 6 0.48-0.76
20 5 0.78-0.92 1 0.61-0.85
Reoperation on TV by TV insufficiency
TV insufficiency No TV insufficiency
Years No. at risk 95% CI No. at risk 95% CI
1 157 . 48 .
5 124 0.1-0.39 30 0.001-0.04
10 81 0.16-0.49 16 0.04-0.15
20 35 0.31-0.7 4 0.1-0.26
30 6 0.42-0.86 2 0.13-0.33
Recatheterization on RV-PA conduit by conduit size
RV-PA 11 mm RV-PA >11 mm
Years No. at risk 95% CI No. at risk 95% CI
1 228 0.15-0.29 80 0.01-0.11
5 110 0.37-0.54 45 0.14-0.4
10 50 0.52-0.7 34 0.23-0.52
20 13 0.66-0.84 6 0.51-0.85
30 1 0.82-0.93 2 0.6-0.89
Reoperation on RV-PA conduit by conduit size
RV-PA 11 mm RV-PA >11 mm
Years No. at risk 95% CI No. at risk 95% CI
1 150 0.03-0.11 55 .
5 72 0.4-0.58 42 0.11-0.35
10 24 0.65-0.82 21 0.35-0.66
20 3 0.74-0.9 2 0.58-0.88
TV, Truncal valve; CI, confidence interval; RV-PA, right ventricle to pulmonary artery.

236.e6 The Journal of Thoracic and Cardiovascular Surgery c January 2022